losartan-potassium and Kidney-Failure--Chronic

Vitamin D has been shown to have multiple pleiotropic effects beyond bone and mineral metabolism, with purported roles in cardiovascular disease, cancer, and host immunity. Vitamin D deficiency is common in patients with end-stage kidney disease (ESKD); however, current clinical practice has favored the use of the active hormone. Whether vitamin D deficiency should be corrected in patients with ESKD remains unclear, as few randomized trials have been conducted. In this systematic review, we summarize the current evidence examining whether vitamin D supplementation improves outcomes, beyond mineral metabolism, in patients with ESKD. Data from randomized controlled trials of adults with ESKD were obtained by searching Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the Web of Science Core Collection from inception to February 2023. Twenty-three trials composed of 2489 participants were identified for inclusion. Data were synthesized by two independent reviewers and summarized in tables organized by outcome. Outcomes included measures of mortality, cardiovascular disease, inflammation, muscle strength/function, nutrition, patient well-being, and outcomes specific to ESKD including erythropoietin usage, pruritus, and dialysis access maturation. The Cochrane risk of Bias Tool (RoB 2, 2019) was used to assess study quality. Overall, our findings indicate a minimal and varied benefit of native vitamin D supplementation. From the largest studies included, we determine that vitamin D has no demonstrated effect on patient-reported measures of well-being or utilization of erythropoietin, nor does it change levels of the inflammation biomarker

Topics: Adult; Cardiovascular Diseases; Dietary Supplements; Erythropoietin; Humans; Kidney Failure, Chronic; Minerals; Randomized Controlled Trials as Topic; Renal Dialysis; Vitamin D; Vitamin D Deficiency; Vitamins

Anemia is a common medical problem among patients with cancer and chronic kidney disease (CKD). Although anemia in patients with CKD is often treated with iron and erythropoietin-stimulating agents, there are controversies with regard to the use of erythropoietin-stimulating agents in cancer patients. In this article, we review the treatment of anemia in patients with cancer and CKD, in addition to summarizing the current guidelines in treatment of anemia in these patients.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Neoplasms; Renal Insufficiency, Chronic

Hypertension among patients on hemodialysis is predominantly systolic (either isolated or combined with diastolic hypertension), whereas the scenario of isolated diastolic hypertension is rare and more common in younger patients. Uncontrolled hypertension that persists despite aggressive antihypertensive drug therapy is a reflection of the volume overload that is a prominent mediator of systolic and diastolic BP elevation. Clinical-trial evidence supports the notion that dry-weight probing is an effective strategy to improve BP control, even when overt clinical signs and symptoms of volume overload are not present. Accelerated arterial stiffness influences the patterns and rhythms of interdialytic ambulatory BP and is a major determinant of isolated systolic hypertension in hemodialysis. Posthoc analyses of the Hypertension in Hemodialysis patients treated with Atenolol or Lisinopril (HDPAL) trial, however, suggest that arterial stiffness does not make hypertension more resistant to therapy and is unable to predict the treatment-induced improvement in left ventricular hypertrophy. A combined strategy of sodium restriction, dry-weight adjustment, and antihypertensive medication use was effective in improving ambulatory BP control regardless of the severity of underlying arteriosclerosis in HDPAL. Other nonvolume-dependent mechanisms, such as erythropoietin use, appear to be also important contributors and should be taken into consideration, particularly in younger hemodialysis patients with diastolic hypertension. In this article, we explore the role of volume overload, arterial stiffness, and erythropoietin use as causes of systolic vs diastolic hypertension in patients on hemodialysis. We conclude with clinical practice recommendations and with a call for a "volume-first" approach when managing hemodialysis hypertension.

Topics: Atenolol; Diastole; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Humans; Hypertension; Incidence; Kidney Failure, Chronic; Lisinopril; Male; Renal Dialysis; Risk Assessment; Systole; Vascular Stiffness; Water-Electrolyte Imbalance

Prolyl-hydroxylase inhibitors are a novel class of orally administered drugs that are under development for the treatment of anemia in patients with chronic kidney disease. This review discusses the biology of these drugs and their target - hypoxia-inducible factor and potential advantages and disadvantages of these therapies. Finally, we will discuss current trials in patients with both chronic kidney disease and end-stage renal disease.. Recent smaller studies have found that prolyl-hydroxylase are as effective as erythropoietin in treating anemia of chronic kidney disease. We do not yet know if they have the same cardiovascular and cancer-related risk profile and these questions will be answered by large phase III trials that are ongoing.. Although prolyl hydroxylase inhibitors have much potential, questions remain regarding their efficacy and safety. Should these concerns prove to be unfounded, the treatment of anemia in chronic kidney disease will likely be transformed over the next decade.

Topics: Administration, Oral; Anemia; Erythropoiesis; Erythropoietin; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Intracellular Signaling Peptides and Proteins; Kidney Failure, Chronic; Mitochondrial Proteins; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Kidney transplantation represents a renal replacement therapy for end-stage renal failure, with outcomes improving from year to year. With the improved survival prognosis, treatment of complications of chronic kidney disease after transplantation is becoming increasingly important. In particular, posttransplantation anemia (PTA) is often protracted, which could be related to a variety of factors, including the renal function status, graft rejection episodes, and infectious causes. PTA occurs in about 30-40% of transplant recipients, and is known to affect the function of the transplanted kidney as well as patient survival. Early PTA is associated with a risk of death and cardiovascular disorders, however, during this phase, priority is given to the appropriate maintenance of immunosuppression rather than to the treatment of anemia. Maintenance-phase PTA exerts a strong influence on the survival, prognosis of the transplanted kidney, quality of life, etc. Unlike the disease state and treatment of usual renal anemia, it has been suggested that PTA may possibly reflect the functional state of the transplanted kidney. Therefore, it has been suggested that proper renal function may be maintained by ensuring a normal hemoglobin level in kidney transplant recipients. Proper management of PTA could be expected to be associated with an improved prognosis of the transplanted kidney and improved patient survival in kidney transplant recipients. It is advisable to provide appropriate treatment by setting target levels in accordance with the dialysis vintage, primary disease, cardiovascular complications, and kidney transplant function and delineation of the transplant recipient characteristics.

Topics: Anemia; Anemia, Iron-Deficiency; Anti-Bacterial Agents; Antiviral Agents; Blood Transfusion; Erythropoietin; Graft Rejection; Hematinics; Hemolysis; Humans; Immunosuppressive Agents; Infections; Iron Compounds; Kidney Failure, Chronic; Kidney Transplantation; Neoplasms; Sex Factors; Time Factors

Protein carbamoylation is a non-enzymatic post-translational modification that binds isocyanic acid, which can be derived from the dissociation of urea or from the myeloperoxidase-mediated catabolism of thiocyanate, to the free amino groups of a multitude of proteins. Although the term 'carbamoylation' is usually replaced by the term "carbamylation" in the literature, carbamylation refers to a different chemical reaction (the reversible interaction of CO

Topics: Biomarkers; Cardiovascular Diseases; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Protein Processing, Post-Translational; Urea

Normochromic normocytic anemia is a common complication in chronic kidney disease (CKD) and is associated with many adverse clinical consequences. Erythropoiesis-stimulating agents (ESAs) act to replace endogenous erythropoietin for patients with end-stage renal disease having anemia. Today, ESAs remain the main tool for treating anemia associated with CKD. In current practice, the use of ESA is not limited to the patients on renal replacement therapy but has extended to nondialysis patients under palliative care (PC). Current evidence on ESA usage in patients with CKD decided to forego dialysis often have to take reference from studies conducted in other groups of patients with CKD, including pre-dialysis patients and those on renal replacement therapy. There is paucity of studies targeting use of ESAs in renal PC patients. Small-scale retrospective study in renal PC patients had suggested clinical advantage of ESAs in terms of hemoglobin improvement, reduction in fatigue, and hospitalization rate. With the expected growth in elderly patients with CKD decided to forego dialysis and manage conservatively, there remains an urgent need to call for large-scale prospective trial in exploring efficacy of ESAs in this population, targeting on quality of life and symptoms improvement outcome. This article also reviews the mechanism of action, pharmacology, adverse effects, and clinical trial evidence for ESA in patients with CKD under renal PC.

Topics: Anemia; Drug Monitoring; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Palliative Care; Quality of Life; Renal Dialysis; Retrospective Studies; Time Factors

The FDA first licensed erythropoiesis stimulating agents (ESA) for use in patients with ESRD in 1989. Hemoglobin targets for treatment with ESAs were established at the outset on the basis of descriptive pre-ESA literature and Phase I-III data in patients with ESRD. Postrelease literature in ESA-treated patients accumulating over time initially supported improvement in indices of both cardiovascular and other organ function as well as quality of life with therapy. Recommended treatment targets for hemoglobin would evolve further in the United States from four iterations of evidence- and opinion-based practice guidelines appearing between 1997 and 2007. Several randomized, controlled trials published from 1998 to 2009 examined normalization and near-normalization of hemoglobin in patients with both ESRD and CKD; they raised fundamental questions as to the safety of robust correction of anemia. These findings, taken together with subsequent actions of the FDA in ESA labeling and CMS's quality expectations for hemoglobin in payment for dialysis treatments, would result in a comprehensive reassessment of the hemoglobin targets in ESA therapy. A marked decrease in both national ESA utilization and hemoglobin attainment has ensued as a result. This discussion addresses the history of the striking changes in enthusiasm for hemoglobin-targeted anemia therapy from 1989 to the present, and similarly examines the evolution of ferritin-targeted iron administration, which has followed different-and markedly slower-historical development.

Topics: Anemia; Clinical Trials, Phase I as Topic; Clinical Trials, Phase III as Topic; Drug Delivery Systems; Erythropoiesis; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Prognosis; Renal Dialysis; Risk Assessment; Treatment Outcome

Since more than two decades erythropoiesis-stimulating agents are the main pillar for treatment of anemia associated with chronic kidney disease. Methoxy polyethylene glycol-epoetin beta (MPG-EPO), also called continuous erythropoietin receptor activator, is the longest acting erythropoiesis-stimulating agent currently available. MPG-EPO is characterized by an elimination half-life of approximately 137 h and offers extended dosing intervals up to 4 weeks. Numerous phase I/II studies and a comprehensive clinical phase III program demonstrated the feasibility of MPG-EPO therapy for anemia correction and maintenance of stable hemoglobin levels in adult chronic kidney disease patients. Due to patent disputes MPG-EPO was only available outside the US market so far. In view of a prevailing US market introduction, this review focuses on efficacy and safety data from pivotal trials, summarizes recent clinical research and finally tries to substantiate potential benefits associated with the use of this anti-anemic drug.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Polyethylene Glycols; Recombinant Proteins

End-stage renal disease results in anemia caused by shortened erythrocyte survival, erythropoietin deficiency, hepcidin-mediated impairment of intestinal absorption and iron release, recurrent blood loss, and impaired responsiveness to erythropoiesis-stimulating agents (ESAs). Iron malabsorption renders oral iron products generally ineffective, and intravenous (IV) iron supplementation is required in most patients receiving maintenance hemodialysis (HD). IV iron is administered at doses far exceeding normal intestinal iron absorption. Moreover, by bypassing physiologic safeguards, indiscriminate use of IV iron overwhelms transferrin, imposing stress on the reticuloendothelial system that can have long-term adverse consequences. Unlike conventional oral iron preparations, ferric citrate has recently been shown to be effective in increasing serum ferritin, hemoglobin, and transferrin saturation values while significantly reducing IV iron and ESA requirements in patients treated with HD. Ferric pyrophosphate citrate is a novel iron salt delivered by dialysate; by directly reaching transferrin, its obviates the need for storing administered iron and increases transferrin saturation without increasing serum ferritin levels. Ferric pyrophosphate citrate trials have demonstrated effective iron delivery and stable hemoglobin levels with significant reductions in ESA and IV iron requirements. To date, the long-term safety of using these routes of iron administration in patients receiving HD has not been compared to IV iron and therefore awaits future investigations.

Topics: Administration, Intravenous; Anemia; Comparative Effectiveness Research; Dialysis Solutions; Drug Delivery Systems; Erythropoietin; Hematinics; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Long Term Adverse Effects; Renal Dialysis; Trace Elements; Transferrin

Treatment with recombinant human erythropoietin (rHuEPO) in dialysis patients has been shown to be highly effective in terms of correcting anaemia and improving quality of life. There is debate concerning the benefits of rHuEPO use in predialysis patients which may accelerate the deterioration of kidney function. However the opposing view is that if rHuEPO is as effective in predialysis patients, improving the patient's sense of well-being may result in the onset of dialysis being delayed. This is an update of a review first published in 2001 and last updated in 2005.. The objective of this review was to ascertain the effects of rHuEPO treatment in predialysis patients primarily in terms of the timing of the onset of dialysis; but also that predialysis rHuEPO: 1) corrects haemoglobin/haematocrit (markers of anaemia); 2) improves quality of life; and 3) is not associated with an increased incidence of adverse events such as hastening of the onset of dialysis, increased hypertension, clotting of arterio-venous fistulae or seizures.. We searched the Cochrane Kidney and Transplant's Specialised Register (up to 29 June 2015) through contact with the Trials' Search Co-ordinator using search terms relevant to this review.. Randomised controlled trials (RCTs) or quasi-RCTs comparing the use of rHuEPO with no treatment or placebo in predialysis patients.. Only published data were used. Quality assessment was performed by two assessors independently. Data were abstracted by a single author onto a standard form, a sample of which was checked by another author. Results were expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI).. Nineteen studies (enrolling 993 participants) were included. Due to the age of the included studies (most performed prior to 2000) the risk of bias was judged to be unclear in the majority of the studies for most of the domains. There was an improvement in haemoglobin (MD 1.90 gm/L, 95% CI -2.34 to -1.47) and haematocrit (MD 9.85%, 95% CI 8.35 to 11.34) with treatment and a decrease in the number of patients requiring blood transfusions (RR 0.32, 95% CI 0.12 to 0.83). The data from studies reporting quality of life or exercise capacity demonstrated an improvement in the treatment group. Most of the measures of progression of kidney disease showed no statistically significant difference. No significant increase in adverse events was identified.. Treatment with rHuEPO in predialysis patients corrects anaemia, avoids the requirement for blood transfusions and also improves quality of life and exercise capacity. We were unable to assess the effects of rHuEPO on progression of kidney disease, delay in the onset of dialysis or adverse events. Based on the current evidence, decisions on the putative benefits in terms of quality of life are worth the extra costs of predialysis rHuEPO need careful evaluation.

Topics: Anemia; Disease Progression; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins

The management of anaemia in patients with chronic kidney disease has been transformed by development of erythropoiesis-stimulating agents (ESAs). Following expiry of the patent of the originator epoetin alfa in Europe, a number of biosimilar ESAs have been licensed for use in the nephrology setting. Biosimilars are biological medicines that are approved via stringently defined regulatory pathways on the basis that they have demonstrated comparable safety, efficacy and quality to their reference product.. As nurses have a pivotal role in patient care, not only administering medications but also educating patients about their treatment options, it is important that nurses understand the differences between biosimilar medicines and their reference products and appreciate the stringent regulatory requirements for approval of biosimilars.. In this review, we use epoetin zeta as a case study to highlight practical considerations of using biosimilar ESAs in the management of patients with kidney disease.. Biosimilar products, such as epoetin zeta, may offer a range of features to patients, nurses and physicians, such as greater flexibility over dose and route of administration, in addition to greater access to biological medicines through cost savings.. Renal nurses play a significant role in the management of patients with kidney disease and anaemia, not only having an important role in the delivery of medicine but also in the education of patients. This review discusses some of the practical aspects associated with the use of biosimilar medicines to assist nurses in making informed decisions over their use.

Topics: Anemia, Iron-Deficiency; Biosimilar Pharmaceuticals; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins

Trials raising concerns about erythropoiesis-stimulating agents, revisions to their labeling, and changes to practice guidelines and dialysis payment systems have provided strong stimuli to decrease erythropoiesis-stimulating agent use and increase intravenous iron administration in recent years. These factors have been associated with a rise in iron utilization, particularly among hemodialysis patients, and an unprecedented increase in serum ferritin concentrations. The mean serum ferritin concentration among United States dialysis patients in 2013 exceeded 800 ng/ml, with 18% of patients exceeding 1200 ng/ml. Although these changes are broad based, the wisdom of these practices is uncertain. Herein, we examine influences on and trends in intravenous iron utilization and assess the clinical trial, epidemiologic, and experimental evidence relevant to its safety and efficacy in the setting of maintenance dialysis. These data suggest a potential for harm from increasing use of parenteral iron in dialysis-dependent patients. In the absence of well powered, randomized clinical trials, available evidence will remain inadequate for making reliable conclusions about the effect of a ubiquitous therapy on mortality or other outcomes of importance to dialysis patients. Nephrology stakeholders have an urgent obligation to initiate well designed investigations of intravenous iron in order to ensure the safety of the dialysis population.

Topics: Anemia, Iron-Deficiency; Animals; Cross-Sectional Studies; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Ferritins; Hematinics; Humans; Infusions, Intravenous; Iron Compounds; Kidney Failure, Chronic; Prognosis; Randomized Controlled Trials as Topic; Renal Dialysis; Risk Assessment; Treatment Outcome

Renal hypoxia is known to play an important role in the pathophysiology of acute renal injury as well as in chronic kidney diseases. The mediators of hypoxia are the transcription factors HIF (hypoxia-inducible factors), that are highly regulated. Under normoxic conditions constitutively expressed HIF-α subunits are hydroxylated by prolyl hydroxylases (PHD1, PHD2, and PHD3) and subsequently degraded by proteasomes.. This narrative review is based on the material searched for and obtained via PubMed and MEDLINE up to January 2015.. The MAPK organizer 1 (Morg1) has been identified to act as a scaffold protein of PHD3 and suppression of Morg1 leads to the stabilization of HIF-α, which forms in the absence of oxygen a heterodimer with HIF-β, translocates to the nucleus and promotes the transcription of HIF target genes.. This review summarizes the current knowledge regarding the role of hypoxia, HIF signalling, and Morg1 in acute and chronic renal injury.

Topics: Acute Kidney Injury; Adaptor Proteins, Signal Transducing; Aryl Hydrocarbon Receptor Nuclear Translocator; Erythropoietin; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Failure, Chronic; Signal Transduction

Epoetin alfa (EPO) and darbepoetin alfa (DPO) are erythropoiesis-stimulating agents that are widely and interchangeably used for the treatment of anemia in patients with advanced chronic kidney disease and end-stage renal disease. No study has specifically compared the risks of hard study outcomes between EPO and DPO, including mortality.. Systematic review of the literature and meta-analysis.. Patients enrolled in randomized trials comparing EPO versus DPO for the treatment of anemia in adults with chronic kidney disease, including those requiring dialysis.. We conducted a systematic search of the literature (PubMed, CENTRAL, SCOPUS, and EMBASE, all years) and industry resources, using predefined search terms and data abstraction tools. We then summarized key characteristics and findings of these trials and performed a random-effects meta-analysis of trials with at least 3 months' duration to identify the summary OR of mortality between patients randomly assigned to DPO versus EPO.. DPO versus EPO.. All-cause mortality.. We identified 9 trials that met the stated inclusion criteria. Overall, 2,024 patients were included in the meta-analysis, of whom 126 died during follow-up, which ranged from 20 to 52 weeks. We found no significant difference in mortality between patients randomly assigned to DPO versus EPO (OR, 1.33; 95% CI, 0.88-2.01). No treatment heterogeneity across studies was detected (Q statistic=4.60; P=0.8).. Generalizability to nontrial populations is uncertain.. Few trials directly comparing DPO and EPO have been conducted and follow-up was limited. In aggregate, no effect of specific erythropoiesis-stimulating agent on mortality was identified, but the confidence limits were wide and remained compatible with considerable harm from DPO. Absent adequately powered randomized trials, observational postmarketing comparative effectiveness studies comparing these erythropoiesis-stimulating agents are required to better characterize the long-term safety profiles of these agents.

Topics: Anemia; Cause of Death; Darbepoetin alfa; Double-Blind Method; Epoetin Alfa; Erythropoietin; Half-Life; Hematinics; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Anaemia is a common complication in people with chronic kidney disease (CKD) and mainly develops as a consequence of relative erythropoietin (EPO) deficiency. Anaemia develops early in the course of disease and peaks among people with end-stage kidney disease (ESKD). Many types of EPO - also called erythropoiesis-stimulating agents (ESAs) - are used to treat anaemia in people with ESKD.ESAs have changed treatment of severe anaemia among people with CKD by relieving symptoms and avoiding complications associated with blood transfusion. However, no benefits have been found in relation to mortality rates and non-cardiac fatal events, except quality of life. Moreover, a relationship between ESA use and increased cardiovascular morbidity and mortality in patients with CKD has been reported in studies with fully correcting anaemia comparing with partial anaemia correction. Until 2012, guidelines recommended commencing ESA treatment when haemoglobin was less than 11 g/dL; the current recommendation is EPO commencement when haemoglobin is between 9 and 10 g/dL. However, advantages in commencing therapy when haemoglobin levels are greater than 10 g/dL but less than 11 g/dL remain unknown, especially among older people whose life expectancy is limited, but in whom EPO therapy may improve quality of life.. To assess the clinical benefits and harms of early versus delayed EPO for anaemia in patients with ESKD undergoing haemodialysis or peritoneal dialysis. We searched the Cochrane Kidney and Transplant Specialised Register to 8 July 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.. We planned to include randomised controlled trials (RCTs) and quasi-RCTs evaluating at the clinical benefits and harms of early versus delayed EPO for anaemia in patients with ESKD undergoing haemodialysis or peritoneal dialysis. Studies comparing EPO with another EPO, placebo or no treatment were eligible for inclusion.. It was planned that two authors would independently extract data from included studies and assess risk of bias using the Cochrane risk of bias tool. For dichotomous outcomes (all-cause mortality, cardiovascular mortality, overall myocardial infarction, overall stroke, vascular access thrombosis, adverse effects of treatment, transfusion), we planned to use the risk ratio (RR) with 95% confidence intervals (CI). We planned to calculate the mean difference (MD) and CI 95% for continuous data (haemoglobin level) and the standardised mean difference (SMD) with CI 95% for quality of life if different scales had been used.. Literature searches yielded 1910 records, of these 1534 were screened after duplicates removed, of which 1376 were excluded following title and abstract assessment. We assessed 158 full text records and identified 18 studies (66 records) that were potentially eligible for inclusion. However, none matched our inclusion criteria and were excluded.. We found no evidence to assess the benefits and harms of early versus delayed EPO for the anaemia of ESKD.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Renal Dialysis

The synthesis of recombinant human erythropoietin has marked a turning point in the treatment of anaemia secondary to chronic kidney disease. However, the potentially fatal cardio- and cerebrovascular complications of the intake of high-doses of ESAs (erythropoiesis-stimulating agents), such as those observed in athletes who resort to doping, reason out the ever-prevalent debate concerning the balance between the risks and benefits of ESA administration for therapeutic purposes. Hence, there is still a discussion as to what values haemoglobin should ideally be maintained at. Additional concerns arise in cancer patients due to the ability of erythropoietin to act as an angiogenic and, in general, as a cell growth factor, because this might favour the progression of neoplastic disease. We summarized the prominent points of the latest guidelines on the management of anaemia in nephropathic patients, also identifying the possible risks that may result from the tendency to aim at too low haemoglobin levels.

Topics: Anemia; Erythropoietin; Guidelines as Topic; Humans; Kidney Failure, Chronic; Neoplasms; Recombinant Proteins

A previous meta-analysis indicated that l-carnitine significantly increased hemoglobin and decreased the required erythropoietin dose in maintenance hemodialysis patients.. An updated systematic review and meta-analysis of randomized controlled trials (RCTs) was performed to reevaluate effects of l-carnitine.. The Cochrane Library, PubMed, and EMBASE databases (31 December 2012) were searched to identify RCTs that investigated effects of l-carnitine in adults with end-stage kidney disease that required maintenance hemodialysis.. Forty-nine RCTs (1734 participants) were included. l-Carnitine significantly decreased serum low-density lipoprotein (LDL) (mean difference: -5.82 mg/dL; 95% CI: -11.61, -0.04 mg/dL) and C-reactive protein (CRP) (-3.65 mg/L; -6.19, -1.12 mg/L). There were no significant differences in triglycerides (-0.89 mg/dL; -29.32, 27.53 mg/dL), cholesterol (0.14 mg/dL; -6.15, 6.42 mg/dL), high-density lipoprotein (1.13 mg/dL; -2.44, 4.70 mg/dL), hemoglobin (0.68 g/dL; 0.14, 1.50 g/dL), hematocrit (2.04%; -1.39, 5.48%), albumin (1.65 g/L; -0.22, 3.51 g/L), or the required erythropoietin dose (-0.76 KU/wk; -1.75, 0.23 KU/wk). No adverse effects were reported.. This meta-analysis failed to confirm the previous findings regarding the effects of l-carnitine on hemoglobin and the erythropoietin dose but showed that l-carnitine significantly decreased serum LDL and CRP. The extent of the decrease in LDL was not clinically relevant, whereas the significant decrease in CRP was both statistically and clinically relevant. However, the relevance of decrease in CRP with hard endpoints such as all-cause mortality and cardiovascular complications still remains to be clarified.

Topics: C-Reactive Protein; Carnitine; Cholesterol; Databases, Factual; Dietary Supplements; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Renal Dialysis; Triglycerides

Topics: Aged; Algorithms; Anemia; Anemia, Iron-Deficiency; Cardiovascular Diseases; Cohort Studies; Comorbidity; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Inflammation; Iron; Kidney Failure, Chronic; Multicenter Studies as Topic; Peptides; Renal Dialysis

Erythropoiesis-stimulating agents (ESA) and iron are the main tools for treating anaemia associated with chronic kidney disease (CKD). Pharmaceutical research has focused on modified epoetins or different strategies to stimulate erythropoiesis with the idea of improving relative disadvantages of the molecules already available in the market.. Following a literature search on PubMed using anaemia, haemoglobin, erythropoietin (EPO), hypoxia-inducible transcription factor (HIF) inhibitors and chronic kidney disease as keywords, we critically analysed new strategies for increasing erythropoiesis, looking in depth at their peculiar characteristics and possible advantages in the clinical setting.. In recent years the ESA market is facing a number of hurdles making it less appealing than before. Economic recession or stagnation has raised the need of sustainability of medical treatment. New treatments must bring clear benefits compared to existing drugs. In addition to this, ESA consumption has been progressively reduced, fearing possible risks of increased cardiovascular events especially when given at excessive doses. New drugs may also undergo premature stopping because of unexpected adverse reactions as for peginesatide. At present, the most promising approach to anaemia treatment in CKD patients is the manipulation of the HIF system. The regulation of activin A pathway is another option with good potential, also considering the additional advantage of increasing bone mass.

Topics: Anemia; Antibodies, Monoclonal; Erythropoietin; Hematopoiesis; Humans; Kidney Failure, Chronic; Receptors, Erythropoietin

The benefits of erythropoiesis-stimulating agents (ESA) for dialysis patients have been demonstrated. However, it remains unclear whether the efficacy and safety of new, longer-acting ESA given less frequently is equivalent to recombinant human erythropoietin (rHuEPO) preparations. This is an update of a review first published in 2002 and last updated in 2005.. This review aimed to establish the optimal frequency of ESA administration in terms of effectiveness (correction of anaemia, and freedom from adverse events) and efficiency (optimal resource use) of different ESA dose regimens.. We searched the Cochrane Renal Group's Specialised Register to 21 March 2013 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.. We included randomised control trials (RCTs) comparing different frequencies of ESA administration in dialysis patients.. Two authors independently assessed study eligibility, risk of bias and extracted data. Results were expressed as risk ratio (RR) or risk differences (RD) with 95% confidence intervals (CI) for dichotomous outcomes. For continuous outcomes the mean difference (MD) or standardised mean difference (SMD) with 95% confidence intervals (CI) was used. Statistical analyses were performed using the random-effects model.. This review included 33 studies (5526 participants), 22 of which were added for this update. Risk of bias was generally high; only nine studies were assessed at low risk of bias for sequence generation and 14 studies for allocation concealment. Although only four studies were placebo-controlled, all were considered to be at low risk of performance or detection bias because the primary outcome of haemoglobin level was a laboratory-derived assessment and unlikely to be influenced by lack of blinding. We found that 16 studies were at low risk of attrition bias and five were at low risk of selection bias; only one study reporting sources of support was not funded by a pharmaceutical company.We compared four different interventions: Continuous erythropoietin receptor agonists (CERA) versus other ESA (darbepoetin or rHuEPO); different frequencies of darbepoetin administration; darbepoetin versus rHuEPO; and different frequencies of rHuEPO administration.There were no significant differences in maintaining final haemoglobin between CERA administered at two weekly intervals (4 studies, 1762 participants: MD 0.08 g/dL, 95% CI -0.04 to 0.21) or four weekly intervals (two studies, 1245 participants: MD -0.03 g/dL, 95% CI -0.17 to 0.12) compared with rHuEPO administered at two to three weekly intervals. In one study comparing CERA administered every two weeks with darbepoetin administered once/week, there was no significant difference in final haemoglobin (313 participants: MD 0.30 g/dL, 95% CI 0.05 to 0.55). In comparisons of once/week with once every two weeks darbepoetin (two studies, 356 participants: MD 0.04 g/dL, 95% CI -0.45 to 0.52) and once every two weeks with monthly darbepoetin (one study, 64 participants: MD 0.40 g/dL, 95% CI -0.37 to 1.17) there were no significant differences in final haemoglobin levels. There was marked heterogeneity among studies comparing weekly darbepoetin with once every two weeks and was possibly related to different administration protocols. Eight studies compared weekly darbepoetin with rHuEPO given two to three times/week; no statistical difference in final haemoglobin was demonstrated (6 studies, 1638 participants: MD 0.02 g/dL, 95% CI -0.09 to 0.12). Fourteen studies compared different frequencies of rHuEPO. No statistical difference was demonstrated in final haemoglobin (7 studies, 393 participants: SMD -0.17 g/dL, 95% CI -0.39 to 0.05). Adverse events did not differ significantly within comparisons; however, mortality and. Longer-acting ESA (darbepoetin and CERA) administered at one to four week intervals are non-inferior to rHuEPO given one to three times/week in terms of achieving haemoglobin targets without any significant differences in adverse events in haemodialysis patients. Additional RCTs are required to evaluate different frequencies of ESA in peritoneal and paediatric dialysis patients and to compare different longer-acting ESA (such as darbepoetin compared with CERA).

Topics: Anemia; Drug Administration Schedule; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis

Topics: Anemia; Biosimilar Pharmaceuticals; Epoetin Alfa; Erythropoietin; Europe; Hematinics; Humans; Hypoxia-Inducible Factor 1; Kidney Failure, Chronic; Recombinant Proteins; United States; United States Food and Drug Administration

Anemia is one of the most common problems of patients with advanced chronic kidney disease (CKD). Its main causes in this population are: iron deficiency and a decreased renal synthesis of erythropoietin. Up to the 80's of the twentieth century, treatment of anemia in CKD was limited to blood and red blood cells transfusions. However during last three decades there has been a huge progress in the field, starting with introduction into clinical practice of human recombinant erythropoietin (rHuEPO), followed by an appearance of agents with a longer duration of action, darbepoetin alfa and methoxy polyethylene glycol-epoetin beta, all of which are shortly reviewed in this paper.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins

During the past century, few proteins have matched erythropoietin (Epo) in capturing the imagination of physiologists, molecular biologists, and, more recently, physicians and patients. Its appeal rests on its commanding role as the premier erythroid cytokine, the elegant mechanism underlying the regulation of its gene, and its remarkable impact as a therapeutic agent, arguably the most successful drug spawned by the revolution in recombinant DNA technology. This concise review will begin with a synopsis of the colorful history of this protein, culminating in its purification and molecular cloning. It then covers in more detail the contemporary understanding of Epo's physiology as well as its structure and interaction with its receptor. A major part of this article focuses on the regulation of the Epo gene and the discovery of HIF, a transcription factor that plays a cardinal role in molecular adaptation to hypoxia. In the concluding section, a synopsis of Epo's role in disorders of red blood cell production will be followed by an assessment of the remarkable impact of Epo therapy in the treatment of anemias, as well as concerns that provide a strong impetus for the development of even safer and more effective treatment.

Topics: Anemia; Cell Hypoxia; Erythropoietin; Gene Expression Regulation; Hematopoiesis; History, 19th Century; History, 20th Century; Humans; Hypoxia-Inducible Factor 1; Kidney Failure, Chronic; Receptors, Erythropoietin; Recombinant Proteins; Transcription Factors

Anemia occurs frequently in patients with chronic kidney disease (CKD), especially in the later stages, and the main etiologies are decreased production of erythropoietin (EPO) as well as iron and vitamin deficiencies. For these reasons, it is essential to detect anemia in patients with CKD and to investigate the etiology. If anemia (Hb < 100 g/l) persists after substitution of deficiencies, treatment with recombinant human erythropoietin (rHuEPO) should be considered. New guidelines (KDIGO - August 2012) have just been published by the National Kidney Foundation (NKF) for the management of anemia in patients with renal failure. This article reviews the principles and innovations in management in 2013.

Topics: Anemia; Erythropoietin; Humans; Iron Metabolism Disorders; Kidney Failure, Chronic; Models, Biological; Nephrology; Recombinant Proteins

Iron Deficiency Anaemia (IDA) has been shown to be the most common cause of anaemia worldwide. It is accepted that people with chronic kidney disease (CKD) develop anaemia as their kidney function declines.. To better understand IDA in CKD, it is necessary to appreciate the normal iron metabolism and utilisation of iron and how these processes can be disordered in patients with CKD. The problems related to infection / inflammation and oxidative stress are examined. Whilst National and international guidelines recommend specific tests for IDA, these and alternative tests are reviewed.. Whilst iron supplementation is necessary for CKD patients with IDA, iron metabolism and utilisation can be affected by factors such as infection or inflammation. Iron is essential element for all life, it can be toxic to cells through the process of oxidative stress. The recommended tests for IDA may be affected by factors such as infection and inflammation. Alternative tests are available, which may be a more accurate indicator of IDA as they are not affected by external factors.

Topics: Anemia, Iron-Deficiency; Erythropoietin; Guideline Adherence; Hepcidins; Humans; Infections; Inflammation; Iron; Kidney Failure, Chronic; Oxidative Stress; Reference Values

The objectives of this study were to survey the current research and provide an update on the uses and benefits of erythropoietin (EPO) in pregnancy and the postpartum period.. A review of MEDLINE (1947 to present) was performed. Search terms included "erythropoietin," "pregnan*," with subheadings of "administration & dosage," "pharmacokinetics," "therapeutic use," "fetus," "fertility.". We reviewed relevant articles published from 2002 to 2012. Case reports, observational studies, case-control studies, randomized controlled trials, retrospective analyses, animal studies, and review articles were included. Articles were selected if they discussed a use of EPO in pregnancy or the immediate postpartum period, as well as use of EPO in the neonate.. Authors independently reviewed and extracted data. Of the 65 articles reviewed, 45 were included. Erythropoietin was used in the treatment of maternal anemia. Because of the molecule's large size, recombinant EPO does not appear to cross the placenta. No fetal morbidity or mortality was noted. Therefore, this is a safe therapy that can be used in pregnancy. Use of EPO may be especially important for women who decline blood products. Neonatal uses of EPO show benefit in the treatment of anemia due to blood type incompatibility.. Erythropoietin is gaining popularity as a therapeutic option during pregnancy and the postpartum period. Further investigation is needed to establish a standard dosage and dosing interval. New studies reviewing its use in the neonate for perinatal-hypoxic injury and anemia due to blood type incompatibility provide exciting opportunities for further therapeutic use.. Obstetricians and gynecologists, family physicians.. After completing this CME activity, physicians should be better able to treat anemia in pregnancy, including causes and interventions; assess renal disease in pregnancy, targets of hemoglobin, precautions, and treatment considerations; and evaluate erythropoietin use in neonates and fetuses, including benefits, complications, and areas for upcoming research/uses.

Topics: Anemia; Erythropoietin; Female; Hematinics; Humans; Infant, Newborn; Kidney Failure, Chronic; Postpartum Hemorrhage; Pregnancy; Pregnancy Complications, Hematologic; Puerperal Disorders; Severity of Illness Index; Uterine Hemorrhage

Protein-bound uremic toxins such as indoxyl sulfate cannot be removed efficiently by hemodialysis. These protein-bound uremic toxins have emerged as important risk factors for the progression of chronic kidney disease (CKD) as well as cardiovascular disease (CVD).. Indoxyl sulfate shows toxic effects on a variety of cells such as renal proximal tubular cells, glomerular mesangial cells, vascular smooth muscle cells, vascular endothelial cells, cardiomyocytes, cardiac fibroblasts, monocytes, osteoblasts and osteoclasts. This review overviews the cellular toxicity of indoxyl sulfate, its molecular mechanism and its role in the progression of CKD and CVD. Further, this review summarizes the clinical effects of AST-120 and the other strategies to reduce serum levels of indoxyl sulfate.. Protein-bound uremic toxins such as indoxyl sulfate have emerged as target molecules for therapeutic intervention of not only CKD but also CVD. An oral sorbent AST-120 reduces serum level of indoxyl sulfate by adsorbing indole in the intestine. The modulation of intestinal bacteria by prebiotics/probiotics might be effective in reducing the production of indole in the intestine followed by reduced serum levels of indoxyl sulfate. An alternative approach might be antagonist which can counteract indoxyl sulfate-induced cellular effects and signaling pathways.

Topics: Bone and Bones; Carbon; Cardiovascular System; Disease Progression; Erythropoietin; Humans; Indican; Kidney; Kidney Failure, Chronic; Oxides; Protein Binding; Reactive Oxygen Species

People living with end-stage kidney disease (ESKD) often develop anaemia. Erythropoiesis-simulating agents (ESAs) are often given to people living with ESKD to maintain haemoglobin at a level to minimise need for transfusion. However, about 5% to 10% of patients with ESKD exhibit resistance to ESAs, and observational studies have shown that patients requiring high doses of ESA are at increased risk of mortality.. This review aimed to study the effects of interventions for the treatment of ESA-resistant anaemia in people with ESKD.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE for randomised controlled trials (RCT) that involved participants with ESKD on dialysis or who were pre-dialysis patients with chronic kidney disease (stage 5). Date of last search: April 2013.. ESA resistance was defined as failure to achieve or maintain haemoglobin/haematocrit levels within the desired target range despite appropriate ESA doses (erythropoietin ≥ 450 U/kg/wk intravenously or ≥ 300 U/kg/wk subcutaneously; darbepoetin ≥ 1.5 µg/kg/wk) in people who were not nutritionally deficient, or who had haematological or bleeding disorders. Extended inclusion criteria for ESA hyporesponsive state were: erythropoietin dose ≥ 300 U/kg/wk and ≥ 150 U/kg/wk for intravenous administration; or ≥ 200 U/kg/wk and ≥ 100 U/kg/wk for subcutaneous administration; or darbepoetin dose ≥ 1.0 µg/kg/wk).. Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random effects model and results expressed as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI).. Titles and abstracts of 521 records were screened, of which we reviewed 99 from the full text. Only two studies matched our inclusion criteria. One study compared intravenous vitamin C versus no study medication for six months in 42 ESKD patients on haemodialysis who required intravenous erythropoietin (dose ≥ 450 U/kg/wk). The other included study compared high-flux dialyser versus low-flux dialyser for six months in 48 haemodialysis patients who required subcutaneous erythropoietin (dose ≥ 200 U/kg/wk). Because interventions differed, data could not be combined for quantitative meta-analysis.. There was inadequate evidence identified to inform recommendation of any intervention to ameliorate ESA hyporesponsiveness. Adequately powered RCTs are required to establish the safety and efficacy of interventions to improve responsiveness to ESA therapy.

Topics: Anemia; Drug Resistance; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Renal Dialysis

Hypoxia-inducible factor (HIF) is a transcriptional master regulator that takes control of the gene expressions under hypoxia. Several lines of evidence have shown that chronic hypoxia in tubulointerstitium results in irreversible renal disease. Recently, HIF1 was reported to organize a cluster of histone-modifying enzymes by binding to their promoter regions in various kinds of cell lines. However, its function in renal disease remains largely unknown. We focused on the epigenetic regulation on the progression of chronic kidney disease and have reviewed the latest knowledge in this area with special emphasis on the involvement of HIF. For example, a set of HIF1 downstream target genes also were reported to be regulated by cooperative combination of HIF1 and histone demethylase. We suggest a novel epigenetic pathway that affects the final common pathway to end-stage renal disease in addition to the tubulointerstitial hypoxia. We emphasize the importance of figuring out the epigenetic mechanisms of renal failure to find the novel therapeutic approach of chronic kidney disease.

Topics: Chromatin Assembly and Disassembly; Diabetic Nephropathies; Epigenesis, Genetic; Erythropoietin; Fibrosis; Humans; Hypoxia-Inducible Factor 1; Kidney Failure, Chronic; Kidney Tubules

Topics: Anemia; Erythropoietin; Health Care Reform; Humans; International Cooperation; Kidney Failure, Chronic; Practice Patterns, Physicians'; Renal Dialysis; Retrospective Studies; United States

Because kidneys consume a large amount of oxygen and are relatively inefficient in oxygen uptake, they are susceptible to hypoxia, especially in patients with advanced chronic kidney disease accompanied by loss of peritubular capillaries. Accumulating evidence suggests that chronic tubulointerstitial hypoxia acts as a final common pathway leading to end-stage renal disease. Some biologically active uremic retention molecules, considered as uremic toxins, accumulate as the renal function declines, and at this moment, more than 90 bioactive uremic toxins have been identified. Uremic toxins per se have been proven to accelerate the progression of renal failure. However, the causal relationship between uremic toxin and tubulointerstitial hypoxia remains unclear. Our studies provided direct evidence that uremic toxin dysregulates oxygen metabolism in the kidney. Indoxyl sulfate (IS), a representative protein-bound uremic toxin, increased oxygen consumption in proximal renal tubules, decreased renal oxygenation, and consequently aggravated hypoxia in the remnant rat kidneys. The increase in tubular oxygen consumption by IS was dependent on sodium-potassium adenosine triphosphatase and oxidative stress. Our work also indicated a possible connection between IS and the desensitization of the oxygen-sensing mechanism in erythropoietin-producing cells, which may partly explain inadequate erythropoietin production in hypoxic kidneys of end-stage renal disease patients. Studies of uremic toxins will open a new avenue in development of novel therapeutic approaches of kidney disease.

Topics: Animals; Cell Proliferation; Erythropoietin; Homeostasis; Humans; Hypoxia; Indican; Kidney; Kidney Failure, Chronic; Kidney Tubules; Oxidative Stress; Oxygen Consumption; Rats; Uremia

There are almost 100 different substances called uremic toxins. Nicotinamide derivatives are known as new family of uremic toxins. These uremic compounds play a role in an increased oxidative stress and disturbances in cellular repair processes by inhibiting poly (ADP-ribose) polymerase activity. New members of this family were discovered and described. Their toxic properties were a subject of recent studies. This study evaluated the concentration of 4-pyridone-3-carboxamid-1-β-ribonucleoside-triphosphate (4PYTP) and 4-pyridone-3-carboxamid-1-β-ribonucleoside-monophosphate (4PYMP) in erythrocytes of patients with chronic renal failure. Serum and red blood cells were collected from chronic renal failure patients on conservative treatment, those treated with hemodialysis, and at different times from those who underwent kidney transplantation. Healthy volunteers served as a control group. Nicotinamide metabolites were determined using liquid chromatography with mass spectrometry based on originally discovered and described method. Three novel compounds were described: 4-pyridone-3-carboxamid-1-β-ribonucleoside (4PYR), 4PYMP, and 4PYTP. 4PYR concentration was elevated in the serum, whereas 4PYMP and 4PYTP concentrations were augmented in erythrocytes of dialysis patients. Interestingly, concentrations of these compounds were less elevated during the treatment with erythropoietin-stimulating agents (ESAs). After successful kidney transplantation, concentrations of 4PYR and 4PYMP normalized according to the graft function, whereas that of 4PYTP was still elevated. During the incubation of erythrocytes in the presence of 4PYR, concentration of 4PYMP rose very rapidly while that of 4PYTP increased slowly. Therefore, we hypothesized that 4PYR, as a toxic compound, was actively absorbed by erythrocytes and metabolized to the 4PYMP and 4PYTP, which may interfere with function and life span of these cells.

Topics: Absorption; Adult; Child; Erythrocytes; Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Nucleosides; Nucleotides; Oxidative Stress; Poly Adenosine Diphosphate Ribose; Pyridones; Renal Dialysis

Anemia is a very common complication of chronic kidney disease (CKD). Anemia confers significant risk of cardiovascular disease and contributes to decreased quality of life. Anemia in CKD patients can be multi-factorial, including but not invariably due to the underlying renal insufficiency. Identifying the type of anemia is important in this group of patients and can often be challenging. Diagnosing anemia of renal disease due to erythropoietin (EPO) deficiency is a diagnosis of exclusion. Erythropoiesis stimulating agents (ESA) are the mainstay for the treatment of anemia secondary to CKD. However, over the last four years the use of ESA in the treatment of anemia in CKD patients has undergone a severe interrogation as several trials have reported adverse outcomes with targeting higher hemoglobin (Hb) levels with these agents. Thereby, this review describes the pathophysiology of anemia in CKD patients, diagnosis and the current role of ESA's as it relates to anemia of CKD as well as safety and efficacy of ESA's.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Hematinics; Humans; Incidence; Kidney Failure, Chronic; Risk Factors; United States

We formed the GEnetics of Nephropathy-an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10(-9)). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated.

Topics: Adaptor Proteins, Signal Transducing; Adult; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythropoietin; Finland; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Ireland; Kidney Failure, Chronic; Phenotype; Promoter Regions, Genetic; United States; White People

Stimulation of erythropoiesis is one of the most efficient ways of doping. This type of doping is advantageous for aerobic physical exercise and of particular interest to endurance athletes. Erythropoiesis, which takes place in bone marrow, is under the control of EPO, a hormone secreted primarily by the kidneys when the arterial oxygen tension decreases. In certain pathological disorders, such as chronic renal failure, the production of EPO is insufficient and results in anemia. The pharmaceutical industry has, thus, been very interested in developing drugs that stimulate erythropoiesis. With this aim, various strategies have been, and continue to be, envisaged, giving rise to an expanding range of drugs that are good candidates for doping. Anti-doping control has had to deal with this situation by developing appropriate methods for their detection. This article presents an overview of both the drugs and the corresponding methods of detection, and thus follows a roughly chronological order.

Topics: Anemia; Animals; CHO Cells; Chromatography, High Pressure Liquid; Cricetinae; Doping in Sports; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Erythropoiesis; Erythropoietin; Hematinics; History, 20th Century; History, 21st Century; Humans; Isoelectric Focusing; Kidney Failure, Chronic; Male; Mass Spectrometry; Performance-Enhancing Substances; Recombinant Proteins; Substance Abuse Detection

Cardiorenal anemia syndrome (CRAS) refers to the simultaneous presence of anemia, heart failure (HF), and chronic kidney disease (CKD) that forms a pathologic triad with an observe impact on morbidity and mortality. Certain researches were made regarding the usage of erythropoietin (EPO) in patients with the above mentioned disorders. This leads to the improvement of left ventricular function, quality of life and physical tolerance with decreased risk of hospitalization. Despite successful anemia treatment with EPO in dialysis patients with CKD, HF and cardiorenal syndrome type 2, it should be important to reveal the target Hb level and role of EPO in this category of patients. According to European guidelines in 85% of hemodialysis patients targeted Hb level should be no more than 11g/dl, moreover, the treatment of anemia can be organized before dialysis and it will certainly increase the quality of life in this type of patients.

Topics: Anemia; Cardio-Renal Syndrome; Erythropoietin; Heart Failure; Hospitalization; Humans; Kidney Failure, Chronic; Quality of Life; Renal Dialysis; Treatment Outcome; Ventricular Function, Left

Topics: Anemia; Clinical Trials as Topic; Drug Resistance; Erythropoietin; Genetic Variation; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Practice Guidelines as Topic; Precision Medicine; Reference Values

Topics: Anemia; Anemia, Iron-Deficiency; Avitaminosis; Disease Management; Drug Resistance; Erythropoietin; Ferritins; Hemoglobins; Humans; Inflammation; Iron; Kidney Failure, Chronic; Practice Guidelines as Topic; Reference Values; Renal Dialysis; Time Factors; Transferrin

Topics: Adult; Anemia; Anti-Bacterial Agents; Appendicitis; Erythropoietin; Female; Humans; Infant, Newborn; Iron; Kidney Failure, Chronic; Meningomyelocele; Nephritis, Interstitial; Polyradiculopathy; Pregnancy; Pregnancy Complications; Pregnancy Complications, Hematologic; Pregnancy Outcome; Renal Dialysis; Urinary Bladder, Neurogenic; Urinary Tract Infections

Routine administration of erythropoietin (EPO)-stimulating agents (ESAs) for the control of anemia has improved the quality of life of subjects with chronic kidney disease (CKD). However, a wide variation in individual response to ESA is often observed. The reasons for EPO resistance include demographic variables such as age and gender distribution, morbidity pattern, and modality of dialysis. Despite suggestions by observational data, there is no biological characteristic that puts children at a disadvantage for adequate response to ESA. On the contrary, children possess a superior capacity for red cell production, including extramedullary erythropoiesis. The reasons for larger requirement of ESA in children (than in adults) are greater inflammatory burden, disproportionate blood loss, and greater EPO dosing by pediatric physicians. To minimize the harmful (including fatal) consequences of EPO resistance, surveillance programs must replenish nutrient (for example, iron and folate) stores, minimize oxidative hemolysis, control hyperparathyroidism, avoid catheter infection, and optimize uremic clearance. This clinical approach is justified by the inadequacy of laboratory diagnosis of pertinent etiological factors. Indeed, the best proof for functional nutrient deficiency is often a therapeutic trial. Finally, there are upcoming therapeutic agents that exploit the capacity for an endogenous EPO synthesis in CKD subjects, and may therefore minimize the off-target effect of excess dosages.

Topics: Anemia; Drug Resistance; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic

The number of patients with end-stage renal disease (ESRD) is rising very rapidly as the number of elderly and patients with diabetes increases in Korea. ESRD Registry Committee of the Korean Society of Nephrology (KSN) collected dialysis therapy data in Korea through an online registry program on the KSN website. The status of renal replacement therapy in Korea at the end of 2009 was as follows. First, total number of patients with ESRD was 56,396 (hemodialysis [HD], 37,391; peritoneal dialysis [PD], 7,618; functioning kidney transplant [KT], 11,387). The prevalence of ESRD was 1,113.6 patients per million population (PMP). Proportion of patients undergoing renal replacement therapy was 66.3% with HD, 13.5% with PD, and 20.2% with KT. Second, a total of 8,906 (HD, 6,540; PD, 1,125; KT, 1,241; incidence rate of 175.9 PMP) patients developed ESRD in 2009. Third, the most common primary causes of ESRD were diabetic nephropathy (45.4%), hypertensive nephrosclerosis (18.3%), and chronic glomerulonephritis (11.1%). Fourth, mean urea reduction rate was 67.5% and 73.8% in male and female patients, respectively, undergoing HD. Mean Kt/V was 1.38 in male patients and 1.65 in female patients. Fifth, the overall 5-year survival rate of male patients undergoing dialysis was 65.4% and that of female patients was 67.4%.

Topics: Adult; Aged; Anemia; Comorbidity; Erythropoietin; Female; Hematinics; Humans; Incidence; Kidney Failure, Chronic; Male; Middle Aged; Prevalence; Recombinant Proteins; Registries; Renal Dialysis; Republic of Korea; Risk Factors; Survival Rate; Time Factors; Treatment Outcome

To determine the impact of adjuvant ascorbic acid therapy on erythropoietin-hyporesponsive, anemic patients undergoing hemodialysis.. The online databases of PubMed, Cochrane library, IPA, CINAHL, EMBASE, clinicaltrial.gov, WHO trial registry and PyschINFO were used.. Studies comparing ascorbic acid to a control, with participants receiving erythropoietin and hemodialysis, and reported outcomes for hemoglobin or transferring saturation.. Two independent researchers reviewed titles and abstracts to determine relevance and extracted study design, dose, duration, baseline values, and outcomes.. Five studies met all the criteria and were used for final analysis. The calculated weighted mean difference between hemoglobin in the ascorbic acid group versus the control group was 0.96 g/dL (95% CI, 0.78 to 1.14). The calculated weighted mean difference between transferrin saturation in the ascorbic acid treatment group versus the control was 8.26% (95% CI, 6.59 to 9.94).. Adjuvant ascorbic acid significantly raises hemoglobin levels in patients with erythropoietin hyporesponsiveness undergoing hemodialysis. The significant rise in transferrin saturation indicates that this positive effect on erythropoietin response may be due to increased iron utilization.

Topics: Adult; Anemia; Antioxidants; Ascorbic Acid; Erythropoietin; Female; Hemoglobins; Humans; Injections, Intravenous; Iron; Iron Overload; Kidney Failure, Chronic; Male; Middle Aged; Randomized Controlled Trials as Topic; Renal Dialysis

Erythropoiesis stimulating agents (ESA) are widely used for hemoglobin correction in patients suffering from renal anemia. However, their beneficial non-hematopoietic effects on renal deterioration have not been adequately assessed. The Primavera study is the first prospective, controlled trial to assess whether ESA treatment could ameliorate progression of chronic kidney disease (CKD) in non-anemic patients. Primavera is a single-blind, 24-month trial in which patients are randomized to placebo or to C.E.R.A., a continuous erythropoietin receptor activator. Patients with type 2 diabetes or who have undergone kidney transplantation are eligible to enter the study if they have CKD stage III (estimated GFR [eGFR] 30-59 mL/min/1.73 m(2)), urinary albumin to creatinine ratio (UACR) ≥ 50 g/g and ≤ 1500 g/g, or total urine protein ≥ 50mg/24h and ≤ 1500mg/24h, and hemoglobin 11-14 g/dL. The primary efficacy endpoint is the change in eGFR from baseline to month 24. Secondary efficacy endpoints are the changes in UACR, serum cystatin C and serum creatinine from baseline. Safety endpoints include adverse events and discontinuation due to pre-specified adverse events. An interim analysis will be performed after all patients have completed the first year. The planned sample size is 400 patients (200 type 2 diabetics, 200 transplant recipients) conferring 90% power to detect a prespecified significant difference of 1.5 mL/min/1.73 m(2) in the annual reduction in eGFR between treatment groups. The results of Primavera are expected in 2013.

Topics: Anemia; Erythropoiesis; Erythropoietin; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Polyethylene Glycols; Randomized Controlled Trials as Topic; Treatment Outcome

It is estimated that 15-30% of geriatric cats will develop chronic kidney disease (CKD), and that 30-65% of these cats will develop anemia as their renal disease worsens. Anemia of renal disease is multifactorial in its pathogenesis, but the main cause is reduced production of erythropoietin, a renal hormone that controls the bone marrow's production of red blood cells, as kidney disease progresses.. It is important to recognize the presence of anemia of renal disease so that adequate treatment may be instituted to improve quality of life and metabolic function. Erythrocyte-stimulating agents (ESAs), such as epoetin alfa, epoetin beta and darbepoetin alfa, have been developed to counteract the effects of decreased erythropoietin production by the kidneys. These treatments, which are the focus of this review, have 83% similarity in amino acid sequence to the feline hormone. On average, the target packed cell volume (>25%) is reached within 3-4 weeks of ESA therapy.. The use of ESAs has been associated with a number of complications, such as iron deficiency, hypertension, arthralgia, fever, seizures, polycythemia and pure red cell aplasia (PRCA). Darbepoetin has a prolonged half-life compared with epoetin and thus can be given only once a week, instead of three times a week. The incidence of PRCA appears to be decreased with darbepoetin use when compared with epoetin use in cats.. There is limited published evidence to date to underpin the use of ESAs in cats. This review draws on the relevant publications that currently exist, and the authors' personal experience of using these therapies for over 5 years.

Topics: Anemia; Animals; Cat Diseases; Cats; Darbepoetin alfa; Diagnosis, Differential; Drug Administration Schedule; Erythropoietin; Hematinics; Kidney Failure, Chronic; Male; Recombinant Proteins

As late provision of specialist care, before starting dialysis therapy, is believed to be associated with increased morbidity and mortality, a systematic review was undertaken to evaluate clinical outcomes relating to early versus late referral of patients to nephrology services.. Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE were searched up until September 2008 for studies of early versus late nephrology referral in adult (>18 years) patients with chronic kidney disease. Early referral was defined by the time period at which patients were referred to a nephrologist.. No randomized controlled trials were found. Twenty-seven longitudinal cohort studies were included in the final review, providing data on 17,646 participants; 11,734 were referred early and 5912 (33%) referred late. Comparative mortality was higher in patients referred to a specialist late versus those referred early. Odds ratios (OR) for mortality reductions in patients referred early were evident at 3 months (OR 0.51; 95% confidence interval [CI], 0.44-0.59) and remained at 5 years (OR 0.45; 95% CI, 0.38-0.53), both P <.00001. Initial hospitalization was 8.8 days shorter with early referral (95% CI, -10.7 to -7.0 days; P <.00001). Differences in mortality and hospitalization data between the 2 groups were not explained by differences in prevalence of diabetes mellitus, previous coronary artery disease, blood pressure control, serum phosphate, and serum albumin. However, early referral was associated with better preparation and placement of dialysis access.. Our analyses show reduced mortality and hospitalization, better uptake of peritoneal dialysis, and earlier placement of arteriovenous fistula for hemodialysis with early nephrology referral.

Topics: Adult; Arteriovenous Shunt, Surgical; Cause of Death; Creatinine; Early Medical Intervention; Erythropoietin; Hemoglobinometry; Humans; Kidney Failure, Chronic; Length of Stay; Nephrology; Peritoneal Dialysis; Referral and Consultation; Renal Dialysis; Survival Rate; Treatment Outcome

Despite new therapeutic options and treatment strategies, anemia still remains one of the major complications of chronic kidney disease (CKD), especially in patients undergoing chronic hemodialysis for end-stage renal disease. Successful management of anemia is a central part of patient care that may improve clinical outcomes. Although the National Kidney Foundation Dialysis Outcomes Quality Initiative (NKF-DOQI) working group reformulated its recommendations by stating that the hemoglobin target in patients receiving erythropoiesis stimulatory agents (ESA) should generally be 11-12 g/dl, this target value can not be achieved in many of them, despite treatment with high doses of ESA. The aim of the present review is to provide an update of the recent literature on causes and possible management of ESA-resistant anemia in CKD patients.

Topics: Anemia; Anemia, Iron-Deficiency; Drug Resistance; Erythropoiesis; Erythropoietin; Hematinics; Humans; Inflammation; Kidney Failure, Chronic; Patient Compliance; Recombinant Proteins; Renal Dialysis

Management of anaemia in chronic renal insufficiency (CRI) represents an important medico-economic challenge because of the great number of patients and the cost of the erythropoiesis-stimulating agent (ESA). The aim of this study was to identify determinants of the costs associated with these treatments in order to choose, with equal efficacy, the most efficient ASE.. A bibliographic research was realised by Medline database interrogation.. Among the direct medical costs, five studies showed that acquisition of epoetine alfa (EA) compared to darbepoetin alfa (DA) was less expensive. Concerning the costs associated with the route of administration, the subcutaneous injection (SC) of epoetine allowed a gain in costs because of the decrease of doses compared to the intravenous (IV) route. The switch from EA in SC to DA in IV, for hemodialysis patients, was associated with a reduction of the number of injections and with a treatment's cost lower by DA than by EA. Costs related to the regimen of administration, notably those related to nursing, medical and pharmaceutical time, were negligible towards those associated to the acquisition of the ASE. Finally, the costs of the therapeutic follow-up and treatment of the adverse effects of the ASE were similar between the EA and the DA.. The costs associated with the prices of acquisition of the ASE, negotiated by the structure of care, represent the most important part of the direct medical costs.

Topics: Anemia; Darbepoetin alfa; Direct Service Costs; Drug Costs; Epoetin Alfa; Erythropoietin; France; Health Care Costs; Hematinics; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Recombinant Proteins

Premature cardiovascular disease (CVD) is a frequent complication in patients with chronic kidney disease (CKD). The traditional (Framingham) risk factors only partly explain the high prevalence of CVD in these patients and nontraditional risk factors/markers such as oxidative stress, persistent inflammation, cardiovascular ossification, endothelial dysfunction and anaemia are prevalent and seem to play an important role in the pathogenesis of CVD in CKD patients. In addition, the so-called reverse epidemiology phenomenon, which occurs in advanced kidney disease, complicates the search for causative mechanisms. Here we review a few recently developed concepts regarding the high incidence of CVD in CKD patients.

Topics: Anemia; Cardiovascular Diseases; Chronobiology Disorders; Endothelium, Vascular; Erythropoietin; Humans; Inflammation; Kidney Failure, Chronic; Netherlands; Ossification, Heterotopic; Oxidative Stress; Prevalence; Risk Assessment; Risk Factors

Successful treatment and prevention of kidney disease in dogs requires a multi-dimensional approach to identify and eliminate causes or exacerbating factors, provide professional evaluation on a regular basis and implement a comprehensive treatment programme when necessary. Over the years, many therapeutic and preventive interventions have been developed or advocated for chronic kidney disease in dogs, but evidence of efficacy or effectiveness is often lacking or highly variable. Accordingly, the main objective of this systematic review was to identify and critically appraise the evidence supporting various aspects of managing canine chronic kidney disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animal Feed; Animals; Antihypertensive Agents; Antioxidants; Calcitriol; Dog Diseases; Dogs; Erythropoietin; Evidence-Based Practice; Fatty Acids, Omega-3; Fluid Therapy; Kidney Failure, Chronic

The recombinant human erythropoietins and allied proteins (epoetin alfa, attempted copies and biosimilar variants of epoetin alfa, epoetin beta, epoetin delta, epoetin zeta, epoetin theta, epoetin omega, darbepoetin alfa, and methoxy-polyethylene glycol-epoetin beta) are among the most successful and earliest examples of biotechnologically manufactured products to be used in clinical medicine. This article charts a brief history of their use in clinical medicine, mainly dealing with chronic kidney disease, paying special attention to how these agents were introduced into clinical medicine and what has happened subsequently; in 2009, there were several developments that could be regarded as a "perfect storm" in terms of the long-term use of these compounds in chronic kidney disease and oncology and, likely, elsewhere. We are now very much at a "crossroads," where mature reflection is required, because with the latest trials and meta-analyses, these therapies seem not only expensive but also very much a clinical tradeoff (increased risk of adverse effects versus a small gain in fatigue scores). How we arrived at this crossroads is a useful illustration of how easy it is, without properly designed randomized, controlled trials, to assume that clinical benefit must follow therapeutic interventions.

Topics: Anemia; Biomarkers; Erythropoiesis; Erythropoietin; Evidence-Based Medicine; Hematinics; Hemoglobins; History, 20th Century; History, 21st Century; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Assessment; Treatment Outcome

The triad of diabetes mellitus, anemia, and chronic kidney disease (CKD) define a group of patients at high risk for death and cardiovascular complications. The approval of epoetin alfa in 1989 transformed the treatment of anemia in patients with CKD. However, evidence has emerged from randomized controlled trials that correcting anemia with erythropoiesis-stimulating agents in CKD patients is associated with increased risk. Most recently, the TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) study of anemic type 2 diabetic patients with CKD reported that treatment with darbepoetin conferred no benefit in mortality or in attenuating cardiovascular or renal events. Instead, there was a twofold higher rate of stroke and thromboembolic complications and a higher rate of cancer deaths in patients randomized to treatment with darbepoetin. Furthermore, there was an inconsistent and modest improvement in health-related quality of life. TREAT raises questions about whether anemia in type 2 diabetic patients should be treated and under what circumstances.

Topics: Anemia; Darbepoetin alfa; Diabetes Mellitus, Type 2; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins

Anaemia is common in congestive heart failure (CHF) and is associated with increased mortality, morbidity and progressive renal failure. The common causes of the anaemia are the associated renal failure and excessive cytokine production, both of which can cause depression of the erythropoietin (EPO) production in the kidney and depression of EPO response in bone marrow. The cytokines can also induce iron deficiency by increasing hepcidin production from the liver, which both reduces gastrointestinal iron absorption and reduces iron release from iron stores located in the macrophages and hepatocytes. Attempts to control this anaemia will have to consider the use of both erythropoiesis stimulating agents (ESA) as well as oral and, probably more importantly, intravenous (IV) iron. Studies of anaemia in CHF with ESA and oral or IV iron and even with IV iron alone have shown a positive effect on hospitalisation, fatigue and shortness of breath, cardiac and renal function, quality-of-life, exercise capacity and reduced beta natriuretic peptide and have not demonstrated an increase in cardiovascular damage related to therapy. Although some studies and meta-analyses have revealed improvement in these parameters others have not. Adequately powered long-term placebo-controlled studies of ESA and of IV iron in CHF are needed and are currently being carried out.

Topics: Anemia; Anemia, Iron-Deficiency; Cytokines; Darbepoetin alfa; Electric Countershock; Erythropoietin; Heart Failure; Hematinics; Humans; Iron; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors

The European Renal Best Practice (ERBP), which are issued by ERA-EDTA, are suggestions for clinical practice in areas in which evidence is lacking or weak, together with position statements on recently published randomized controlled trials, or on existing guidelines and recommendations. In 2009, the Anaemia Working Group of ERBP published its first position statement about the haemoglobin target to aim for with erythropoietin-stimulating agents (ESA) and on issues that were not covered by K-DOQI in 2006-07. This second position paper of the group follows the publication of the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Study. This multi-centre, placebo-controlled trial compared cardiovascular and renal outcomes in 4038 patients with type 2 diabetes, chronic kidney disease not on dialysis, and anaemia who were randomized to complete anaemia correction (haemoglobin target of 13 g/dL using darbepoetin alpha) or placebo (with a haemoglobin rescue value of 9 g/dL). Following the findings of the TREAT study, the Anaemia Working Group of ERBP maintains its view that 'Hb values of 11-12 g/dL should be generally sought in the CKD population without intentionally exceeding 13 g/dL' and that the doses of ESA therapy to achieve the target haemoglobin should also be considered. More caution is suggested when treating anaemia with ESA therapy in patients with type 2 diabetes not undergoing dialysis (and probably in diabetics at all CKD stages). In those with ischaemic heart disease or with a previous history of stroke, possible benefits should be weighed up against an increased risk of stroke recurrence, when deciding which Hb level to aim for. These recommendations are not intended to represent a new guideline as they are not the result of a systematic review of the evidence.

Topics: Anemia; Cardiovascular Diseases; Clinical Trials as Topic; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Treatment Outcome

Renal dysfunction and neurohormonal and proinflammatory cytokine activation appear to contribute to anemia of chronic disease in most patients, resulting in inappropriate erythropoietin production and defective iron utilization. Under normal conditions, reduced tissue oxygenation caused by chronic anemia results in non-hemodynamic and hemodynamic compensatory responses to enhance oxygen carrying capacity. Erythropoiesis is the predominant non-hemodynamic response to hypoxia, but because erythropoiesis is defective in heart failure, hemodynamic mechanisms may predominate in chronic severe anemia. Hemodynamic responses are complex and involve a vasodilation-mediated high-output state with neurohormonal activation. The high output state initially helps to increase oxygen transport. However, the hemodynamic and neurohormonal alterations could potentially have deleterious long-term consequences and may contribute to anemia's role as an independent risk factor for adverse outcomes.

Topics: Anemia, Iron-Deficiency; Cytokines; Disease Progression; Erythropoietin; Heart Failure; Hemodynamics; Humans; Kidney Failure, Chronic; Prognosis; Renin-Angiotensin System; Risk Factors

Anemia is highly prevalent in patients with chronic heart failure (CHF) and is associated with poor clinical outcome. Increased prevalence of anemia in CHF has been linked to advanced age, female gender, renal function impairment, severity of symptoms, and clinical settings. Overall, the anemia of CHF shares many common features with the anemia of chronic disease. Both impaired iron metabolism and inflammatory stress appear to be the key mediators of the anemia of CHF.

Topics: Age Factors; Anemia, Iron-Deficiency; Disease Progression; Erythropoietin; Female; Heart Failure; Humans; Inflammation; Iron, Dietary; Kidney Failure, Chronic; Male; Prevalence; Prognosis; Renin-Angiotensin System; Risk Factors; Sex Factors; Stress, Physiological; United States

Anemia resulting from iron and erythropoietin deficiencies is a common complication of advanced chronic kidney disease (CKD). This article covers major advances in our understanding of anemia in patients with CKD, including newly discovered regulatory molecules, such as hepcidin, to innovative intravenous iron therapies. The use of erythropoiesis-stimulating agents (ESA) in the treatment of anemia has undergone seismic shift in the past 3 years as a result of adverse outcomes associated with targeting higher hemoglobin levels with these agents. Potential mechanisms for adverse outcomes, such as higher mortality, are discussed. Despite the disappointing experience with ESAs, there is a tremendous interest in other novel agents to treat anemia in CKD. Lastly, while awaiting updated guidelines, the authors outline their recommendations on how to best manage patients who are anemic and have CKD.

Topics: Anemia, Iron-Deficiency; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Cardiovascular Diseases; Erythropoietin; Ferrosoferric Oxide; Heart Failure; Hematinics; Hepcidins; Humans; Indicators and Reagents; Iron, Dietary; Kidney Failure, Chronic

Anemia is one of the most common and morbid complications of chronic kidney disease, causing unpleasant symptoms and reducing the quality of life. The availability of recombinant human erythropoietin (rHuEPO) in 1989 has been one of the most important developments in the care of this population in the past several decades. Treatment with erythropoiesis-stimulating agents (ESAs) has improved patients' lives, but recent studies have found that higher hemoglobin (Hgb) targets cause harm, resulting in more cautious treatment. Despite widespread recognition by clinicians and patients of the value of this biological agent, the high cost and new concerns over safety have led to a reexamination of its use. Although rHuEPO is prescribed by individual physicians and target Hgb is guided by current evidence in the context of individual patients, critics within and outside the medical community have charged that rHuEPO is being overused, that financial motives are driving its use, and that patients are suffering from adverse consequences. Regulatory agencies, including the Centers for Medicare and Medicaid Services and the US Food and Drug Administration, have weighed in as well. In this review article, issues related to the current and future status of ESA treatment will be considered with a view to assessing factors that result in a lack of clarity and need for further study. It is essential that the renal community vigorously support additional rigorous research to expand the evidence base for optimal anemia management so that the debate over appropriate ESA use remains where it belongs, in the scientific domain.

Topics: Anemia; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; Treatment Outcome; United States; United States Food and Drug Administration

Erythropoiesis stimulating agents (ESAs) are effective drugs that correct anemia in patients with chronic kidney disease (CKD). Recombinant human erythropoietin (EPO), the first ESA that became available more than 20 years ago, is similar to the naturally occurring molecule. In subsequent years, pharmacological research focused on the development of new agents with improved characteristics, with the creation of high molecular weight ESAs having been the first approach. In more recent years, new agents have been developed, including peginesatide (Hematide; Affymax Inc/Takeda Pharmaceutical Co Ltd), which is a dimeric peptide with a chemical structure unrelated to EPO that is being evaluated in phase III clinical trials. In addition, the clinical development of two inhibitors of hypoxia-inducible transcription factor has been resumed recently, while other approaches, such as gene therapy and EPO fusion proteins, and the inhibition of GATA and hematopoietic cell phosphatase remain far from being applicable in clinical practice. New iron compounds, which are becoming increasingly available, will facilitate an integrated approach to anemia management using both iron and/or ESAs, according to the clinical needs of patients. This review discusses new therapeutic options (already available or still under development) for the treatment of CKD-associated anemia, including ESAs and intravenous iron molecules.

Topics: Anemia; Erythropoietin; Gene Expression Regulation; Genetic Therapy; Hematinics; Humans; Iron Compounds; Kidney; Kidney Failure, Chronic; Peptides; Recombinant Proteins; Renal Insufficiency, Chronic

Anemia secondary to end-stage renal disease (ESRD) is an important but complex syndrome which directly contributes to significant morbidity and mortality in this patient population. The interactions between uremia, bone marrow biology and erythropoietin (EPO) responsiveness are of significant interest to improve our basic understanding of anemia management in ESRD. Nocturnal home hemodialysis is an intensive mode of renal replacement therapy, which has been associated with an improvement in EPO responsiveness. The aims of the present review are (1) to update the recent advances in uremia associated perturbations in bone marrow-derived hematopoietic stem cells and (2) to discuss the potential mechanistic explanations by which augmented uremia clearance may directly affect EPO responsiveness.

Topics: Anemia; Cytokines; Erythropoietin; Hemodialysis, Home; Humans; Kidney Failure, Chronic

Iron deficiency is prevalent in patients with chronic kidney disease (CKD), and use of oral and intravenous iron in patients with CKD who do not require dialysis might obviate or delay the need for treatment with eythropoiesis-stimulating agents (ESAs). Patients on hemodialysis have lower intestinal iron absorption, greater iron losses, and require greater iron turnover to maintain the ESA-driven red cell mass than do healthy individuals. In these patients, intravenous iron reduces ESA dose requirements and increases the likelihood of maintaining levels of hemoglobin within the desired range. Oral iron is inferior to intravenous iron in patients on hemodialysis, in part because elevated serum levels of hepcidin prevent intestinal absorption of iron. Increased levels of hepcidin also impair the normal recycling of iron through the reticuloendothelial system. Levels of serum ferritin and transferrin saturation below 450 pmol/l and 20%, respectively are indicative of iron deficiency, but values above the normal range lack diagnostic value in patients with CKD on dialysis. The availability of various iron preparations and new developments in delivering iron should enable adequate provision of iron to patients with CKD. This Review examines the efficacy, safety and use of iron supplementation therapy for the treatment of anemia in patients with CKD.

Topics: Anemia, Iron-Deficiency; Antimicrobial Cationic Peptides; Erythropoietin; Hematinics; Hepcidins; Humans; Iron; Kidney Failure, Chronic; Renal Dialysis

epoetin zeta is a recently introduced recombinant erythropoietin, designed to be biologically similar to epoetin alfa. This posthoc analysis evaluated the impact of switching patients with chronic kidney disease (CKD) on hemodialysis from epoetin alfa to epoetin zeta, or vice versa, on hemoglobin concentration, epoetin dose, and patient safety.. data were analyzed from three published trials: two 24-week randomized, double-blind (maintenance and induction) studies and a 56-week, open-label, follow-on study involving adult patients with CKD stage 5, maintained on hemodialysis, and receiving epoetin alfa or epoetin zeta. Patients had either completed and switched treatments within the maintenance study, or had completed the induction or maintenance study on epoetin alfa and then switched to, and completed at least 12 weeks of follow-up treatment on, epoetin zeta. Mean hemoglobin levels and epoetin dose were evaluated pre- (0-4 weeks before) and post- (8-12 weeks after) switch, and were considered equivalent for the two treatments if the upper and lower limits of the 95% confidence intervals (CIs) for the intraindividual differences in mean values fell within accepted limits.. overall, 481 patients were included in the analysis. Mean hemoglobin concentration was maintained at target levels (10.5-12.5 g/dL) throughout the drug switch. The mean differences in hemoglobin concentration and associated 95% CIs following the switch remained within prespecified equivalence limits (± 1.0 g/dL). The 95% CIs of the mean difference in weekly epoetin dose postswitch also remained within prespecified equivalence margins (± 45 IU/kg; upper limit 17.83 IU/kg, lower limit -10.91 IU/kg). Both treatments were similarly well tolerated.. our data suggest that epoetin alfa and epoetin zeta therapy can be interchanged without any clinically significant alteration in efficacy, safety, or epoetin dose, in patients with CKD on dialysis receiving stable epoetin maintenance therapy.

Topics: Adult; Aged; Anemia; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Therapeutic Equivalency; Young Adult

Hepcidin is a key regulator controlling iron intestinal absorption and distribution through the body. The article by van der Putten et al. examined the association between hepcidin-25 and erythropoietin responsiveness and inflammation in erythropoietin-naive, iron-replete patients with chronic heart failure and chronic kidney disease. A cross-sectional observation revealed that serum hepcidin-25 was elevated almost twofold when compared with levels in healthy subjects. Hepcidin-25 was inversely correlated with hemoglobin (r(2) = 0.18; p < 0.02), and positively with ferritin (r(2) = 0.51; p < 0.01) and transferrin saturation (r(2) = 0.14; p < 0.03), while it did not correlate with levels of IL-6 and highly sensitive C-reactive protein. They found that 2-week erythropoietin therapy (50 IU/kg/week) significantly decreased hepcidin-25 levels. The magnitude of the decrease in hepcidin-25 levels correlated with the increase in reticulocytes (r(2) = 0.23; p < 0.03) and soluble transferrin receptor (r(2) = 0.23; p = 0.03), but not with inflammatory markers. A decline in hepcidin-25 correlated with the increment of hemoglobin after 6 months (r(2) = 0.49; p < 0.01). The findings convincingly suggest that hepcidin-25 may be useful in predicting erythropoietin responsiveness in stable chronic heart failure patients. However, further studies will be needed to establish clinically available methods to reliably measure hepcidin-25 level.

Topics: Anemia; Antimicrobial Cationic Peptides; Biomarkers; C-Reactive Protein; Cystatin C; Erythropoietin; Glomerular Filtration Rate; Heart Failure; Hepcidins; Humans; Iron; Kidney Failure, Chronic; Mass Screening; Recombinant Proteins; Statistics as Topic; Treatment Outcome

End-stage renal disease (ESRD) affects more than 1500 people per million population in countries with a high prevalence, such as Japan, Taiwan, and the US. Approximately two-thirds of people with ESRD receive haemodialysis, one quarter have kidney transplants, and one tenth receive peritoneal dialysis.. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of different doses for peritoneal dialysis? What are the effects of different doses and membrane fluxes for haemodialysis? What are the effects of interventions aimed at preventing secondary complications? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).. We found 26 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.. In this systematic review we present information relating to the effectiveness and safety of the following interventions: cinacalcet, darbepoetin, erythropoietin, haemodialysis (standard-dose, increased-dose), high membrane-flux haemodialysis, increased-dose peritoneal dialysis, low membrane-flux haemodialysis, mupirocin, sevelamer, standard-dose dialysis, and statins.

Topics: Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Peritoneal Dialysis; Renal Dialysis; Renal Insufficiency, Chronic

Topics: Animals; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Erythropoietin; Humans; Hypoxia; Kidney Failure, Chronic; Models, Biological; Polymorphism, Single Nucleotide; Promoter Regions, Genetic

In the haematopoietic system, the principal function of erythropoietin (EPO) is the regulation of RBC production. Consequently, following the cloning of the EPO gene, recombinant human EPO (rHuEPO) forms have been widely used for treatment of anaemia in chronic kidney disease and chemotherapy-induced anaemia in cancer patients. However, a steadily growing body of evidence indicates that the therapeutic benefits of rHuEPO could be far beyond the correction of anaemia. Several articles have been recently published on the tissue-protective, nonhaematological effects of rHuEPO that prevent ischaemia-induced tissue damage in several organs including the kidney.In this review, we focus on nonhaematological effects of rHuEPO in various experimental settings of acute and chronic kidney injury. Because this tissue-protective action of rHuEPO is not the result of correction of anaemia-related tissue hypoxia, we will also discuss potential molecular pathways involved. Finally, we will review the current literature on clinical studies with rHuEPO or analogous substances and progression of chronic kidney disease, and propose possible clinical renoprotective strategies.

Topics: Animals; Erythropoietin; Humans; Kidney Diseases; Kidney Failure, Chronic; Receptors, Erythropoietin; Recombinant Proteins

Recent studies, in which the cardiovascular risk and mortality associated with high and low hemoglobin target values, respectively, have been investigated, challenged the concept that hemoglobin normalization improves prognosis.. The results of these studies are reviewed with respect to differences in study populations, study design and methodological limitations to provide guidance for their interpretation and relevance for clinical practice.. There are important differences with respect to enrolled populations, design and conduct of the studies. Each study has its specific, inherent methodological limitations. Importantly, there is no statistically significant and consistent pattern of negative results for cardiovascular and mortality outcomes, although in general outcomes are not in favor of hemoglobin normalization. On the other hand, the reported data on quality of life are consistently and significantly better with higher hemoglobin values.. Recent evidence from large outcome studies suggested an increased risk associated with hemoglobin normalization. On the other side, several study-inherent and methodological limitations must be considered before simply extrapolating the negative findings of these studies into clinical practice. However, until new evidence becomes available from ongoing and future clinical studies, an upper Hb limit of 12 g/dl should not be exceeded.

Topics: Cardiovascular Diseases; Clinical Trials as Topic; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins; Treatment Outcome

Optimal management of anemia in patients with chronic kidney disease remains a divisive issue within the nephrology community. Because the evidence provided by successive randomized controlled trials has often proven to be incongruent, it is natural to consider whether methodological issues may be responsible. Using four large trials [US Normal Hematocrit, Canadian European Normalization of Hemoglobin, Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) and Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR)], this review article highlights several methodological issues that may be important when trial evidence is translated into clinical practice. Issues discussed include heterogeneity of enrollment criteria, failure to conceal treatment allocation, generalizability of study interventions, systematic use of imbalanced co-interventions [especially dose of erythropoietin stimulating agent (ESA), confusion regarding stopping rules and interim analyses and failure to account for imbalances in important patient characteristics generated at randomization.

Topics: Anemia; Clinical Trials as Topic; Data Interpretation, Statistical; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins; Treatment Outcome

In patients with chronic kidney disease, erythropoietin resistance is common, costly, and has implications beyond the management of anemia because the presence of erythropoietin resistance portends mortal outcomes. Exploring the provenance of erythropoietin resistance may be facilitated by the consideration of the pathogenetic triad of iron-restricted erythropoiesis, inflammation, and bone marrow suppression. Challenging to diagnose because of difficulty in interpreting tests of iron deficiency, iron-restricted erythropoiesis should be considered in patients who require high doses of erythropoietin, have low transferrin saturation (eg, <20%-25%), and do not have very high ferritin (eg, <1,200 ng/mL); a therapeutic trial of intravenous iron may be worthwhile. Aluminum intoxication is a rare cause of iron-restricted erythropoiesis that may manifest as microcytic hypochromic anemia. A decrease in serum albumin concentration may signal the presence of inflammation, which may be manifest (such as because of a recent illness or infection) or occult; the latter include clotted synthetic angioaccess, failed renal allograft, dialysis catheter, periodontal disease, underlying malignancy, or uremia per se. Marrow hyporesponsiveness may be improved by increasing the delivered dialysis dose, using ultrapure dialysate, maintaining adequate vitamin B12 and folate stores, or by treating hyperparathyroidism. In summary, improving the outcomes of erythropoietin-resistant patients will require complete patient assessment that goes beyond considerations of iron and erythropoietin dose alone. Given that erythropoietin dose is associated with mortality, mitigating erythropoietin resistance has the potential to improve patient outcomes.

Topics: Anemia, Iron-Deficiency; Drug Resistance; Erythropoietin; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Recombinant Proteins; Treatment Outcome

The management of anemia in the United States during the past 2 decades and since the introduction of erythropoietin (EPO) has continuously evolved, shaped by the interplay of reimbursement, evidence, clinical performance measurement, and, most recently, risk management. A fee-for-service reimbursement system has driven average EPO doses higher than anywhere else in the world, despite opportunities to decrease such dosing through more effective iron management and subcutaneous administration. Calls by Congress for Medicare to constrain ESA costs and FDA relabeling of erythropoietic-stimulating agents (ESAs), in the wake of The Correction of Hemoglobin and Outcomes in Renal Insufficiency and The Cardiovascular risk Reduction by Early Anemia Treatment with Epoetin Beta trials, have in 2007 led to the first decrease in mean hemoglobin levels in US hemodialysis patients since EPO was introduced in 1989. The implementation of a case-mixed adjusted bundled payment system for ESRD services in 2011 will turn ESAs from a profit center to a cost center for dialysis providers. This is likely to have profound implications regarding anemia management directed at curtailing ESA dosing, including subcutaneous administration, more aggressive iron therapy, and decreased target hemoglobin levels. Medicare has developed a third generation of clinical performance measures (CPMs) for ESRD providers (facilities and physicians) to ensure that quality is maintained in the new fiscal environment. Unlike the previous generations, these new CPMs emphasize an upper limit of hemoglobin as well as a lower one. Payment for performance based on these CPMs will likely be a key driver of future practice patterns for anemia management.

Topics: Anemia, Iron-Deficiency; Drug Costs; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins; Reimbursement Mechanisms; United States

Treatment for anemia has come a long way in the last 20 years since the first recombinant human erythropoietins were licensed for the management of anemia in chronic kidney disease. The first-generation epoetins were succeeded by the development and production of a longer-acting erythropoietin (EPO) analog, darbepoetin alpha, which allowed less frequent dosing, usually once weekly or once every 2 weeks. More recently, another EPO-related molecule has been manufactured called Continuous Erythropoietin Receptor Activator with an even longer half-life, and although for patent reasons this is not available in the United States, it is licensed and is already being used in Europe. Other molecules are in development or are becoming licensed in Europe, including biosimilar epoetin products/follow-on biologics, and elsewhere in the world there are cheaper-production "copy" epoetins. Indeed, it is estimated that up to 80 such products may be sold in countries with less stringent regulatory control of pharmaceutical products. Two different biosimilar epoetins have already been licensed in Europe, one under 2 different brand names and one under 3 different brand names, and others may follow. Hematide is a synthetic peptide-based EPO receptor agonist that, interestingly, has no structural homology with EPO, and yet is still able to activate the EPO receptor and stimulate erythropoiesis. This agent is currently in phase III clinical trials. Research continues for orally active antianemic therapies, and several strategies are being investigated, although none is imminently available. Two new intravenous iron preparations have recently been developed, one in the United States (Ferumoxytol; AMAG Pharmaceuticals, Inc., Cambridge, MA) and one recently licensed in Europe (ferric carboxymaltose [Ferinject; Vifor Pharma, Zurich, Switzerland]). In conclusion, the development of effective therapies for the treatment of anemia has been a highly active field, both scientifically and economically, over the last two decades.

Topics: Anemia, Iron-Deficiency; Drug Industry; Erythropoietin; Hematinics; Humans; Iron Compounds; Kidney Failure, Chronic; Recombinant Proteins

The purpose was to evaluate changes in the left ventricular mass index (LVMi) among anemic chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients treated with recombinant human erythropoietin (EPO).. A systematic review of the literature, reporting LVMi for patients before and after EPO therapy, was performed. The change in LVMi from baseline to the end of treatment was calculated and stratified by severity of anemia at baseline, target hemoglobin (Hb), and stage of kidney disease.. Fifteen eligible studies involving 1731 patients were identified. Cohorts with severe anemia at baseline (<10 g/dl), when given EPO using a lower target level (Hb 12 g/dl or Hct > 36%). The effect size was similar in direction for both CKD and ESRD cohorts.. Aggregated results from multiple studies suggest that in severe anemia conventional Hb targets for EPO therapy are associated with a reduction in LVMi, but that in moderate anemia target Hb above 12 g/dl does not have a significant beneficial impact on LVMi compared with conventional targets.

Topics: Anemia; Biomarkers; Chronic Disease; Erythropoietin; Hematinics; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Kidney Failure, Chronic; Recombinant Proteins; Severity of Illness Index; Time Factors; Treatment Outcome

Mortality in dialysis patients is extremely high, with an annual death rate of approximately 23%. Sudden cardiac death (SCD) is the single largest cause of death in dialysis patients accounting for approximately 60% of all cardiac deaths and 25% of all-cause mortality. Interventions aiming at reducing cardiovascular mortality, especially SCD, in dialysis patients are therefore extremely important and clinically highly relevant. The purpose of this review is to give an outline of the epidemiology of SCD in dialysis patients and to provide a comprehensive overview of several interventional strategies (medical therapies, changing dialysis modality, and revascularization). Furthermore, it will discuss the current knowledge regarding the value of preventive implantable cardioverter defibrillator implantation and address future implications of the interventional strategies mentioned.

Topics: Adrenergic beta-Antagonists; Death, Sudden, Cardiac; Defibrillators, Implantable; Erythropoietin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Failure, Chronic; Myocardial Revascularization; Recombinant Proteins; Renal Dialysis; Risk Factors

Association between androgens and erythropoiesis has been known for more than seven decades. Androgens stimulate hematopoietic system by various mechanisms. These include stimulation of erythropoietin release, increasing bone marrow activity and iron incorporation into the red cells. Before the discovery of recombinant erythropoietin (rhEpo), androgens were used in the treatment of anemia associated with renal disease, bone marrow suppression, and hypopituitarism. Anabolism is an additional advantage of androgen therapy. Furthermore, in light of recent reports regarding adverse effects of rhEpo, the role of androgen therapy in various types of anemias should be readdressed. Polycythemia remains a known side effect of androgen therapy. In this review, we will briefly discuss the initial animal and human studies which demonstrated the role of androgens in the treatment of anemia, their mechanism of action, a detailed account of the efficacy of androgens in the treatment of various anemias, the erythropoietic side effects of androgens and finally, the relationship between hematocrit levels and cardiovascular disease.

Topics: Aging; Androgens; Anemia; Anemia, Aplastic; Animals; Bone Marrow; Coronary Disease; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Humans; Iron; Kidney Failure, Chronic; Male

Since their inception nearly two decades ago, erythropoietin-stimulating agents (ESAs) have revolutionized the care of patients with renal anemia. Until recently, treatment options included the epoetins and darbepoetin alfa. As the use of these agents for chronic kidney disease (CKD) became widespread, the introduction of ESAs--touted for their longer-acting properties--was excitedly anticipated.. To review the option of methoxy polyethylene glycol-epoetin beta for ESA therapy in patients with renal anemia.. Peer-reviewed scientific literature, published abstracts and renal business journals were reviewed in the writing of this opinion.. Methoxy polyethylene glycol-epoetin beta (CERA) is an effective long-acting ESA approved for treatment of renal anemia and available for use outside of the United States. CERA corrects and maintains hemoglobin (Hb) levels in patients with CKD and its efficacy mirrors that of the epoetins and darbepoetin alfa. CERA holds promise for its safety record, administration requirements, and the potential impact on social and pharmacoeconomic barriers to treatment for patients with renal anemia.

Topics: Anemia; Animals; Erythropoietin; Humans; Kidney Diseases; Kidney Failure, Chronic; Polyethylene Glycols; Recombinant Proteins; Time Factors

Topics: Anemia; Animals; Diabetic Nephropathies; Disease Progression; Epoetin Alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Nephrotic Syndrome; Proteinuria; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins

Several million patients with chronic kidney disease (CKD) have benefited from the use of erythropoiesis-stimulating agents (ESAs) to correct severe anemia. However, mortality data now suggest that treating CKD patients to achieve a hemoglobin (Hb) level >13 g/dl can be harmful. For levels of 11.5-13 g/dl, there is no evidence of either harm or benefit compared with a lower Hb level. Quality of life studies are variable in quality but do suggest superior outcomes and functional status. In the 9 years following 1997, the target Hb level recommended by international guidelines tended to increase, especially for patients without accompanying cardiovascular disease. However, strangely enough, the most recent target level of the Kidney Disease Outcomes Quality Initiative is 11-12 g/dl, which is exactly the range advocated by the same group a decade earlier. The relative importance of quality of life compared with other outcomes, the use of iron, and the impact of venous thrombotic events continue to be debated. In addition, new issues have arisen from the introduction of "biosimilar" erythropoietins, biopharmaceuticals that refer to the existing agents and are submitted for marketing authorization after the existing agents' protection expires. Biosimilars can resemble the agents on which they are modeled but cannot fully copy their properties. The complexity in molecular structure, the possible presence of impurities (which may include bacterial endotoxins), and the inherent immunogenicity of such agents have required authorities to develop a sophisticated regulatory framework.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic

Renal parenchymal hypoxia has recently been documented in a host of clinical and experimental conditions characterized by tubulointerstitial changes and progressive chronic kidney disease (CKD). The nature of renal hypoxia under these settings, its causes and modes of detection are outlined in this review. Cellular hypoxia response, mediated in part by hypoxia-inducible factors (HIF), includes protective components, such as erythropoietin and heme-oxygenase-1, as well as the induction of harmful mediators. Prevention of the progression of CKD include strategies that attenuate renal parenchymal hypoxia, perhaps with selective intensification or inhibition of protective and harmful components, respectively of the hypoxia adaptive response.

Topics: Cell Hypoxia; Disease Progression; Erythropoietin; Heme Oxygenase-1; Humans; Hypoxia; Kidney Diseases; Kidney Failure, Chronic; Kidney Tubules

Observational studies have shown a strong positive correlation between the severity of anemia and the risk of poor outcomes in patients with chronic kidney disease (CKD). This observation was initially taken to imply that adverse outcomes in CKD are caused by anemia. However, the assumption of causality ignores the possibility that anemia and adverse outcomes might be unrelated and that both are caused by underlying inflammation, oxidative stress and comorbid conditions. Randomized clinical trials of anemia correction have revealed an increased risk of adverse cardiovascular outcomes in patients assigned to normal, rather than subnormal, hemoglobin targets. As a result, correction of anemia is now considered potentially hazardous in patients with CKD. Notably, individuals who did not reach the target hemoglobin level in the clinical trials, despite receiving high doses of erythropoietin and iron, experienced a disproportionately large share of the adverse outcomes. These observations point to overdose of erythropoietin and iron, rather than anemia correction per se, as the likely culprit. This Review explores the reasons for the apparent contradiction between the findings of observational studies and randomized clinical trials of anemia treatment in CKD. I have focused on data from basic and translational studies, which are often overlooked in the design and interpretation of clinical studies and in the formulation of clinical guidelines.

Topics: Anemia; Animals; Blood Platelets; Blood Pressure; Causality; Chronic Disease; Comorbidity; Dose-Response Relationship, Drug; Drug Overdose; Endothelin-1; Erythropoietin; Hemoglobins; Humans; Hypertension; Kidney Diseases; Kidney Failure, Chronic; Morbidity; Nitric Oxide; Oxidative Stress

Topics: Anemia; Antibody Formation; Erythropoietin; Hematinics; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

The renal interstitial compartment, situated between basement membranes of epithelia and vessels, contains two contiguous cellular networks. One network is formed by interstitial fibroblasts, the second one by dendritic cells. Both are in intimate contact with each other. Fibroblasts are interconnected by junctions and connected to basement membranes of vessels and tubules by focal adhesions. Fibroblasts constitute the "skeleton" of the kidney. In the renal cortex, fibroblasts produce erythropoietin and are distinguished from other interstitial cells by their prominent F-actin cytoskeleton, abundance of rough endoplasmic reticulum, and by ecto-5'-nucleotidase expression in their plasma membrane. The resident dendritic cells belong to the mononuclear phagocyte system and fulfil a sentinel function. They are characterized by their expression of MHC class II and CD11c. The central situation of fibroblasts suggests that signals from tubules, vessels, and inflammatory cells converge in fibroblasts and elicit an integrated response. Following tubular damage and inflammatory signals fibroblasts proliferate, change to the myofibroblast phenotype and increase their collagen production, potentially resulting in renal fibrosis. The acquisition of a profibrotic phenotype by fibroblasts in renal diseases is generally considered a main causal event in the progression of chronic renal failure. However, it might also be seen as a repair process.

Topics: 5'-Nucleotidase; Actins; Animals; Dendritic Cells; Erythropoietin; Fibroblasts; Fibrosis; Humans; Kidney Cortex; Kidney Failure, Chronic; Mice; Nephritis, Interstitial

The pathophysiological condition, in which combined cardiac and renal dysfunction amplifies a progression in the failure of the individual organ, has been denoted as severe cardiorenal syndrome (SCRS). An interactive network of cardiorenal connectors, i.e., the renin-angiotensin system (RAS), nitric oxide (NO) and reactive oxygen species (ROS) balance, the sympathetic nervous system (SNS), and inflammation, has been proposed as the cornerstones of the pathophysiology of SCRS. Because erythropoietin (Epo) production declinesin chronic renal failure (CRF) and Epo sensitivity might decrease by the cardiorenalconnectors in patients with the SCRS, it is not surprising thatanaemia is a commonly occurring state coinciding with CRF and chronic heart failure (CHF). Epo treatment in patients with SCRS acts via haematopoietic effects, but also may intervenes in the vicious circle of cardiorenal connectors with subsequent deteriorating effects on cardiac, renal, and vascular function. It appears that regular Epo treatment in anaemic patients with diminished renal function improves cardiac performance, delays the progression of kidney disease, and may be of clinical benefit even to patients suffering from CHF with relatively mild anaemia. Despite growing evidence about Epo having positive effects on both renal and cardiac function, little is known about the underlying mechanisms of action.

Topics: Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Syndrome

Cardiovascular disease (CVD) is a major cause of mortality in patients with mild to moderate chronic kidney disease (CKD) and end-stage renal disease (ESRD). Dyslipidemia has been established as a well-known traditional risk factor for CVD in the general population and it is well known that patients with CKD exhibit significant alterations in lipoprotein metabolism. In this review the pathogenesis and treatment of renal dyslipidemia are discussed.. Studies on lipid abnormalities in CKD stages 1-4, in nephrotic syndrome, and in hemodialysis and peritoneal dialysis patients are analyzed, as well as the lipid profile of kidney graft recipients. Also, the results of the effects of epoietin treatment and hypolipidemic drugs in CKD patients are reported.. Disturbances in lipoprotein metabolism are evident even at the early stages of CKD and usually follow a downhill course that parallels the decline of renal function. However, several intrinsic or exogenous factors can influence the phenotypic expression of these alterations. According to the literature, current evidence suggests that unlike dialysis patients, mild to moderate CKD patients could be benefit from the use of statins.. The use of statins is indicated in patients with mild to moderate CKD, while in subjects with ESRD lipid-lowering therapy should be individualized.

Topics: Dyslipidemias; Epoetin Alfa; Erythropoietin; Humans; Hypertriglyceridemia; Kidney Failure, Chronic; Kidney Transplantation; Lipid Metabolism; Lipids; Models, Biological; Nephrotic Syndrome; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis; Treatment Outcome

The triad of chronic kidney disease, heart failure and anemia is well described and frequently encountered in clinical practice. While individually these disease states are associated with significant morbidity and mortality, the presence of the triad portends an even worse prognosis. Anemia is prevalent among cohorts of patients with chronic kidney disease and heart failure, indicating that its presence may serve as a central unifying hypothesis to explain poor outcomes in these populations. Observational and interventional trials of erythropoietin-stimulating agents, however, have had variable results on cardiovascular end points. Data are now emerging that suggest that treating erythropoietin deficiency in and of itself may be as or more important than the absolute levels of hemoglobin attained. Future research in this arena must focus on the optimal dose of erythropoietin administered to hemoglobin level achieved that will result in improved cardiovascular outcomes for patients with heart failure and kidney disease.

Topics: Anemia; Comorbidity; Erythropoiesis; Erythropoietin; Female; Forecasting; Heart Failure; Humans; Kidney Failure, Chronic; Male; Prognosis; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Assessment; Severity of Illness Index; Survival Analysis; Syndrome

Anemia is a common comorbidity in patients with heart failure and is associated with worse long-term outcomes. Although the cause of anemia in heart failure is unclear, the weight of evidence suggests that renal dysfunction, along with neurohormonal and proinflammatory cytokine activation in heart failure, favors the development of anemia of chronic disease, with defective iron utilization, inappropriate erythropoietin production, and depressed bone marrow function. Similarly, the mechanisms by which anemia worsens heart failure outcomes are unknown but may be related to increased myocardial workload. If anemia is a mediator and not just a marker of poor outcomes, correcting anemia could become an important and novel therapeutic target to improve long-term outcomes in such patients. Indeed, several small-sized studies have shown the beneficial effects of empirically treating anemia in heart failure patients with recombinant erythropoietin and intravenous iron. However, the ideal threshold at which therapy should be initiated and the extent of correction considered safe and desirable in the individual patient with heart failure need to be known. These issues become more important because of increasing safety concerns that recombinant erythropoietin therapy for treating anemia may be associated with adverse cardiovascular outcomes in patients with chronic kidney disease and may worsen cancer in patients receiving chemotherapy to treat various types of cancer. Therefore, further prospectively designed studies are required to address some of these questions. Fortunately, 2 large mortality morbidity trials, TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) in patients with chronic kidney disease and RED-HF (Reduction of Events with Darbepoetin alfa in Heart Failure) in heart failure patients, are in progress and are likely to provide definitive answers.

Topics: Anemia; Biomarkers; Bone Marrow; Erythropoietin; Female; Heart Failure; Humans; Inflammation; Iron Compounds; Kidney Failure, Chronic; Male; Receptors, Erythropoietin; Risk Factors

Recent trials have demonstrated a trend for increased mortality when patients with end-stage renal disease (ESRD) or chronic kidney disease (CKD) are treated with erythropoietin-stimulating agents (ESAs) to hemoglobin levels higher than recommended (>13 g/dl). Recent studies suggest that higher doses of ESAs, in themselves, may be at least partly responsible for this mortality risk. This is important, as more than 90% of patients with ESRD and approximately 20% of patients with CKD receive ESAs. Two new studies address this.

Topics: Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic

Chronic kidney disease (CKD) is now recognized as a risk factor of both end-stage renal disease (ESRD) and independently cardiovascular disease (CVD). Therefore, a specific renoprotective intervention is strongly recommended, including blood pressure control as well as anemia improvement with erythropoietin stimulating agents (ESAs). Treatment of renal anemia with ESAs has been proved to improve quality of life (QOL) and finally reduce patient mortality. Recently, Silverberg, et al. created a novel clinical entity of Cardio-Renal Anemia (CRA) syndrome, in which anemia plays a key role for worsening both CKD and cardiac performance in a vicious circle. An appropriate and vigorous treatment of anemia has now been accepted to terminate or weaken the circle. Recently, two large-scaled randomized controlled trials were reported, being the CREATE (cardiovascular risk reduction by early anemia treatment with epoetin beta) study and the CHOIR (correction of hemoglobin and outcomes in renal insufficiency) study. They demonstrated that early initiation of ESA treatment and targeting at higher hemoglobin level (near normal level) failed to show the lowering effects for cardiovascular events as compared to a group in which Hb targeting was lower (sub-normal level) in pre-dialysis CKD patients. While there has been many argues in these reports especially about baseline patients characteristics, being a quite high incidence of severe cardiovascular co-morbidity. Thus, further evidences should be accumulated to resolve a proper target level of Hb in ESA treatment.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Disease Progression; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Diseases; Kidney Failure, Chronic; Prognosis; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors; Syndrome

Erythropoietin (Epo) is a peptide hormone that stimulates erythropoiesis. There are several agents in clinical use and in development that either act as ligands for the cell surface receptors of Epo or promote Epo production, which stimulates erythropoiesis. These are known as erythropoietic agents. The agents already in use include epoetin alfa, epoetin beta, and darbepoetin alfa. Newer agents under active investigation include continuous erythropoietin receptor activator (CERA) or proline hydroxylase inhibitors that increase hypoxia-inducible factor-1 (HIF-1), thereby stimulating Epo production and iron availability and supply. Erythropoietic agents have been shown to promote neuronal regeneration and to decrease post-stroke infarct size in mouse models. They have also been reported to shorten survival when used to treat anemia in many cancer patients and to increase thromboembolism. In contrast, rapid decrease of Epo levels as observed in astronauts and high-altitude dwellers upon rapid descent to sea level leads to the decrease of erythroid mass, a phenomenon known as "neocytolysis." The relative decrease in the serum Epo level is known to occur in some subjects with otherwise unexplained anemia of aging. Anemia by itself is a predictor of poor physical function in the elderly and is a significant economic burden on society. One out of every five persons in the United States will be elderly by 2050. Erythropoietic agents, by preventing and treating otherwise unexplained anemias of the elderly and anemia associated with other disease conditions of the elderly, have the potential to improve the functional capacity and to decrease the morbidity and mortality in the elderly, thereby alleviating the overall burden of medical care in society.

Topics: Aged; Anemia; Animals; Critical Illness; Erythropoiesis; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Mice; Peptides; Peptides, Cyclic; Polyethylene Glycols; Receptors, Erythropoietin; Recombinant Proteins

In recent years, the question of hemoglobin (Hb) stability in patients with chronic renal failure has attracted the interest of medical experts. One of the most important reasons behind this interest is that maintaining the hemoglobin level within the new narrower target range is highly challenging in clinical practice. According to the results available from observational trials, instability of inter-patient hemoglobin levels may be associated with increased morbidity and mortality. To clarify the questions and answers related to this topic and to prepare an updated summary, we reviewed the scientific literature. With the help of the PubMed portal, the incidence, clinical importance, and reasons of Hb variability were summarized according to the available scientific literature. Hb variability is affected by multiple factors which are connected to the general condition of the patient as well as medical interventions and treatments. Also the fluctuation of serum Hb level is a physiological process and is a healthy sign of the capability of the normal human body to adapt. The characteristics and extent of Hb variability vary in patients with chronic renal failure and this topic requires further clinical research. More precise studies are needed in order to explore the differences in possible Hb variability as well as the change in variability caused by particular treatment methods. Finally, based on the available data, the results of future research, and on board scientific consensus, in a strategy for treatment of renal anemia, we should take into account the questions related to Hb stability and variability.

Topics: Anemia, Hypochromic; Comorbidity; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Risk Factors

Therapy with erythropoiesis-stimulating agents (ESAs) is a well-established treatment for renal anemia. ESAs are highly effective at correcting the underlying anemia, restoring energy levels and increasing patient well-being and quality of life. Anemia correction has considerable secondary benefits in terms of morbidity and mortality reduction. However, because of the relatively short halflife of ESAs, they generally have to be administered one to three times weekly in most patients. In order to overcome this shortcoming, in recent years pharmacological research has tried to modify the molecular structure of recombinant human erythropoietin (rHuEpo) in order to improve pharmacokinetics and pharmacodynamics and to allow a reduction in the frequency of administration. Covalent addition of the water-soluble polyethylene glycol moiety has been successfully used to improve the pharmacokinetics of a number of proteins and reduce their immunogenicity. A modified version of rHuEPO incorporating this large polymer chain, called continuous erythropoiesis receptor activator (CERA), has been recently synthesized. Data from animal studies indicate that CERA has a prolonged half-life in comparison with rHuEPO that may allow less frequent administration. Results of phase II and III clinical trials suggest that this agent is effective in maintaining hemoglobin levels after switching from rHuEPO therapy or darbepoetin alpha when administered up to once a month. This less frequent administration schedule may be an advantage for patients and healthcare providers. In addition, this agent may give increased hemoglobin stability over time.

Topics: Anemia; Animals; Clinical Trials as Topic; Drug Carriers; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Polyethylene Glycols; Recombinant Proteins

Several recent articles have examined the time-dependent effects of epoetin therapy and the variability of hemoglobin (HGb) levels and what epoetin does in hemodialysis patients. A recent preliminary report also found that HGG cycling was common among hemodialysis patients, with only 10% of patients remaining within their initial HGb range (less than 11 g/dl, 11 to 12.5 g/dl, greater than 12.5 g/dl) during a six-month period. Factors associated with HGb cycling were changes in epoetin dose, intravenous-iron administration or a change in dose and hospitalization. What is not known is whether there are adverse clinical outcomes associated with HGb variability, although preliminary data indicate, perhaps predictably, that a decreasing HGb level is associated with a higher mortality risk. This is certainly an area that merits further study.

Topics: Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Life expectancy in haemodialysis patients is reduced fourfold on average versus healthy age-matched individuals. The purpose of this review is to present empirical evidence that intradialytic exercise can mitigate primary independent risk factors for early mortality in end-stage renal disease. These risk factors include measures of skeletal muscle wasting, systemic inflammation, cardiovascular functioning and dialysis adequacy. Overall, the available literature provides support for the integration of exercise within the conventional outpatient haemodialysis unit. The amelioration of various physiological risk factors through an appropriate exercise prescription may enhance survival in this vulnerable cohort. Investigations are required to determine the effects of various doses of intradialytic exercise on a broad range of clinical outcomes, and more thoroughly elucidate the relationship between exercise-induced adaptations and survival advantage in end-stage renal disease.

Topics: C-Reactive Protein; Erythropoietin; Exercise; Humans; Interleukin-6; Kidney Failure, Chronic; Muscle, Skeletal; Oxygen Consumption; Recombinant Proteins; Renal Dialysis

Erythropoietin (EPO) is a haematopoietic cytokine, mainly generated in the renal cortex, and its secretion and action is impaired in chronic kidney disease (CKD). Early renal damage in diabetes mellitus (DM) is usually not detected because diabetes-induced nephron hypertrophy maintains glomerular filtration rate (GFR) and an elevated plasma creatinine concentration is a relatively late manifestation of diabetic nephropathy. However, anaemia occurs more frequently in subjects with DM when compared with those with non-DM renal disease. While reduced production and a blunted response to EPO occurs in DM with early renal damage, other factors including chronic inflammation, autonomic neuropathy and iron deficiency are also important. Although recombinant human erythropoietin (rhEPO) has been an effective therapeutic agent in CKD anaemia, it appears to be more effective in patients with DM, even in earlier stages. Nevertheless, patients with DM are also more likely to be iron deficient, a barrier to effective rhEPO therapy. The effect of treatment on the reliability of haemoglobin A(1c) as an index of glycaemic control must be remembered. It is proposed that anaemia and its causes must be important components of care in subjects with early diabetic renal damage.

Topics: Anemia; Creatinine; Diabetic Nephropathies; Erythropoietin; Female; Humans; Iron; Iron Deficiencies; Kidney Failure, Chronic; Male; Recombinant Proteins

Nearly two decades ago, recombinant human erythropoietin transformed the management of chronic kidney disease anemia by allowing a more sustained increase in hemoglobin than was possible by intermittent blood transfusion. The treatment was highly effective, but because of the fairly short half-life of the molecule at approximately 6 to 8 h, injections usually had to be administered two to three times weekly. A second-generation erythropoietin analogue, darbepoetin alfa, was then created, with a longer elimination half-life in vivo that translated into less frequent dosing, usually once weekly or once every 2 wk. More recently, another erythropoietin-related molecule has been produced called Continuous Erythropoietin Receptor Activator with an even greater half-life, and other molecules are in development or are being licensed, including biosimilar epoetin products and Hematide. The latter is a synthetic peptide-based erythropoietin receptor agonist that, interestingly, has no structural homology with erythropoietin, and yet is still able to activate the erythropoietin receptor and stimulate erythropoiesis. The search goes on for orally active antianemic therapies, and several strategies are being investigated, although none is imminently available. This article reviews the latest progress with these novel erythropoietic agents in this new era in anemia management.

Topics: Anemia; Erythropoiesis; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic

Although many studies have found a high prevalence of anaemia in patients with congestive heart failure (CHF), few have carefully examined the relationship between the CHF and the prevalence of anaemia and chronic renal insufficiency (CRI). Patients with advanced renal failure, significant anaemia, diffuse atherosclerosis, respiratory disease and more elderly patients have been systematically excluded from the great majority of the randomised clinical trials.. Both anaemia and renal insufficiency are very common associated diseases associated with increased mortality, morbidity and rate of hospitalisation in CHF patients. Impaired renal function is associated with adverse outcomes because it represents a marker of coexistent disease and more diffuse atherosclerosis. In patients with CHF, progressive renal dysfunction leads to a decrease in erythropoietin (EPO) levels with reduced erythrocyte production from bone marrow. This may explain the common association between CHF, anaemia and CRI in clinical practice. The normalisation of haemoglobin concentration by EPO in patients with CHF and CRI results in improved exercise capacity by increasing oxygen delivery and improving cardiac function.. In this review, we describe the mechanisms linking anaemic status, CRI and CHF, the prognostic relevance of each disease, treatment implications, and potential benefit of EPO administration.

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Iron; Kidney Failure, Chronic; Prognosis; Syndrome

Pure red cell aplasia in patients who are treated for anemia of chronic kidney disease with erythropoiesis-stimulating agents such as epoetin was first reported in 1998. Although the incidence of pure red cell aplasia peaked in 2002, it remains important for nephrologists to know how to investigate a suspected case of pure red cell aplasia and how to identify other causes of hyporesponsiveness to erythropoiesis-stimulating agents, which account for the vast majority of such cases. The authors reviewed the current status of information in the literature and drew on their personal experiences with patients regarding the diagnosis and management of epoetin-induced pure red cell aplasia. The mechanism for development of epoetin-induced pure red cell aplasia remains unconfirmed. It generally occurs after the production of neutralizing anti-erythropoietin antibodies. Elucidation of a suspected pure red cell aplasia case requires a systematic approach, beginning with simple measurements such as blood cell counts, because most cases of erythropoiesis-stimulating agent hyporesponsiveness are attributable to other causes. If these criteria indicate that the patient's response to erythropoiesis-stimulating agent therapy is very poor, then bone marrow examination and measurement of anti-erythropoietin antibodies is justified. If pure red cell aplasia is confirmed, then cessation of erythropoiesis-stimulating agent therapy and initiation of immunosuppressive therapy are recommended. Continued study of epoetin-induced pure red cell aplasia is needed to help nephrologists prevent or manage future cases and will have implications for the use of other protein-based therapeutic agents.

Topics: Anemia; Antibodies; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Red-Cell Aplasia, Pure

Two randomised controlled trials of anaemia management published in the last year have fuelled the current haemoglobin controversy and led the United States Food and Drug Administration to issue a public health advisory warning concerning the use of erythropoiesis-stimulating agents and target haemoglobin levels. There is much more to the haemoglobin controversy than purely target haemoglobin levels. This article seeks to outline some of the current issues involved.

Topics: Anemia; Drug Approval; Erythropoietin; Evidence-Based Medicine; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Product Labeling; Randomized Controlled Trials as Topic; Recombinant Proteins

The cardiovascular state and life quality of patients suffering from chronic renal insufficiency is primarily determined by their haemostatic status. Renal anemia can positively be diagnosed if the glomerular filtration rate diminishes significantly (<60 ml/min/1,73 m 2 ). Other causes of anemia besides renal insufficiency can be excluded in these instances. The primary aim of erythropoietin treatment is to abolish the transfusion demand of patients suffering from renal insufficiency as this could lead to antibody formation and the transduction of viral infections. In case the existence of renal anemia is proved, the target values must be determined. A target value of >11 g/dl hemoglobin should be achieved for at least 85% of the patients in order to get an average hemoglobin level of 12-12,5 g/dl for the whole patient population. During the treatment of renal anemia regulating the iron metabolism of patients is of primary importance. A >5% rate of the hypochromic red blood cells in the blood circulation implies iron deficiency; but a value above 10% positively indicates iron deficiency. The transferric saturation values under 20% indicate functional iron deficiency and this indicator is a good means of following iron treatment. In the case of patients receiving dialysis parenteral input is advised because of poor iron absorption. In national clinical practice several erythropoietin products are available (erythropoietin-alpha, erythropoietin-beta, alpha-darbepoetin and continuous erythropoietin receptor activator, a new product now being introduced). When selecting the appropriate treatment strategy for each patient, the application method, the effect range and cost efficiency of the selected erythropoietin product must be taken into consideration.

Topics: Anemia, Hypochromic; Darbepoetin alfa; Drug Resistance; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; Renal Dialysis

Patients with end-stage renal disease treated with maintenance hemodialysis suffer substantial impairments in health-related quality of life (HRQOL). Despite widespread efforts, there are few interventions that improve the overall well-being and quality of life of this patient population. The current review provides a description of HRQOL as an essential, yet arguably overlooked health-related domain in hemodialysis patients, and discusses interventions that have been evaluated to improve the functional status and well-being of this population, with a particular focus on therapy with recombinant human erythropoietin. We review the controversy surrounding recombinant human erythropoietin as it relates to HRQOL, and describe the delicate balance faced by renal providers who seek to reduce hemodialysis patients' morbidity and mortality while simultaneously striving to improve patients' HRQOL.

Topics: Anemia; Erythropoietin; Fatigue; Health Status; Humans; Kidney Failure, Chronic; Quality of Life; Renal Dialysis

For 20 years, anemia has been treated with erythropoietin-stimulating agents (ESA). Until recently there have been only two ESA: recombinant erythropoietin and darbepoetin. In 2007 a third agent was approved for clinical use, CERA.. This review covers all of the peer-reviewed literature regarding ESA. The review also covers unique aspects of the regulatory publications with the FDA and European Agency for the Evaluation of Medicinal Products.. CERA is effective at correcting renal anemia. Compared to previous ESA, CERA has a dramatically lengthened half-life, making it the only ESA licensed for once-a-month dosing. However, like the previous ESA, CERA has not been shown to reduce morbidity or mortality and has only been shown to correct anemia and improve quality of life.

Topics: Anemia; Controlled Clinical Trials as Topic; Drug Administration Schedule; Erythropoietin; European Union; Half-Life; Hematinics; Humans; Kidney Failure, Chronic; Polyethylene Glycols; Quality of Life; Recombinant Proteins; United States; United States Food and Drug Administration

Topics: Anemia; Antimicrobial Cationic Peptides; Clinical Trials as Topic; Drug Monitoring; Erythropoietin; Hematinics; Hemoglobins; Hepcidins; Homeostasis; Humans; Iron; Kidney Failure, Chronic; Nephrology; Risk Factors

End-stage renal disease is a troublesome health problem worldwide. The most usual renal replacement therapy is conventional haemodialysis (CHD), performed three times a week, 3.5-4 h per session. It has been proposed that this schedule is unphysiologic and that daily haemodialysis would be a more appropriate schedule. One of the variants of daily haemodialysis is the so-called short daily haemodialysis (SDHD), performed five to seven times per week, 1.5-3 h per session. The objective of this paper is to compare, through a systematic review, the clinical effectiveness and safety of SDHD versus CHD.. The following databases were searched: MEDLINE, EMBASE, NHS Centre for Reviews and Dissemination (HTA, DARE and NHS EED), Cochrane, ISI Web of Knowledge, IME and IBECS. Two independent reviewers decided which papers were to be included after applying inclusion and exclusion criteria. Any discrepancy was resolved by consensus. The quality of the included papers was measured using a quality scale developed for the purpose of this report.. Seventeen original articles were included. There were no randomized controlled trials. SDHD seems to be more effective than conventional dialysis. Patients on daily haemodialysis seem to present less vascular access problems, better control of hypertension and in turn a reduction in the antihypertensive treatment, better quality of life, lower incidence of ventricular hypertrophy, lower consumption of rHuEPO due to the better control of anaemia and a reduction in the use of phosphate binders as a consequence of the better control of plasmatic phosphorous.. SDHD might result in a better clinical effectiveness, mainly through a better control of the arterial tension and, therefore, a lower consumption of antihypertensive drugs, and a better quality of life than CHD.

Topics: Anemia; Antihypertensive Agents; Catheters, Indwelling; Erythropoietin; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Nutritional Status; Quality of Life; Recombinant Proteins; Renal Dialysis; Safety; Treatment Outcome

Topics: Anemia; Animals; Darbepoetin alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Rats; Renal Dialysis

Recombinant human erythropoietin has been used for more than 20 years for the treatment of renal anaemia, with epoetin-alfa and -beta representing the common traditional preparations. By the modification of the molecule's carbohydrate moiety or structure a longer duration of erythropoietin receptor stimulation was achieved. The administration of these new molecules (darbepoetin, C.E.R.A.) once or twice a month is also sufficient to achieve serum haemoglobin target levels, making the treatment safer and more comfortable both for the patients and the personnel. These recently developed synthetic erythropoietin receptor stimulating molecules, along with recombinant human erythropoietin, are together called "Erythropoiesis Stimulating Agents". In haemodialysed patients the intravenous route is preferred, but the subcutaneous administration can substantially reduce dose requirements. In praedialysed, transplanted or peritoneally dialysed patients, erythropoiesis stimulating agents should preferably be given subcutaneously both for economic and practical reasons. There are ongoing clinical trials with erythropoiesis stimulating molecules that can be administered by inhalation or per os. Current evidence suggests that the serum haemoglobin level should preferably not exceed 12 g/dl with the use of erythropoiesis stimulating agents. No cardiovascular protective effect of higher serum haemoglobin levels was demonstrated in two large clinical trials. Further well-designed studies are necessary to set evidence-based haemoglobin targets for erythropoiesis stimulating treatment. Arguments for a more widespread use of agents with extended duration include medical, financial and patient satisfaction reasons. The release of new erythropoiesis stimulating agents may further simplify the treatment of renal anaemia.

Topics: Administration, Cutaneous; Administration, Inhalation; Administration, Oral; Anemia; Darbepoetin alfa; Epoetin Alfa; Erythropoiesis; Erythropoietin; Heart Failure; Hematinics; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Infusions, Intravenous; Kidney Failure, Chronic; Receptors, Erythropoietin; Recombinant Proteins; Renal Dialysis

End stage renal disease (ESRD) affects over 1500 people per million population in countries with a high prevalence, such as the USA and Japan. Approximately two thirds of people with ESRD receive haemodialysis, a quarter have kidney transplants, and a tenth receive peritoneal dialysis.. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of different doses and osmotic agents for peritoneal dialysis? What are the effects of different doses and membrane fluxes for haemodialysis? What are the effects of interventions aimed at preventing secondary complications? We searched: Medline, Embase, The Cochrane Library and other important databases up to April 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).. We found 20 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.. In this systematic review we present information relating to the effectiveness and safety of the following interventions: cinacalcet, darbepoetin, dextrose solutions, erythropoietin, haemodialysis (standard-dose, increased-dose), high-membrane-flux haemodialysis, icodextrin, increased-dose peritoneal dialysis, low-membrane-flux haemodialysis, mupirocin, sevelamer, and standard-dose dialysis.

Topics: Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Renal Dialysis; Renal Insufficiency, Chronic

Effective treatment of anemia in end-stage renal disease (ESRD) results in reduced fatigue and improved quality of life. The National Kidney Foundation's 2006 anemia treatment guidelines recommend maintaining hemoglobin (Hb) at >11 g/dl, while noting that there is insufficient evidence to routinely maintain Hb levels > or =13.0 g/dl. Success in achieving Hb levels within these targets requires careful monitoring and adjustments to treatment. In addition, causes for diminished response and refractory anemia must be adequately evaluated. In this article, factors important for achieving Hb 11-13 g/dl in patients with ESRD are reviewed.

Topics: Anemia; Erythropoietin; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Both chronic kidney disease (CKD) and type II diabetes mellitus (DM) are increasing in frequency among Western populations and both are potent risk factors for the development of anaemia. The presence of CKD and diabetes together represent the most important aetiopathogenic combination for the development of anaemia. New evidence has highlighted some of the underlying mechanisms which make diabetic patients more susceptible to dyserythropoiesis, particularly once they have developed concomitant CKD. In addition, recent publications from large-scale epidemiological studies have highlighted the impact of anaemia on diabetic patients. The purpose of this review was to focus on the pathophysiology and impact of anaemia in DM.

Topics: Anemia; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Quality of Life

The new National Kidney Foundation's Kidney Disease Outcome Quality Initiative clinical practice guidelines for anemia management in chronic kidney disease include several important modifications to the previous recommendations. These changes may have major implications in clinical practice and outcome of the chronic kidney disease patient population. Among the important guideline modifications are the elimination of the upper thresholds for hemoglobin (12 g/dL), transferrin saturation ratio (TSAT, v 50%) and ferritin (800 ng/ml). There are, however, additional recommendations pertaining to anemia management when hemoglobin is above 13 g/dL or serum ferritin above 500 ng/ml. The KDOQI anemia working group explains that the upper ferritin level of 500 ng/ml is not a stopping point for IV iron administration, but adds that decisions regarding IV iron administration should weigh erythropoietin responsiveness, hemoglobin and transferrin saturation level, and the patient's clinical status.The selected upper ferritin level of 500 ng/ml lacks adequate scientific evidence in the CKD population. Approximately half of all maintenance hemodialysis patients in the United States may have a serum ferritin above 500 ng/ml. Serum ferritin in 500-1,200 ng/ml range is not associated with increased death risk in hemodialysis patients if controlled for the confounding effect of malnutrition and inflammation. Given the lack of support from the literature, any attempt to contemplate an upper limit for serum ferritin would be arbitrary, and would not serve to improve the quality of treatment in the CKD population.

Topics: Anemia, Iron-Deficiency; Cause of Death; Drug Monitoring; Erythropoietin; Evidence-Based Medicine; Ferritins; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Patient Selection; Practice Guidelines as Topic; Proportional Hazards Models; Recombinant Proteins; Renal Dialysis; Risk Factors; Severity of Illness Index; United States

Recombinant human erythropoietin is commonly used for treatment of anaemia. Our aim was to determine whether targeting different haemoglobin concentrations with such treatment is associated with altered all-cause mortality and cardiovascular events in patients with anaemia caused by chronic kidney disease.. We did a meta-analysis of randomised controlled clinical trials that were identified in medical databases and trial registration websites. Trials were eligible for inclusion if they assessed the effects of targeting different haemoglobin concentrations in patients with anaemia caused by chronic disease who were randomly assigned to treatment with recombinant human erythropoietin, recruited at least 100 patients, and had a minimum follow-up of 12 weeks.. We analysed nine randomised controlled trials that enrolled 5143 patients. There was a significantly higher risk of all-cause mortality (risk ratio 1.17, 95% CI 1.01-1.35; p=0.031) and arteriovenous access thrombosis (1.34, 1.16-1.54; p=0.0001) in the higher haemoglobin target group than in the lower haemoglobin target group in the fixed effects model without heterogeneity between studies. There was a significantly higher risk of poorly controlled blood pressure (1.27, 1.08-1.50; p=0.004) in the higher haemoglobin target group than in the lower target haemoglobin group with the fixed effects model; however, this was not significant in the random effects model (1.31, 0.97-1.78; p=0.075). The incidence of myocardial infarction was much the same in the two groups.. To target higher haemoglobin concentrations when treating patients with anaemia caused by chronic kidney disease with recombinant human erythropoietin puts such patients at increased risk of death. Current guidelines do not include an upper limit for the target haemoglobin concentration; such an upper limit should be considered in future recommendations.

Topics: Aged; Anemia; Blood Pressure; Cardiovascular Diseases; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors

Topics: Aged; Anemia; Cost of Illness; Erythropoietin; Evidence-Based Medicine; Geriatrics; Hematinics; Humans; Kidney Failure, Chronic; Neoplasms; Patient Selection; Quality of Life; Recombinant Proteins; Treatment Outcome

Pregnancy, although rare in the patient with end-stage renal disease, is not uncommon in the transplant recipient. Physicians taking care of transplant recipients must be able to inform patients about the potential risks of pregnancy in this setting. The patient and her partner must know that the risks associated with pregnancy increase with worsening kidney function and hypertension. Current consensus opinion is that pregnancy can be relatively safely undertaken by 1 year after transplant if the patient has had no rejections during the year, allograft function is adequate, there are no infections that could affect the fetus, the patient is not taking teratogenic medications, and immunosuppressive medication dosing is stable. Consideration must be given to immunosuppression during pregnancy both with respect to the specific agents as well as the level of dosing. None of the medications are FDA category A; all are B or higher. Part of planning for pregnancy should include an evaluation of immunosuppression medication and a plan to modify the regimen prior to conception if its use may be risky for the developing fetus. Rejection can occur during a kidney transplant, so maintaining adequate immunosuppression is important. Other issues that need to be managed when caring for a pregnant transplant patient include: potential for infection (urinary tract infections are very common), hypertension, and anemia. The type of delivery, posttransplant contraception, and breast-feeding also need to be addressed.

Topics: Anemia; Counseling; Erythropoietin; Female; Graft Rejection; Humans; Hypertension; Immunocompromised Host; Immunosuppressive Agents; Infections; Kidney Failure, Chronic; Kidney Transplantation; Patient Care Team; Preconception Care; Pregnancy; Pregnancy Complications; Recombinant Proteins; Time Factors

Topics: Anemia; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Multicenter Studies as Topic; Patient Dropouts; Randomized Controlled Trials as Topic; Recombinant Proteins; Research Design

Topics: Anemia; Antineoplastic Agents; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Practice Guidelines as Topic

Barriers to the treatment of anemia in patients with chronic kidney disease (CKD), the role of pharmacists in screening patients for anemia and developing guidelines for the use of anemia therapies in patients with CKD, the goals of and considerations in developing pharmacist-managed anemia management clinics, and the potential benefits of these clinics are described.. The complexity of patients with CKD, patient nonadherence to the treatment regimen, a shortage of nephrologists, and a lack of familiarity with clinical practice guidelines and recommendations for treating anemia in these patients are possible barriers to the treatment of anemia. Pharmacists can play a role in improving the treatment of anemia in patients with CKD by screening for anemia, developing guidelines for the use of anemia therapies, and providing patient education to promote adherence to the treatment regimen. The optimal upper limit for hemoglobin concentration during treatment with erythropoietin-stimulating agents (ESA) in patients with CKD remains to be determined, but it should not routinely exceed 13.0 g/dL. Extended dosing of darbepoetin alfa and the new agent continuous erythropoiesis receptor activator appears effective. Iron status often is not assessed in patients with CKD because of difficulty interpreting iron laboratory values and identifying iron deficiency. The usefulness of iron supplementation is not limited to patients with iron deficiency. The intravenous (i.v.) or oral route of administration may be used for iron supplementation in predialysis patients and peritoneal dialysis patients, but the i.v. route is recommended for hemodialysis patients. Adverse effects and drug interactions limit the use of oral iron supplements. Administration of parenteral iron is time consuming and accompanied by concerns about iron accumulation and uncertainty about the optimal maximum serum ferritin concentration. Improved access to care and clinical outcomes and reduced costs have been documented in pharmacist-managed anemia management clinics.. Pharmacists can help overcome barriers to treating anemia in patients with CKD. Clinical and economic benefits are associated with pharmacist-managed anemia management clinics.

Topics: Anemia; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Pharmaceutical Services; Polyethylene Glycols; Recombinant Proteins

The prevalence of chronic kidney disease (CKD) and anemia in the United States, classification scheme for CKD, definition of anemia, etiology and consequences of anemia in patients with CKD, and the clinical and economic benefits of correcting anemia are described.. Approximately 20 million people in the United States population have CKD, and 2-4 million of these may also have anemia, which often goes undetected and untreated. Patients with CKD are now classified into five stages based on the degree of kidney function impairment. Here, anemia is caused by insufficient erythropoietin production, and may occur as early as stage 3 CKD. Potential consequences of anemia include cognitive impairment, angina, and the cardiorenal anemia syndrome, a triad of worsening anemia, worsening CKD, and worsening congestive heart failure. Treatment of anemia in predialysis patients with stage 2-4 CKD may slow renal disease progression and improve energy, work capacity, health-related quality of life, and cardiac function. Optimizing the hemoglobin or hematocrit value before initiating dialysis may reduce mortality. Anemia contributes to significant healthcare costs associated with CKD. Substitution of the subcutaneous route of administration for the intravenous route of administration for epoetin alfa can reduce drug acquisition and healthcare costs, the two largest components of healthcare costs in CKD patients. Efforts to slow the progression of CKD could also have a substantial impact on hospitalizations and costs.. Correcting anemia has the potential to improve clinical and economic outcomes in patients with CKD.

Topics: Anemia; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Kidney Failure, Chronic; Male; Prevalence; Quality of Life; Recombinant Proteins; Renal Dialysis; United States

Erythropoietin is the major hormone regulator of erythrocyte production promoting the survival, as well as the differentiation and maturation, of erythroid progenitor cells. In addition to these well-characterized effects, it appears that an erythropoietin-responsive non-erythroid mechanism also mediates the selective destruction of young circulating erythrocytes (neocytes) when red cell mass becomes excessive - a process termed 'neocytolysis'. Endothelial cells appear to respond to a rapid decrease in circulating levels of erythropoietin by secreting cytokines (including TGF-alpha), which signal reticuloendothelial phagocytes to destroy neocytes. The result is a more rapid decrease in red cell mass than can be explained by natural erythrocyte senescence alone. The current pharmacologic approach to treatment of anaemia in chronic kidney disease may cause neocytolysis and could keep therapy from reaching its full potential. Understanding neocytolysis and its relationship to fluctuating serum erythropoietin levels might help to better understand optimal treatment with erythropoietic agents.

Topics: Anemia; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Models, Biological; Practice Guidelines as Topic; Practice Patterns, Physicians'; Risk Assessment; Risk Factors

The erythropoietin analogs have been an important advance for the treatment of the anemia of kidney disease, resulting in reduced need for blood transfusion and improved quality of life. Recent studies, however, have indicated risks associated with targeting higher levels of hemoglobin (Hb). As a result, in March 2007, the US Food and Drug Administration (FDA) substantially changed prescribing information for these drugs to alert clinicians to these risks. In this review, we consider the recent literature, the change in FDA warnings, and new National Kidney Foundation Anemia Guidelines. Suggestions for new Hb targets during erythropoiesis-stimulating agent treatment are presented.

Topics: Anemia; Drug Labeling; Erythropoietin; Foundations; Hemoglobins; Humans; Kidney Failure, Chronic; Practice Guidelines as Topic; Quality of Life; Risk; United States; United States Food and Drug Administration

To compare real-world dosing patterns, drug costs, and hematologic outcome in anemic chronic kidney disease (CKD) patients, not receiving dialysis, who switched from darbepoetin alfa (DARB) to epoetin alfa (EPO) in a community practice setting.. This retrospective observational chart review from a US nephrology clinic included 153 anemic CKD patients > or = 18 years of age who did not receive dialysis during the study period, switched from DARB to EPO between 8/2003 and 8/2005, and received > or = 2 doses of both agents. Paired t-test and McNemar's chi-square were performed comparing pre-switch and post-switch outcomes.. Mean interval between doses increased from 24.3 +/- 11.1 days with DARB to 28.8 +/- 19.8 days with EPO (p = 0.001). Weighted mean pre-switch weekly dose for DARB was 25 mug, while weighted mean post-switch weekly dose for EPO was 7090 Units, resulting in a dose ratio (Units EPO:microg DARB) of 287:1. These doses resulted in mean weekly costs of $110 (DARB) and $86 (EPO). Mean hemoglobin (Hb) levels increased over time from 10.8 g/dL at 6 months pre-switch to 11.1 g/dL 6 months after EPO initiation (p = 0.0132). Mean Hb levels were > 11 g/dL, but below 12 g/dL, while patients received EPO.. Patients switching from DARB to EPO had a greater mean interval between doses, lower drug costs, and consistently maintained recommended Hb levels over time.. The reverse direction (EPO to DARB) was not investigated. Although treatment outcomes were not assessed in a randomized, controlled setting, the study's observational nature provided actual evidence in a real-world setting.

Topics: Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Drug Administration Schedule; Drug Costs; Epoetin Alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Treatment Outcome

Anemia is a common complication of chronic kidney disease (CKD), with erythropoietin deficiency being the major contributing factor. The availability of erythropoiesis-stimulating agents (ESAs) has been a seminal advance in the treatment of anemia related to chronic kidney disease. Over the course of the last decade and a half, newer generations of ESAs have become available. The first-generation ESAs or epoetins have a relatively shorter half-life and have traditionally been administered up to 3 times per week intravenously or subcutaneously to maintain adequate hemoglobin (Hb) levels. At the turn of the century, darbepoetin alfa, a hyperglycosylated form, became available for clinical use. It conferred greater metabolic stability in vivo owing to two additional N-linked carbohydrate chains attached to the protein backbone and has a half-life 3 times longer than that of epoetin. Recently developed and undergoing phase III clinical trials is the third-generation ESA, Continuous Erythropoiesis Receptor Activator (CERA), which has a methoxy-polyethylene glycol polymer chain integrated and has a longer elimination half-life than the first- and second-generation ESAs. Its receptor binding characteristics also differ from those of previous ESAs. Its major advantage is that extended dosing intervals are possible in the management of anemia related to erythropoietin deficiency.

Topics: Anemia; Clinical Trials as Topic; Drug Carriers; Erythropoietin; Humans; Kidney Failure, Chronic; Nanomedicine; Nanostructures; Particle Size; Polyethylene Glycols; Recombinant Proteins

Topics: Anemia; Clinical Trials as Topic; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Quality of Life; Renal Dialysis; Survival Analysis; United States

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Female; Gene Expression; Glomerular Filtration Rate; Hemoglobins; Humans; Iron; Kidney Diseases; Kidney Failure, Chronic; Male; Prognosis; Quality of Life; Recombinant Proteins; Renal Dialysis; Risk Factors

Biopharmaceuticals have revolutionized the treatment and management of many diseases. The advent of recombinant erythropoietins has greatly benefited patients with anemia related to chronic kidney disease and cancer, virtually eliminating the need for blood transfusions. Currently, the patents for many biopharmaceutical molecules have expired or are approaching expiration and a number of biosimilars manufacturers are aiming to claim part of the market share. Unlike the situation for synthetic "small molecule" drugs, identical copies of far more complex biopharmaceuticals cannot be produced. A biopharmaceutical can be 100 to 1000 times larger than a synthetic chemical drug, with extremely complex three-dimensional structure and biological functions which are often not completely understood. Due to their nature and complexity, these fascinating therapeutic molecules are products of highly controlled biological processes. This review takes a look at how biosimilars are fundamentally different from their originator products by examining the biopharmaceutical production process and how it can influence the structure and function of the final drug product.

Topics: Anemia; Animals; Biopharmaceutics; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Kidney Failure, Chronic; Molecular Structure; Protein Engineering; Protein Processing, Post-Translational; Recombinant Proteins

Anemia treatment in nondialysis chronic kidney disease (ND-CKD) and dialysis CKD patients (D-CKD) has been recently scrutinized in the literature and by the lay press. New evidence suggests that patients receiving epoetin and achieving higher hemoglobin have a higher risk of death and cardiovascular complications. Data from the Centers for Medicare & Medicaid Services demonstrate upward spiraling costs of injectables, especially epoetin, in the care of CKD patients. There is considerable literature favoring the use of subcutaneous administration of epoetin compared to intravenous route in hemodialysis patients. Evidence clearly shows that the subcutaneous route achieves the target hemoglobin level at a lower administered dose. Thus, the same clinical effect can be achieved at a lower cost. Despite the economic and evidentiary justifications for subcutaneous administration of epoetin, adoption of this strategy has been limited, especially in the United States. Reasons include: inflexibility by dialysis providers because of reduced profitability, claims that patients oppose the subcutaneous route because of pain at the site of injection, concerns regarding pure red cell aplasia associated with subcutaneous administration, and greater hemoglobin cycling with the subcutaneous route. In this article, the advantages and disadvantages of the subcutaneous route are reviewed.

Topics: Anemia; Biological Availability; Diffusion of Innovation; Drug Costs; Epoetin Alfa; Erythropoietin; Evidence-Based Medicine; Half-Life; Hematinics; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Metabolic Clearance Rate; Nephrology; Patient Selection; Practice Guidelines as Topic; Practice Patterns, Physicians'; Recombinant Proteins; Renal Dialysis; Treatment Outcome; United States

An evidence-based evaluation of peer-reviewed original research published during 1980 to 2004 and examining the relationship between hemoglobin and/or hematocrit values and all-cause mortality in dialysis patients was conducted to compare the studies' designs, analytic strategies, and results.. The search targeted MEDLINE and EMBASE and included publications referenced in the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative Anemia Guidelines. Both randomized clinical trials (RCTs) and observational studies were considered.. Of 7 RCTs and 20 observational studies identified, 5 trials and 13 studies were included in evidence tables. The trials were underpowered to study mortality and enrolled different patient populations, limiting their generalizability. Although none reached statistical significance, trials focusing on a general dialysis population tended to show either no effect or a benefit of greater hemoglobin level target, whereas trials enrolling cardiac patients suggested increased mortality associated with greater hemoglobin levels. The observational studies were heterogeneous in design, used varying exposure categorizations, and controlled for different covariates, but generally were supportive of increased mortality associated with a hemoglobin level less than the reference range. Evidence of benefits or risks of hemoglobin levels greater than the reference was variable.. RCT-based evidence relating hemoglobin and/or hematocrit values to mortality in dialysis patients is limited. The relationship may be modified by the presence of preexisting conditions (cardiac disease). The published literature is insufficient for generalization of risks or benefits of a hemoglobin level greater than 11 to 12 g/dL (>110 to 120 g/L). There is a need for better designed RCTs focusing on mortality as a primary outcome and enrolling patients without cardiac disease. Observational studies should adequately control for relevant confounders (eg, baseline comorbidities) and assess effect modification in the analysis.

Topics: Adult; Anemia; Cause of Death; Erythropoietin; Evaluation Studies as Topic; Evidence-Based Medicine; Female; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Topics: Adult; Anemia; Erythropoietin; Female; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Recombinant Proteins

Erythropoietin (EPO) is an endogenous hormone produced primarily by the kidney which controls the production of erythrocytes. The main stimulus to production is low tissue oxygen (hypoxia) and EPO triggers the formation of red blood cells by binding to a receptor on erythroid progenitor target cells. Alteration in the EPO regulatory system produces a change in circulating EPO in a variety of disease states, such as renal anaemia and polycythaemia. The availability of recombinant EPO in the 1980s transformed the treatment of anaemia, particularly anaemia of end stage renal disease, and led to the development of more sensitive and specific assays for the measurement of EPO. There are more widespread uses for EPO and preliminary studies indicate that EPO may be useful as a neuroprotective agent by reducing inflammation near the site of injury. The use of EPO to boost endurance in athletes has attracted unwanted publicity, although analytical techniques are now available that can differentiate between endogenous and recombinant EPO. Different types of erythropoietic agents have been developed with a longer plasma half-life and the ability to maintain haemoglobin levels for longer periods and reduce the need for frequent dosing with EPO.

Topics: Anemia; Erythropoietin; Hormone Replacement Therapy; Humans; Immunoassay; Kidney Failure, Chronic; Sports Medicine

The partial correction of ESRD anemia by recombinant human erythropoietin (EPO) has resulted both in generalized improvement in quality of life and physical activity and in reduced mortality and hospitalization rate. The question remains as to whether normalizing hemoglobin (Hgb) is desirable in patients with chronic kidney disease (CKD). This review provides an analysis and commentary on the available reports and, for the most part, randomized, controlled trials on the topic. In dialysis patients, normalization of Hgb is associated with improved quality of life and exercise capacity but not with reduced mortality and hospitalization rate. Moreover, no significant changes in the degree of left ventricular hypertrophy have been demonstrated. By contrast, an increased mortality rate has been reported for hemodialysis patients with overt cardiovascular disease (CVD) when randomly assigned to normal hematocrit by EPO. Data regarding patients who have CKD but are not yet on renal replacement therapy are scarce, and the effects of EPO on renal disease progression require further elucidation through controlled trials. The conclusion that can be drawn from the available studies is that Hgb >11 g/dl is the minimum required to achieve improved quality of life in patients with CKD, whereas values >12 g/dl are not recommended for patients with overt CVD. Finally, Hgb normalization might reasonably be restricted to a selected population of younger, employed, and active individuals, provided that they do not have CVD.

Topics: Chronic Disease; Clinical Trials as Topic; Disease Progression; Erythropoietin; Hemoglobins; Humans; Kidney Diseases; Kidney Failure, Chronic; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Treatment Outcome

Erythropoietin and its receptor, a cytokine hormone long-known for its pro-erythropoietic effect, has been found to be expressed on a variety of tissues, including the cardiovascular system. Recent experimental studies in the ischemia-reperfusion model have demonstrated that erythropoietin has a significant cardioprotective and pro-angiogenic effect. This effect is quantified by a reduction in the relative infarct and apoptosis area and improved recovery of mechanical function. Despite potentially detrimental effects, erythropoietin has been used extensively in the last decade for treatment of anemia associated with chronic renal failure, and it has been found to be a safe drug in humans. The potential role of erythropoietin in the treatment of ischemic heart disease in humans has yet to be demonstrated in preliminary clinical trials.

Topics: Anemia; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Myocardial Ischemia; Neovascularization, Physiologic

We have recently proposed severe cardiorenal syndrome (SCRS), in which cardiac and renal failure mutually amplify progressive failure of both organs. This frequent pathophysiological condition has an extremely poor prognosis. Interactions between inflammation, the renin-angiotensin system, the balance between the nitric oxide and reactive oxygen species and the sympathetic nervous system form the cardiorenal connectors and are cornerstones in the pathophysiology of SCRS. An absolute deficit of erythropoietin (Epo) and decreased sensitivity to Epo in this syndrome both contribute to the development of anemia, which is more pronounced than renal anemia in the absence of heart failure. Besides expression on erythroid progenitor cells, Epo receptors are present in the heart, kidney, and vascular system, in which activation results in antiapoptosis, proliferation, and possibly antioxidation and anti-inflammation. Interestingly, Epo can improve cardiac and renal function. We have therefore reviewed the literature with respect to Epo and the cardiorenal connectors. Indeed, there are indications that Epo can diminish inflammation, reduce renin-angiotensin system activity, and shift the nitric oxide and reactive oxygen species balance toward nitric oxide. Information about Epo and the sympathetic nervous system is scarce. This analysis underscores the relevance of a further understanding of clinical and cellular mechanisms underlying protective effects of Epo, because this will support better treatment of SCRS.

Topics: Animals; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Oxidative Stress

Anemia is a common complication of chronic kidney disease. Although mechanisms involved in the pathogenesis of renal anemia include chronic inflammation, iron deficiency, and shortened half-life of erythrocytes, the primary cause is deficiency of erythropoietin (EPO). Serum EPO levels in patients with chronic kidney disease are usually within the normal range and thus fail to show an appropriate increase with decreasing hemoglobin levels, as found in nonrenal anemias. Studies elucidating the regulation of EPO expression led to the identification of the hypoxia inducible factor-hypoxia responsive element system. However, despite much progress in understanding the molecular mechanisms through which cells can sense oxygen availability and translate this information into altered gene expression, the reason why EPO production is inappropriately low in diseased kidneys remains incompletely understood. Both alterations in the function of EPO-producing cells and perturbations of the oxygen-sensing mechanism in the kidney may contribute. As with other anemias, the consequences of renal anemia are a moderate decrease in tissue oxygen tensions and counterregulatory mechanisms that maintain total oxygen consumption, including a persistent increase in cardiac output.

Topics: Anemia; Animals; Diabetic Nephropathies; Erythropoiesis; Erythropoietin; Hemolysis; Humans; Hypoxia-Inducible Factor 1; Inflammation; Iron Deficiencies; Kidney; Kidney Failure, Chronic; Receptors, Erythropoietin; Uremia

Despite an increase in the use and average dose of erythropoiesis-stimulating agents (ESA) over the past 15 years, a substantial percentage of patients still do not achieve hemoglobin targets recommended by international guidelines. A clear relationship among hemoglobin or hematocrit levels, ESA dose, and increase in dialysis dose has been pointed out by a number of prospective or retrospective studies. This is particularly true in patients receiving inadequate dialysis. Increasing attention also has been paid to the relationship between dialysis, increased inflammatory stimulus, and ESA response because dialysate contamination and low-compatible treatments may increase cytokine production and consequently inhibit erythropoiesis. The biocompatibility of dialysis membranes and flux are other important factors. However, in highly selected, adequately dialyzed patients without iron or vitamin depletion, the effect of these treatment modalities on anemia seems to be smaller than expected. The role of on-line treatments still is controversial given that it is still difficult to discriminate between the effect of on-line hemodiafiltration per se from that of an increased dialysis dose. Very preliminary results obtained with short or long nocturnal daily hemodialysis on anemia correction are encouraging.

Topics: Anemia; Animals; Drug Contamination; Erythropoiesis; Erythropoietin; Evidence-Based Medicine; Hemodialysis Solutions; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Toxins, Biological

Anemia, defined as a hemoglobin level of less than 12 g/dL, often is seen in congestive heart failure (CHF). It is associated with an increased mortality and morbidity and increased hospitalizations. Compared with nonanemic patients the presence of anemia also is associated with worse cardiac clinical status, more severe systolic and diastolic dysfunction, a higher beta natriuretic peptide level, increased extracellular and plasma volume, a more rapid deterioration of renal function, a lower quality of life, and increased medical costs. The only way to determine if anemia is merely a marker for more severe CHF or actually is contributing to the worsening of the CHF is to correct the anemia and see if this favorably influences the CHF. In several controlled and uncontrolled studies, correction of the anemia with subcutaneous erythropoietin (EPO) or darbepoetin in conjunction with oral and intravenous iron has been associated with an improvement in clinical status, number of hospitalizations, cardiac and renal function, and quality of life. However, larger, randomized, double-blind, controlled studies still are needed to verify these initial observations. The effect of EPO may be related partly to its nonhematologic functions including neovascularization; prevention of apoptosis of endothelial, myocardial, cerebral, and renal cells; increase in endothelial progenitor cells; and anti-inflammatory and antioxidant effects. Anemia also may play a role in increasing cardiovascular morbidity in chronic kidney insufficiency, diabetes, renal transplantation, asymptomatic left ventricular dysfunction, left ventricular hypertrophy, acute coronary syndromes including myocardial infarction and chronic coronary heart disease, and in cardiac surgery. Again, controlled studies of correction of anemia are needed to assess its importance in these conditions. The anemia in CHF mainly is caused by a combination of renal failure and CHF-induced increased cytokine production, and these can both lead to reduced production of EPO, resistance of the bone marrow to EPO stimulation, and to cytokine-induced iron-deficiency anemia caused by reduced intestinal absorption of iron and reduced release of iron from iron stores. The use of angiotensin-converting enzyme inhibitor and angiotensin receptor blockers also may inhibit the bone marrow response to EPO. Hemodilution caused by CHF also may cause a low hemoglobin level. Renal failure, cardiac failure, and anemia therefore all interact

Topics: Anemia; Animals; Attitude; Cardiology; Erythropoietin; Heart Diseases; Heart Failure; Hemoglobins; Humans; Internal Medicine; Iron; Kidney Failure, Chronic; Natriuretic Peptide, Brain; Nephrology; Recombinant Proteins

Anemia is prevalent in renal transplant recipients (RTRs), as it is in all chronic kidney disease (CKD) populations. Mild anemia occurs in up to 40% of RTRs, and more severe anemia (110 g/L) occurs in about 9% to 22% of patients. As in CKD, impaired graft (renal) function is a major predictor of anemia identified in nearly all studies, suggesting a major role for erythropoietin deficiency. Chronic inflammation, malnutrition, iron deficiency, and medications (angiotensin converting enzyme inhibitors, angiotensin receptor blockers, mycophenolate, azathioprine, and sirolimus) are contributory factors seen in some, but not all, studies. Although pathophysiologic and observational data strongly support a causal association between low hemoglobin levels and cardiovascular outcomes in RTRs, no randomized controlled trial to date has been able to show a clear benefit of anemia treatment on cardiovascular outcomes or mortality in either RTR or other CKD populations. This important paradox has led some investigators to question the causal nature of the association between anemia and heart disease. Resolution of this paradox, at least for patients with stage 2/3 CKD, will depend on the outcome of randomized controlled trials currently in progress. Similar trials sorely are needed in renal transplant populations. In the interim, current opinion favors treating persistent anemia in RTRs to achieve targets similar to those recommended for dialysis and CKD patients.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Oxidative Stress; Randomized Controlled Trials as Topic; Risk Factors

Red cell production in chronic kidney disease is usually too low to maintain a normal haemoglobin, and thus anaemia develops in a large proportion of patients. The ability to stimulate erythropoiesis in the bone marrow by the use of therapeutic agents has only been possible in the last 20 years, initially with recombinant human erythropoietin (epoetin), and later darbepoetin alfa. Many new agents are, however, in clinical development, and these include CERA, Hematide, and HIF stabilisers, in addition to the imminent launch of biosimilar epoetins. The main issue with biosimilars is the unknown risk of immunogenicity. CERA is a large molecule, approximately twice the size of epoetin, which was created by integrating a single polymer chain into the erythropoietin molecule. CERA has a much prolonged half-life, and Phase II and III clinical trials have investigated administration of CERA every 3 or 4 weeks. Hematide is derived from original research on the erythropoietin-mimetic peptides, and is in Phase II of its clinical trial programme. Again, this compound is being investigated as a once-monthly administration. The HIF stabilizers are orally-active inhibitors of the enzyme that degrades hypoxia-inducible factor (prolyl hydroxylase), and this leads to upregulation of erythropoietin gene expression. Other strategies for stimulating erythropoiesis, briefly described in this review, are at an earlier stage of development. This is an exciting and rapidly developing area of scientific and translational research.

Topics: Anemia; Enzyme Inhibitors; Erythropoiesis; Erythropoietin; Humans; Hypoxia-Inducible Factor 1; Kidney Failure, Chronic; Peptides; Polyethylene Glycols; Procollagen-Proline Dioxygenase; Recombinant Proteins; Up-Regulation

Iron-deficiency frequently develops in patients with chronic kidney disease who are treated with recombinant human erythropoietin (rHuEPO). It results in reduced effectiveness of anemia therapy; patients may fail to reach hemoglobin targets or may require excessively large doses of rHuEPO. It has been recognized widely that iron management, monitoring for iron deficiency, and effective iron supplementation forms a core component of anemia therapy. This review discusses the physiology of iron balance, derangements in iron balance in chronic kidney disease (CKD), and the diagnosis and treatment of iron deficiency in patients treated with rHuEPO.

Topics: Anemia; Erythropoietin; Humans; Iron; Iron Deficiencies; Kidney Failure, Chronic; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis; Safety

Anemia in the setting of chronic kidney disease is a well-recognized phenomenon that is associated with decreasing renal function and deficiency of or resistance to erythropoietin. However, anemia in the post-renal transplantation setting has received comparatively less attention in the literature. In this review, we aim critically to appraise the available literature regarding posttransplantation anemia, concentrating in particular on the prevalence of posttransplantation anemia, its etiopathogenesis, potential effects on morbidity and mortality, and the rationale for intervention and treatment. Despite deficiencies in the literature, we conclude that posttransplantation anemia is a common phenomenon that can occur either early or late posttransplantation, and its causation is usually multifactorial and includes contributions notably from poor or decreasing renal function, immunosuppression, and iron deficiency. Conversely, there is a shortage of well-conducted prospective studies looking at the morbidity attributable to posttransplantation anemia and a lack of trial evidence to determine whether intervention improves patient morbidity and outcome.

Topics: Anemia, Iron-Deficiency; Cardiovascular Diseases; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Prevalence; Recombinant Proteins; Risk Factors

Topics: Anemia; Clinical Trials as Topic; Erythropoietin; Evidence-Based Medicine; Humans; Kidney Failure, Chronic; Recombinant Proteins; Treatment Outcome

Topics: Antihypertensive Agents; Blood Volume; Diagnosis, Differential; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Platelet Aggregation Inhibitors; Renin-Angiotensin System; Risk Factors; Vascular Resistance

Topics: Cardiovascular Diseases; Endocrine System Diseases; Erythropoietin; Humans; Kidney Failure, Chronic; Natriuretic Agents; Renin-Angiotensin System; Risk; Vitamin D

Anaemia affects 60% to 80% of patients with chronic kidney disease (CKD) reduces quality of life and is a risk factor for early death. Treatment options are blood transfusion, erythropoietin (EPO) and darbepoetin alfa. Recently higher haemoglobin (Hb) and haematocrit (HCT) targets have been widely advocated because of positive associations with improved survival and quality of life from observational studies.. To assess the benefits and harms of different Hb or HCT targets in CKD patients receiving any treatment for anaemia.. We searched The Cochrane Renal Group's specialised register, Cochrane Central Register of Controlled Trials (CENTRAL, in The Cochrane Library) MEDLINE (from 1966), EMBASE (from 1980) and reference lists of retrieved articles. Date of most recent search: April 2006. Randomised controlled trials (RCTs) and quasi-RCTs comparing different Hb/HCT targets in patients with the anaemia of CKD.. Two reviewers independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and results expressed as relative risks (RR) for dichotomous outcomes and weighted mean difference (MD) for continuous outcomes, with 95% confidence intervals (CI).. Twenty two trials (3707 patients) were included. Hb > or = 133 g/L was not associated with a reduction in the risk of all-cause mortality compared with 120 g/L in dialysis and pre-dialysis patients. In pre-dialysis patients, there was a significantly lower end of treatment creatinine clearance with Hb < 120 g/L compared to > 130 g/L (MD -4.17, 95% CI -6.33 to -2.02) but no significant difference in the risk of end-stage kidney disease (ESKD) (RR 1.05, 95% CI 0.50 to 2.22). Lower Hb targets resulted in an increased risk for seizures (RR 5.25, 95% CI 1.13 to 24.34) and a reduced risk of hypertensive episodes (RR 0.50, 95% CI 0.33 to 0.76). There were no significant differences in the risk of vascular access thrombosis.. There was no significant difference in the risk of death for low (< 120 g/L) versus higher Hb targets (>133 g/L). Lower Hb targets were significantly associated with an increased risk for seizures but a reduced risk of hypertension. In general study quality was poor. There is a need for more adequately powered, well-designed and reported trials. Trials should be pragmatic, focusing on hard end-points (mortality, ESKD, major side effects) or outcomes which were previously not studied adequately (e.g. seizures, quality of life).

Topics: Anemia; Erythropoietin; Hematocrit; Hemoglobin A; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Renal Dialysis; Risk Assessment

Topics: Anemia; Darbepoetin alfa; Diabetes Mellitus; Epoetin Alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins; Treatment Outcome

The effect of erythropoietin (EPO) administration on the responsiveness of the renin-angiotensin-aldosterone system (RAAS) has not been established. Because patients with chronic kidney disease (CKD) require EPO for their management as CKD progresses, it is important to ascertain whether EPO treatment alters the RAAS. If EPO administration stimulates renin-angiotensin or aldosterone (ALDO) this intervention would mediate cardiovascular and renal injury, and consequently promote cardiovascular events and/or exacerbate the progression of renal disease. We reviewed the available publications investigating the effects of EPO on the RAAS. In CKD patients following EPO administration plasma renin activity (PRA) was unchanged in all three and ALDO was not altered in the two studies in which it was determined. In end-stage renal disease (ESRD) patients undergoing dialysis following EPO administration, four studies reported a decrease in PRA levels whereas the remaining nine disclosed no change in PRA levels. The changes in ALDO levels after EPO administration in ESRD patients were discrepant with two studies reporting an increase, two reporting a decrease and the remaining three disclosing no change.

Topics: Erythropoietin; Humans; Kidney Failure, Chronic; Renin; Renin-Angiotensin System

Treating chronic kidney disease (CKD) anemia successfully requires not only making the correct diagnosis and choosing the appropriate treatment but also taking the steps needed to ensure that residents have access to treatment. This can be challenging with regard to the erythropoiesis-stimulating proteins (ESPs). To ensure access to these products, physicians must be health insurance literate, knowing how different Medicare parts cover the erythropoietin (EPO) products. For example, Medicare Part A places the responsibility for medications on the provider. This means that a long-term care facility is responsible for covering the cost of medications used during the Medicare Part A skilled stay. Medicare Part B covers medications that are provided "incident to" a physician service, including injectables provided by physicians in their offices or during dialysis treatments. Managed care plans, which provide coverage under Medicare Part C, are responsible for all of the benefits available under Medicare Parts A and B. The newest Medicare Part is D, the prescription drug benefit introduced in January 2006. Medicare Part D covers most medications administered to residents in a long-term care facility. For the dually eligible-that is, residents covered by both Medicare and Medicaid-the Medicare Part D program replaces Medicaid drug coverage. Unfortunately, the criteria by which these prescription plans choose to cover products such as ESPs are not based on any specific standard but vary greatly by plan as each has the right to determine coverage criteria. In addition to individualized plan criteria, each plan defines its own process for prior authorization, appeals, and exceptions. Understanding the basic rules of coverage is essential to ensuring access to the ESPs for residents with anemia of CKD.

Topics: Anemia; Blood Component Transfusion; Drug Prescriptions; Erythropoietin; Health Services Accessibility; Humans; Insurance Coverage; Kidney Failure, Chronic; Medicaid; Medicare; Nursing Homes; United States

Anemia is a common comorbidity of chronic kidney disease (CKD). As the diseased kidney loses its ability to produce the erythropoietin essential to the production of hemoglobin, anemia ensues. The age-related rise in CKD makes anemia in CKD a problem of increasing prevalence among residents of long-term care facilities. CKD refers to the entire continuum of renal disease that progresses from mildly impaired kidney function (stage 1, glomerular filtration rate [GFR] > or =90 mL/min/1.73 m(2)) to significant deterioration, requiring dialysis or kidney transplant in what is categorized as stage 5 (GFR <15 mL/min/1.73 m(2)). The definition of anemia is controversial. The WHO defines anemia as hemoglobin <13 g/dL for men and <12 g/dL for women. The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative, which is the criteria used for Medicare reimbursement, defines anemia in adult men and postmenopausal women as hemoglobin <12 g/dL, or <11 g/dL in a premenopausal woman.

Topics: Age Distribution; Aged; Aging; Anemia; Cause of Death; Disease Progression; Erythropoietin; Global Health; Glomerular Filtration Rate; Hemoglobins; Humans; Incidence; Kidney Failure, Chronic; Kidney Transplantation; Morbidity; Nursing Homes; Prevalence; Renal Dialysis; United States

Anemia is a frequent complication of chronic kidney disease (CKD). Inadequate production of erythropoietin by the failing kidneys leads to decreased stimulation of the bone marrow to produce red blood cells (RBCs). Anemia of CKD develops early and worsens with progressive renal insufficiency. Although over 40% of patients with CKD are anemic, anemia in this population is under-recognized and undertreated. Of considerable importance, anemia is a risk factor for cardiovascular disease and is associated with higher rates of hospitalization and mortality. Despite the availability of erythropoiesis-stimulating proteins (ESPs) to stimulate RBC production in CKD patients, approximately three fourths of patients initiating dialysis have a hemoglobin <11 g/dL. The recognition of anemia of CKD begins with an estimation of glomerular filtration rate (GFR), which can be far lower than a normal serum creatinine might suggest, especially in the elderly and in those with poor nutrition and muscle mass. If GFR is <60 mL/min/1.73 m(2), hemoglobin should be checked. The anemia is diagnosed when the hemoglobin is <12 g/dL in a man or a postmenopausal woman, or <11 g/dL in a premenopausal woman. The cause of anemia should be investigated in these individuals; this can range from erythropoietin deficiency due to CKD, to deficiency of vitamin B(12) and/or folate, iron deficiency, blood loss, inflammation, malignancy, and aluminum intoxication. After other causes of anemia have been excluded, CKD is the most likely etiology, and it should be treated with an ESP. Currently, epoetin alfa and darbepoetin alfa are the only 2 ESPs approved for use in the United States. Extended dosing of ESP has potential advantages for the patient and may also improve resource utilization. Consequently, both agents have been tested for dosing at extended intervals. Adequate iron stores--defined as transferrin saturation >20% and ferritin >100 mg--as well as ESP administration are needed to produce an appropriate increase in hemoglobin. Poor response to treatment with ESP can be due to many factors, including presence of iron deficiency, inflammation, continued blood loss, and hemoglobinopathy.

Topics: Age Distribution; Aged; Anemia; Causality; Creatine; Darbepoetin alfa; Drug Administration Schedule; Drug Monitoring; Epoetin Alfa; Erythropoietin; Female; Ferritins; Glomerular Filtration Rate; Hematinics; Hemoglobins; Humans; Iron Compounds; Kidney Failure, Chronic; Male; Nutritional Status; Practice Guidelines as Topic; Recombinant Proteins; Risk Factors; Sex Characteristics; Transferrin; Treatment Failure

Recombinant human erythropoietin has become an essential part of the management of anemic patients with end-stage renal disease. It is also used to treat the anemia associated with cancer and other diseases, and it improves quality of life. In recent years, studies in animals and humans have focused on the use of rHuEPO for other indications. It has been found to play a role in both cardioprotection and neuroprotection. It has effects on the immune system, and can cause regression in hematologic diseases such as multiple myeloma. It may also improve the response of solid tumors to chemotherapy and radiation therapy. On the other hand, concerns have been raised following two studies of patients with solid tumors in whom those treated with rHuEPO had diminished survival. Criticism of the design of these studies makes it clear that large, well-designed, randomized trials must be performed to determine the role of rHuEPO in the treatment of cancer, and more generally to clarify the full clinical benefits of the drug, while minimizing the harm.

Topics: Anemia; Animals; Erythropoietin; Humans; Kidney Failure, Chronic; Mice; Neoplasms; Quality of Life; Recombinant Proteins

Topics: Anemia; Bias; Cardiovascular Diseases; Confounding Factors, Epidemiologic; Drug Monitoring; Erythropoietin; Evidence-Based Medicine; Hemoglobins; Humans; Kidney Failure, Chronic; Morbidity; Quality of Life; Randomized Controlled Trials as Topic; Research Design; Treatment Outcome

Correcting the renal anemia in dialysis patient require the optimal management of the erythropoietic stimulating agents (ESA) available on the market. In other words, that means that the prescription of these agents should be performed according to the specific pharmacokinetic and pharmacodynamic profiles of these agents. Two major classes of ESA are presently available for clinicians: one being considered as short acting substances (epoetine alfa and Epoetine Beta); the other one being considered as long acting substances (darbepoetin alfa). Several other agents are being currently evaluated or waiting for approval. For the short acting ESA, subcutaneous administration has been proved able to reduce weekly needs by 20 to 30% for the same efficacy, while the optimal frequency dosing being once and twice per week. For long acting ESA, the beneficial effect of the subcutaneous administration tend to disappear in hemodialysis patient, while the optimal frequency dosing being once a week to once every two week. These treatment schedules of prescription must be adapted according to the dialysis modality (hemodialysis, peritoneal dialysis) and the basal needs for ESA. The efficiency of ESA is also conditioned by the dialysis quality and efficiency, the iron repletion state, the blood losses and the presence of resistance factors. The optimal management of anemia in dialysis patient relies on an optimized dosing of ESA, a reduction of blood losses and a suppression of resistance factors to ESA action.

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Hematocrit; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Renal Dialysis

This paper reviews literature data on iron replacement (loading) for peritoneal dialysis patients. The 3 main sources of clinical guidelines (American NKF-K/DOQI, European EBPG and French AFSSAPS) agree about the definition of iron deficience, but are not similar about the haemoglobin/hematocrit targets for EPO treatment, and for the route of iron administration (oral versus intravenous). Iron requirements are less in PD HD patients. That could be explained by several factors: less blood losses, preservation of a residual renal function, better digestive iron absorption due to a greater hepcidin excretion. Intravenous route for iron sucrose is more efficient than oral route. Taking into account the iron requirements for PD patients, monthly 200 mg iron sucrose infusions over 5 mn seem to be safe and sufficient for most patients.

Topics: Anemia, Iron-Deficiency; Erythropoietin; Europe; France; Humans; Iron; Kidney Failure, Chronic; Kidney Function Tests; Peritoneal Dialysis; Renal Dialysis; United States

Topics: Anemia; Anemia, Iron-Deficiency; Creatinine; Darbepoetin alfa; Disease Progression; Erythropoietin; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Practice Guidelines as Topic; Renal Dialysis

Improving anemia in patients with chronic renal failure (CRF) and congestive heart failure (CHF) also improves left ventricular hypertrophy (LVH). No previous meta-analyses have been conducted to further examine this association, including the association between LVH and mortality in these patients.. Literature searches on MEDLINE, EMBASE, and OVID were performed using Cochrane Library protocols. Two hundred sixteen abstracts were reviewed preliminarily for inclusion in the meta-analysis of epoetin alfa, anemia and 5 pre-selected parameters of LVH. One hundred seventy-nine abstracts were reviewed for LVH and mortality. The predominant hematologic and left ventricular function changes observed during epoetin alfa treatment in patients with CHF and CRF are (1) increases in hemoglobin (Hb) and hematocrit (Hct); (2) decreases in left ventricular mass (LVM) and LVM index; (3) increase in ejection fraction (EF); and (4) decreases in left ventricular end-diastolic and end-systolic volume. Three independent factors-target Hb, duration of disease, and duration of follow-up-each had a statistically significant association with Hb, Hct, and EF, respectively. A separate meta-analysis using 3 risk models showed LVH is strongly and positively associated with both cardiovascular and all-cause mortality, with two- to three-fold increases in risk.. LVH is common in patients with CRF and CHF. Current findings indicate epoetin alfa therapy results in anemia amelioration, as evidenced by higher Hb and Hct levels, and reduction of key LVH parameters. LVM regression is associated with lower incidence of cardiovascular-related morbidity and mortality, therefore epoetin alfa therapy may provide a survival benefit.

Topics: Adult; Anemia; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Hematinics; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Regression Analysis; Ventricular Function, Left

The absolute majority of maintenance hemodialysis (MHD) patients die within 5 years of commencing dialysis treatment, mostly because of cardiovascular (CV) disease. The strongest and most common correlates of death in MHD patients are not conventional CV risk factors, but markers of protein-energy malnutrition and inflammation, together also known as malnutrition-inflammation complex syndrome (MICS). Paradoxically, classic risk factors such as obesity and hypercholesterolemia are associated with better survival in MHD patients. It has been hypothesized that this so-called reverse epidemiology is caused by the overwhelming prevalence and dominating effect of MICS in MHD patients. Hence, the key to improving survival and quality of life in MHD patients may be a better understanding of MICS and its interactions with CV disease and outcome. The Nutritional and Inflammatory Evaluation in Dialysis Patients (NIED) study is a longitudinal multicenter cohort study that aims to examine these hypotheses. At any given semiannual round, approximately 360 MHD patients from 8 DaVita dialysis facilities in the Los Angeles area are examined; 900 MHD patients will be cumulatively studied by the end of this 5-year prospective study (October 2001 to September 2006). Repeated measures of markers of nutritional status and inflammation are performed by 10 to 12 dialysis unit dietitians while patients attend their routine HD treatment in their dialysis facilities. All-cause and CV mortality, hospitalization, and quality of life are studied as outcome measures. The collaborating dietitians are the main evaluators and play crucial roles in all aspects of the study. This article reviews the design and infrastructure of the NIED study and reports preliminary findings of the first 12 to 30 months of the study.

Topics: Body Composition; Cholesterol, LDL; Dietary Proteins; Dietetics; Erythropoietin; Homocysteine; Hospitalization; Humans; Inflammation; Kidney Failure, Chronic; Malnutrition; Nutrition Assessment; Nutritional Status; Quality of Life; Renal Dialysis

The number of diabetic patients with renal disease increased significantly in the last years worldwide. Anemia is an important and frequent component of diabetic nephropathy that may begin early in the course of the chronic renal disease of diabetics, and is more severe in diabetic patients with renal disease than in non - diabetic renal patients controlled for the same level of renal function. The reason for the anemia is decreased erythropoietin level caused by diminished production and, in a lesser degree, by increased excretion of erythropoietin in the urine. There is a close connection between diabetic nephropathy, anemia and cardiovascular complications. On the basis of small studies correction of anemia may decrease the progression of diabetic nephropathy and cardiovascular complications. However, the result of ongoing large randomised controlled studies are required to get "evidence-based" data to prove that correction of anemia has beneficial effects on microvascular and macrovascular diabetic complications, particularly cardiac disease, and on progression of diabetic nephropathy.

Topics: Anemia, Hypochromic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Epoetin Alfa; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins; Time Factors

In patients with renal failure, severe anemia and associated fatigue, cognitive and sexual dysfunctions have a significant impact on the quality of life. Anemia also represents an important etiological factor in the development of left ventricular hypertrophy. An inadequate production of a glycoprotein hormone, erythropoietin (EPO), is the major cause of anemia in presence of a reduction in the glomerular filtration rate. EPO is the primary regulator of the growth and survival of the erythroid progenitor. The treatment of anemia in chronic renal failure has been revolutionized by the introduction of recombinant human EPO. The vast majority of patients responds very well to treatment, although 5-10% of patients shows some resistance to EPO, the most common cause of which is iron deficiency. Several studies have recently been started in order to investigate the effects of preventing renal anemia from ever developing in uremic patients. The hemoglobin concentration target in pre-dialysis and dialysis patients is the subject of continuous re-assessment.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Anemia; Epoetin Alfa; Erythropoietin; Forecasting; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins; United States

European and US guidelines for renal anaemia management recommend subcutaneous (s.c.) epoetin as the preferred route of administration in pre-dialysis, peritoneal dialysis and haemodialysis patients. However, the restriction of Eprex/Erypro to intravenous (i.v.) administration in Europe has increased the interest of health care professionals regarding the optimal route of administration for all epoetin formulations. There are five major considerations for the 'optimal' route of epoetin administration: efficacy; dosing frequency; convenience; safety and tolerability; and cost. Although epoetin bioavailability is lower after s.c. administration, its efficacy is higher, owing to its prolonged elimination half-life compared with i.v. epoetin. Several studies and clinical surveys comparing s.c. and i.v. administration have demonstrated that equivalent target haemoglobin levels can be maintained at much lower doses of epoetin when administered s.c. Furthermore, s.c. epoetin dosing frequency can be reduced in some patients to once every 2 weeks, without compromising efficacy. Devices such as the Reco-Pen have been specifically designed to facilitate self-administration of s.c. epoetin-beta. An upsurge in the incidence of pure red cell aplasia (PRCA) was linked to the epoetin-alpha product Eprex/Erypo in Europe, and an increase in PRCA cases of the same magnitude was not seen in patients taking other epoetin products s.c. Therefore, PRCA should not be used as an argument against s.c. administration. The reduced dose with s.c. administration of epoetin-beta provides significant cost benefits, without compromising either safety or efficacy, and may also increase patient satisfaction and compliance with treatment.

Topics: Anemia; Drug Administration Schedule; Drug Costs; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome

The combination of diabetes and chronic kidney disease is associated with increased mortality and reduced quality of life. Recent studies have shown that, in general, late referral of patients to the renal unit increases mortality, and that patients with diabetes who are referred late have a particularly poor prognosis. Several co-morbid conditions have been shown to contribute to poor patient outcomes, including both cardiovascular disease and anaemia. In patients with diabetic nephropathy, anaemia is more severe and is seen earlier than in patients with non-diabetic renal disease. Although the treatment of anaemia with recombinant human erythropoietin (rhEPO; epoetin) is well established, the only data currently available concerning the effects of early intervention in patients with diabetic nephropathy are from small-scale studies. Therefore, two large-scale studies have been designed to provide information on the efficacy of epoetin treatment and on how current management strategies might be improved. The Anaemia CORrection in Diabetes (ACORD) study will provide information on the potential cardiac benefits of early anaemia management in patients with early, type 2 diabetic nephropathy. The Individualised Risk-profiling In DIabEtes Mellitus (IRIDIEM) study will provide evidence-based guidance in risk factor management, by assessing the efficacy of individualized interventions.

Topics: Anemia; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins; Referral and Consultation; Survival Rate

Studies have shown that both intravenous (i.v.) and subcutaneous (s.c.) administration of epoetin-beta therapy are effective and well tolerated in the treatment of renal anaemia; however, the s.c. route provides enhanced efficacy with a lower dose compared with the i.v. route and it is more cost-effective. Epoetin dosing frequency is an important issue for health care professionals and patients. Recent studies have shown that epoetin-beta administered once weekly and once every 2 weeks can maintain stable target haemoglobin and haematocrit levels in dialysis patients. Such reduced dosing frequencies may improve patient satisfaction and compliance with treatment, and encourage patients to self-administer. Furthermore, less frequent dosing administration would be associated with economic benefits in terms of reduced nursing time in the clinic or out-patient setting. Where this is clinical practice, fewer injections and visits to the clinic should also improve patients' quality of life. A range of effective dosing regimens with epoetin-beta administered via either pre-filled syringes, multidose vials or injector pens allows physicians to tailor treatment to an individual patient's preference.

Topics: Anemia; Drug Administration Schedule; Erythropoietin; Hematinics; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Recombinant Proteins

Acquired pure red cell aplasia (PRCA) is a rare condition. Traditionally it has been described in association with various etiologies such as parvovirus B19 infection, auto-immune disorders and drugs. Immunologically mediated PRCA is by far the commonest cause in adults, particularly since 1998, when a marked increased incidence of PRCA was noted in chronic renal failure patients receiving subcutaneous (SC) recombinant erythropoietin (rEpo). Typically these patients had been given erythropoietin for correction of anemia of renal failure and subsequently present with severe transfusion dependent anemia. Most cases were associated with SC administration of human serum albumin (HSA) free erythropoieitin alfa product (Eprex). Early recognition and withdrawal of erythropoietin therapy is essential. Treatment with immunosuppressive therapy, particularly in conjunction with renal transplant results in good response with resolution in the majority of cases. The pathogenesis is related to interaction of multiple factors such as formulation change and improper storage leading to increased immunogenicity of the recombinant product. The incidence peaked in 2001 and 2002, subsequently dropping considerably from 2003. This can be explained by the institution of measures such as more stringent handling and storage conditions, improvements in formulation of HSA free Eprex and switch to intravenous (IV) administration for Eprex in dialysis patients. The evidence to date on this condition is summarized in this review.

Topics: Autoimmune Diseases; Epoetin Alfa; Erythropoietin; Humans; Incidence; Kidney Failure, Chronic; Parvoviridae Infections; Parvovirus; Recombinant Proteins; Red-Cell Aplasia, Pure

Treatment with recombinant human erythropoietin (rHu EPO) in dialysis patients has been shown to be highly effective in terms of correcting anaemia and improving quality of life. There is debate concerning the benefits of rHu EPO use in pre-dialysis patients which may accelerate the deterioration of renal function. However the opposing view is that if rHu EPO is as effective in pre-dialysis patient's, improving the patients sense of well-being may result in the onset of dialysis being delayed.. To assess the effects of rHu EPO use in pre-dialysis patients with renal anaemia.. The initial search included 13 electronic databases (1980 to May 2001) an internet search (August 1997), handsearching of Kidney International (1983 to May 1997), contact with known investigators and biomedical companies, and reference list of relevant articles. For this update we searched the Cochrane Renal Group's specialised register (June 2004) and The Cochrane Library (Issue 3, 2004).. Randomised controlled trials (RCTs) or quasi-RCTs comparing the use of rHu EPO with no treatment or placebo in pre-dialysis patients.. Only published data were used. Quality assessment was performed by two assessors independently. Data were abstracted by a single author onto a standard form, a sample of which was checked by another author. Results were expressed as relative risk (RR) or weighted mean difference (WMD) with 95% confidence intervals (CI).. Fifteen trials (461 participants) were included. There was a marked improvement in haemoglobin (WMD 1.82 g/dL, 95% CI 1.35 to 2.28) and haematocrit (WMD 9.85%, 95% CI 8.35 to 11.34) with treatment and a decrease in the number of patients requiring blood transfusions (RR 0.32, 95% CI 0.12 to 0.83). The data from studies reporting quality of life or exercise capacity demonstrated an improvement in the treatment group. Most of the measures of progression of renal disease showed no statistically significant difference. No significant increase in adverse events was identified.. Treatment with rHu EPO in pre-dialysis patients corrects anaemia, avoids the requirement for blood transfusions and also improves quality of life and exercise capacity. We were unable to assess the effects of rHu EPO on progression of renal disease, delay in the onset of dialysis or adverse events. Based on the current evidence, decisions on the putative benefits in terms of quality of life are worth the extra costs of pre-dialysis rHu EPO need careful evaluation.

Topics: Anemia; Disease Progression; Erythropoietin; Humans; Kidney Failure, Chronic; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins

The benefits of recombinant human erythropoietin (rHuEPO) administration in dialysis patients have been demonstrated, however the optimal frequency regimen have yet to be established.. To assess the effects of different frequency regimens of rHuEPO administration in dialysis patients on anaemia correction, quality of life and optimal use.. We searched 13 electronic databases (1980 to May 2001) the internet (August 1997), handsearched Kidney International (1983 to May 1997), contacted known investigators, biomedical companies, and screened reference lists of relevant articles. Most recent search: The Cochrane Renal Group's specialised register (June 2004) and The Cochrane Library (Issue 3, 2004).. Randomised controlled trials (RCTs) or quasi-RCTs comparing different frequencies of rHuEPO administration in dialysis patients. We compared haemodialysis and CAPD patients and subcutaneous and intravenous administration.. Quality assessment was performed by two assessors. Data were abstracted by a single author onto a standard form, and a sample was checked by another author. Results were expressed as relative risk (RR) or weighted mean difference (WMD) with 95% confidence intervals (CI).. Eleven studies (719 patients) were included. There was no significant difference in maintaining target haemoglobin for once versus twice weekly administration (one study, 20 patients: RR 1.00, 95% CI 0.42 to 2.40) or mean haemoglobin after 12 weeks of therapy between haemodialysis and CAPD patients (two studies: WMD -0.21 g/dL, 95% CI -0.98 to 0.56) At the end of study for once versus thrice weekly administration (three studies: SMD -0.31, 95% CI -0.67 to 0.06) and at the end of maintenance phase (one study: WMD -0.2 g/dL, 95% CI -0.65 to 0.25) there was no significant difference. More rHuEPO was required by haemodialysis patients receiving once weekly versus twice weekly doses (WMD 12.0 U/kg, 95% CI 0.24 to 23.76). No difference was found for CAPD patients alone or combined (WMD 4.38 U/kg, 95% CI -11.28 to 20.04). Once versus thrice weekly administration was not significant (WMD 10.00 U/kg, 95% CI -80.87 to 100.87). There was no difference in the frequency of adverse events.. There is no significant difference between once weekly versus thrice weekly subcutaneous administration of rHuEPO. Once weekly administration would require an additional 12 U/kg/wk for patients on haemodialysis, however this is based on one very small study. Cost of additional rHuEPO needs to assessed with regard to patient preference and compliance.

Topics: Anemia; Drug Administration Schedule; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis

Guidelines for anemia management in renal disease are supported by substantial evidence demonstrating improvement in quality of life and objective markers of physical and cognitive performance. Randomized control studies demonstrating a survival benefit or improved cardiovascular outcomes are inconsistent. However, observational studies clearly demonstrate reduced mortality and hospitalization rate in patient cohorts on hemodiaLysis with hemoglobin measurements within the recommended target ranges. Data from patients in the predialysis phase of chronic kidney disease and those on peritoneal dialysis are limited and studies assessing the clinical impact of adherence to guidelines should be further explored in these populations. Available evidence suggests a proactive approach to anemia management should be practiced.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Iron Compounds; Kidney Failure, Chronic; Practice Guidelines as Topic; Recombinant Proteins; Renal Dialysis; Treatment Outcome

After 1998, the number of reported cases of pure red cell aplasia (PRCA) increased dramatically among patients with chronic renal failure treated with exogenous erythropoietin, although the incidence of this condition has now abated. Antibody-positive PRCA has been most commonly associated with use of the Eprex brand of epoetin-alpha. ESA (erythropoiesis-stimulating agent)-associated PRCA remains rare, and suspected cases should undergo a thorough diagnostic work-up before laboratory testing for anti-ESA antibody-positive status. This article provides an overview of the recent history and growing understanding of ESA-associated PRCA together with current approaches to the management of this rare side effect of an otherwise valuable therapy.

Topics: Epoetin Alfa; Erythropoietin; Humans; Incidence; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Darbepoetin alfa; Dialysis Solutions; Erythropoietin; Glucans; Glucose; Humans; Icodextrin; Kidney Failure, Chronic; Peritoneal Dialysis; Polyamines; Renal Dialysis; Sevelamer

Anemia is a common complication of chronic kidney disease, particularly in patients who are on dialysis. The use of recombinant human erythropoietin has led to the eradication of severe anemia in the dialysis population. Correction of anemia in these patients has been associated with better quality of life and clinical outcomes. Some hemodialysis patients have anemia that either is relatively refractory to epoetin therapy or requires very high doses of epoetin (i.e., hyporesponsiveness), despite having adequate iron stores, and are thus unable to achieve or maintain target hemoglobin levels. Several pharmacologic agents have been studied for effects on improving response to epoetin, either to counter hyporesponsiveness or simply to reduce epoetin use for purely economic reasons. This review examines the available literature regarding the efficacy of these potential pharmacologic adjuvants to epoetin in the treatment of anemia in patients on maintenance hemodialysis, with special emphasis on androgens, vitamin C (ascorbic acid), and L-carnitine. A review of published guidelines and recommendations for use of these agents in hemodialysis patients is provided.

Topics: Adjuvants, Pharmaceutic; Androgens; Anemia, Iron-Deficiency; Antioxidants; Ascorbic Acid; Carnitine; Erythropoietin; Female; Humans; Iron; Kidney Failure, Chronic; Male; Practice Guidelines as Topic; Renal Dialysis; Treatment Outcome

Darbepoetin alfa (Aranesp), Nespo) is an amino acid substituted analog of human erythropoietin (EPO) that promotes erythrocyte survival, proliferation, and differentiation. Approved in Europe and the US for the treatment of anemia associated with chronic kidney disease (CKD), it is characterized by delayed clearance and a more prolonged elimination half-life than recombinant human erythropoietin (rhEPO; epoetin alfa and beta), permitting an extended interval between doses. Darbepoetin alfa is generally well tolerated, and clinical trials of 20-52 weeks' duration have demonstrated the efficacy of subcutaneous and intravenous administration at 1- or 2-week intervals in the initial treatment of anemia associated with CKD both in dialysis patients and in patients not yet on dialysis. Trials of up to 52 weeks' duration demonstrated that in the majority of patients with CKD, treatment with darbepoetin alfa at up to 4-week intervals maintained hemoglobin (Hb) levels established by prior erythropoietic treatment, while in patients undergoing dialysis, intravenous or subcutaneous darbepoetin alfa administered at 1- or 2-week intervals was noninferior to rhEPO administered once, twice, or three times per week in maintaining established Hb levels.

Topics: Anemia; Animals; Clinical Trials as Topic; Darbepoetin alfa; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Humans; Kidney Failure, Chronic; Treatment Outcome

Topics: Anemia; Critical Illness; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Treatment Outcome

Congestive heart failure (CHF) and chronic kidney disease (CKD) often progress to end stage even with optimum medical therapy. One factor that is common to both conditions is anemia, which is present in about a third of CHF patients. CHF can cause or worsen both anemia and CKD, and CKD can cause or worsen both anemia and CHF. Thus, a vicious circle exists between these three conditions, with each causing or worsening the other. We have called this condition the cardio-renal-anemia syndrome. Anemia in CHF is associated with increased mortality and hospitalization, reduced cardiac function and evidence of more severe CHF and CKD than in nonanemic patients. Intervention studies in anemic CHF patients have shown that optimum medical treatment of CHF and the correction of the associated anemia with subcutaneous erythropoietin and oral iron or intravenous iron sucrose can improve cardiac function, patients' functional status, renal function and quality of life, and reduce the frequency of hospitalization and the dose of diuretics required.

Topics: Anemia; Disease Progression; Drug Therapy, Combination; Erythropoietin; Heart Failure; Humans; Iron; Kidney Failure, Chronic; Treatment Outcome

Anaemia is a frequent complication of diabetic nephropathy. It has only recently been recognised that in diabetic patients anaemia is seen not only in preterminal renal failure, but also frequently in patients with only minor derangement of renal function. At any level of glomerular filtration rate (GFR) anaemia is more frequent and severe in diabetic compared to nondiabetic patients. A major cause of anaemia is an inappropriate response of erythropoietin to anaemia. Additional factors are iron deficiency and iatrogenic factors, e.g. ACE inhibitor treatment. When serum creatinine is still normal, the erythropoietin concentration is predictive of more rapid loss of glomerular function. When serum creatinine is elevated, the haemoglobin values are predictive of the rate of progression. It is currently under investigation whether reversal of anaemia attenuates the rate of progression. Because most of the late complications of diabetes (retinopathy, neuropathy, heart disease, peripheral arterial disease) involve ischaemic tissue damage, it would be intuitively plausible that treatment with human recombinant erythropoietin should be beneficial, but definite evidence for this hypothesis is currently not available.

Topics: Anemia; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Erythrocytes, Abnormal; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Myocardial Ischemia; Peripheral Vascular Diseases

The incidence of both congestive heart failure (CHF) and end-stage renal disease both are increasing. Anemia is common in both conditions and is associated with a marked increase in mortality and morbidity in both CHF and chronic kidney insufficiency (CKI). Each of these 3 conditions can cause or worsen the other 2. In other words, a vicious circle frequently is present in which CHF can cause or worsen both anemia and CKI, in which CKI can cause or worsen both anemia and CHF, and in which anemia can cause or worsen both CHF and CKI. We have called this vicious circle the cardio renal anemia syndrome. Optimal treatment of CHF with all the recommended CHF medications at their recommended doses will, in our experience, frequently fail to improve the CHF and CKI if anemia is present and is not corrected. On the other hand, correction of the anemia with subcutaneous erythropoietin and intravenous iron has caused a great improvement in the CHF including a marked improvement in patient and cardiac function and a marked reduction in the need for hospitalization and for high-dose diuretics. It also frequently has caused renal function to improve or at least stabilize. In addition, patients' quality of life and exercise capacity also have improved with the correction of the anemia. In CKI patients, anemia also may play an important role in increasing the risk for death, coronary heart disease, stroke, and progression to end-stage renal disease. Erythropoietin may have a direct positive effect on the heart and brain unrelated to correction of the anemia by reducing cell apoptosis and by increasing neovascularization, both of which could prevent tissue damage. This could have profound therapeutic implications not only in CHF but in the future treatment of myocardial infarction, coronary heart disease, strokes, and renal failure.

Topics: Age Factors; Aged; Anemia, Iron-Deficiency; Animals; Cohort Studies; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Follow-Up Studies; Heart Failure; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Middle Aged; Recombinant Proteins; Renal Dialysis; Risk Assessment; Severity of Illness Index; Survival Rate; Treatment Outcome

Analysis of the biologic effects of erythropoietin and pathophysiology of chronic kidney diseases (CKD) suggests that treatment with erythropoiesis-stimulating agents (ESA) could slow the progression of CKD. By decreasing hypoxia and oxidative stress, it could prevent the development of interstitial fibrosis and the destruction of tubular cells. It could have direct protective effects on tubular cells through its antiapoptotic properties. It could help maintain the integrity of the interstitial capillary network through its effects on endothelial cells. Thus, suggesting that correcting anemia with ESA could slow the progression of CKD is biologically plausible. In patients with CKD, three small prospective studies and a retrospective study have suggested that treatment with ESA may have protective effects. Post-hoc analysis of the Reduction in Endpoints in Noninsulin-dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan study has also shown that anemia was an independent risk factor for progression of nephropathy in patients with type 2 diabetes. In addition, a large clinical trial, which had to be stopped prematurely because of labeling change for subcutaneous administration of epoetin alfa, suggests that complete normalization of hemoglobin levels is safe in CKD patients not on dialysis and without severe cardiovascular disease. Thus, it seems reasonable to advocate starting a large randomized, prospective study to determine if normalization of hemoglobin concentration can effectively slow the progression of CKD.

Topics: Anemia; Apoptosis; Clinical Trials as Topic; Diabetic Nephropathies; Disease Progression; Epoetin Alfa; Erythrocyte Count; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Nephrons; Prospective Studies; Protein Binding; Receptors, Erythropoietin; Recombinant Proteins; Retrospective Studies; Risk Factors

The present work reviews the mechanisms and close association between glomerular and tubular damage and its relationship to renal functional impairment. In addition, we present an overview of the pathways involved in the progression of tubulointerstitial fibrosis and a brief summary of the treatments used to retard the progression to end-stage renal failure.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Progression; Erythropoietin; Humans; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Neovascularization, Physiologic; Nephritis, Interstitial; Renal Insufficiency

A neurohumoral link between kidneys and the heart has been established, particularly in the context of hypertension and cardiomyopathy. Beyond this neuro-endocrine pathway, another connecting system theoretically recruits growth factors that are selectively produced by the kidneys and have the ability to promote a distant reaction at the level of bone marrow. This reaction differentiates and circulates vascular progenitor cells capable of repairing the injured cardiovascular system. Reducing injuries (prevention) stabilizes disease processes by reducing tissue damage and destruction but the gradual degradation of the body's natural repair mechanisms eventually allows progressive reactivation of disease processes. In this light, a focus on tissue repair rather than injury prevention may hold the key to controlling chronic heart diseases. This article examines the medical therapies, including recombinant human erythropoietin, that have been shown to improve the function and survival of endothelial progenitor cells and promote the healing of damaged tissue.

Topics: Endothelium, Vascular; Erythropoietin; Growth Substances; Heart Diseases; Homeostasis; Humans; Inflammation; Kidney Failure, Chronic; Stem Cells

The combination of heart failure and chronic kidney disease (CKD) has received comparatively little attention in terms of clinical research versus investigations of each state individually. It has been known for over a decade that anemia, a cardinal feature of CKD, is associated with higher cardiovascular event rates in late-stage and end-stage renal disease. Although the biological mechanisms linking anemia, renal failure, and heart failure are incompletely understood, more prevalent anemia is consistent in patients with more severe heart failure and is associated with higher mortality rates. Impaired erythropoietin production and resistance to erythropoietin are major contributors to anemia in patients with heart failure. By targeting hemoglobin levels in anemic patients with CKD, through the use of recombinant erythropoietin (epoetin) therapy, it has been hoped that anemia, CKD, and heart failure outcomes can be improved. Darbepoetin alfa was engineered to contain more N-linked carbohydrate chains than erythropoietin, and has an approximately 3 times longer serum half-life. Several clinical trials have addressed the hypothesis that darbepoetin alfa can effectively treat renal anemia at dose frequencies of once per week, or less often, with positive outcomes.

Topics: Anemia; Cardiomyopathies; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins

The need for erythropoietin (rhuEPO) or darbepoetin-alpha and iron is lower in patients undergoing peritoneal dialysis (PD) than in patients treated with hemodialysis (HD) because blood losses are reduced, residual renal function and elimination of inhibitors of erythropoiesis are improved and inflammation is less than in HD treatment. In addition, comorbidities of PD patients are probably lower than those of HD patients, and this factor may also contribute to anemia being less in PD patients than in those on HD. Furthermore, the frequency of blood transfusions is lower in PD patients, with or without rhuEPO treatment. However, in PD patients also, anemia is associated with hospitalization rate and mortality. Anemia can be corrected by subcutaneous injections of rhuEPO-beta (1-3 times per week) or darbepoetin-alpha (once a week or twice a month). Adjuvant treatment of anemia includes correction of iron deficiency by oral or intravenous iron, androgen substitution in elderly male PD patients and adequate calcitriol supplementation. Factors that may negatively influence anemia in PD patients are inflammation, infection, antihypertensive therapy with ACE inhibitors or angiotensin II blockers and neutralizing antibodies against rhuEPO or darbepoetin-alpha.

Topics: Anemia; Calcitriol; Chemotherapy, Adjuvant; Comorbidity; Darbepoetin alfa; Erythropoietin; Humans; Iron; Kidney Failure, Chronic; Peritoneal Dialysis; Practice Guidelines as Topic; Practice Patterns, Physicians'; Prognosis; Treatment Outcome

The erythrocytes of patients suffering from chronic renal failure (CRF) are exposed to an increased activity of free radicals. These compounds are generated by uremic toxins and hemodialysis itself. They cause the peroxidation of lipids and proteins in red blood cell membrane. It leads to a decrease of erythrocytes' stability and a lower resistance to hemolysis. The advanced oxidation protein products and advanced glycation end products (AOPP and AGE) also contribute to these changes. The described processes deepen the anemia in CRF and make difficulties in its treatment. In addition, the quoted references present a lot of disturbances in activities of the enzymes and metabolic pathways, which provide antioxidant reactions. This group consists of: superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase (CAT), glutathione reductase (GSSG-R) end the enzymes of the pentose-phosphate shunt (PPS). The intensity of changes is according to the stage of the disease and the efficiency of treatment. Its most appropriate form is renal transplantation.

Topics: Erythropoietin; Free Radicals; Humans; Kidney Failure, Chronic; Oxidative Stress; Pentose Phosphate Pathway; Renal Dialysis

The importance of anemia in chronic kidney disease (CKD) has become increasingly well recognized over recent years, as have the benefits of treating anemic CKD patients with recombinant human erythropoietin (rHuEPO, epoetin). As well as reducing the need for blood transfusions and the complications associated with renal failure in CKD patients, rHuEPO treatment decreases patient morbidity and mortality, particularly as a result of cardiovascular disease. The strong correlation between anemia, renal failure and cardiac failure is one that has received much attention recently, with each factor recognized to cause the other to worsen in a 'vicious cycle'. Recent studies have concentrated on the possible benefits of anemia treatment in patients with CHF. Currently available data suggest improvements in CHF symptoms, left ventricular ejection fraction (LVEF) and a reduction of hospitalizations associated with anemia correction through epoetin treatment. Available data from CKD patients suggest that anemia management should begin as early as possible, although the optimal target level for individual patients is as yet unclear. In addition to the currently available evidence, additional large, randomized, controlled studies are required to further define the morbidity/mortality benefits of epoetin treatment in CHF patients with anemia.

Topics: Anemia; Chronic Disease; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Prognosis

Topics: Adult; Anemia; Blood Transfusion; Erythropoiesis; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Nutritional Physiological Phenomena; Renal Dialysis

The correction of anemia in dialysis patients with erythropoietin (EPO) can be frustrated by insufficient iron. To address this effect, we preloaded candidate EPO patients with intravenous iron in the early 1990s. Preloading with 900-1,525 mg of iron yielded the following results: 70% of patients had increasing hematocrits (HCTs) without EPO, and 40% of patients had HCTs greater than 30%. Apparent lack of iron led to blood loss studies. Routes evaluated were blood sampling, dialyzer clotting, blood in the dialyzer circuit and postdialysis bleeding. Projected annual losses were between 2,516 and 5,126 ml, depending on circuit and posttreatment losses. In terms of red cell loss, the results are comparable to those in the early days of dialysis before the introduction of current technology. Extension of these studies to daily dialysis predicts possible losses with this 6 times a week therapy of between 4,663 and 9,884 ml per year.

Topics: Anemia, Iron-Deficiency; Blood Coagulation; Catheters, Indwelling; Erythropoiesis; Erythropoietin; Hemorrhage; Humans; Infusions, Intravenous; Iron; Iron-Dextran Complex; Kidney Failure, Chronic; Models, Biological; Premedication; Recombinant Proteins; Renal Dialysis

To compare rates of pure red cell aplasia (PRCA) over time in patients with chronic renal failure treated with subcutaneous injections of two brands of epoetin alfa (either Eprex or Epogen) or epoetin beta (NeoRecormon).. Cases of antibody-mediated PRCA associated with epoetin alfa-treated patients were obtained from public databases and company websites and limited to time periods when exposure data also were available The subcutaneous exposure rates per 100 000 patient-years were calculated for the periods 1989-1998 and 1999-2002.. The event rate for antibody-mediated PRCA for Epogen and Eprex were similar from 1989 to 1998, but the number of cases of Eprex-associated PRCA has increased markedly since 1999, even after accounting for subcutaneous exposure. In contrast, rates have remained low for Epogen and NeoRecormon.. The recent increase in PRCA appears to be product specific and cannot be explained solely as a consequence of increased use of the subcutaneous route of administration.

Topics: Epoetin Alfa; Erythropoietin; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Recombinant human erythropoietin (epoetin alfa) has been used in clinical settings for more than a decade. Its indications have expanded considerably from its original use as hormone therapy in the treatment of anemia in adults with chronic kidney disease. Since the introduction of epoetin alfa, a greater understanding of anemia pathophysiology and the interactions of erythropoietin, iron, and erythropoiesis has been elucidated. Anemia is now independently associated with increased mortality and disease progression. Potential survival benefits associated with correction of anemia in various patient populations are leading to consideration of earlier, more aggressive treatment of mild to moderate anemia with epoetin alfa. Moreover, this agent's therapeutic use may extend beyond currently accepted roles. Epoetin alfa is undergoing evaluation with promising results in a variety of new clinical settings, including anemia associated with congestive heart failure, ribavirin-interferon alfa treatment of hepatitis C virus infection, and critical illness. Preclinical studies also have established erythropoietin and its recombinant equivalent to be a pleiotropic cytokine with antiapoptotic activity and neuroprotective actions in the central nervous system. The therapeutic potential of epoetin alfa appears yet to be fully realized.

Topics: Anemia; Clinical Trials as Topic; Cytokines; Epoetin Alfa; Erythropoiesis; Erythropoietin; Heart Failure; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; United States

Numerous randomized, controlled trials have demonstrated that recombinant human erythropoietin (rHuEPO, epoetin alfa) significantly raises hemoglobin levels, reduces transfusion requirements, and improves quality of life in anemic patients with chronic renal failure. However, this accumulation of data has yet to be systematically examined. The objectives of this meta-analysis were to quantify the effects of epoetin alfa on clinical efficacy, quality of life, hospitalizations, and transfusions by collecting and analyzing the published body of evidence.. Sixteen published studies fulfilled all inclusion criteria and were subjected to data extraction. Data specifically related to hemoglobin and/or hematocrit levels, quality-of-life measurements, number and length of hospitalizations, and number of blood transfusions were then pooled across studies using a random effects meta-analysis. Simple combined estimates of the preselected variables were calculated, and adjusted estimates were made using meta-regression.. Baseline hemoglobin levels (<8 g/dL) increased substantially (40% to 50%) after epoetin alfa administration to a nonanemic state (Hb >11 g/dL) for the pooled study group. Substantial improvements (10% to 70%) were observed for all measures of quality of life. In addition, patients who received epoetin alfa had substantial reductions in hospitalization rate, hospital length of stay, transfusion rate, and number of units transfused.. This meta-analysis strongly suggests that epoetin alfa therapy for patients with chronic renal failure provides important clinical and quality-of-life benefits while substantially reducing hospitalizations and transfusions.

Topics: Anemia; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins

Endogenous erythropoietin (EPO) consists of a central polypeptide core covered by post-translationally linked carbohydrates. Three of the four currently available erythropoiesis stimulating agents (ESA)--epoetin-alpha, epoetin-beta and epoetin-omega- are composed of an identical amino acid sequence, but glycosylation varies as a result of type- and host cell-specific differences in the production process. Epoetin-alpha and epoetin-beta resemble each other with respect to molecular characteristics and pharmacokinetic data, although epoetin-beta has a higher molecular weight, a lower number of sialylated glycan residues and possibly slight pharmacokinetic advantages such as a longer terminal elimination half-life. A serious adverse effect of long-term administration of ESA is pure red cell aplasia. This effect has been observed predominantly with subcutaneous use of epoetin-alpha produced outside the US after albumin was removed from the formulation. In comparison with the intravenous route, subcutaneous administration of epoetin has been reported to have a dose-sparing effect in some studies. Epoetin-beta has been the subject of studies aimed at proving efficacy with a reduced administration frequency but results are not unequivocal. Epoetin-omega is produced in a different host cell than all other erythropoietic agents, hence glycosylation and pharmacokinetics are different. Small-scale clinical studies found epoetin-omega to be slightly more potent than epoetin-alpha. Epoetin-delta is a recently approved agent produced by human cells that are genetically engineered to transcribe and translate the EPO gene under the control of a newly introduced regulatory DNA sequence. However, epoetin-delta is not yet on the market and few data are available. The erythropoietin analogue darbepoetin-alpha carries two additional glycosylation sites that permit a higher degree of glycosylation. Consequently, in comparison with the other epoetins, darbepoetin-alpha has a longer serum half-life and a higher relative potency, which further increases with extension of the administration interval. Dosage requirements of darbepoetin-alpha do not appear to differ between the intravenous and subcutaneous routes of administration. The less frequent administration of darbepoetin-alpha in comparison to the other epoetins may reduce drug costs in the long term, but the variability in dosage or dosage frequency required within a single patient is high. Further studies should be aimed a

Topics: Anemia; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Stimulation, Chemical

Several studies showed that anaemia is commonly observed in patients with Chronic Heart Failure (CHF) and is associated with worsened symptoms and survival. When anaemia in these patients is treated with erythropoietin (EPO), a significant improvement in cardiac function and symptoms was observed. Although it was originally believed that EPO specifically acted on haematopoietical cells, recent evidence demonstrated several non-haematopoietical effects. Ischaemia/reperfusion experiments in rat heart and brain showed large infarct reduction when treated with EPO. Other effects of EPO are related to its pro-angiogenic effects on endothelial cells, which could be of potential value in patients with ischaemic heart disease. These preclinical findings suggest that EPO may have potential effects in cardiovascular disease beyond correction of haemoglobin levels.

Topics: Anemia; Apoptosis; Cardiac Output, Low; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Humans; Kidney Failure, Chronic; Myocardial Ischemia; Neovascularization, Pathologic; Recombinant Proteins; Stroke

The pharmacoeconomics of erythropoietic therapy for the treatment of anemia is receiving renewed attention due to the current availability of two agents. Epoetin alfa has been the standard of therapy for patients with renal disease and cancer-related anemia for more than a decade. Darbepoetin alfa, an alternative agent, is now approved for anemia resulting from renal disease and cancer chemotherapy.. Although direct comparative trials have not been performed with these agents, information published in the last several years regarding their clinical efficacy, safety, and dosing is sufficient, in most cases, to compare costs. With the disclaimer that any efficacy comparison of competing products using published reports has certain limitations, a cost-minimization approach from a provider's perspective was conducted.. To provide background for the economic evaluation, pharmacokinetic and pharmacodynamic data for these two agents are discussed. Recent clinical trials in the nephrology and oncology therapeutic areas are summarized, highlighting study designs, dosing regimens, patient entry criteria, study endpoints, and published results. Cost data, based on average wholesale prices (AWP) in 2003, are compared and calculated from available clinical data with an emphasis on efficacy.. These evaluations largely conclude that epoetin alfa is the better pharmacoeconomic value of the two currently available erythropoietic agents.

Topics: Anemia; Antineoplastic Agents; Cost-Benefit Analysis; Darbepoetin alfa; Dose-Response Relationship, Drug; Economics, Pharmaceutical; Epoetin Alfa; Erythrocytes; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Neoplasms; Recombinant Proteins; Treatment Outcome

Topics: Anemia; Cost-Benefit Analysis; Erythropoietin; France; Humans; Kidney Failure, Chronic; Patient Care Planning; Prognosis

Dialysis guidelines recommend aggressive management of anemia, including the use of intravenous iron (i.v.Fe) when indicated. However, few published data are available to guide the use of i.v.Fe in children, and studies are difficult to compare. In this meta-analysis we sought to combine evidence by pooling clinical trial data to determine if i.v.Fe therapy helped increase hematocrit, serum levels of hemoglobin, ferritin, and transferrin saturation (TSAT), and reduce erythropoietin use. We searched MEDLINE and other databases, publications, and other sources to identify as many published and unpublished trials as possible. Of 379 possible studies, nine met the criteria for inclusion and analysis. Across all nine studies, 141 patients were studied, for durations of 2 weeks to 12 months. Pooled results identified an increase in hemoglobin, hematocrit, ferritin, and TSAT levels, and reduced use of erythropoietin, with effect sizes (in standardized weighted mean differences) ranging from 0.62 (95% confidence interval 0.11-1.13) to 1.86 (1.58-2.15) standard deviation improvements. Current practice is based largely on extrapolation from adult data and a few small pediatric trials. The pooled pediatric data suggest that i.v.Fe is effective and produces moderate to large effects on the reported outcomes. Prospective, multi-center trials are needed to determine the optimal utilization of i.v.Fe in children.

Topics: Adolescent; Child; Child, Preschool; Clinical Trials as Topic; Erythropoietin; Ferritins; Hematocrit; Hemoglobins; Humans; Infusions, Intravenous; Iron; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Transferrin

Topics: Anemia; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Humans; Kidney Failure, Chronic

Anaemia is a common complication of chronic kidney disease (CKD). It is often more severe and occurs at an earlier stage in patients with diabetic nephropathy than in patients with CKD of other causes. This anaemia results from erythropoietin deficiency, which seems to develop in patients with type 1 diabetes even at relatively "normal" levels of serum creatinine. Early erythropoietin- deficiency anaemia occurs in both type 1 and type 2 diabetes, although the prevalence may be higher in type 1 diabetes. However, numerically most patients with erythropoietin-deficiency anaemia have type 2 diabetes as it is a much more common disease. There is also a greater prevalence in women than men but this is not related to iron stores. In addition, erythropoietin-deficiency anaemia is associated with the presence of autonomic neuropathy in patients with diabetes. Small studies have suggested that recombinant human erythropoietin (rhEPO; epoetin) treatment is effective in correcting erythropoietin-deficiency anaemia in patients with diabetes. Additionally, rhEPO therapy improves quality of life and well-being in these patients. Studies also suggest that treatment with rhEPO to restore a normal haematocrit ameliorates orthostatic hypotension. Given the high cardiovascular risk in patients with diabetic nephropathy, it is important to determine in prospective clinical trials whether early anaemia correction can also improve cardiovascular outcomes.

Topics: Anemia; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins

The introduction of recombinant human erythropoietin (RHuEPO) has dramatically changed the therapeutic approach to the anemia of chronic renal failure. Clinical studies have also demonstrated that RHuEPO is effectiveness in various non-uremic conditions, such as anemia associated with onco-hematological disorders, prematurity, HIV infection and to reduce the exposure to allogeneic blood in surgical patients. In this review, we briefly analyze the main clinical applications of RHuEPO, with particular attention to the potential complications deriving from its use.

Topics: Adult; Anemia; Anemia, Neonatal; Blood Transfusion, Autologous; Child; Clinical Trials as Topic; Erythropoietin; Female; HIV Infections; Humans; Infant, Newborn; Infant, Premature, Diseases; Kidney Failure, Chronic; Male; Multicenter Studies as Topic; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins

Topics: Amino Acids; Bicarbonates; Dietary Proteins; Energy Metabolism; Erythropoietin; Exercise Therapy; Histocompatibility; Humans; Insulin-Like Growth Factor I; Kidney; Kidney Failure, Chronic; Malnutrition; Metabolic Diseases; Prenatal Nutritional Physiological Phenomena; Recombinant Proteins; Renal Dialysis

Topics: Acute Kidney Injury; Animals; Biomarkers; Contrast Media; Endothelin Receptor Antagonists; Endothelin-1; Endotoxemia; Erythropoietin; Fibrosis; Glycopeptides; Heart Failure; Humans; Hypotension; Kidney Failure, Chronic; Peptides, Cyclic; Peritoneal Dialysis; Peritoneum; Prognosis; Recombinant Proteins; Renal Dialysis

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Antihypertensive Agents; Calcium Channel Blockers; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Renal Circulation; Renal Dialysis; Renin-Angiotensin System; Sleep Apnea Syndromes; Sympathetic Nervous System; Vascular Resistance

Topics: Aluminum; Anemia; Angiotensin-Converting Enzyme Inhibitors; Carnitine; Chronic Disease; Drug Resistance; Erythropoietin; Humans; Hyperparathyroidism, Secondary; Inflammation; Iron Deficiencies; Kidney Failure, Chronic; Malnutrition; Recombinant Proteins; Renal Dialysis

Topics: Anemia; Dialysis; Disability Evaluation; Erythropoietin; Health Resources; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; Self Care; Social Support

Topics: Anemia; Angiotensin-Converting Enzyme Inhibitors; Ascorbic Acid; Drug Design; Erythropoietin; Hematinics; Humans; Iron; Japan; Kidney Failure, Chronic; Practice Guidelines as Topic; Prognosis; Quality of Life; Recombinant Proteins; Renal Dialysis

Topics: Anemia, Iron-Deficiency; Ascorbic Acid; Biomarkers; Drug Resistance; Erythropoietin; Ferritins; Humans; Iron; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; Renal Dialysis; Transferrin

Erythropoietin treatment for anaemia in chronic kidney disease (CKD) brings important clinical benefits, but restricted healthcare budgets necessitate value-for-money therapies, requiring economic considerations also to be taken into account when selecting a treatment regimen. Subcutaneous (s.c.) administration of epoetin is effective at a lower dose than intravenous (i.v.) administration, offering the potential for substantial reductions in costs of treatment. Unlike epoetin alfa, which is contra-indicated by the s.c. route in Europe in patients with CKD, epoetin beta (NeoRecormon) can be safely and effectively given by either route. The multidose presentations of epoetin beta (Reco-Pen, multidose vials) may provide further opportunity for dose reduction. The tolerability of s.c. epoetin beta is excellent and superior compared with epoetin alfa or darbepoetin alfa. Epoetin beta given once weekly is as effective as two- or three-times weekly, and the dosing frequency can be further reduced to once every 2 weeks in patients who are stable on once-weekly dosing. Reduced dosing frequency is more convenient for the patient and may save nursing time in dialysis units. Overall, s.c. epoetin beta, compared with alternative treatments, may represent a cost-effective treatment option for anaemia management as it combines a well-established safety and efficacy record, favourable local tolerability, and the convenience of once-weekly dosing with the potential to reduce treatment costs by up to 30%.

Topics: Anemia; Cost Savings; Cost-Benefit Analysis; Economics, Pharmaceutical; Erythropoietin; Humans; Kidney Failure, Chronic

Mortality in dialysis patients is greater than that in the general population across all age groups. The disparity in mortality is greatest among patients aged under 35 years. Chronic kidney disease (CKD) is associated with the malnutrition, inflammation and atherosclerosis (MIA) syndrome, which helps to explain the high mortality rates among patients with CKD. Paradoxically, CKD patients exhibit signs of immune suppression as well as immune system activation. Chronic inflammation and immune system activation are not only integral to the MIA syndrome, but also may underlie resistance to erythropoietin treatment in patients with anaemia. Chronic immune system activation is reflected by abnormally raised T-lymphocyte and monocyte expression of both pro- and anti-inflammatory cytokines. Patients who respond well to erythropoietin treatment exhibit fairly normal expression of these cytokines. Patients who persistently fail to respond, however, express abnormally raised levels of the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), which are also known to inhibit erythropoiesis. Paradoxically, these patients also express abnormally high levels of the anti-inflammatory cytokines interleukin (IL)-10 and IL-13. Although anti-inflammatory in nature, these cytokines might also affect erythropoiesis. One strategy to overcome the problem of chronic inflammation in anaemic patients with CKD may be treatment with the phosphodiesterase inhibitor, pentoxifylline. Preliminary results suggest that once-daily treatment with 400 mg of pentoxifylline orally not only can reduce T-cell expression of TNF-alpha and IFN-gamma, but can also restore the response to erythropoietin and improve haemoglobin levels. Ongoing studies will investigate further the use of pentoxifylline in erythropoietin resistance.

Topics: CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cytokines; Epoetin Alfa; Erythropoietin; Humans; Inflammation; Interferon-gamma; Interleukins; Kidney Failure, Chronic; Pentoxifylline; Phosphodiesterase Inhibitors; Recombinant Proteins; Renal Dialysis; Treatment Outcome; Tumor Necrosis Factor-alpha

Anemia has recently been recognized as an important comorbid condition and potentially novel therapeutic target in patients with heart failure (HF). Anemia is common in HF patients, with a prevalence ranging from 4% to 55% depending on the population studied. Multiple potential mechanisms of interaction exist between anemia and the clinical syndrome of HF, including hemodilution, inflammatory activation, renal insufficiency, and malnutrition. A growing body of literature from observational databases and clinical trials suggests that anemia is an independent risk factor for adverse outcomes in patients with HF. Although preliminary data suggest that treatment of anemia may result in significant symptomatic improvement in HF, aggressive treatment of anemia may also be associated with increased risk of hypertension or thrombosis. Multiple ongoing studies will provide definitive data on the balance of risks and benefits of anemia treatment in chronic HF.

Topics: Anemia; Comorbidity; Erythropoietin; Heart; Heart Failure; Hematocrit; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Risk Factors

A special form of anemia was observed during the treatment with recombinant human erythropoietin having been applied for more than 15 years. The pure red-cell anemia due to antibodies against erythropoietin was described in chronic renal failure patients. Since oncological patients are also treated with rhuEPO it is interesting to know whether this side effect could be observed in the patients with solid tumors as well. It should be considered in tumorous patients when coexistence of antibodies against rhuEPO with pure red-cell aplasia is demonstrated, and its other causes as immunological disease, thymoma, viral infections (eg. Parvovirus B12, Hepatitis B or C) are excluded. The author collected literature data and found the absence of reports on this side effect in cases of treatment with rhuEPO in cancer patients. The rhuEPO treatment is a safe method for the cure of cancer anemia as antibodies against rhuEPO have not been shown together with PRCA among cancer patients. The possible explanation could be the shorter application time in cancer compared to the chronic renal failure patients. The side effect observed in chronic renal failure patients calls the attention to the precise compliance with the instructions of the manufacturers.

Topics: Antineoplastic Agents; Drug Administration Schedule; Erythropoietin; Humans; Kidney Failure, Chronic; Neoplasms; Recombinant Proteins; Red-Cell Aplasia, Pure

Certain populations with chronic hepatitis C face special challenges in attaining optimal adherence to antiviral therapy, including patients coinfected with human immunodeficiency virus, patients undergoing dialysis for end-stage renal disease, and liver transplant recipients. These patient groups may stand to gain particular benefit from the expanding use of hematopoietic growth factors to manage the cytopenic effects of antiviral therapy for hepatitis C. This article reviews the rationale, current evidence, and future prospects for the adjunctive use of growth factors in these special populations with hepatitis C.

Topics: Anemia; Antiviral Agents; Clinical Trials as Topic; Comorbidity; Drug Therapy, Combination; Erythropoietin; Forecasting; Granulocyte Colony-Stimulating Factor; Hepatitis C, Chronic; HIV Infections; Humans; Interferons; Kidney Failure, Chronic; Liver Transplantation; Neutropenia; Patient Compliance; Recombinant Proteins; Recurrence; Renal Dialysis; Ribavirin

Topics: Anemia; Disease Management; Erythropoietin; Humans; Iron; Kidney Failure, Chronic; Renal Dialysis

Anemia affects almost all patients with chronic kidney disease (CKD), reduces quality of life, and is a risk factor for early death. Higher hemoglobin (Hb) targets have been widely advocated because of data from observational studies showing that higher Hb is associated with improved survival and quality of life, but higher Hb targets may cause access thrombosis and hypertension and are costly. This study aimed to evaluate the benefits and harms of different Hb targets in CKD on the basis of randomized trial evidence. A comprehensive search of the Cochrane Trials Registry, Medline, Embase, and reference lists was performed. Two independent reviewers assessed studies for inclusion criteria and extracted data on all-cause mortality, cardiovascular disease, strokes, hypertension, seizures, hyperkalemia, access thrombosis, and quality of life. Analysis was by a random-effects model, and results are expressed as relative risk (RR) or weighted mean difference with 95% confidence intervals (CI). Nineteen relevant trials were identified. Twelve trials (638 patients) compared use of erythropoietin versus no erythropoietin treatment, and seven trials (2058 patients) compared higher versus lower Hb targets. Compared with Hb values of >130 g/L or more in the CKD population with cardiovascular disease, Hb values of <120 g/L were associated with lower all-cause mortality (RR, 0.84; 95% CI, 0.71 to 1.00). Hb values of 100 g/L or less reduced the risk of hypertension (RR, 0.50; 95% CI, 0.33 to 0.76) but increased the risk of seizures (RR, 5.25; 95% CI, 1.13 to 24.34). From the available trial evidence, in CKD patients with cardiovascular disease, the benefits associated with higher Hb targets (reduced seizures) are outweighed by the harms (increased risk of hypertension and death). There is insufficient data to guide decisions in patients without cardiovascular disease or in the predialysis population.

Topics: Anemia; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic

Topics: Animals; Blood Platelets; Cell Differentiation; Cell Division; Central Nervous System; Erythropoietin; Humans; Kidney Failure, Chronic; Neoplasms; Neuroprotective Agents; Recombinant Proteins

Topics: Aged; Anemia; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic

Over the past few years, anemia has emerged as a powerful independent predictor of adverse outcomes in chronic heart failure (CHF). It affects up to 50% of patients with CHF, depending on the definition of anemia used and on the population studied. Even small reductions in hemoglobin are associated with worse outcome. However, the causes of anemia in CHF remain unclear, although impairment of renal function and inflammatory cytokines are proposed mechanisms. Both may act through impairment of the synthesis or action of erythropoietin. Preliminary studies have demonstrated improvement in symptoms, exercise tolerance, quality of life, and reductions in hospitalizations when patients with severe CHF were treated with erythropoietin. The benefits and the potential risks of such therapies will be further addressed in upcoming larger randomized trials. The recent interest in anemia reflects a new perspective in heart failure therapy, focusing on non-cardiovascular comorbidities.

Topics: Aged; Anemia; Anemia, Iron-Deficiency; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cytokines; Erythropoietin; Female; Heart Failure; Hemodilution; Humans; Kidney Failure, Chronic; Male; Prevalence; Prognosis; Risk Factors

Topics: Anemia; Centers for Medicare and Medicaid Services, U.S.; Erythropoietin; Evidence-Based Medicine; Health Policy; Humans; Kidney Failure, Chronic; Medicare; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Recombinant Proteins; Reimbursement, Disproportionate Share; United States

Anaemia affects 60-80% of patients with renal impairment, reduces quality of life and is a risk factor for early death. Treatment options are blood transfusion, erythropoietin (EPO) alpha or beta and darbepoetin alfa. Recently higher haemoglobin (Hb) and haematocrit targets have been widely advocated because of positive data from observational studies. However, higher targets may lead to access thrombosis and hypertension and are costly.. This review assesses the benefits and harms of low (Hb 100 g/L or HCT > 30%) targets in pre- and post-dialysis patients receiving any treatment for anaemia.. We searched The Cochrane Renal Group specialised register (September 2002), Cochrane Controlled Trials Register (The Cochrane Library, Issue 3, 2002) MEDLINE (1966 - September 2002), EMBASE (1988 - September 2002) and reference lists of retrieved articles.. Randomised controlled trials (RCTs) and quasi-RCTs comparing low Hb/HCT targets (Hb 100 g/dL) in patients with anaemia of chronic renal disease.. Two reviewers independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes, with 95% confidence intervals (95% CI).. Fifteen trials were identified in which 2096 patients were included. Twelve trials (673 patients) compared placebo with EPO and three trials (1423 patients) compared two doses of EPO. Hb values of 100 g/L (obtained with low EPO doses) were associated with lower mortality compared to Hb values of 140 g/L or more (obtained with high EPO doses) in the population with chronic renal disease and cardiovascular impairment (two trials, 1379 patients: RR 0.82; 95% CI 0.68 to 0.99). Lower targets obtained with a placebo resulted in an increased risk for seizures (four trials, 219 patients: RR 5.25; 95% CI 1.13 to 24.34) as compared to higher targets reached with EPO treatment. Finally, there was a reduced risk for hypertensive episodes with lower Hb targets reached with a placebo as compared to higher targets reached with EPO (six trials, 387 patients: RR 0.50; 95% CI 0.33 to 0.76). Quality of life was not adequately evaluated in the studies.. Lower Hb targets of 100 g/L were associated with a lower risk of death in the population with cardiovascular impairment and chronic renal disease as compared to Hb 140 g/L. Lower Hb targets (Hb < 100 g/L) were also significantly associated with an increased risk for seizures and a reduced risk of hypertension compared to Hb > 100 g/L. There is a need of more adequately powered, well-designed and reported trials in this area. In particular, randomised controlled trials comparing the benefits and harms of low (Hb < 100 g/L) versus intermediate (Hb 130 g/L) and high (Hb 140 g/L) targets in the pre-dialysis population with chronic renal disease are necessary. In fact, there is a large deficiency of trials in the pre-dialysis population. The new trials should focus on hard outcomes and also look at outcomes which were previously not studied adequately, such as seizures and quality of life, which is to be assessed with validated measures.

Topics: Anemia; Erythropoietin; Hematocrit; Hemoglobin A; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Renal Dialysis; Risk Assessment

Anemia is seen in chronic kidney insufficiency (CKI), dialysis patients, congestive heart failure (CHF), and renal transplantation. Anemia can lead to progressive cardiac damage as well as progressive renal damage. It is not generally appreciated that CHF itself may be a very common contributor to both the production of anemia as well as to the progression of the renal failure. Correction of the anemia with erythropoietin and, as necessary, intravenous iron, may prevent the deterioration of both the heart and the kidneys. We suggest that there is a triangular relationship, a vicious circle, between CHF, CKI and anemia where each of these three can both cause and be caused by the other. We call this syndrome the cardio-renal anemia (CRA) syndrome. All physicians, especially cardiologists and internists who treat CKI and CHF, should be made aware of the dangers of anemia in CKI and CHF and should work with nephrologists to correct it.

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Iron; Kidney Failure, Chronic

Anemia is common in chronic renal failure. Guidelines for the diagnosis and treatment of anemia in adult patients are available. With respect to the diagnosis and treatment in children on peritoneal dialysis, the European Pediatric Peritoneal Dialysis Working Group (EPPWG) has produced guidelines. After a thorough diagnostic work-up, treatment should aim for a target hemoglobin concentration of at least 11 g/l. This can be accomplished by the administration of erythropoietin and iron preparations. Although there is sufficient evidence to advocate the intraperitoneal administration of erythropoietin, most pediatric nephrologists still apply erythropoietin by the subcutaneous route. Iron should preferably be prescribed as an oral preparation. Sufficient attention has to be paid to the nutritional intake in these children. There is no place for carnitine supplementation in the treatment of anemia in pediatric peritoneal dialysis patients.

Topics: Anemia; Carnitine; Child; Erythropoietin; Europe; Humans; Iron; Kidney Failure, Chronic; Practice Guidelines as Topic

Topics: Erythropoietin; Humans; Immunogenetics; Injections, Subcutaneous; Kidney Failure, Chronic; Red-Cell Aplasia, Pure; Self Administration

Anaemia correction with recombinant human erythropoietin (rh-EPO, epoetin) in end-stage renal disease (ESRD) patients has been associated with improved survival and quality of life, as well as lower overall treatment costs. Few studies, however, have evaluated the benefits of epoetin treatment given to chronic kidney disease (CKD) patients during the pre-dialysis period. A retrospective study of 89 193 incident haemodialysis patients in the Medicare system (age > or =67 years) assessed consistency of epoetin treatment before the start of dialysis and the outcome of patients once they reached ESRD. Patients were grouped according to consistency of epoetin treatment based on the available months of treatment in the 2-year period before starting dialysis. Only 15.6% of patients in the study received any epoetin before the initiation of dialysis. Patients who received no or infrequent epoetin (i.e. received epoetin in <50% of possible months) had a significantly higher relative risk of cardiac disease and death than patients treated with epoetin more frequently. Patients who received no or infrequent epoetin also had significantly higher rates of hospitalization and overall treatment costs at the time of initial dialysis. These findings suggest that early epoetin treatment warrants further investigation in prospective, randomized studies. In summary, it is evident that the care of CKD patients can be improved. Evidence suggests that timely initiation of epoetin treatment to correct renal anaemia appears to be associated with improved survival of ESRD patients in the first year after start of dialysis and reduced costs of treatment.

Topics: Anemia; Cardiovascular Diseases; Comorbidity; Cost-Benefit Analysis; Erythropoietin; Hospitalization; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Retrospective Studies

Interstitial fibrosis plays a key role in the progression of chronic kidney diseases. Analysis of the biologic effects of erythropoietin and of the pathophysiology of interstitial fibrosis suggest that treatment with epoetin may slow the progression of chronic kidney disease, both by decreasing interstitial fibrosis and by protecting against its consequences. The results of two small prospective studies and of a retrospective one also suggest that treatment with epoetin may have such protective effects.

Topics: Anemia; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Kidney Function Tests; Male; Randomized Controlled Trials as Topic; Risk Assessment; Severity of Illness Index; Treatment Outcome

Documentation of anemia-related assessments, interventions, and outcomes is an integral component of proper anemia management for patients with ESRD. In addition to promoting vital communication among medical professionals, documentation helps fulfill regulatory, legal, and payer reimbursement requirements, thereby ensuring that nursing contributions to patient well-being are recognized and that access to care is preserved.

Topics: Anemia; Continuity of Patient Care; Documentation; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Nurse's Role; Physician's Role; Practice Guidelines as Topic; Recombinant Proteins

Topics: Anemia; Carnitine; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Platelet Aggregation; Renal Dialysis

The introduction of recombinant human erythropoietin (RHuEPO) has revolutionised the treatment of patients with anaemia of chronic renal disease. Clinical studies have demonstrated that RHuEPO is also useful in various non-uraemic conditions including haematological and oncological disorders, prematurity, HIV infection, and perioperative therapies. Besides highlighting both the historical and functional aspects of RHuEPO, this review discusses the applications of RHuEPO in clinical practice and the potential problems of RHuEPO treatment.

Topics: Anemia; Blood Transfusion; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Kidney Transplantation; Neoplasms; Postoperative Complications; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Anaemia is prevalent in patients with chronic kidney disease and end stage renal disease. If left untreated, it greatly affects patient survival, quality of life and functional status. Epoetin and darbepoetin are two biotechnology drugs that effectively stimulate the production of red blood cells. These drugs have been shown to significantly increase haemoglobin concentrations and improve quality of life. So far, there have been no head-to-head pharmacoeconomic studies that have compared epoetin to darbepoetin. Health system decision makers need to evaluate important considerations when comparing these agents. These considerations include drug acquisition costs, the patient population being treated, the location of drug administration (in-patient versus ambulatory) and federal government reimbursement. This review details these important pharmacoeconomic considerations.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Practice Guidelines as Topic

A literature review on fish oil supplementation in the population undergoing chronic hemodialysis therapy suggests that supplementation may be beneficial for various challenges to health and well-being prevalent in this population. One study indicated that pruritus symptoms improved with fish oil supplementation, but not with supplementation with two other oils. In a study designed to determine whether fish oils could prevent vascular access graft thrombosis, graft patency rates were approximately 76% in the fish oil and approximately 15% in the placebo group (P>.03). In a pilot study, subjects given fish oil required 16% less erythropoietin and experienced a 3.6% increase in serum albumin levels. Some studies suggest that fish oil supplementation in hemodialysis patients is cardioprotective, with one study finding that "fish eaters" are half as likely to die as "non-fish eaters." Potential risks of supplementation include gastrointestinal distress, prolonged bleeding, and vitamin A toxicity, although the likelihood of serious side effects is probably low. Dietitians are in a position to advise physicians and/or patients regarding appropriate dosages and ways to minimize risks when supplementation seems warranted. Future research could compare the benefits of fish consumption with those of fish oil supplementation and explore the benefits of other n-3 fatty acid sources, such as flaxseed.

Topics: Cardiovascular Diseases; Catheters, Indwelling; Dietary Supplements; Erythropoietin; Female; Fish Oils; Humans; Kidney Failure, Chronic; Male; Pruritus; Renal Dialysis; Seafood; Serum Albumin; Thrombosis

Darbepoetin alfa is a novel erythropoiesis-stimulating protein developed for the treatment of anemia. It is a hyperglycosylated analog of recombinant human erythropoietin with the same mechanism of action as erythropoietin, but with a three-fold longer terminal half-life after intravenous administration than recombinant human erythropoietin and the native hormone both in animal models and in humans. Clinical studies in patients with chronic renal failure either receiving or not receiving dialysis have shown that darbepoetin alfa is equivalent to recombinant human erythropoietin in terms of increases in hemoglobin concentration, percentage of patients achieving target hemoglobin concentration and average time to reach target hemoglobin concentration, although darbepoetin alfa is administered less frequently (once weekly or every other week). Clinical trials in cancer patients either receiving or not receiving chemotherapy have demonstrated that darbepoetin alfa is safe and effective in alleviating anemia at dose intervals of once every 1, 2 or 3 weeks, and results suggest that it may achieve greater and more rapid responses than recombinant human erythropoietin in cancer patients. Furthermore, an improvement in health-related quality of life has been observed in association with anemia correction using darbepoetin alfa therapy in these patients. Darbepoetin alfa has been approved for intravenous and subcutaneous administration by the European Commission and the FDA for the treatment of anemia in patients with chronic renal failure. Additionally, this product was recently approved by the FDA for the treatment of anemia in patients with nonmyeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy. The recommended starting dose in chronic renal failure patients is 0.45 microg/kg once weekly for both intravenous and subcutaneous administration, with subsequent titration based on the hemoglobin concentration. In cancer patients, the recommended starting dose is 2.25 microg/kg once weekly by subcutaneous injection and subsequent titration. The adverse event profile of darbepoetin alfa is similar to that of recombinant human erythropoietin in both settings. There are no reports of antibody formation associated with darbepoetin alfa in chronic renal failure patients, and three cases of antibody formation, with neutralizing activity in one of the cases, have been reported in cancer patients. However, no cases of antibody-medi

Topics: Anemia; Animals; Clinical Trials as Topic; Darbepoetin alfa; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Neoplasms; Stimulation, Chemical; Treatment Outcome

Erythropoietin is a hypoxia-induced hormone that is essential for normal erythropoiesis. The production of recombinant human erythropoietin (rHuEpo) has revolutionized the treatment of anemia associated with chronic renal failure and chemotherapy, and has been used as prophylaxis to prevent anemia after surgery. The erythropoietin receptor is widely distributed in the cardiovascular system, including endothelial cells, smooth muscle cells and cardiomyocytes. Epo has potentially beneficial effects on the endothelium including anti-apoptotic, mitogenic and angiogenic activities. On the other hand, some reports suggest that rHuEpo may have pro-thrombotic or platelet-activating effects. Hypertension develops in 20-30% of renal patients treated with rHuEpo. Many patients with heart failure have anemia. Despite some potential adverse effects, early studies in heart failure patients with anemia suggest that rHuEpo therapy is safe and effective in reducing left ventricular hypertrophy, enhancing exercise performance and increasing ejection fraction. Further studies are warranted to define the role of rHuEpo in chronic heart failure and other cardiovascular settings.

Topics: Anemia; Cardiovascular System; Cell Division; Chromogranins; Endothelium, Vascular; Erythropoietin; GTP-Binding Protein alpha Subunits, Gs; Heart Failure; Humans; Hypertension; Kidney Failure, Chronic; Muscle, Smooth, Vascular; Myocytes, Cardiac; Nerve Tissue Proteins; Platelet Activation; Receptors, Erythropoietin; Recombinant Proteins; Thrombosis

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Clinical Trials as Topic; Darbepoetin alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Prospective Studies

Up to 64% of patients referred to nephrologists with chronic kidney insufficiency (CKI) have evidence of congestive heart failure (CHF), and most of these patients are also anemic. We have called this triad of anemia, CKI, and CHF the cardio renal anemia (CRA) syndrome. The 3 components of this syndrome form a vicious circle, with each one capable of causing or worsening the other 2. Anemia is found in one-third to one-half of CHF patients and can either cause or worsen the CHF, and can increase the mortality, hospitalization, and malnutrition in this condition. Anemia is also associated with a worsening of renal function in CHF and CKI, causing a more rapid progression to dialysis than is found in those without anemia. Uncontrolled CHF can cause rapid deterioration of renal function and may also cause anemia. Chronic kidney insufficiency can cause anemia and worsen the CHF.. Aggressive therapy of CHF with all the accepted CHF medications in the accepted doses will often fail to improve the CHF if anemia is also present but is not corrected. However, when the anemia was corrected with subcutaneous erythropoietin and, in some cases, with intravenous iron, the cardiac and patient function and quality of life improved, the need for hospitalization and for high-dose oral and intravenous diuretics was strikingly reduced, and renal function, which had previously been deteriorating, stabilized.. Nephrologists should carefully assess the cardiac status of all CKI patients, including routinely getting an echocardiogram and possibly measuring B-type natriuretic peptide. Where CHF is present, the indicated CHF agents in the indicated doses should be used.. Studies show that most cardiologists and internists do not recognize, investigate, or treat the anemia frequently seen in their CHF patients. In our experience cooperation between nephrologists and these specialists has increased their awareness about anemia, resulting in its earlier correction, and thus preventing the deterioration of the CHF, the CKI, and the anemia itself.

Topics: Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic

Erythropoietic therapy has transformed the management of the anemia associated with chronic renal failure over the past decade. The first agents that proved effective in stimulating erythropoiesis were the epoetins (alfa and beta), which are recombinant human erythropoietins (EPOs). The EPO molecule was recently modified using site-directed mutagenesis to produce darbepoetin alfa with a longer circulating half-life in vivo. The development of epoetin-induced pure red cell aplasia associated with anti-EPO antibodies shook the nephrology community last year, and gradually new information is emerging on the cause of this rare but important condition. Pure red cell aplasia has provoked new discussions on the best route (intravenously or subcutaneously) for administering erythropoietic therapy. Further research has been published regarding some of the more traditional, although still hotly debated, issues concerning renal anemia management, such as target hemoglobin, factors affecting the response to EPO, and adjuvant therapy to EPO. This review addresses these topics and focuses largely on the publications relevant to these areas of clinical anemia management.

Topics: Anemia; Antibody Formation; Chemotherapy, Adjuvant; Erythropoietin; Hematocrit; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Protein-energy malnutrition (PEM) and inflammation are common and usually concurrent in maintenance dialysis patients. Many factors that appear to lead to these 2 conditions overlap, as do assessment tools and such criteria for detecting them as hypoalbuminemia. Both these conditions are related to poor dialysis outcome. Low appetite and a hypercatabolic state are among common features. PEM in dialysis patients has been suggested to be secondary to inflammation; however, the evidence is not conclusive, and an equicausal status or even opposite causal direction is possible. Hence, malnutrition-inflammation complex syndrome (MICS) is an appropriate term. Possible causes of MICS include comorbid illnesses, oxidative and carbonyl stress, nutrient loss through dialysis, anorexia and low nutrient intake, uremic toxins, decreased clearance of inflammatory cytokines, volume overload, and dialysis-related factors. MICS is believed to be the main cause of erythropoietin hyporesponsiveness, high rate of cardiovascular atherosclerotic disease, decreased quality of life, and increased mortality and hospitalization in dialysis patients. Because MICS leads to a low body mass index, hypocholesterolemia, hypocreatininemia, and hypohomocysteinemia, a "reverse epidemiology" of cardiovascular risks can occur in dialysis patients. Therefore, obesity, hypercholesterolemia, and increased blood levels of creatinine and homocysteine appear to be protective and paradoxically associated with a better outcome. There is no consensus about how to determine the degree of severity of MICS or how to manage it. Several diagnostic tools and treatment modalities are discussed. Successful management of MICS may ameliorate the cardiovascular epidemic and poor outcome in dialysis patients. Clinical trials focusing on MICS and its possible causes and consequences are urgently required to improve poor clinical outcome in dialysis patients.

Topics: Acute-Phase Reaction; Anemia; Chronic Disease; Erythropoietin; Humans; Inflammation; Kidney Diseases; Kidney Failure, Chronic; Protein-Energy Malnutrition; Quality of Life; Recombinant Proteins; Renal Dialysis; Syndrome; Wasting Syndrome

End-stage renal disease (ESRD) is characterized by a high mortality rate, which is mainly caused by cardiovascular disease. In patients with ESRD, high levels of pro-inflammatory cytokines and increased oxidative stress are common features and may contribute to the development of malnutrition, anaemia, resistance to recombinant human erythropoietin (epoetin) and atherosclerosis. The onset of inflammation is multi-factorial and is a predictor of poor outcome in ESRD. Although the inflammation may reflect the underlying cardiovascular disease, the acute-phase response may also contribute to both oxidative stress and progressive vascular injury. The acute-phase response in these patients may be influenced by a number of factors, and possibly the dialysis procedure itself. Inflammation and the acute-phase response interact with the haematopoietic system at several levels, resulting in reduced erythropoiesis, accelerated destruction of erythrocytes and blunting of the reactive increase in erythropoietin in response to reduced haemoglobin levels. In patients with ESRD, epoetin resistance has been linked with inflammation, which is often associated with a state of functional iron deficiency. Patients with ESRD are thought to have a reduced capacity in their control of oxidative stress and there is evidence that suggests that a relationship may exist between inflammation, oxidative stress and the treatment of anaemia with epoetin. Controlled trials are needed before evidence-based recommendations for the management of inflammation-induced anaemia and resistance to epoetin can be defined.

Topics: Anemia; Arteriosclerosis; Cytokines; Dialysis; Drug Resistance; Erythropoietin; Hematinics; Humans; Inflammation; Kidney Failure, Chronic; Malnutrition; Oxidative Stress

The importance of iron in the manufacture of erythrocytes is self-evident. In recent years, the treatment of anaemia of end-stage renal disease with recombinant human erythropoietin (epoetin) has been optimized by adequate iron supply. Intravenous therapy with dextran-free iron compounds has become the ideal and necessary companion of epoetin therapy. Anxiety has been expressed by clinicians and researchers over the impact of excess levels of iron following i.v. administration. Their concerns have included the potential for short-term side effects such as anaphylactic reactions and response to 'free iron'. Long-term concerns have included the possibility of increased infection, oxidative stress and cardiovascular disease with higher levels of iron. The literature also implies that i.v. iron could be a 'two-edged sword', i.e. on the one hand, it optimizes epoetin therapy, while on the other, it puts the patient at greater risk of other complications. This review assesses the evidence for these concerns and concludes that i.v. therapy with dextran-free iron compounds, such as iron sucrose, optimizes epoetin therapy with no direct evidence of any short-term or long-term complications.

Topics: Anemia; Chemotherapy, Adjuvant; Drug Hypersensitivity; Erythropoietin; Ferritins; Heart Diseases; Hematinics; Humans; Infections; Infusions, Intravenous; Iron Compounds; Kidney Failure, Chronic; Oxidative Stress; Recombinant Proteins

Anaemia secondary to chronic kidney disease is a complex syndrome. Adequate dialysis can contribute to its correction by removing small, and possibly middle/large molecules, that may inhibit erythropoiesis. A clear relationship between higher haemoglobin or haematocrit levels, lower recombinant human erythropoietin (epoetin) dose and increase in dialysis dose has been reported in a number of prospective and retrospective studies. This is particularly true in patients receiving inadequate dialysis. Increased attention has also been paid to the relationship between dialysis, increased inflammatory stimulus and response to erythropoietic therapy, as dialysate contamination and low-compatible treatments may increase the production of cytokines and consequently inhibit erythropoiesis. As middle-/large-molecular-weight inhibitors can only be adsorbed or removed by more permeable membranes, the biocompatibility of dialysis membranes and flux are also important factors. In highly selected, adequately dialysed patients without iron or vitamin depletion, however, the effect of these treatment modalities on anaemia appears to be smaller than expected. The role of on-line treatments is still controversial; moreover, it is still difficult to discriminate between the effects of on-line haemodiafiltration per se (use of high-flux biocompatible membranes and pyrogen-free dialysate) from that of an increased dialysis dose. Prospective, randomized, adequately sized studies on this topic are still needed. Results, albeit very preliminary, obtained with short or long nocturnal daily haemodialysis on anaemia correction are encouraging. Adequate dialysis is not only a tool for reducing morbidity and mortality of haemodialysis patients, but is also a way of optimizing responsiveness to erythropoietic therapy, allowing easier achievement of anaemia correction in a higher percentage of patients.

Topics: Anemia; Erythropoiesis; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Renal Dialysis

New drugs, recently available for treatment of different forms of anaemia, have somehow changed the therapeutic scenario in paediatric haematology. The aim of this review is to focus on the newest molecules discussing indications, clinical usefulness and related problems. Erythropoietin, the specific growth factor of red cell precursors, is now an established option for anaemia of chronic renal failure, prematurity, bone marrow transplantation and chemotherapy. Anti-CD20 monoclonal antibody, a novel cytotoxic molecule for mature B lymphocytes, has proven to be effective in the treatment of refractory autoimmune cytopenias. Haemoglobin analogues are currently under investigation, in order to obtain a synthetic oxygen-carrier that can substitute blood transfusions. Finally drugs that are able to increase the production of haemoglobin F have been used in thalassemias and haemoglobinopathies. For patients with sickle cell disease, hydroxyurea is no longer an experimental tool; it has given rise to several trials, where it has proven to be effective in terms of both clinical and haematological improvement.

Topics: Adult; Age Factors; Anemia; Anemia, Hemolytic, Autoimmune; Anemia, Sickle Cell; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Antisickling Agents; Blood Substitutes; Bone Marrow Transplantation; Butyrates; Child; Clinical Trials as Topic; Erythropoietin; Fetal Hemoglobin; Forecasting; Hemoglobinopathies; Hemoglobins; Humans; Hydroxyurea; Infant, Newborn; Infant, Premature, Diseases; Kidney Failure, Chronic; Organ Transplantation; Rituximab; Thalassemia; Tissue Donors

Topics: Aldosterone; Calcitriol; Endocrine System Diseases; Erythropoietin; Hormones; Human Growth Hormone; Humans; Kidney Failure, Chronic; Leptin; Parathyroid Hormone

The normal hematocrit is not a random number, but one that maximizes oxygen delivery. While the feedback loop wherein tissue oxygen pressure determines the production of erythropoietin, which further drives the production of red blood cells in the bone marrow, explains how the hematocrit is generated, it does not speak to how the hematocrit is regulated. The regulation of the hematocrit requires the coordination of the plasma volume and the red cell mass. By controlling red cell mass via erythropoietin and plasma volume through excretion of salt and water, the kidney is able to generate the hematocrit. It is hypothesized that the kidney functions as a critmeter by sensing the relative volumes of each component of the blood through the common signal of tissue oxygen tension. The kidney's unique ability to sense ECF volume through tissue oxygen signal allows it to coordinate these two volumes to produce the normal hematocrit. Hence, it may be the kidneys ability to report a measure of ECF volume as a tissue oxygen signal and thus to regulate the hematocrit that establishes it as the logical site of erythropoietin production. The critmeter is proposed to be a functional unit located at the tip of the cortical labyrinth at the juxta-medullary region of the kidney where erythropoietin is made physiologically. Renal vasculature and nephron segment heterogeneity in sodium reabsorption likely provides the anatomical construct to generate the marginal tissue oxygen pressure required to trigger the production of erythropoietin. The balance of oxygen consumption for sodium reabsorption and oxygen delivery is reflected by the tissue oxygen pressure. This balance hence determines RBC mass adjusted to plasma volume. Factors that affect blood supply and sodium reabsorption in a discordant manner may modulate the critmeter, e.g. angiotensin II. The objective of this work is to describe the hypothesis of the kidney's function as a critmeter, including the anatomical and physiological components, and the role of the renin-angiotensin system in modulating erythropoietin. Clinical examples of the dysregulation of the critmeter may be found in the anemia of renal failure and in sports anemia.

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Kidney; Kidney Failure, Chronic; Models, Biological; Oxygen; Plasma Volume; Renin-Angiotensin System; Sports

Since the nineties of the previous century, incidence of pure red-cell aplasia (PRCA) in patients with chronic renal failure (CRF) and renal anaemia treated with recombinant human erythropoietin (rHuEPO) has significantly increased. Due to the positive effects of rHuEPO on quality of life, lowering of morbidity and mortality of patients with CRF, such increased incidence has attained a widespread interest, though PRCA remains only a rare complication. The responsibility for the development of PRCA lies with the neutralizing anti-erythropoietin antibodies. The rise of antibodies and development of PRCA is related to the subcutaneous administration of erythropoietin and in the vast majority of patients to the treatment with Eprex, one of the epoetins alpha. At present, the most probable explanation is a change of the stabilizer in Eprex formulation, which is related to the increased immunogeneity of the product. The subcutaneous administration of rHuEPO, preferred for medical and economical reasons in both American and European guidelines, is known for its higher immunization power. Properties of the product, emphasized by the route of administration, can cause the rise of these antibodies. To prevent the rise of anti-erythropoietin antibodies and the development of PRCA, regulatory authorities and Eprex producers decided that Eprex cannot be administered to CRF patients subcutaneously, but only intravenously. Also the requirements on the handling of Eprex have become more stringent. Limitations do not concern either epoetin beta (NeoRecormon) or other epoetins alpha (of which the latter are not available in this country). Therapy of PRCA in patients treated with rHuEPO is based on suspension of rHuEPO and on the immunosuppressive therapy. Many questions concerning PRCA in CRF patients treated with rHuEPO remain unsolved. It is necessary to study further the ethiopathogenesis of this complication and possibly adjust preventive and therapeutic measures.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Red-Cell Aplasia, Pure

Topics: Anemia; Erythrocytes; Erythropoiesis; Erythropoietin; Evidence-Based Medicine; Humans; Iron; Kidney Failure, Chronic; Practice Guidelines as Topic; Recombinant Proteins

Renal replacement therapy (RRT)--encompassing hemodialysis, peritoneal dialysis, and kidney transplantation--provides life-sustaining treatment for the expanding end-stage renal disease (ESRD) population. There is an excess burden of ESRD in African-American, Hispanic, Native Americans, and Asian/Pacific Islanders. Moreover, there is mounting evidence to suggest that significant racial and ethnic disparities exist in RRT--including referral and initiation of dialysis, adequacy of dialysis, and anemia management--with non-white patients usually at a disadvantage. In addition, there are cultural and sociodemographic differences that lead to racial variation in the choice of ESRD modality. Lastly, in certain ethnic ESRD populations, there are a series of complex issues, from biologic to socioeconomic, which limit kidney transplantation--the treatment of choice. Despite these inequalities, which are often associated with negative outcomes, these non-white groups have better hemodialysis survival rates than white patients. It is essential to develop strategies to address the disparities in ESRD treatment among minority groups in order to minimize the differences in RRT provision and identify the factors that confer improved dialysis survival-thus improving care for all Americans with kidney disease.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Peritoneal Dialysis; Recombinant Proteins; Renal Replacement Therapy

Novel approaches to anemia associated with cancer and chemotherapy are reviewed. Anemia in cancer patients is usually related to treatment with antineoplastic agents or to the disease itself. The normal concentration of endogenous erythropoietin ranges from 0.1 to 0.2 microU/mL and may increase to 2-10 microU/mL in patients with severe anemia. Many cancer patients with anemia do not have an increase in erythropoietin levels, however. Recombinant human erythropoietin (epoetin alfa), the standard for treating anemia caused by chronic renal failure, is also used to treat cancer chemotherapy-related anemia. It resolves anemia, decreases the need for transfusions, and may improve a patient's quality of life. A newer erythropoiesis-stimulating protein, darbepoetin alfa, was initially evaluated in patients with chronic renal disease. In patients who had never taken epoetin alfa, darbepoetin alfa was able to achieve a hemoglobin concentration of 11 g/dL by four weeks in most patients, and 97% of patients maintained on epoetin alfa were successfully switched to the other drug. Similar positive results were achieved in patients with solid tumors receiving chemotherapy, patients with anemia of chronic disease associated with cancer, and patients with lymphoproliferative malignancies. Darbepoetin alfa has a longer half-life than epoetin alfa, enabling less frequent administration. No difference in toxicity between the two agents has been reported. Epoetin alfa and darbepoetin alfa are effective in the treatment of anemia in patients with cancer.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Half-Life; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia, Hypochromic; Disease Progression; Erythropoietin; Humans; Kidney Failure, Chronic; Peritoneal Dialysis; Recombinant Proteins

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Neoplasms

Darbepoetin alfa is a new erythropoiesis-stimulating protein that has five carbohydrate chains compared with three in recombinant human erythropoietin (r-HuEPO, epoetin alfa). Owing to its increased carbohydrate content, the terminal half-life of darbepoetin alfa is 2-3-fold greater than that of r-HuEPO in patients with chronic kidney disease or cancer. This pharmacokinetic property may allow for less frequent administration of darbepoetin alfa compared with r-HuEPO. Although several regimens are still being tested, a predictable increase was observed in serum concentrations of darbepoetin alfa and no clinically relevant accumulation was seen with once-weekly administration for up to 48 weeks. Preliminary data in patients with cancer suggest that concurrent chemotherapy may influence the pharmacokinetics of darbepoetin alfa. Therefore, the timing of dosing relative to chemotherapy may be important. Darbepoetin alfa, through its potential for less frequent dosing, offers a more convenient treatment option than r-HuEPO for patients with anemia secondary to cancer or kidney disease.

Topics: Anemia; Animals; Antineoplastic Agents; Area Under Curve; Biological Availability; Clinical Trials as Topic; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Neoplasms

Anemia of chronic kidney disease (CKD) results primarily from a deficiency of the hormone erythropoietin. Treatment of anemia in the early stages of CKD is essential to reduce the risk of developing anemia-associated complications and to improve health-related quality of life. Treatment with recombinant human erythropoietin (r-HuEPO, epoetin alfa) can correct erythropoietin deficiency and increase red blood cell production, but the short half-life of r-HuEPO necessitates frequent injections. Reducing the frequency of administration has potential benefits for both patients and health care providers. Darbepoetin alfa is a new erythropoietic protein with greater biologic activity and a longer dosing interval than those of r-HuEPO. It has been shown to be effective when administered once/week and once every 2, 3, or 4 weeks, and is well tolerated. With the ability to simplify anemia management by allowing less frequent dosing, darbepoetin alfa offers an effective alternative to r-HuEPO for the treatment of anemia of CKD.

Topics: Anemia; Animals; Clinical Trials as Topic; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Recombinant Proteins

Recombinant human erythropoietin (r-HuEPO, epoetin alfa), is an established and effective treatment for anemia associated with both chronic kidney disease (CKD) and cancer and has improved the management of anemia over alternatives such as transfusion. Darbepoetin alfa is a new erythropoietic agent with a 3-fold longer half-life and increased in vivo potency relative to r-HuEPO. These properties allow patients to be treated with longer dosing intervals than with r-HuEPO. Relative potency between r-HuEPO and darbepoetin alfa is not a fixed relationship but is dependent on several factors. Clinical study results suggest that greater relative potency differences are seen between r-HuEPO and darbepoetin alfa when the dosing intervals are longer and when r-HuEPO dose requirements are higher. Although 200 U of r-HuEPO contains the same peptide mass as 1 microg of darbepoetin alfa, a fixed ratio of 200:1 does not necessarily predict an appropriate dose conversion between the two drugs across the entire spectrum of dose ranges. When converting patients with CKD from r-HuEPO to darbepoetin alfa, dosing should be based on relevant clinical data. Appropriate guidance for conversion of patients with CKD from r-HuEPO to darbepoetin alfa is provided in the approved United States package insert for darbepoetin alfa. In patients who are prescribed darbepoetin alfa, either by conversion from r-HuEPO or as de novo treatment, therapy should begin according to recommendations in the package insert, after which, doses should be titrated individually according to each patient's hemoglobin response. Dosing data from oncology clinical studies, although not necessarily applicable to CKD, indicate similar potency ratios between r-HuEPO and darbepoetin alfa, and in addition affirm the finding that, as the interval between doses of darbepoetin alfa is increased, hemoglobin response is maintained.

Topics: Anemia; Clinical Trials as Topic; Darbepoetin alfa; Drug Administration Schedule; Drug Labeling; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Injections, Intravenous; Kidney Failure, Chronic; Neoplasms; Recombinant Proteins; Therapeutic Equivalency

Patients with chronic kidney disease (CKD) almost invariably develop anaemia, which is associated with increased morbidity and mortality, and reduced quality of life. Anaemia begins early in the course of CKD, and although treatment with erythropoietin is effective, the condition is often under-treated. Because of the growing body of scientific literature on the significant morbidity and mortality associated with anaemia of CKD, a Renal Anaemia Management Period (RAMP) was proposed. This is defined as the time after onset of CKD when anaemia develops and requires early diagnosis and treatment. The RAMP was developed to call attention to the need to improve outcomes for patients with CKD and possibly lower the economic burden by correcting anaemia earlier. It is an important opportunity for preventive care and has the potential to limit costs associated with comorbidities of CKD.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Treatment Outcome

Anemia is a common complication of chronic renal insufficiency, one that leads to a reduced quality of life and an increased burden on the heart. In recent years, it has been shown that anemia is underrecognized and undertreated in these patients. The benefits of recombinant human erythropoietin treatment in this patient population have been well shown. The major side effect, hypertension, is particularly important in chronic renal insufficiency, requiring careful monitoring. In this review, the benefits of anemia therapy are weighed against the risks and costs. On balance, it is concluded that anemia treatment meets a basic and important health need in these patients.

Topics: Anemia; Drug Monitoring; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins

Recent epidemiologic studies show that iron deficiency occurs in the vast majority of patients with chronic kidney disease (CKD). In patients with CKD, increased iron losses and, to a lesser extent, poor oral absorption, can lead to iron-deficiency anemia. Correction of iron-deficiency anemia is preferable by the oral route, however, data on oral iron use are limited in this population. In CKD patients, parenteral iron administered with recombinant human erythropoietin (rHuEpo), is the best potential option for the correction of anemia. Nondextran iron preparations are preferable because of a reduced incidence of serious adverse events. Parenteral iron in CKD patients may not be entirely innocuous and, although commonly used, have not received Food and Drug Administration approval for use in this patient population. Exposure to intravenous (IV) iron may lead to oxidative stress, renal injury, infection, cardiovascular disease, and osteomalacia. Studies are needed to confirm the existence and magnitude of these complications. The current data suggest that the overall risk-benefit ratio favors use of IV iron when compared with untreated or partially treated iron-deficiency anemia.

Topics: Anemia, Iron-Deficiency; Clinical Trials as Topic; Erythropoietin; Humans; Infections; Iron; Kidney Failure, Chronic; Oxidative Stress; Recombinant Proteins

Darbepoetin alfa (Aranesp, Amgen, Inc., Thousand Oaks, California) is a new erythropoietic protein that corrects anaemia associated with chronic kidney disease (CKD) in the majority of patients. Darbepoetin alfa contains five N-linked carbohydrate chains compared with three in recombinant human erythropoietin (rHuEPO). The two additional sialic acid-containing carbohydrate chains prolong the serum half-life of darbepoetin alfa, resulting in greater biological activity and a reduced dosing frequency compared with rHuEPO. Clinical studies in patients with CKD have demonstrated that darbepoetin alfa is effective in correcting anaemia in rHuEPO-naive patients and in patients who have been converted from rHuEPO therapy. Darbepoetin alfa provides long-term maintenance of haemoglobin levels when administered once weekly or once every other week, with the possibility of once-monthly dosing in some patients. Darbepoetin alfa is well tolerated and has a safety profile similar to that of rHuEPO. Owing to its half-life being three times longer than rHuEPO, darbepoetin alfa can be administered at an extended dosing interval, without compromising efficacy. Lessfrequent dosing has potential benefits for both patients with CKD and healthcare providers. These benefits include reduced visits to the clinic, fewer injections and a reduced demand on staff and treatment facilities.

Topics: Anemia; Animals; Darbepoetin alfa; Erythropoietin; Humans; Kidney Failure, Chronic

Although the benefits of recombinant human erythropoietin (rHu EPO) administration in dialysis patients have been demonstrated the optimal frequency regimen has not as yet been established. Treatment with rHu EPO is expensive, there is therefore a need for optimising the efficiency of its administration.. The objectives of this review were to assess the effects of different frequency regimens of rHu EPO administration in dialysis patients in terms of i) effectiveness (correction of anaemia, quality of life and freedom from adverse events) ii) efficiency (optimal resource use) of different rHu EPO dose regimen policies.. We searched MEDLINE (1980 to May Week 3 2001), EMBASE (1984 to Week 24 2001), BIOSIS (1985 to January 1997), CINAHL (1982 to October 1997), The Cochrane Library (Issue 1, 1997), CHEMABS (1984 to November 1996), SIGLE (1980 to June 1996), CRIB (10th edition, 1995), UK NRR (14th consolidation, September 1996), RSC ( 1980 to February 1997), HealthSTAR (1995 to October 1997), IBSS (1984 to July 1997), NEED (July 1997) and reference lists of relevant articles. We contacted biomedical companies and investigators in the field and we hand searched Kidney International (including all supplements but excluding all conference proceedings except for 1994) July 1983 to May 1997 inclusive. The Internet was also searched on: August 1997. We had also identified some studies from a previous broad search for all randomised controlled trials (RCTs) relevant to the management of end-stage renal disease. Date of the most recent search: June 2001.. All randomised or quasi randomised controlled trials comparing different frequencies of rHu EPO administration in dialysis patients. Subgroup analyses were performed comparing haemodialysis and CAPD patients and also subcutaneous and intravenous administration.. Only published data were used. Data were abstracted by a single investigator on to a standard form. The data abstracted were relevant to the predetermined outcome measures: measures of correction of anaemia, rHu EPO dose, quality of life measures, adverse events, number of withdrawals from study, mortality. Where appropriate, a summary relative risk (RR) was calculated for dichotomous data and a weighted mean difference (WMD) or standardised mean difference (SMD) for continuous data.. Eight studies met our inclusion criteria. When once a week administration was compared with twice weekly there was no significant difference in the ability to maintain the target haemoglobin (RR 1.00, 95% CI 0.42 to 2.40). Mean haemoglobin after twelve weeks of therapy was not different between the two groups (WMD -0.21g/dl, 95% CI -0.98 to 0.56). No difference was found in mean haemoglobin or haematocrit at the end of any studies which compared once with thrice weekly administration of rHu EPO (SMD -0.31, 95% CI -0.67 to 0.06). A single study which compared once with more that thrice weekly administration showed no significant difference in mean haemoglobin at the end of the maintenance phase (mean difference -0.2g/dl, 95% CI -0.65 to 0.25). The dosage of erythropoietin required by those on haemodialysis receiving rHu EPO once weekly was just significantly more (WMD 12.0 U/kg, 95% CI 0.24 to 23.76) than those receiving it twice weekly but the confidence interval is wide. No such difference was found for CAPD patients nor when the results were combined (WMD 5.15 U/kg, 95% CI -3.74 to 14.05). The result was not significant when comparing once weekly with thrice weekly administration (WMD 10.00 U/kg, 95% CI -80.87 to 100.87). There was no difference in the frequency of adverse events between any of the groups studies.. There is no significant difference between once weekly versus thrice weekly subcutaneous administration of rHu EPO. Once weekly administration of rHu EPO would require an additional 12U/kg/week for patients on haemodialysis, however this is based on one very small study. The cost of this additional hRu EPO nee, however this is based on one very small study. The cost of this additional hRu EPO needs to assessed, in particular with regard to patient preference and compliance.

Topics: Anemia; Drug Administration Schedule; Erythropoietin; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis

Chronic kidney disease (CKD) affects over 6.2 million people in the U.S. and most commonly results from diabetes and/or hypertension. Patients with CKD have an increased risk of anemia and hypertension. Anemia occurs early in CKD and can be effectively treated with epoetin alfa. Hypertension can be managed with lifestyle modifications and medications. Nurses play a vital role in managing these patients by providing early CKD/anemia screening and intervention, education, patient monitoring, and support for patients and caregivers.

Topics: Algorithms; Anemia; Decision Trees; Diabetes Complications; Erythropoietin; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Life Style; Mass Screening; Nurse's Role; Quality Assurance, Health Care; Risk Factors; Severity of Illness Index; United States

Anemia management programs typically strive to maintain hemoglobin (Hb) levels in the target range of 11 to 12 g/dL recommended by the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI). Although nephrology clinicians are constantly alert for conditions that cause hyporesponse to Epoetin alfa therapy, management protocols generally focus on assessing and managing acute disorders that affect the production of red blood cells. A more difficult clinical challenge is how to systematically manage patients with conditions that chronically affect the erythropoietic response and are intractable to routine therapies. This article addresses the etiology and management of chronic conditions that require a specialized anemia management approach to ensure that patients can achieve targeted Hb levels and associated clinical and quality of life benefits. Examples include chronic inflammatory disorders, severe secondary hyperparathyroidism, malignancies, human immunodeficiency virus (HIV), and kidney transplant failure.

Topics: Aged; Anemia; Chronic Disease; Erythropoiesis; Erythropoietin; Female; HIV Infections; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Neoplasms

The effectiveness of anemia management in patients with end stage renal disease (ESRD) has increased over the past 4 years. However, approximately 26% of treated patients still do not meet the minimum hemoglobin (Hgb) value of 11 g/dl that is recommended by the K/DOQI Clinical Practice Guidelines (National Kidney Foundation [NKF], 2001). One of the main obstacles to good patient outcome may be iron deficiency, which is common in both the predialysis and dialysis period. Since iron is needed for Hgb synthesis, iron depletion exacerbated anemia and reduces the response to recombinant erythropoietin (rEPO) therapy. Health care providers can significantly improve patient outcome by addressing iron deficiency more rigorously. A good starting point is the establishment of an iron deficiency management protocol that includes early evaluation of iron status and aggressive iron therapy. Iron therapy, in turn, can be optimized by administering safe and effective iron supplements and by implementing maintenance iron regimens to prevent the recurrence of iron deficiency. By making these simple improvements to their treatment approach, clinicians can enhance the effectiveness of anemia management in patients with ESRD.

Topics: Algorithms; Anemia, Iron-Deficiency; Decision Trees; Drug Monitoring; Erythropoietin; Ferritins; Hemoglobins; Humans; Iron Compounds; Kidney Failure, Chronic; Patient Care Planning; Renal Dialysis; Transferrin

In renal failure, severe anemia and associated fatigue, cognitive and sexual dysfunction have a significant impact on the patient's quality of life. Anemia has also been identified as an important etiologic factor in the development of left ventricular hypertrophy. The major cause of anemia in presence of a reduction of glomerular filtration rate is an inadequate production of a glycoprotein hormone, the erythropoietin (EPO). EPO is the primary regulator of the growth and survival of erythroid progenitor. The introduction of recombinant human erythropoietin (rHuEPO) has revolutionized the treatment of anemia in chronic renal failure. The vast majority of patients respond very well to treatment, but 5-10% of patients show some resistance to EPO, the most common cause of which is iron deficiency. Several studies are recently commenced to investigate the effects of preventing renal anemia ever developing. The target of hemoglobin concentration in pre-dialysis and dialysis patients are object of continuous re-examinations.

Topics: Anemia; Animals; Cardiovascular Diseases; Disease Progression; Dogs; Drug Resistance; Erythropoietin; Hemodynamics; Hemoglobins; Humans; Iron Deficiencies; Kidney Failure, Chronic; Quality of Life; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Anaemia is an important component of diabetic nephropathy but only recently has it attracted the attention of diabetologists and nephrologists. In diabetic patients, anaemia is the result of diminished erythropoietin production and, to a lesser degree, of increased excretion of erythropoietin in the urine, whereas erythropoietin responsiveness remains unchanged. Although erythropoietin concentrations are predictive of the rate of progression of renal disease, epidemiological studies have failed to show lower haemoglobin concentrations in patients with diabetic compared with non-diabetic renal disease with impaired renal function. However, inappropriately low erythropoietin concentrations and anaemia have been reported in subcohorts of diabetic patients. Further studies are required to determine whether reversal of anaemia has beneficial effects on microvascular and macrovascular diabetic complications, particularly cardiac disease, retinopathy and peripheral arterial disease.

Topics: Anemia; Chronic Disease; Diabetes Mellitus; Diabetic Nephropathies; Erythropoietin; Humans; Kidney Diseases; Kidney Failure, Chronic; Prevalence

Topics: Age Factors; Databases, Factual; Diabetic Nephropathies; Diet, Protein-Restricted; Erythropoietin; Female; Glomerulonephritis; Humans; Internet; Japan; Kidney Failure, Chronic; Male; Morbidity; Prognosis; Reference Standards; Renal Dialysis; Sex Factors; Time Factors

Topics: Anemia; Apoptosis; Erythropoietin; Fibrosis; Humans; Hypoxia; Kidney Failure, Chronic; Kidney Tubules; Models, Biological; Oxidative Stress; Recombinant Proteins

Darbepoetin alfa is a super-sialylated analog of human erythropoietin that has a longer circulating half-life in vivo compared to both native and recombinant hormone. It has the same mechanism of action as erythropoietin, stimulating the same surface membrane receptor and triggering the same intracellular chain of events. An extra two N-linked carbohydrate chains, however, gives darbepoetin alfa greater metabolic stability in vivo, and its terminal half-life after intravenous administration is approximately three times longer than for intravenous erythropoietin. This in turn allows injections of the drug to be given less frequently, and studies have shown that once-weekly and once-every-other-week dosing can maintain the hemoglobin concentration in patients with renal anemia. The recommended starting dose for darbepoetin alfa is 0.45 microg/kg once weekly for both IV and SC administration, with subsequent titration based on the hemoglobin concentration. The adverse event profile is very similar to that seen with rHuEPO, and no antibodies have been detected in several thousand patients exposed to the drug, some of whom have been treated for up to five years now. Following a clinical research program that began in November 1996, darbepoetin alfa was finally approved by the European Commission in June 201, and by the FDA in September 201.

Topics: Anemia; Animals; Antibodies; Darbepoetin alfa; Drug Evaluation, Preclinical; Erythropoietin; Humans; Kidney Failure, Chronic

Anaemia occurs earlier and is more severe in diabetic patients with end-stage renal disease (ESRD) than in non-diabetic ESRD patients controlled for the same level of renal function. In contrast to non-diabetic patients, diabetic ESRD patients demonstrate an impaired physiological response to anaemia; endogenous serum erythropoietin levels are low in relation to the level of anaemia. The reasons for the anaemia are probably a combination of tubulointerstitial damage and autonomic neuropathy. The use of angiotensin-converting enzyme inhibitors, which has been reported to be associated with an inhibition of erythropoiesis, does not seem to have a clinically significant effect on haemoglobin levels. In order to address all the independent risk factors in diabetic ESRD, optimal management of these patients should involve interdisciplinary care (diabetologist and nephrologist) and consideration of correction of anaemia.

Topics: Anemia; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic

Much needs to be achieved in improving survival and quality of life for chronic renal failure patients. Progress in attaining this goal may accrue from attention to underlying pathophysiologic processes early and throughout a person's life. The endocrine perturbations described in this article--alterations in the homeostasis of phosphorus, calcium, vitamin D and parathyroid hormone; erythropoietin deficiency; and sexual dysfunction in uremia--provide good examples for the need to identify early and manage prospectively over time manifestations of chronic renal failure. The complexity of the skeletal and extraskeletal sequelae of dysregulated mineral metabolism and the complications of chronic anemia have been discussed, while stressing possible implications of these endocrine abnormalities for both morbidity and mortality. There is a great need for more randomized clinical trials to evaluate new and old treatment approaches, with the goal of developing better evidence-based practice guidelines.

Topics: Calcium; Erythropoietin; Female; Hormones; Humans; Infertility; Kidney Failure, Chronic; Male; Parathyroid Hormone; Phosphorus; Sexual Dysfunction, Physiological; Vitamin D

Topics: Aged; Anemia; Chronic Kidney Disease-Mineral and Bone Disorder; Clinical Trials as Topic; Disease Progression; Electrolytes; Epidemiologic Methods; Erythropoietin; Hemodialysis Solutions; Humans; Hypertension; Kidney Failure, Chronic; Male; Models, Biological; Nutrition Disorders; Quality of Life; Renal Dialysis; Toxins, Biological; Uremia

Topics: Combined Modality Therapy; Comorbidity; Diet, Protein-Restricted; Diet, Sodium-Restricted; Disease Progression; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Humans; Hypertension; Kidney Diseases; Kidney Failure, Chronic; Kidney Function Tests; Prognosis; Renal Dialysis; Vasculitis; Water-Electrolyte Balance

In many patients with chronic renal insufficiency a depletion of stored and cellular iron (absolute iron deficiency), a blockade of iron in body stores (functional iron deficiency) or an iron overload can be shown. The factors leading to absolute iron deficiency are: 1) loss of iron as a result of blood loss by the gastrointestinal tract, taking blood specimens for laboratory tests and related to dialytic procedure; 2) enhanced use of iron during intensive erythropoiesis stimulated by recombinant human erythropoietin; 3) dietary iron deficiency or impaired iron uptake from the gastrointestinal tract; 4) other forms of gastrointestinal tract impairment; 5) pharmaceutical substances forming inabsorbable iron complexes and/or diluting the acidity of the gastric juice; 6) certain demographic factors. Functional iron deficiency develops during treatment with recombinant human erythropoietin and in the infectious state and during the inflammatory process. The use of recombinant human erythropoietin accelerates erythropoesis and by so increases iron requirement frequently far higher than the ability of iron stores to "transfer" iron to the bone marrow--this may be a result of ineffective mobilisation of iron stores and/or ineffective transport. In the infectious process the use of iron is impaired because of augmented cytokines production which leads to increase iron uptake and storage in the reticulo-endothelial system. Iron overload is caused by excessive iron intake, e.g. parenteral iron administration or repeated blood transfusions.

Topics: Erythropoietin; Humans; Iron; Iron Deficiencies; Iron, Dietary; Kidney Failure, Chronic; Recombinant Proteins

More than a decade has passed since the first patient with end-stage renal failure was treated with erythropoietin (EPO) and more than 85% of patients now receive this therapy. In the year 2002 more than 60% of dialysis patients will be elderly, and the treatment of anemia will be more complex due to the aditional causes: folate, iron and vitamin deficiency in this population. Correction of anemia with EPO brings about partial regression of left ventricular hypertrophy and some data suggest that such treatment reduces cardiovascular mortality in patients without advance cardiac disease. Normalization of hematocrit with EPO increases oxygen supply to the brain tissue with improvement in brain function. The improvement in the ability to recognize, discriminate and hold stimuli in memory for difficult tasks is particularly important for elderly people. No differences have been noted in the incidence of clotting of vascular access in patients treated with EPO compared with hemodialysis patients not so treated. Also no one has demostrated that treatment with EPO accelerates renal decline in patients with progressive renal insufficiency. In elderly people with anemia secondary to advanced renal failure, EPO therapy improves physical, cognitive and sexual function, and health related quality of life.

Topics: Age Factors; Aged; Aged, 80 and over; Anemia, Iron-Deficiency; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Prognosis; Quality of Life; Renal Dialysis; Risk Assessment; Treatment Outcome

Evidence suggests that an individualized and flexible approach may be beneficial to end-stage renal disease (ESRD) patients. This article discusses this approach in relation to three issues: target haemoglobin (Hb) level, epoetin dosing frequency/administration and patient management/education programmes. Trial data indicate that each patient's condition should be taken into account when assigning target Hb values. Normalization of Hb is unlikely to be protective in patients with well-established cardiac disease. However, in patients without severe cardiac conditions, normalization is associated with benefits, such as reduction of cardiovascular risk factors and improved quality of life. Data are awaited from trials examining the impact of anaemia correction in patients not yet on renal replacement therapy (RRT). Two large, randomized controlled trials of haemodialysis patients have demonstrated that once-weekly epoetin beta is as effective and as well tolerated as administration two or three times weekly. Additionally, one of these trials showed that once-weekly and three times weekly administrations were equivalent therapeutically in terms of maintaining both stable haematocrit levels and epoetin beta dose requirements. These results suggest that the epoetin beta route and frequency of administration can be individualized according to patient/physician preference. Renal management programmes, which incorporate a multidisciplinary team approach, strategies for early referral of patients and patient education, have an impact on patient outcomes and on RRT modality choice. An individualized programme will help to optimize the use of treatments aimed at delaying the progression of renal failure and its co-morbidities. In conclusion, evidence suggests that an individualized and flexible approach to target Hb values, epoetin beta route and frequency of administration, and patient education/management programmes may be beneficial to patients with ESRD. As early intervention has an impact on patient outcome and the progression of risk factors, this approach may also be appropriate for patients who are not yet receiving RRT.

Topics: Anemia; Drug Administration Schedule; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; Renal Replacement Therapy; Treatment Outcome

The relationship between haemoglobin (Hb) level and survival in patients with chronic kidney disease (CKD) is complex. This paper explores the physiological basis for the hypothesis that Hb level and survival are causally related in this patient group, and assesses the current state of knowledge from clinical studies. Issues related to the methodology and analysis of clinical studies limit the certainty with which conclusions regarding the direct relationship between Hb level and survival can be drawn. The data support the concepts that Hb level is associated with survival in patients both with and without CKD, that changes in Hb level are associated with cardiovascular disease (CVD), and that CVD is prevalent in patients with CKD. Hb level is affected by nutritional status, inflammation, and the availability and effectiveness of human recombinant erythropoietin (rHuEPO) therapy, as well as by the degree of kidney function. Thus, the complexity of the relationships between Hb level, CVD and survival in patients with CKD requires further study from both the mechanistic and the clinical perspective. Properly designed clinical trials with survival as an endpoint, as well as data from prospectively measured modifiers of Hb levels and other markers of CVD, are needed to determine the physiological and statistical interaction of these factors in clinical practice.

Topics: Apoptosis; Coronary Disease; Erythropoietin; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Survival Analysis

Preoperative autologous blood donation has served as a model for blood loss anaemia. Studies in these patients, along with clinical trials of i.v. iron and recombinant human erythropoietin (rHuEPO) therapy, have furthered our understanding of the relationship between erythropoietin, iron, and erythropoiesis. With supplemental oral iron, the endogenous erythropoietic response to routine autologous blood donation and to the anaemia of chronic illness has been shown to be modest, but predictable. In more aggressive donation and more severe anaemia, the endogenous erythropoietic response is more substantial, but still predictable. Studies in patients undergoing aggressive phlebotomy whilst receiving rHuEPO demonstrate a wide variation in response to rHuEPO dose. This variability is not related to age or gender and suggests factors such as iron-restricted erythropoiesis may be responsible. Supporting evidence arises from the superior erythropoietic response observed in patients with haemochromatosis. These patients maintain very high serum iron and transferrin saturation levels. In response to serial phlebotomy these patients can mount an endogenous erythropoietin response up to five-times greater than healthy individuals. When treated with rHuEPO, patients with haemochromatosis respond with much greater RBC expansion volumes than patients receiving rHuEPO and iron supplementation. Studies show no difference in the degree of endogenously stimulated erythropoiesis between patients with measurable iron stores and those without. However, when treated with rHuEPO, increased erythropoiesis has been observed in patients with measurable iron stores compared with those without. This suggests that, while oral iron supplementation may be sufficient to keep pace with endogenously stimulated erythropoiesis, it may not be adequate to prevent iron-restricted erythropoiesis during rHuEPO therapy. Some studies have suggested that i.v iron may prevent iron-restricted erythropoiesis during rHuEPO therapy although further research is needed. The availability of better tolerated i.v. iron preparations provides an ideal opportunity to study the value of iron therapy in patients with acute blood loss, particularly those undergoing rHuEPO therapy.

Topics: Anemia; Dietary Supplements; Erythropoiesis; Erythropoietin; Humans; Iron; Kidney Failure, Chronic; Recombinant Proteins

In most patients with chronic kidney disease, provision of sufficient human recombinant erythropoietin (rHuEPO) and iron replacement therapy will effectively correct renal anaemia. Folate deficiency has been implicated as a contributory factor in renal anaemia and hyporesponsiveness to rHuEPO treatment. As such, the necessity of regular folate supplementation has been debated over the last decade. Although folate loss through dialysis is greater than by urinary excretion, these losses are easily balanced by a normal mixed diet containing 60 g protein/day. Thus, unless patients show significant folate depletion, additional supplementation of folic acid does not appear to have a beneficial effect on erythropoiesis or on responsiveness to rHuEPO therapy. However, a diagnosis of folate deficiency should be considered in patients with chronic renal insufficiency and significant elevation in mean cell volume or hypersegmented polymorphonuclear leucocytes; in patients with malnutrition or a history of alcohol abuse, or in patients hyporesponsive to rHuEPO treatment, especially when accompanied by macrocytosis. Measurements of serum folate are not necessarily indicative of tissue folate stores and red blood cell (RBC) folate measures provide a more accurate picture. Low RBC folate concentrations in these patients indicate the need for folate supplementation. Folate supplementation can also reduce elevated levels of homocysteine in dialysis patients, which may contribute to the high cardiovascular morbidity prevalent in these individuals. High-dose folate therapy (5-15 mg/day) has been shown to reduce plasma homocysteine levels by 25-30% and appears to be well tolerated provided the patient has adequate vitamin B(12) stores. Although long-term benefits of this intervention for cardiovascular protection and patient survival have yet to be established, folic acid is considered a relatively non-toxic and well-tolerated vitamin.

Topics: Anemia; Dietary Supplements; Erythropoietin; Folic Acid; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Hyperparathyroidism is usually listed among the possible reasons for impaired response to recombinant human erythropoietin (rHuEPO) in patients with renal disease. However, its relevance in the context of other causes of renal anaemia, and the mechanisms by which it may worsen anaemia, are not entirely clear. Possible pathogenic links between anaemia and parathyroid hormone (PTH) include reduced erythropoiesis due to calcitrol deficiency, and direct or indirect effects of PTH on erythropoietin release, red blood cell (RBC) production, survival, and loss. Studies of these mechanisms have produced disparate results, possibly because secondary hyperparathyroidism may have only a relatively minor role in anaemia that may be masked by the confounding effects of other factors with greater impact. Variations in medical treatment or study methodology may also have affected study results. Severe parathyroid overfunction may contribute to the severity of anaemia in uraemic patients and diminish rHuEPO responsiveness in a minority of patients. However, overall, the importance of hyperparathyroidism appears to be minor compared with other factors such as iron deficiency or inflammation.

Topics: Anemia; Drug Resistance; Erythropoietin; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Osmotic Fragility; Parathyroid Hormone; Parathyroidectomy; Treatment Failure

End-stage renal disease (ESRD) is characterized by a high mortality rate, derived largely from cardiovascular disease (CVD). In patients with ESRD, high levels of pro-inflammatory cytokines and increased oxidative stress are common features that may contribute to malnutrition, anaemia, recombinant human erythropoietin (rHuEPO) resistance, and atherosclerosis. Inflammation predicts poor outcome in ESRD. It is multifactorial in cause and, while it may reflect the underlying CVD, the acute-phase response may also contribute to both oxidative stress and progressive vascular injury. In patients with ESRD, the acute-phase response may be influenced by a number of factors unrelated to dialysis and perhaps by the dialysis procedure itself. Inflammation and the acute-phase response interact with the haematopoietic system at several levels resulting in reduced erythropoiesis, accelerated destruction of erythrocytes, and blunting of the reactive increase in erythropoietin in response to reduced haemoglobin levels. In patients with ESRD, rHuEPO resistance has been linked with inflammation, the latter of which is often associated with a state of functional iron deficiency. Patients with ESRD are thought to have a reduced capacity to handle oxidative stress. There is recent evidence that a relationship may exist between inflammation and oxidative stress and treatment of anaemia with rHuEPO. However, iron may also generate oxidative stress. Controlled trials are needed before evidence-based recommendations for the management of inflammation-induced anaemia and resistance to rHuEPO can be defined.

Topics: Anemia; Cardiovascular Diseases; Cytokines; Drug Resistance; Erythropoietin; Humans; Inflammation; Kidney Failure, Chronic; Oxidative Stress; Recombinant Proteins; Treatment Failure

Suboptimal response to recombinant human erythropoietin (rHuEPO) is common in a substantial percentage of patients with chronic kidney disease. Consequently, a higher dose of rHuEPO is needed to attain target haematocrit (Hct) in such patients. Variables that affect rHuEPO dose requirements can be broadly divided into modifiable and immutable characteristics. To date, most of the scientific studies on rHuEPO hyporesponsiveness have focused on modifiable variables that affect rHuEPO response, such as iron status and dialysis adequacy, while exploration of immutable variables has received less attention. This review addresses the key immutable variables that have been suggested as potential determinants of rHuEPO dose requirement. Several investigators, on the basis of analysis of large patient databases, have suggested that diabetic individuals, women, and Black patients on haemodialysis (HD) require a higher dose of rHuEPO than their respective counterparts to attain target Hct. It is unclear whether the observed differences in achieved Hct are due to inherent biological differences in responsiveness to rHuEPO or failure of the investigators to account for modifiable variables that affect rHuEPO dose requirement. Protocol studies with specific a priori hypotheses have failed to confirm some of the findings from these large database analyses. Factors, such as nutritional status, pregnancy, duration of end-stage renal disease, and type of HD vascular access can all potentially modulate response to rHuEPO and should also be considered.

Topics: Age Factors; Dose-Response Relationship, Drug; Erythropoietin; Female; Hematocrit; Humans; Kidney Failure, Chronic; Male; Nutritional Status; Recombinant Proteins; Renal Dialysis; Sex Characteristics

Iron supplementation is essential for adequate response to recombinant human erythropoietin (rHuEPO) or darbepoetin alfa. Oral iron therapy is often ineffective as the quantity of iron absorbed after oral intake may be insufficient to keep pace with the demands of rHuEPO-stimulated erythropoiesis in patients with end-stage renal disease (ESRD). Currently available i.v. iron preparations include dextran, iron gluconate, and iron sucrose. As rare, but serious, adverse reactions to i.v. iron dextran have been reported, alternative preparations may be preferred. Careful monitoring of iron parameters is required to avoid the effects of over-treatment. Renal anaemia and iron therapy are associated with oxidative stress, leading to a shortening of the lifespan of red blood cells (RBC) and resistance to rHuEPO. rHuEPO therapy may also enhance oxidative stress on RBC. Oxidative stress can be attenuated or prevented by supplementation with vitamin E or melatonin. Vitamin E therapy has also been shown to have a rHuEPO-sparing effect. Disturbances of carnitine metabolism may contribute to the development of renal anaemia in ESRD patients. Oral or i.v. L-carnitine therapy results in an increase in haematocrit and a significant decrease in rHuEPO requirement in HD patients. As yet, there is no general recommendation for L-carnitine supplementation for ESRD patients with renal anaemia.

Topics: Anemia; Carnitine; Dietary Supplements; Erythropoietin; Humans; Iron; Kidney Failure, Chronic; Oxidative Stress; Recombinant Proteins

Iron supplementation is probably the most important factor affecting response to treatment with recombinant human erythropoietin (rHuEPO) in patients with renal anaemia. However, the adequacy of dialysis is also significant. Many factors affect the process of dialysis and its effects. The purity of water used to make up the dialysate from concentrate is important. Inhibitors of erythropoiesis including ions and disinfectants may often be present in treated mains water. In addition, microbiological and pyrogenic contamination of the dialysate frequently occurs, sometimes leading to development or aggravation of anaemia in haemodialysis (HD) patients and also causing an immune response via cytokine activation. Inhibitors of erythropoiesis are also present in endogenous blood in patients with impaired renal function. Adequate dialysis is responsible for removing these mainly small, and possibly medium and large inhibitor molecules, thereby improving anaemia and enhancing response to rHuEPO. The biocompatibility and flux of the membrane used in HD may also have an effect. The removal of medium or large inhibitors of erythropoiesis is inefficient with cellulose membranes, but can potentially be achieved by using more permeable, high-flux membranes. However, in patients with adequate dialysis and sufficient iron and vitamin supplementation, the beneficial effects of a switch from standard cellulose to high-flux membranes have yet to be proven conclusively. Another area in which positive results on correction of anaemia have been seen in small studies is in the use of on-line haemodiafiltration, haemofiltration, or sterile dialysate. However, further large, controlled studies are needed to confirm these effects.

Topics: Anemia; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Renal Replacement Therapy

Erythropoietic agents have transformed the management of renal anaemia. Two forms of recombinant human erythropoietin (rHuEPO) have been available since the early 1990s, and more recently, a second-generation erythropoietic agent, darbepoetin alfa, has been granted a licence for treating this condition. The endogenous erythropoietin molecule may contain anything from 4 to 14 sialic acid residues. The various isoforms have different biological potencies in vivo owing to their different metabolic clearance rates. However, there is a continuing debate about those organs potentially involved in the metabolism of the erythropoietin molecule; the kidneys, liver, and bone marrow have all been suggested as possible participants. Darbepoetin alfa contains two extra N-linked glycosylation consensus sequences increasing the potential maximum number of sialic acid residues from 14 up to 22. In vitro, the affinity of darbepoetin alfa for the erythropoietin receptor is less than for the natural ligand, but this is more than compensated for by the increased potency in vivo. One of the most important factors determining the biological activity of erythropoiesis-stimulating agents is the length of time that the serum concentration of the protein remains above the threshold necessary for erythropoiesis. The pharmacokinetic profile of darbepoetin alfa is distinct from that of rHuEPO, the major difference being the much longer elimination half-life and slower clearance in vivo of darbepoetin alfa leading to prolonged erythropoietic activity. Stimulation of erythropoiesis depends both on an ambient circulating level of erythropoietin and on the mechanisms governing the interaction of the hormone with its receptor. Our knowledge regarding the latter is limited and it is difficult to predict the optimum frequency of administration for an erythropoietic agent. In general, rHuEPO is given two or three times weekly. A small number of studies have supported the once-weekly use of rHuEPO. All clinical trials so far conducted on darbepoetin alfa have demonstrated success with once-weekly and once every other week dosing.

Topics: Anemia; Bone Marrow; Darbepoetin alfa; Erythropoietin; Humans; Kidney; Kidney Failure, Chronic; Liver; Metabolic Clearance Rate; Recombinant Proteins; Tissue Distribution

Topics: Anemia; Erythropoietin; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic

Anemia associated with end stage renal disease can diminish quality of life substantially. Maintaining a stable hematocrit and stable hemoglobin levels affords many advantages. Improvement of anemia management is possible with the implementation of continuous quality improvement (CQI). Our review of the literature motivated us to switch from iron dextran injection, which can induce anaphylactic reactions and has other associated problems, to sodium ferric gluconate complex injection. This enables us to safely provide iron supplementation without the precautions that were in place for iron dextran. Our methods for creating and implementing CQI in the dialysis program at our university hospital are described.

Topics: Algorithms; Anaphylaxis; Anemia, Iron-Deficiency; Decision Trees; Erythropoietin; Ferric Compounds; Ferritins; Hemoglobins; Humans; Iron-Dextran Complex; Kidney Failure, Chronic; Outcome and Process Assessment, Health Care; Practice Guidelines as Topic; Renal Dialysis; Total Quality Management; Transferrin

Anemia is a frequent problem in patients with chronic kidney disease (CKD) who are not yet receiving dialysis and can lead to major health complications is left untreated. The successful management of these patients entails repletion of iron stores, often through use of intravenous iron, particularly in patients receiving erythropoietin therapy. To encourage patient compliance with anemia management protocols, the nephrology nurse can play a key role in patient education in reducing barriers to proper management and in raising the awareness of the benefits of treating this condition.

Topics: Algorithms; Anemia, Iron-Deficiency; Creatinine; Decision Trees; Drug Monitoring; Erythropoietin; Ferrous Compounds; Hematocrit; Humans; Kidney Failure, Chronic; Nurse's Role; Patient Education as Topic; Renal Dialysis; Risk Factors

The National Kidney Foundation Kidney Disease Outcomes Quality Initiative and other groups support maintaining transferrin saturation (TSAT) levels above 20% and serum ferritin levels above 100 ng/ml to ensure adequate erythropoiesis in hemodialysis patients receiving erythropoietin. However, researchers have found that even patients with TSATs above 20% may still have functional iron deficiency. This article presents information that supports the fact that maintenance of TSATs between 30% and 50%, through the use of continuous intravenous iron therapy, results in improvement of anemia, reduction in erythropoietin dose requirements, and an increase in the reticulocyte hemoglobin content. The implications of these findings for clinical practice are also discussed.

Topics: Algorithms; Anemia, Iron-Deficiency; Clinical Protocols; Decision Trees; Drug Monitoring; Erythropoietin; Evidence-Based Medicine; Ferritins; Humans; Iron-Dextran Complex; Kidney Failure, Chronic; Renal Dialysis; Total Quality Management; Transferrin; Treatment Outcome

The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative recommends a target hemoglobin (Hb) level of 11 to 12 g/dL (hematocrit [Hct] of 33% to 36%) for both peritoneal dialysis and hemodialysis patients. However, national tracking data indicate that peritoneal dialysis patients have consistently lower Hb/Hct levels. This article focuses on anemia management challenges that are unique to the peritoneal dialysis population. Nursing knowledge and management of Epoetin alfa dosing and administration techniques, peritonitis and other infections, and iron supplementation may help improve anemia-related outcomes in peritoneal dialysis patients.

Topics: Adult; Anemia, Iron-Deficiency; Drug Monitoring; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hematocrit; Hemoglobins; Humans; Iron Compounds; Kidney Failure, Chronic; Male; Middle Aged; Patient Compliance; Peritoneal Dialysis; Recombinant Proteins; Total Quality Management

Topics: Adaptation, Physiological; Anemia; Cardiovascular System; Cognition Disorders; Drug Costs; Epoetin Alfa; Erythropoietin; Exercise; Heart Failure; Hematocrit; Hemodynamics; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Iron; Kidney Failure, Chronic; Multicenter Studies as Topic; Practice Guidelines as Topic; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Reference Values; Renal Dialysis; Risk; Thrombophilia; Treatment Outcome

Topics: Adult; Aged; Anemia; Child; Comorbidity; Drug Costs; Epoetin Alfa; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Multicenter Studies as Topic; Myocardial Infarction; Occupations; Peritoneal Dialysis; Physical Fitness; Practice Guidelines as Topic; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Reference Values; Renal Dialysis; Thrombophilia; Treatment Outcome

Topics: Anemia; Appointments and Schedules; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Kinetics; Models, Biological; Molecular Weight; Patient Acceptance of Health Care; Quality of Life; Renal Dialysis; Survival Analysis; Time Factors; Treatment Outcome; Urea

Topics: Anemia; C-Reactive Protein; Drug Resistance; Erythropoietin; Humans; Inflammation; Kidney Failure, Chronic

Recombinant human erythropoietin (rHuEPO) has revolutionized the treatment of anemia of chronic renal failure. RHuEPO has been shown to increase survival, decrease hospitalizations, improve brain and cognitive function, and improve quality of life for renal patients. Much has been learned about the normal and pathologic physiology of anemia because rHuEPO has become available to investigators, and this has been widely applied. Additional work is needed in better defining the sites of production of endogenous EPO as well as the nature and control of the oxygen sensor(s) in the kidney. Remaining clinical issues related to this remarkable compound include predicting and overcoming resistance; avoiding iron deficiency; determining the appropriate target hemoglobin; increasing the use strategies such as subcutaneous administration to increase efficiency; and devising a more rational payment scheme.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anaphylaxis; Anemia; Comorbidity; Drug Therapy, Combination; Erythropoietin; Humans; Iron-Dextran Complex; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Anaemia is a common occurrence in patients with cancer and contributes to the clinical symptomatology and reduced quality of life (QOL) seen in cancer patients. Many aspects of reduced QOL, including fatigue, are known to be associated with suboptimally low levels of haemoglobin. Even mild-to-moderate anaemia adversely affects patient-reported QOL parameters. Red blood cell transfusions are associated with many real and perceived risks, inconveniences, costs, and only temporary benefits. Recombinant human erythropoietin (rHuEPO) is an effective therapy to increase haemoglobin values in over half of anaemic cancer patients receiving concurrent chemotherapy. These increased haemoglobin values are closely correlated with improvements in QOL. Despite these objectively defined benefits, less than 50% of anaemic patients undergoing cytotoxic chemotherapy receive rHuEPO, in contrast to patients with chronic renal failure on dialysis, where anaemia is universally and aggressively treated to more optimal haemoglobin values. However, there are several barriers that may limit more widespread use of rHuEPO. These include inconvenience associated with frequent dosing; failure of a large proportion (40 to 50%) of patients to respond; relatively slow time to response; absence of reliable early indicators of response; and current lack of rigorous pharmacoeconomic data demonstrating cost-effectiveness. Darbepoetin alfa is a novel erythropoiesis stimulating protein (NESP) that is biochemically distinct from rHuEPO, and which has been proven to stimulate red blood cell production. The molecule has a 3-fold longer half-life and increased biological activity that will allow less frequent dosing, facilitating improved management of the anaemia of cancer. With this new option for therapy, further avenues of investigation should lead to renewed interest in the clinical benefits of optimal haemoglobin levels for patients with cancer.

Topics: Anemia; Antineoplastic Agents; Case Management; Clinical Trials as Topic; Darbepoetin alfa; Erythrocyte Transfusion; Erythropoietin; Fatigue; Forecasting; Health Care Costs; Humans; Hypoxia; Incidence; Kidney Failure, Chronic; Multicenter Studies as Topic; Neoplasms; Quality of Life; Radiation Tolerance; Recombinant Proteins; Treatment Outcome

Studies on human erythropoietin (EPO) demonstrated that there is a direct relationship between the sialic acid-containing carbohydrate content of the molecule and its serum half-life and in vivo biological activity, but an inverse relationship with its receptor binding affinity. These observations led to the hypothesis that increasing the carbohydrate content, beyond that found naturally, would lead to a molecule with enhanced biological activity. Hyperglycosylated recombinant human EPO (rHuEPO) analogues were developed to test this hypothesis. Darbepoetin alfa (novel erythropoiesis stimulating protein, NESP), which was engineered to contain five N-linked carbohydrate chains (two more than rHuEPO), has been evaluated in preclinical animal studies. Due to its increased sialic acid-containing carbohydrate content, NESP is biochemically distinct from rHuEPO, having an increased molecular weight and greater negative charge. Compared with rHuEPO, it has an approximately 3-fold longer serum half-life, greater in vivo potency, and can be administered less frequently to obtain the same biological response. NESP is currently being evaluated in human clinical trials for treatment of anaemia and reduction in its incidence.

Topics: Animals; Darbepoetin alfa; Erythropoietin; Glycosylation; Hematocrit; Humans; Kidney Failure, Chronic; Molecular Structure; Protein Isoforms; Recombinant Proteins; Renal Replacement Therapy

Novel erythropoiesis stimulating protein (NESP, also known as darbepoetin alfa) is a molecule that stimulates erythropoiesis by the same mechanism as both native and recombinant human erythropoietin (rHuEPO). The extra sialic residues on NESP, however, allow it to be more stable in vivo with a 2- to 3-fold longer elimination half-life. Thus, following intravenous administration, the mean elimination half-life of NESP is 25.3 vs 8.5 h for rHuEPO. After subcutaneous administration, the mean terminal half-life for NESP is 48.8 h. The mean bioavailability of NESP after subcutaneous administration is approximately 37%, similar to that reported for rHuEPO. The pharmacokinetic data suggested that patients with renal anaemia would require less frequent dosing with NESP than with rHuEPO. NESP 0.45 microg/kg administered once weekly either intravenously or subcutaneously has been evaluated for the correction of chronic renal failure (CRF)-associated anaemia. The study population included CRF patients not receiving dialysis, along with those on haemodialysis or peritoneal dialysis. In patients who are rHuEPO-naïve, NESP has a similar effect in correcting the anaemia as is seen with rHuEPO, but with less frequent dosing. Similarly, in patients previously receiving rHuEPO, NESP (whether administered intravenously or subcutaneously) is as effective as rHuEPO treatment for maintaining haemoglobin concentration when administered at a reduced frequency (i.e. either once weekly or once every other week). NESP is well tolerated, adverse effects are similar to those seen with rHuEPO, and no antibodies have been detected in >1500 patients exposed to NESP thus far.

Topics: Anemia; Biological Availability; Darbepoetin alfa; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Replacement Therapy; Safety; Uremia

Many patients with chronic diseases such as chronic renal failure, chronic inflammatory bowel disease and rheumatoid arthritis are anaemic. Recently congestive heart failure (CHF) has also been found to be associated with anaemia. In all these diseases this anaemia or chronic disease is at least partially due to excessive production of cytokines and leukotrines that interfere both with the effect of erythropoietin (EPO) at the bone marrow and the release of stored iron in the reticuloendothelial system. Treating this anaemia with subcutaneous EPO and IV iron improves the weakness, fatigue, cachexia, nutritional state, mood, cognitive function and quality of life. In the case of CHF it also improves cardiac function and patient functional class, prevents deterioration of renal function and markedly reduces hospitalization. Very few agents in medicine improve so many aspects of the patient so well and so quickly. Unfortunately (for the suffering patient) this anaemia is often ignored and goes untreated.

Topics: Anemia; Cardiac Output, Low; Chronic Disease; Erythropoietin; Humans; Iron; Kidney Failure, Chronic; Recombinant Proteins

Provision of sufficient available iron is a prerequisite to ensure the optimal response to recombinant human erythropoietin (rHuEpo). Functional iron deficiency (a state when iron supply is reduced to meet the demands for increased erythropoiesis) is the common cause of rHuEpo hyporesponsiveness in dialysis patients who have normal iron status, even when they are iron-overloaded. Iron supplementation is not justified for this hyporesponsiveness in patients with iron overload due to the potential hazards of iron overload aggravated by intravenous iron therapy. Furthermore, in vivo studies indicated that the promising effect of intravenous iron medication to overcome iron-deficient erythropoiesis is not observed in iron-overloaded haemodialysis (HD) patients. Ascorbic acid, a water-soluble antioxidant as well as a reducing agent, has a number of associations with iron metabolism. Recent research highlights that ascorbic acid can potentiate the mobilization of iron from inert tissue stores and facilitates the incorporation of iron into protoporphyrin in iron-overloaded HD patients being treated with rHuEpo. Interest has turned towards the use of ascorbic acid as an adjuvant therapy in this field. This review focuses on the improvement of rHuEpo response by administration of ascorbic acid and discusses its clinical implications and potential issues for nephrologists.

Topics: Ascorbic Acid; Drug Synergism; Erythropoietin; Humans; Injections, Intravenous; Iron; Kidney Failure, Chronic; Recombinant Proteins

The optimal hematocrit target range in children with end-stage renal disease, who are receiving recombinant human erythropoietin, is ambiguous due to the lack of compelling, age-appropriate studies. There are a large number of adult and pediatric studies which show that physical performance as well as morbidity and mortality are positively influenced by partial normalization of the hematocrit to 30 vol% to 36 vol%. Cognition studies performed in adults similarly show improvement with partial correction of hematocrit. Normalization of hematocrit studies show lower mortality rates, incremental further improvement in cognition, and greater resolution of cardiac anomalies when compared with patients with partial correction of anemia. Conversely, cardiac death rates may increase in adult patients receiving hemodialysis with preexisting cardiac disease, and there are concerns about the effect of recombinant human erythropoietin on catheter/shunt/fistula patency and on blood pressure. The high cost of recombinant human erythropoietin and established Medicare and Dialysis Outcomes Quality Initiative target hematocrit ranges have also influenced pediatric nephrologists in their assessment of the risk-benefit ratios, despite new adult data suggesting that maintenance of higher hematocrits may be cost-effective. The rationale of using adult-derived hematocrits in children with end-stage renal disease needs to be re-examined in the context of the unique growth and developmental requirements of children. A prospective, multicenter study which determines the relative benefits and risks of age-adjusted hematocrit normalization in children with renal failure is warranted.

Topics: Anemia; Child; Cognition; Erythropoietin; Heart; Heart Diseases; Hematocrit; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; Renal Dialysis

Topics: Anemia; Drug Resistance; Erythropoietin; Extracorporeal Circulation; Hemodiafiltration; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Cardiac diseases account for almost 50% of deaths in long-term dialysis patients. Left ventricular dysfunction is present in approximately 80% of these patients and is highly predictive of future ischemic heart disease, cardiac failure, and death. Anemia has been identified as one of several risk factors responsible for cardiac complications. Cardiovascular consequences of renal anemia begin relatively early in the course of renal failure and progress with the decline of renal function and also during dialysis therapy. In chronic renal failure patients with severe anemia (hemoglobin levels <10 g/dL), increased cardiac output, high left ventricular mass, left ventricular end-diastolic and end-systolic diameters, and cardiac symptoms improve after partial correction of anemia (hemoglobin levels >11 g/dL according to the European Best Practice Guidelines). It is disappointing that normalization of hemoglobin levels has only minor effects with respect to regression of left ventricular hypertrophy and left ventricular dilation. There is no benefit of hemoglobin normalization on all-cause mortality of dialysis patients or on survival of end-stage renal disease patients with congestive heart failure or ischemic heart disease. Therefore, prevention of renal anemia may be more efficient than its treatment. Hypertension is one of the major side effects of recombinant human erythropoietin (rHuEPO) therapy. Multiple factors are involved in rHuEPO-induced hypertension. High blood pressure can usually be controlled readily in the majority of the patients.

Topics: Anemia; Cardiovascular Diseases; Comorbidity; Erythropoietin; Hematocrit; Humans; Hypertension; Incidence; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Despite the publication of National Kidney Foundation and European Best Practice Guidelines, there is still uncertainty among nephrologists regarding the optimum target haemoglobin (Hb) concentration for patients treated with erythropoietin. For most patients, the target Hb concentration is 11-12 g/dl, resulting in only partial correction of anaemia. However, there is a link between subnormal Hb concentration and the development of cardiovascular disease. Thus, it may be more beneficial to normalize Hb, although this has to be balanced against the concern that full correction of anaemia may result in adverse effects, such as hypertension and progression of renal disease. There is increasing evidence that it may be appropriate to treat each patient individually, and to tailor treatment according to a number of physiological and lifestyle variables, avoiding higher Hb concentrations in certain patient groups (such as those with cardiac problems). This was supported by the results of a survey of nephrologists and specialists in the field of renal anaemia. It was generally agreed that a higher target Hb concentration (12-14 g/dl) might be appropriate for a fit, young patient with no significant co-morbidity, whereas a lower target Hb (10-12 g/dl) might be appropriate for an elderly patient with multiple medical problems. In conclusion, guidelines for target Hb in the US and Europe are probably not applicable to all patients. It is important that renal anaemia patients are considered as individuals, and their treatment tailored accordingly. It is time to establish evidence-based criteria for individualizing renal anaemia treatment.

Topics: Anemia; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Osmolar Concentration

Anaemia is a frequent complication of many diseases but the mechanisms that link reduced blood oxygen content to the long-term consequences of anaemia are incompletely understood. The maintenance of oxygen supply to the tissues during anaemia involves complex cardiovascular adaptations, including an increase in cardiac output, reduced peripheral resistance and increased oxygen extraction from haemoglobin (Hb). In addition, hypoxia-inducible factors are associated with the transcriptional activation of genes involved in adaptive mechanisms that increase oxygen delivery and provide alternative metabolic pathways. The complex pathophysiology of chronic kidney disease alters the adaptations to anaemia in uraemic patients. The increased cardiac output induced by anaemia is associated with left ventricular hypertrophy and cardiac disease in renal patients. Alterations in endothelial cell function, common in renal disease, may diminish endothelium-induced vasodilatation, increase the risk of atherosclerosis and impair angiogenesis. Many potential reasons for erythropoietin-induced hypertension in uraemic patients have been postulated, including increased blood viscosity as haematocrit rises, a reversal of hypoxic vasodilatation, increased blood volume that is not compensated by haemodialysis, ultrafiltration and impaired nitric oxide synthesis, preventing vascular relaxation in response to increased blood viscosity. In view of this impaired vascular reactivity, rapid increases in haematocrit should be avoided during epoetin treatment. As the interaction between anaemia and uraemia is very complex, it is not possible to derive the optimal Hb concentration for individual patients by using simple physiological or pathophysiological models and there is a need for good randomized controlled clinical trials to address this issue.

Topics: Adaptation, Physiological; Anemia; Arteries; DNA-Binding Proteins; Erythropoietin; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Failure, Chronic; Nuclear Proteins; Oxygen; Transcription Factors

The introduction of recombinant human erythropoietin (rh-Epo, epoetin) as a treatment for the anaemia of renal failure has transformed the management of this condition. Nevertheless, a significant number of patients fail to respond. There are many different possible causes of inadequate response to epoetin. Iron deficiency, whether absolute or functional, is considered to be the most important, and it is widely accepted that maintaining adequate iron levels reduces rh-Epo dosage requirement and improves efficacy in haemodialysis patients. Infection and inflammation have been shown to influence responsiveness to rh-Epo by disrupting iron metabolism and eliciting the release of cytokines that inhibit erythropoiesis. Another factor for consideration is severe hyperparathyroidism, which can lead to a reduced number of responsive erythroid progenitor cells. Inadequate dialysis can also negatively impact on rh-Epo therapy, and aluminium overload interferes with iron metabolism and reduces the efficacy of rh-Epo. Deficiencies in vitamin B(12), folic acid and potentially vitamin C can all reduce the efficacy of treatment with rh-Epo. Optimizing patient response to rh-Epo therapy, therefore, requires consideration of many factors, some well established and others that are more controversial, and the list continues to grow with the identification of new factors.

Topics: Anemia; Drug Resistance; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Treatment with recombinant human erythropoietin (rHu EPO) in dialysis patients has been shown to be highly effective in terms of correcting anaemia and improving quality of life. There is debate concerning the benefits of rHu EPO use in pre-dialysis patients. There is a concern that rHu EPO may accelerate the deterioration in renal function, however the opposing view is that if rHu EPO is as effective in pre-dialysis patients that by improving the patients sense of well-being the onset of dialysis could be delayed.. To assess the effects of rHu EPO use in pre-dialysis patients with renal anaemia.. We searched MEDLINE (1980 to May Week 3 2001), EMBASE (1984 to Week 24 2001), BIOSIS (1985 to January 1997), CINAHL (1982 to October 1997), The Cochrane Library (Issue 1, 1997), CHEMABS (1984 to November 1996), SIGLE (1980 to June 1996), CRIB (10th edition, 1995), UK NRR (14TH consolidation, September 1996), RSC ( 1980 to February 1997), HealthSTAR (1995 to October 1997), IBSS (1984 to July 1997), NEED (July 1997) and reference lists of relevant articles. We contacted biomedical companies and investigators in the field and we hand searched Kidney International (including all supplements but excluding all conference proceedings except for 1994) July 1983 to May 1997 inclusive. The internet was also searched on: August 1997. We had also identified some studies from a previous broad search for all randomised controlled trials (RCTs) relevant to the management of end-stage renal disease. Date of the most recent search: June 2001.. RCTs or quasi-RCTs comparing the use of rHu EPO with no rHu EPO or placebo in pre-dialysis patients.. Only published data were used. Data were abstracted by a single investigator onto a standard form. A sample of the data abstracted was double-checked by another reviewer. The data abstracted were relevant to the predetermined outcome measures. Some authors were contacted to clarify how patients were allocated to groups. All authors from included studies were contacted for missing information.. Twelve studies with a total of 232 participants met the inclusion criteria and where possible data from these were summated by meta-analyses (Peto's Odds Ratio (OR) and Weighted Mean Difference (WMD)). The majority of the trials included small numbers and were of short duration (8-10 weeks) with the exception of three trials. There was a marked improvement in haemoglobin (mean difference 2.3g/dL, 95% CI 1.37 to 3.23) and haematocrit (WMD 9.92%, 95% CI 8.78 to 11.05) with the treatment and a decrease in the number of patients requiring blood transfusion (OR 0.25, 95% CI 0.09 to 0.69). The data from all studies which reported quality of life or exercise capacity demonstrated an improvement in the rHu EPO group. None of the measures of progression of renal disease (when a summary statistic was calculated) demonstrated a statistically significant difference. Though the requirement for antihypertensive treatment appears to be increased by rHu EPO (OR 1.84, 95% CI 1.02 to 3.32), there was no other statistically significant increase in adverse events. Based on the limited current evidence, decisions therefore have to be made on whether the putative benefits in terms of quality of life identified in the review are worth the extra costs of pre-dialysis rHu EPO.. This review has shown that treatment with rHu EPO in pre-dialysis patients corrects anaemia and avoids the requirement for blood transfusions. There are also improvements in quality of life and exercise capacity. There may be increased hypertension. Most of the trials were not of sufficient duration to assess the effects of rHu EPO on progression of renal disease. In the long term, questions still remain about whether pre-dialysis rHu EPO either speeds up or delays the onset of dialysis. Thus there is insufficient evidence on the total costs and benefits of treating pre-dialysis patients with rHu EPO.

Topics: Anemia; Disease Progression; Erythropoietin; Humans; Kidney Failure, Chronic; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins

Availability of recombinant human erythropoietin (rHuEPO) has improved the treatment of anemia due to chronic kidney disease (CKD). Iron deficiency is the most common cause of resistance to rHuEPO therapy, contributing to ineffective erythropoiesis and hematocrit/hemoglobin values below the recommended target range (33%-36%/11-12 g/dL). I.v. iron supplementation is necessary to meet increased iron demands from stimulation of erythropoiesis and chronic blood loss; however, questions remain as to the optimal supplementation strategy to maintain appropriate yet safe iron status. Treatment guidelines for anemia management have been developed through the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI).. This review presents the basis of need for the NKF-K/DOQI guidelines and includes detailed information concerning iron physiology, metabolism, iron preparations, and evaluation of iron status.. This review was based on a MEDLINE search and complemented by references from the NKF-K/DOQI guidelines (whose review extended beyond MEDLINE). References focusing on normal iron physiology and metabolism, alterations in iron physiology in patients with CKD, laboratory evaluation methods, and strategies for iron supplementation were obtained from MEDLINE and reviewed for content.. Controversy over appropriate use of iron supplementation has led to disparity in accepted practice procedures. Oral iron (ferrous salts and polysaccharide iron complex) and i.v. iron preparations (iron dextran, sodium ferric gluconate, and iron sucrose) are available. Problems with oral iron supplementation include limited absorption and patient noncompliance. Although most available data on i.v. iron use in the United States are specific to iron dextran preparations, published information based on clinical use of sodium ferric gluconate and iron sucrose products has been promising. The use of chronic i.v. iron administration to sustain iron stores has been more widely accepted to prevent development of absolute and functional iron deficiency.. Although iron therapy is commonly warranted in patients with CKD, questions remain as to the most favorable supplementation strategy to optimize therapy through improvements in hematocrits, efficient use of rHuEPO, and maintenance of appropriate and safe iron levels. Clinicians will need to devise strategies based on the compilation of information from clinical experience and the available literature. Clinical practice guidelines devised by the NKF-K/DOQI have provided a useful tool for the medical community using both these resources.

Topics: Anemia; Bone Marrow; Dietary Supplements; Erythropoietin; Ferritins; Humans; Injections, Intravenous; Iron; Iron Compounds; Kidney Failure, Chronic; MEDLINE; Models, Biological; Practice Guidelines as Topic; Renal Dialysis; Transferrin

Topics: Anemia; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Neoplasms; Recombinant Proteins

Darbepoetin alfa is a novel erythropoiesis-stimulating protein developed for the treatment of anaemia associated with chronic kidney disease. In single-dose studies in patients undergoing dialysis, the mean terminal half-life for intravenous darbepoetin alfa was approximately 3-fold longer than for intravenous recombinant human erythropoitin (r-HuEPO, epoetin alfa; 25.3 vs 8.5 hours). The mean terminal half-life after subcutaneous administration of darbepoetin alfa was 48.8 hours. In randomised nonblind trials in patients undergoing dialysis, darbepoetin alfa (0.45 pg/kg) given once weekly for the correction of anaemia increased haemoglobin (Hb) levels to a similar extent as darbepoetin alfa three times weekly or r-HuEPO two or three times weekly. A double-blind, randomised clinical trial reported that switching patients from a three-times weekly regimen of r-HuEPO to once weekly darbepoetin alfa with additional placebo twice weekly (all intravenously) maintained Hb levels between 9.0 and 13.0 g/dl to a similar extent as continued treatment with r-HuEPO three times weekly. In a randomised nonblind study, r-HuEPO-naive patients with chronic renal insufficiency received either subcutaneous darbepoetin alfa once weekly or r-HuEPO twice weekly. 93% of patients receiving darbepoetin alfa and 92% of patients receiving r-HuEPO achieved a Hb increase of > or = 1.0 g/dl from baseline and the mean increase in Hb level over the initial 4 weeks was similar for both treatments. The number and frequency of adverse events, withdrawals and deaths reported in clinical trials did not differ between patients receiving darbepoetin alfa and patients receiving r-HuEPO. There have been no reports of immune responses to darbepoetin alfa in 1534 patients receiving treatment for up to 2 years.

Topics: Anemia; Darbepoetin alfa; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Half-Life; Hemoglobins; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Treatment Outcome

The management of anemia in patients with end-stage renal disease (ESRD) treated with peritoneal dialysis (PD) has gained increasing attention over the past decade, similar to patients on hemodialysis (HD). However, there are many differences between the 2 renal replacement therapies that pose unique challenges and solutions for monitoring, diagnosis and treatment of anemia in PD patients. These differences are not always evident and may be the result of different patient selection, physical, emotional and motivational factors, specific requirements of the modality or an indeterminate blend of infinite gradations of all these factors. This review will highlight current issues in anemia management in PD patients.

Topics: Anemia; Erythropoietin; Ferritins; Humans; Infusions, Intravenous; Iron; Iron-Dextran Complex; Kidney Failure, Chronic; Peritoneal Dialysis; Recombinant Proteins; Transferrin

Androgens were the mainstay of treatment of renal anemia prior to the introduction of recombinant human erythropoietin. With the introduction of this recombinant hormone, the protocols of treatment of anemia were completely modified, and the use of androgens was relegated to the background. However, several authors have continued showing interest in the use of androgenic steroids for the treatment of anemia. This review examines several aspects of aging on androgenic hormones and hematopoiesis, the effects of androgen administration on hematological parameters, the side effects of these compounds and the future of this treatment for anemia in renal patients.

Topics: Aged; Aging; Androgens; Anemia; Drug Therapy, Combination; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Stimulation of red blood cell precursors by Epoetin alfa results in a predictable, dose-dependent increase in red blood cell mass. Iron is an important substrate that supports red blood cell and hemoglobin development. Patients who receive Epoetin alfa therapy typically require intravenous iron supplementation to ensure proper red cell formation. Target and ceiling iron levels should be determined on the basis of safety considerations, the predicted clinical response, and individual patient replacement needs. Nurses can use clinical parameters such as body weight, baseline and target hemoglobin values, and iron losses from blood and other sources to estimate iron replacement doses, thereby providing a guide for appropriate iron replacement.

Topics: Anemia, Iron-Deficiency; Body Weight; Dose-Response Relationship, Drug; Drug Monitoring; Drug Therapy, Combination; Epoetin Alfa; Erythrocyte Indices; Erythropoiesis; Erythropoietin; Ferritins; Hematinics; Hematocrit; Hemoglobins; Humans; Infusions, Intravenous; Iron Compounds; Iron Overload; Kidney Failure, Chronic; Nurse's Role; Nursing Assessment; Recombinant Proteins; Renal Dialysis; Safety Management; Transferrin

Since many end stage renal disease (ESRD) patients experi inflammation, malnutrition, and anemia, the interplay of these processes should be considered in the approach to patients treated with erythropoietin (EPO). This article reviews the interrelationship between these factors. The systemic inflammatory response caused by exposure to inflammatory stimuli results in anorexia and metabolic disturbances leading to protein calorie malnut tion as well as sequestration of iron and hyporesponsiveness to EPO. The implications of these effects and possible strategies to optimize anemia management in the presence of these conditions are discussed.

Topics: Anemia, Iron-Deficiency; Clinical Protocols; Drug Monitoring; Erythropoietin; Ferritins; Hematinics; Humans; Iron; Iron-Binding Proteins; Iron-Dextran Complex; Kidney Failure, Chronic; Nutritional Status; Nutritional Support; Protein-Energy Malnutrition; Risk Factors; Systemic Inflammatory Response Syndrome; Treatment Outcome

Intravenous iron is required by most dialysis patients receiving erythropoietin (EPO) to maintain an adequate hematocrit. In the United States, there are currently two parenteral iron preparations, iron dextran and iron gluconate, approved for such use, and a third product, iron sucrose, is under development. This article reviews each of these products. Each of the iron products increases the efficacy of EPO use in anemia management. There is considerable experience in the United States and elsewhere with the use of iron dextran. Although it is clinically effective, iron dextran is also associated with significant morbidity from both dose-dependent and -independent side effects. The slow release of iron from this complex necessitates a delay in monitoring iron indices after the administration of large doses of iron dextran. Recommended doses of iron sucrose appear very safe with little risk of anaphylactic reactions. Adverse effects are uncommon and not life threatening. If approved for use in the United States, iron sucrose may be a safe and effective alternative to iron dextran. Iron dissociates from iron gluconate quite rapidly and may increase the production of ionized free iron. Iron gluconate may be a safe alternative to iron dextran for patients with severe reactions, including anaphylaxis. The risk of allergic reactions to iron gluconate is very low. The exact place in therapy for the newer iron complexes remains unclear. Currently available data suggest that iron sucrose and iron gluconate may have diminished adverse effect profiles when compared with iron dextran. Additional clinical experience will establish the role for these new iron products.

Topics: Anemia, Iron-Deficiency; Erythropoietin; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Humans; Infusions, Intravenous; Iron-Dextran Complex; Kidney Failure, Chronic; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis

Erythropoietin has been demonstrated to improve the quality of life in patients with chronic renal failure, and growth hormone has been approved for use in children with chronic renal failure and short stature as a growth promoting agent. Growth factors also have great therapeutic potential to improve glomerular function in the setting of chronic renal failure. Further studies are required to delineate the role of insulin-like growth factor I in the setting of end-stage chronic renal failure.

Topics: Animals; Child; Erythropoietin; Glomerular Filtration Rate; Growth Substances; Human Growth Hormone; Humans; Kidney Failure, Chronic

Topics: Anemia; Antineoplastic Agents; Diphosphonates; Erythropoietin; Humans; Kidney Failure, Chronic; Multiple Myeloma; Recombinant Proteins

The treatment of porphyria cutanea tarda (PCT) in patients with chronic renal failure poses a therapeutic challenge. In the absence of renal failure, phlebotomy and oral antimalarials have been the standard of care for PCT. However, in the presence of renal failure, associated chronic anemia often precludes the use of phlebotomy, and oral antimalarials are usually ineffective. We describe a patient with severe symptomatic PCT and chronic renal failure whose disease was successfully managed with a combination of high-dose erythropoietin and small volume phlebotomy. We also review several previously reported approaches to management of PCT in the setting of renal failure, which include small repeated phlebotomy, erythropoietin, deferoxamine, chloroquine, plasma exchange, high-efficiency/high-flux hemodialysis, cholestyramine, charcoal hemoperfusion, and kidney transplantation. An algorithm for the management of these patients is proposed.

Topics: Adult; Algorithms; Erythropoietin; Female; Humans; Iron Overload; Kidney Failure, Chronic; Phlebotomy; Porphyria Cutanea Tarda; Renal Dialysis

Normochromic normocytic anemia regularly develops in chronic renal failure when the glomerular filtration rate drops below 20-30 ml/min. The reasons include: 1) a moderately reduced red cell life span, 2) blood loss, and 3) an inadequate increase in erythropoiesis relative to the fall in hemoglobin (Hb). The life-span of red blood cells may be shortened by their reduced resistance to mechanical, osmotic or oxidative stress, as well as by extracorpuscular factors. Blood loss results from dialysis, diagnostic sampling and, in particular, occult gastrointestinal bleeding. The predominant cause of inadequate erythropoiesis is a failure to increase erythropoietin (EPO) production in response to the developing anemia. Experience with recombinant EPO has shown that relative EPO deficiency is the key cause of the anemia and that the response of hematopoietic progenitor cells is not usually diminished in renal failure. However, reduced iron availability, inadequate dialysis, infection and hyperparathyroidism can all impair the efficacy of EPO. Therapeutic use of EPO has also shown clearly for the first time that anemia is responsible for a significant proportion of morbidity in patients with chronic renal failure and probably also contributes to increased mortality through its cardiovascular complications.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Renal Dialysis

Erythropoietin (EPO) has revolutionized the treatment of anemia in renal failure patients, both in the pre- and postdialysis phase. Not only does the treatment improve well being, but also it positively influences cardiac function and permits cardiac hypertrophy to regress. EPO can lead to an increase in blood pressure; the mechanisms of this effect are not entirely clear. By optimizing dialysis treatment, paying close attention to volume regulation, giving EPO subcutaneously and in a fashion to increase hematocrit gradually, the occurrence of blood pressure increases can be minimized. Hypertension has not proved to be a serious general problem in the EPO treated patient.

Topics: Anemia; Animals; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Renal Dialysis

The aim of this paper is to review the emerging evidence supporting erythropoietin therapy in improving the long-term prognosis of patients with renal failure, by correcting underlying anaemia.. This paper reviews and discusses data from several large retrospective databases containing the demographic and treatment details of many thousands of patients with renal insufficiency. Each investigation selected for review used appropriate statistical methodologies to determine the effects of erythropoietin on morbidity and mortality.. There is a clear link between anaemia and the development of cardiovascular dysfunction. This is an important finding given that more than 90% of patients become anaemic as a consequence of renal failure. Database analysis has also shown that treatment of anaemic dialysis patients with erythropoietin significantly reduces mortality, often by more than 20%, primarily through effects on the cardiovascular system. In addition, improvements in the exercise capacity and quality of life of patients have been observed despite many patients entering dialysis with a considerable burden of ill health, particularly cardiovascular dysfunction.. Retrospective database analyses have provided a clear understanding of the advantageous effects of erythropoietin treatment on morbidity and mortality in patients with end-stage renal disease. The implications of these findings for further improving treatment strategies in patients with renal insufficiency point to erythropoietin use before the onset of dialysis.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Morbidity; Risk Factors

Cardiovascular disease (CVD) is a major cause of death in patients with chronic renal failure (CRF). It is well recognised that dialysis patients have a high burden of factors that predispose to CVD. What is less clear is the extent of this problem in the pre-dialysis patient. This is the subject of this review.. The role of potentially correctable cardiovascular risk factors in pre-dialysis patients has been examined using published data.. Anaemia is a major cardiovascular risk factor in patients with CRF. Partial correction of renal anaemia with recombinant human erythropoietin leads to improvements in cardiac dysfunction in such patients, such as alleviation of left ventricular hypertrophy. Secondly, malnutrition and inflammation have also been recently identified as potentially correctable cardiovascular risk factors in these patients.. Patients continue to enter dialysis with a considerable cardiovascular burden, many having already suffered a stroke or myocardial infarction. Many risk factors, including malnutrition and inflammation, account for the increased incidence of cardiovascular events. Anaemia is common in pre-dialysis patients, and early corrective treatment may help to reduce the incidence of CVD and hence improve long-term outcome.

Topics: Cardiovascular Diseases; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Risk Factors

Better anemia management has dramatically improved the lives of many patients with end stage renal disease (ESRD). Nephrology professionals frequently use two tools--erythropoietin and supplemental iron--to manage anemia. The National Kidney Foundation Dialysis Outcomes Quality Initiative (NKF-DOQI) suggests that most ESRD patients will need intravenous (i.v.) iron to optimize their response to erythropoietin. In this report, the author reviews published studies showing that i.v. iron reduces erythropoietin dose requirements, resulting in cost savings. She presents data from her center illustrating that i.v. administration of the newly approved Ferrlecit (sodium ferric gluconate) also improves anemia management and reduces erythropoietin dose requirements. The author reviews studies showing the efficacy of i.v. iron as monotherapy for anemia in ESRD patients. These data support the importance of i.v. iron as an agent to be used alone or in conjunction with erythropoietin in the management of anemia in patients with ESRD.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Iron-Deficiency; Cost Savings; Drug Administration Schedule; Drug Costs; Drug Monitoring; Erythropoietin; Female; Ferric Compounds; Humans; Injections, Intravenous; Kidney Failure, Chronic; Renal Dialysis; Time Factors

Topics: Anemia; Apoptosis; Erythropoietin; Hematocrit; Hemolysis; Humans; Kidney Failure, Chronic; Peritoneal Dialysis; Recombinant Proteins; Uremia

Topics: Anemia; Antineoplastic Agents; Blood Transfusion, Autologous; Erythropoietin; Humans; Kidney Failure, Chronic; Neoplasms; Renal Dialysis

Since the introduction of recombinant human erythropoietin (rHuEPO) into clinical nephrology practice 10 years ago, there has been a slow increase in hemoglobin (Hgb) levels, but most patients with the anemia of chronic renal failure are still moderately anemic and have not achieved the target Hgb (11 to 12 g/dL) recommended by the NKF-DOQI anemia guidelines. Functional iron deficiency, insufficient rHuEPO doses and comorbid factors such as inflammation/infection have been the major reasons for not achieving this target. By optimizing iron stores with regular infusions of intravenous iron in the hemodialysis patient (who has significant blood [iron] losses related to the hemodialysis procedure), and giving adequate amounts of rHuEPO, preferably subcutaneously instead of intravenously, the NKF-DOQI recommended target Hb can be achieved in the majority of patients so treated.

Topics: Anemia, Iron-Deficiency; Clinical Trials as Topic; Erythropoietin; Female; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Practice Guidelines as Topic; Prognosis; Recombinant Proteins; Renal Dialysis; Treatment Outcome; United States

Topics: Administration, Oral; Anemia, Iron-Deficiency; Erythropoietin; Female; Humans; Injections, Intravenous; Iron; Kidney Failure, Chronic; Male; Outcome Assessment, Health Care; Prognosis; Recombinant Proteins; Renal Dialysis; Treatment Outcome

It has been 10 years since epoetin-alpha was approved by the federal Food and Drug Administration for use in end-stage renal disease patients. Over this period of time, clinical studies have shown a relationship between the correction of anemia and improved cardiac function, cognitive ability, sexual function, and exercise capacity. Recent large epidemiological studies have shown that mortality and morbidity are reduced when the hematocrit (Hct) level is in the range 33% to 36%, and the National Kidney Foundation's Dialysis Outcomes Quality Initiative (NKF-DOQI) guidelines recommend a target Hct of 33% to 36% to enhance patient outcomes. The most recent mortality studies show that Hcts less than 30% (or hemoglobins less than 110 gm/L) are associated with an 18% to 40% increased associated risk of death and hospitalizations. Higher Hcts in the 33% to 36% range appear to be associated with a 7% reduced risk of death and hospitalizations compared with patients with Hcts of 30% to less than 33%. Patients with sustained Hcts of 33% to 36% over 1 year appear to have the best outcome compared with patients with Hcts that fall. These studies suggest that the factors that may influence patients' ability to move into higher Hct ranges need to be determined to enhance patient outcomes. Dramatic improvement in hemodialysis patient Hct levels has occurred since 1989. Mortality and hospitalization studies support the NKF-DOQI target Hct range of 33% to 36% as providing the best associated outcomes.

Topics: Anemia, Iron-Deficiency; Erythropoietin; Female; Hematocrit; Humans; Kidney Failure, Chronic; Male; Morbidity; Prognosis; Recombinant Proteins; Risk Assessment; Survival Analysis

Cardiovascular disease is a major cause of mortality and morbidity in patients with end-stage renal disease. Anemia, a result of erythropoietin deficiency, is associated with increased all-cause and cardiovascular mortality in this population, and predisposes patients to the development of symptomatic heart disease. Anemia is also associated with the development and progression of left ventricular echocardiographic disorders, which strongly predict cardiac failure and death. Left ventricular dilatation with compensatory hypertrophy, the major pattern of echocardiographic disease progression in hemodialysis patients, is a particularly strong predictor of late mortality. Partial correction of anemia with recombinant human erythropoietin likely reduces left ventricular mass and volume. Complete correction of anemia may prevent progressive left ventricular dilatation in patients with normal left ventricular volumes. A recent trial, however, reports excess mortality and vascular access loss in patients with preexisting symptomatic heart disease when anemia was completely corrected. Consequently, hematocrit target ranges above 32% to 36% cannot be recommended in this population. In patients without symptomatic heart disease, it is not possible to conclude that potential benefits derived from a normalized hematocrit will outweigh potential risks.

Topics: Anemia, Iron-Deficiency; Cardiovascular Diseases; Comorbidity; Echocardiography; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Prognosis; Recombinant Proteins; Renal Dialysis; Risk Factors; Survival Analysis

Since its introduction for clinical use a decade ago, recombinant human erythropoietin (rHuEPO) has revolutionized the management of the anemia of end-stage renal disease. Soon after its release, it became evident that the biological targets of rHuEPO were not limited to the erythroid progenitor cells. Instead, numerous clinical and laboratory studies have shown the modulatory action of rHuEPO on a wide array of cell types and organ systems. The present article is intended to provide an overview of the modulatory actions of rHuEPO on the production and action of vasoregulatory factors and its direct and indirect effects on vascular function and structure.

Topics: Anemia, Iron-Deficiency; Animals; Endothelium, Vascular; Erythropoietin; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Recombinant Proteins; Renin-Angiotensin System; Risk Assessment; Sensitivity and Specificity; Vasoconstriction

There is still controversy concerning the optimal target hemoglobin during treatment with recombinant human erythropoietin (rHuEPO). Some evidence suggests that hemoglobin concentrations higher than currently recommended lead to improvements in cognitive function, physical performance, and rehabilitation. At least in patients with advanced cardiac disease, however, one controlled trial failed to show a benefit from normalizing predialysis hemoglobin concentrations. In contrast, preliminary observations in three additional studies (albeit with limited statistical power) failed to show adverse cardiovascular effects from normalization of hemoglobin, but definite benefit with respect to quality of life, physical performance, and cardiac geometry. These observations are consistent with the notion that hemoglobin concentrations higher than those recommended by the National Kidney Foundation Dialysis Outcomes Quality Initiative Anemia Work Group are beneficial, at least in patients without advanced cardiac disease.

Topics: Anemia, Iron-Deficiency; Angina Pectoris; Controlled Clinical Trials as Topic; Erythropoietin; Female; Heart Function Tests; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Prognosis; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Topics: Acid-Base Equilibrium; Anemia; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium; Dietary Proteins; Energy Intake; Erythropoietin; Humans; Kidney Failure, Chronic; Phosphorus; Renal Replacement Therapy

Effective management of early anaemia in the course of chronic renal insufficiency requires the following: (i) implementing an efficient diagnostic strategy to exclude common contributing factors; (ii) initiating epoetin therapy for the majority of patients; for and (iii) ensuring adequate iron supply erythropoiesis. Diagnostic inquiry is warranted whenever the haemoglobin concentration is below the normal range adjusted for age and gender. The most efficient diagnostic approach is to assume erythropoietin deficiency, exclude iron deficiency, and pursue further diagnostic tests only when red-cell indices are abnormal or when leukopenia or thrombocytopenia are also present. Macrocytosis should prompt an inquiry into alcoholism, B12 deficiency, or folate deficiency. Microcytosis suggests iron deficiency or thalassaemia. Associated cytopenias raise the possibility of alcohol toxicity, pernicious anaemia, malignancy, or myelodysplastic syndrome. Epoetin therapy is warranted whenever the haemoglobin concentration has fallen below 10.0 g/dl. To initiate therapy prior to dialysis, epoetin should be administered at an average dose of 100 IU/kg/week (80-120 IU/kg/week, 50-150 IU/kg/ week) by subcutaneous injection. Haemoglobin concentration should be monitored every 2 weeks and the epoetin dose adjusted by increments or decrements of 25% to maintain a rate of rise of haemoglobin concentration of 0.2-0.6 g/dl (0.3 0.6 g/dl/week, 0.2-0.5 g/dl/week). When the target range is achieved, the dose of epoetin should be continually adjusted to maintain a stable haemoglobin concentration. Transferrin saturation and ferritin concentration should be monitored monthly, and sufficient iron provided to maintain transferrin saturation above 20%. The lower the haemoglobin concentration, the greater the likelihood that future intravenous iron will be required. Oral iron supplements should be avoided, since they are costly, ineffective, and troublesome to patients. Finally, a blunted therapeutic response to epoetin therapy provides important diagnostic information and gnostic inquiry.

Topics: Anemia; Erythropoietin; Humans; Iron; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Increasing use of maintenance parenteral iron in the erythropoietin (EPO) era has been accompanied by growing concern about iron overload. This article attempts to put the issue of iron overload in hemodialysis patients into perspective. The condition is less common in all dialysis patients today than it was in the pre-EPO era, since fewer patients are being transfused and EPO therapy shifts iron into erythroid cells. Patients with end stage renal disease (ESRD) are less likely than patients with hemochromatosis to develop iron-induced organ dysfunction. Diagnosis of iron overload is best accomplished through liver biopsy. Clinically significant iron overload, which rarely occurs if ESRD patients are properly managed, can be treated in most EPO-treated renal failure patients by simply withholding parenteral iron therapy.

Topics: Anemia, Iron-Deficiency; Biopsy; Drug Monitoring; Erythropoietin; Ferritins; Hematinics; Hematocrit; Humans; Iron Overload; Kidney Failure, Chronic; Nursing Assessment; Practice Guidelines as Topic; Renal Dialysis; Risk Factors; Tissue Distribution; Transfusion Reaction

Estimates of the prevalence of anemia during chronic renal insufficiency (CRI) vary depending on how anemia is defined. An analysis of patients beginning dialysis in the United States found that 67% had a hematocrit of less than 30% and 51% had a hematocrit of less than 28%. The anemia of CRI, therefore, appears to be prevalent even as it is underrecognized and undertreated-despite the widespread realization that there is much to be gained by treatment with recombinant human erythropoietin, with little risk of accelerating the progression of kidney disease. It is difficult to separate the effects of anemia in CRI from those of other comorbid conditions, but it is clear that anemia is a strong predictor of mortality and cardiac morbidity. Correction of anemia would be expected to negate the contribution of anemia to the mortality and cardiac morbidity associated with CRI. While this hypothesis is well-validated in hemodialysis patients, data in the population with CRI are preliminary but encouraging. Recent small prospective studies have established that treatment of anemia with recombinant human erythropoietin can reverse some degree of the cardiac morphological changes seen in CRI. While awaiting the results of large long-term clinical trials, the concept of the renal anemia management period (RAMP) draws attention and focus to the need for proactive and aggressive treatment of anemia among patients with CRI. The RAMP is defined as the period of time after the onset of CRI during which anemia develops, requiring diagnosis and treatment. Treatment of anemia during the RAMP has the potential to ameliorate, or even prevent, significant future morbidity in patients with CRI.

Topics: Anemia; Canada; Cardiovascular Diseases; Erythropoietin; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; Renal Replacement Therapy

The introduction of recombinant human erythropoietin (rHuEPO) more than a decade ago provided the first effective treatment for the anemia of chronic renal insufficiency (CRI). The use of rHuEPO in the treatment of anemia has been associated with partial regression of left ventricular hypertrophy among both dialysis and nondialysis patients, and has been shown to reduce the frequency of cardiac complications such as congestive heart failure and number of days of hospitalization among dialysis patients. Despite this evidence, the anemia of CRI remains highly prevalent, underrecognized, and undertreated. A number of considerations arise regarding the management of anemia among patients with CRI. In this article, we review the rationale for treatment of anemia, current management practices, proposed treatment strategies, and the economic implications of improved anemia treatment.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins; Risk Factors

Topics: Anemia; Biological Products; Erythropoietin; HLA Antigens; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Recombinant Proteins; Research

A wide variety of prescribed and over-the-counter (OTC) agents can affect the production or viability of red blood cells, thereby contributing to anemia. An apparent hyporesponse to Epoetin alfa therapy in end-stage renal disease (ESRD) patients can sometimes be traced to a medication prescribed to treat a comorbid condition. The anemic potential of many of these agents has been defined and can often be anticipated or avoided by examining and modifying the regimen. Nurses can help assess and prevent medicine-related hyporesponse to Epoetin alfa by obtaining thorough histories and providing ongoing counseling on the need to minimize exposure to substances that contribute to anemia. A case study is provided to illustrate the use of nursing assessment skills to identify potential drug-related hyporesponse to Epoetin alfa.

Topics: Anemia; Angiotensin-Converting Enzyme Inhibitors; Education, Nursing, Continuing; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Anemia is a common complication of chronic renal failure (CRF). With the availability of recombinant human erythropoietin (rhEPO) over the last decade, much progress has been made in the management of anemia in patients with end-stage renal disease (ESRD) [Eschbach 1995, Gimenez and Scheel 1994, Muirhead et al. 1995, Winearls 1995]. The clearest benefit of rhEPO in ESRD is a substantial reduction in transfusion dependency, which reduces the need for hospital admission and the risk of viral transmission. Improvements in hemostasis and a decrease in human leucocyte antigen (HLA) antibodies have also been reported. Beneficial effects of rhEPO on the cardiovascular system in ESRD include regression of left ventricular hypertrophy (LVH), improvement of angina, and a modest increase in aerobic work capacity. Treatment of anemia with rhEPO has also been shown to improve cognitive function, socialization and quality of life in dialysis patients, although this has not led to better vocational rehabilitation or employment status. It has also been reported that a lower hemoglobin (Hb) content is an independent risk factor for increased mortality in hemodialysis patients [Harnett et al. 1995]. Clearly, therefore, treatment of anemia associated with ESRD is required and beneficial. The optimum treatment of anemia prior to dialysis, however, is still a matter for debate.

Topics: Anemia; Blood Transfusion; Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Recombinant Proteins; Renal Dialysis

Dialysis was first described and used in 1854 to separate substances in aqueous solution based on different rates of diffusion through a semipermeable membrane. In vivo hemodialysis was performed in animals early in the twentieth century. Hemodialysis was first carried out in patients with acute renal failure in The Netherlands during the Second World War and in the United States in 1948. Repetitive hemodialysis for the treatment of chronic renal failure due to end-stage renal disease had to await the development of an acceptable long-lasting vascular access in 1960. The subsequent successful development of a technique to create an adequate arteriovenous fistula in 1972 permitted the rapid growth of dialysis programs, when the cost of this therapy was largely paid for by Medicare. Equipment has been developed to foster home-care hemodialysis and chronic ambulatory peritoneal dialysis. Enhancements in renal replacement therapy included the availability of recombinant human erythropoietin, calcitriol, and effective antihypertensive drugs. Technical advances in hemodialysis followed the use of bicarbonate dialysate, more biocompatible membranes, membranes of higher porosity, and ultrafiltration. Questions remain regarding the evaluation of the adequacy of dialysis which is to be achieved or prescribed. Careful attention to the management of the patient with progressive chronic renal insufficiency is crucial in dealing with the inevitable onset of uremia and the initiation of dialysis and/or renal transplantation. The cost of renal replacement therefore represents a great societal burden. A better understanding of how to prevent onset and progression of specific nephropathies along with the availability of new and more effective equipment for renal replacement therapy has a high priority.

Topics: Calcitriol; Calcium Channel Agonists; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Kidney Transplantation; Recombinant Proteins; Renal Dialysis; Renal Replacement Therapy; United States

The treatment of renal anaemia with human recombinant erythropoietin (r-hu-EPO) in predialysis patients requires a close collaboration between the general practitioner and the nephrologist. This therapeutic option, along with other measures as part of the management of patients with renal insufficiency, is aimed at slowing down the progression of the kidney failure and at maintaining the patient in the best possible metabolic conditions. This paper summarises the benefits and risks of r-hu-EPO administered in renal insufficiency. The practical guidelines for the r-hu-EPO administration should help to assure an optimal and cost-effective utilization of the treatment.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Patient Care Team; Premedication; Recombinant Proteins; Renal Dialysis

The anemia of renal failure is caused by the lack of sufficient quantities of endogenous erythropoietin. With the availability of recombinant human erythropoietin (rHuEPO), however, it has become apparent that to achieve a given target, hematocrit requires proper management of iron replacement, as well as the administration of rHuEPO. Iron deficiency, either absolute or functional, will occur in most, if not all, patients on hemodialysis receiving rHuEPO because of the increased demand for iron driven by the accelerated erythropoiesis that occurs with exogenous rHuEPO administration, coupled with ongoing blood losses from dialyzer and tubing, blood sampling, gastrointestinal blood loss, and blood losses at the time of dialysis needle placement and removal. Blood loss is less of a problem in patients on peritoneal dialysis, but poor iron intake and increased demand for iron are also seen, the latter in patients receiving rHuEPO. It is essential, therefore, for renal health professionals to understand iron metabolism in dialysis patients in order to properly balance the therapy of renal anemia with rHuEPO and supplemental iron.

Topics: Anemia, Iron-Deficiency; Erythropoietin; Humans; Intestinal Absorption; Iron; Iron Deficiencies; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Iron overload was a common complication in patients with chronic renal failure treated with dialysis prior to the availability of recombinant human erythropoietin (rHuEPO) therapy. Iron overload was the result of hypoproliferative erythroid marrow function coupled with the need for frequent red blood cell transfusions to manage symptomatic anemia. The repetitive use of intravenous iron with or without the use of red blood cell transfusions also contributed to iron loading and was associated with iron deposition in liver parenchymal and reticuloendothelial cells; however, there were no abnormal liver function tests or evidence of cirrhosis unless viral hepatitis resulted from the transfusions. With rHuEPO therapy, the excess iron stores were shifted back into circulating red blood cells as the anemia was partially corrected, and red blood cells were lost from circulation by the hemodialysis procedure. After several years of rHuEPO therapy, most hemodialysis patients required iron supplements to replace the continuing blood losses related to hemodialysis. The potential complications of iron overload (parenchymal iron deposition, permanent organ damage, increased risk of bacterial infections, and increased free radical generation) are reviewed in the context of this setting.

Topics: Anemia; Bacterial Infections; Erythropoietin; Free Radicals; Humans; Iron; Iron Overload; Kidney Failure, Chronic; Recombinant Proteins

The management of recombinant human erythropoietin (rHuEPO) treatment in hemodialysis patients requires close monitoring of iron status, because the pharmacologically stimulated erythropoiesis is particularly dependent on a continuous supply of iron. Parameters commonly measured to assess iron status are serum ferritin and the transferrin saturation. Both are indirect measures of iron availability for hemoglobin synthesis and frequently do not permit an assessment of the adequacy of iron supply to the erythron. Using flow cytometry, cell volume and hemoglobin concentration can be measured in individual red blood cells and reticulocytes. Based on these techniques, two parameters have proved to be particularly useful in identifying iron-deficient erythropoiesis. (a) The percentage of hypochromic erythrocytes (defined as red blood cells with a hemoglobin concentration of less than 28 g/dl) has been shown to detect insufficient marrow iron supply with a fairly good accuracy. (b) More recently, determination of the content of hemoglobin in reticulocytes (CHr) has been suggested by a number of authors to be even more sensitive in detecting iron-deficient erythropoiesis. For those who have access to an H*3 hematology analyzer, both indices can be determined at the time of a routine blood count at a minimal incremental cost.

Topics: Anemia, Iron-Deficiency; Erythrocyte Indices; Erythrocytes; Erythropoietin; Hemoglobins; Humans; Iron Deficiencies; Kidney Failure, Chronic; Phlebotomy; Recombinant Proteins; Renal Dialysis; Reticulocytes

Iron supplementation has become an integral part of the management of patients receiving epoetin therapy, and clinicians have found it necessary to learn how and when to use it to the best advantage. Three routes of administration for iron are available: oral, intramuscular, and intravenous. Oral iron has the advantage of being simple and cheap, but it is limited by side-effects, poor compliance, poor absorption, and low efficacy. Intravenous iron is the best means of guaranteeing delivery of readily available iron to the bone marrow, but it requires greater clinical supervision. The i.v. iron preparations vary widely in their degradation kinetics, bioavailability, side-effect profiles, and maximum dose for single administration. Iron dextran is hampered by a small but significant risk of anaphylaxis, whereas all i.v. iron preparations can induce "free iron" reactions if the circulating plasma transferrin is overloaded. Intravenous iron may be given in advance of epoetin therapy, as concomitant treatment to prevent the development of iron deficiency, as treatment of absolute or functional iron deficiency, or as adjuvant therapy to enhance the response to epoetin in iron-replete patients. Markers of iron status that may indicate a need for i.v. iron include a serum ferritin of less than 100 microg/liter, a transferrin saturation of less than 20%, and a percentage of hypochromic red cells more than 10%. Various regimens are available for giving i.v. iron: low-dose administration of 20 to 60 mg every dialysis session in hemodialysis patients, medium-dose administration of 100 to 400 mg, and high-dose administration of 500 to 1000 mg. Iron sodium gluconate can only be given as a low-dose regimen because of toxicity, whereas the only preparation suitable for high-dose administration is iron dextran. Although concerns have been raised regarding iron overload and long-term toxicity with i.v. iron therapy in terms of increased risk of infections, cardiovascular disease, and malignancy, there is little evidence to substantiate this in patients receiving epoetin. Care should be taken, however, to prevent the serum ferritin rising above 800 to 1000 microg/liter and the transferrin saturation above 50%. Provided this is done, the benefits of i.v. iron almost certainly outweigh the risks in terms of optimizing the response to epoetin therapy.

Topics: Administration, Oral; Anemia; Erythropoietin; Ferritins; Humans; Injections, Intramuscular; Injections, Intravenous; Iron; Iron, Dietary; Kidney Failure, Chronic; Recombinant Proteins

Iron deficiency is a common problem in patients treated with hemodialysis. If not detected and treated appropriately, the effectiveness of recombinant human erythropoietin therapy is compromised. Much has been learned in recent years with respect to iron therapy for hemodialysis patients. A series of studies have clearly defined the efficacy of intravenous iron compounds, and recently released clinical practice guidelines have set the appropriate clinical context for the use of these agents. The purpose of this article is to examine the beneficial effects of iron replacement therapy for hemodialysis patients.

Topics: Erythropoietin; Ferritins; Humans; Injections, Intravenous; Iron; Iron Deficiencies; Iron, Dietary; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Transferrin

Iron deficiency represents an important problem in peritoneal dialysis patients, especially during erythropoietin therapy. A combination of serum ferritin, transferrin saturation, and/or the percentage of hypochromic red cells should be used to assess iron status in peritoneal dialysis patients. Primarily, oral iron supplementation should be the preferred therapy. However, most of the studies using oral substitution in erythropoietin-treated peritoneal dialysis patients show a progressive decline of serum ferritin. Therefore, parenteral iron supplementation is required in part of the patients, and the intravenous route should be preferred in these cases. Intravenous iron therapy is recommended if serum ferritin falls below 100 microg/liter and should be stopped if the serum ferritin level is more than 650 microg/liter. The optimal form of intravenous iron supplementation is still unclear. Injections once to three times per week restrict the patients' flexibility, but application of higher doses in longer intervals may lead to an impairment of neutrophil functions, probably connected to a higher risk of infection. We treated 17 stable peritoneal dialysis patients with 100 or 200 mg iron saccharate monthly over a period of six months and found an increase of transferrin saturation (from 12.1+/-1.6 to 20.9+/-2.4%, P = 0.026), serum ferritin (from 100.4+/-32.0 to 372.4+/-54.6 microg/liter, NS) and hematocrit (from 32.0+/-0.8% to 35.1+/-0.9%, P = 0.099). The required erythropoietin dosage could be reduced significantly (from 148.4+/-30.3 to 69.4+/-19.5 U/kg/week, P = 0.025). Side effects occurred in 0.9% after application of 100 mg and in 5.9% after injection of 200 mg iron saccharate. The incidence of catheter infections and peritonitis was the same in the period before and after the start of treatment. Further studies are needed to find the most suitable regime of iron supplementation for peritoneal dialysis patients.

Topics: Administration, Oral; Anemia; Erythropoietin; Ferritins; Humans; Injections, Intramuscular; Injections, Intraperitoneal; Injections, Intravenous; Iron; Iron Deficiencies; Iron, Dietary; Kidney Failure, Chronic; Peritoneal Dialysis; Recombinant Proteins; Transferrin

This article, based on our own studies and those of others, presents evidence to show that the anemia of chronic renal failure in the predialysis period is, to a significant extent, caused by iron deficiency and can be improved in most cases by the administration of intravenous (i.v.) but not oral iron. We estimate that in approximately 30% of all predialysis patients with anemia, a target hematocrit (Hct) of 35% can be reached and maintained by giving i.v. iron alone without exceeding currently acceptable limits of serum ferritin (500 microg/liter) or the percentage of iron saturation (40%). If, in addition, subcutaneous erythropoietin (EPO-usually in only low doses-is added, the combination has an additive effect on the Hct response, and almost all anemic predialysis patients can reach and maintain the target Hct of 35% over a one-year period. Therefore, the advantage of maintaining adequate iron stores with i.v. iron is that if EPO is needed, lower doses will be required to achieve the target Hct than if EPO were used alone. This not only avoids the high cost of EPO therapy but also its associated side-effects, especially hypertension. Using Venofer, a ferric hydroxide sucrose complex, as our i.v. iron supplement, we have seen no anaphylactic reactions in over 20,000 infusions over a four-year period in 360 hemodialysis, 123 predialysis, and 58 peritoneal dialysis patients.

Topics: Administration, Oral; Anemia, Iron-Deficiency; Blood Pressure; Coronary Disease; Drug Hypersensitivity; Erythropoietin; Humans; Injections, Intravenous; Iron; Iron Deficiencies; Iron, Dietary; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

The advent of erythropoietin (rHuEPO) has revolutionized the treatment of anemia in end-stage renal disease. While many studies indicate beneficial effects of rHuEPO in hemodialysis, peritoneal dialysis and predialysis patients, the impact of the drug in renal transplantation is less clear. Treatment with rHuEPO may reduce the degree of allosensitization produced by random blood transfusion while still allowing the possibility of the transplant survival benefit derived from deliberate transfusion. Recovery from anemia post-transplantation is hastened by treatment with rHuEPO, while patients with failing allografts respond to rHuEPO in a fashion similar to dialysis patients, despite the concomitant use of immunosuppressives. The erythropoietic response to rHuEPO is abrogated during episodes of acute rejection, and restored when successful treatment of rejection has occurred. Iron therapy is a critical factor for support of erythropoiesis and prevention of absolute iron deficiency posttransplantation. In patients presenting for renal transplant, the balance of evidence suggests that there is no increase in the rate of delayed graft function, graft loss or vascular thrombosis for patients who had received prior rHuEPO therapy.

Topics: Anemia; Erythropoietin; Graft Rejection; Humans; Iron; Kidney Failure, Chronic; Kidney Transplantation; Polycythemia; Recombinant Proteins

Iron deficiency is the most frequently encountered cause of suboptimal response to recombinant human erythropoietin (rHuEPO). Carefully assessing iron status is of paramount importance in chronic renal failure patients prior to or during rHuEPO therapy. Because there is great need for iron in the EPO-stimulated erythroid progenitors, it is essential that serum ferritin and transferrin saturation levels should be maintained over 300 microg/liter and 30%, respectively. Investigators have shown that oral iron is unlikely to keep pace with the iron demand for an optimal rHuEPO response in uremics. Therefore, patients with iron deficiency will always require intravenous iron therapy. The early and prompt iron supplementation can lead to reductions in rHuEPO dose and hence cost. After the iron deficiency has been corrected or excluded, we must remember all of the possible causes of hyporesponsiveness in every rHuEPO-treated patient. As dose requirements vary, it is not clear which dose of rHuEPO causes this hyporesponsiveness. However, if the patient with iron repletion does not respond well after the induction period, the major causes blunting the response to rHuEPO should be investigated. Most factors are reversible and remediable, except resistant anemia associated with hemoglobinopathy or bone marrow fibrosis, which requires a further increase in the rHuEPO dose. By means of early detection and correction of the possible causes, the goal of increasing therapeutic efficacy can be achieved. Iron overload may lead to an enhanced risk for infection, cardiovascular complication, and cancer. Over-treatment with iron should be avoided in dialysis patients, despite the fact that the safe upper limit of serum ferritin to avoid iron overload is not clearly defined. On the other hand, functional iron deficiency may develop even when serum ferritin levels are increased. Controversy remains as to whether intravenous iron therapy can overcome this form of hyporesponsiveness in iron-overloaded patients. Moreover, a treatment option of iron supplementation is not warranted in these patients, as the potential hazards of iron overload will be worsened. We demonstrated that the mean hematocrit significantly increased from 25.1+/-0.9% to 31+/-1.2% after eight weeks of intravenous ascorbate therapy (300 mg three times a week) in 12 hemodialysis patients with serum ferritin levels of more than 500 microg/liter. The enhanced erythropoiesis paralleled with a rise in transferrin sa

Topics: Aluminum; Anemia; Erythropoietin; Hemoglobinopathies; Hemolysis; Humans; Infections; Inflammation; Iron; Iron Deficiencies; Iron Overload; Kidney Failure, Chronic; Recombinant Proteins; Thalassemia

Intensive iron therapy is now a generally accepted adjunct for the treatment of renal anemia with recombinant human erythropoietin. However, with the emerging role of iron in cardiovascular disease, carcinogenesis, infectious diseases, and other disorders, it is no longer appropriate to assume that any amount of stored iron is safe until proven otherwise. In this article, the history and current status of the "iron hypothesis" on ischemic heart disease are briefly reviewed, followed by comments on iron management practices for renal patients.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Female; Humans; Iron; Iron Overload; Kidney Failure, Chronic; Male; Recombinant Proteins

The number of patients with significant chronic renal failure is expanding rapidly in the United States. All physicians and medical-care providers will have an increasingly important role in the detection and management of renal failure in patients who are not undergoing dialysis. Patients with diabetes or hypertension should be carefully monitored for the development of renal insufficiency by using screening tools such as blood pressure measurement, determination of serum creatinine, urinalysis, and determination of 24-hour urinary microalbuminuria. In order to slow the progression of renal disease, attenuate uremic complications, and prepare patients with renal failure for renal replacement therapy, all medical-care providers should "take care of the BEANS." Blood pressure should be maintained in a target range lower than 130/85 mm Hg, and in many patients, angiotensin-converting enzyme inhibitors may be beneficial. Erythropoietin should be used to maintain the hemoglobin level at 10 to 12 g/dL. Access for long-term dialysis should be created when the serum creatinine value increases above 4.0 mg/dL or the glomerular filtration rate declines below 20 mL/min. Nutritional status must be closely monitored in order to avoid protein malnutrition and to initiate dialysis before the patient's nutritional status has deteriorated. Nutritional care also involves correction of acidosis, prevention and treatment of hyperphosphatemia, and administration of vitamin supplements to provide folic acid. Specialty referral to nephrology should occur when the creatinine level increases above 3.0 mg/dL or when the involvement of a nephrologist would be beneficial for ongoing management of the patient.

Topics: Arteriovenous Shunt, Surgical; Blood Pressure; Creatinine; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Nephrology; Nutritional Status; Recombinant Proteins; Referral and Consultation; Renal Dialysis

Chronic administration of erythropoietin (EPO) is associated with an increase in arterial blood pressure in patients and animals with chronic renal failure (CRF). Several mechanisms have been considered in the pathogenesis of EPO-induced hypertension. These include the possible role of the rise of hematocrit and erythrocyte mass, changes in production or sensitivity to endogenous vasopressors, alterations in vascular smooth-muscle ionic milieu, dysregulation of production or responsiveness to endogenous vasodilatory factors, a direct vasopressor action of EPO, and finally arterial remodeling through stimulation of vascular cell growth.

Topics: Anemia; Animals; Catecholamines; Endothelins; Erythrocyte Volume; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Renin-Angiotensin System; Time Factors; Vasoconstrictor Agents

Erythropoietin (EPO) treatment dramatically changes the life of a child with end-stage renal disease. The administration of recombinant human (rHu)EPO is beneficial and safe in the predialysis period, during hemodialysis or peritoneal dialysis, and after renal transplantation. The goal of hemoglobin correction should be the level at which normal quality of life is possible without adverse events: in children this is usually 10-11 g/dl. rHuEPO is administered once to twice a week subcutaneously to children before dialysis, during peritoneal dialysis, and after transplantation. There is no real benefit of intraperitoneal administration. In children on hemodialysis two to three times a week IV administration is preferred. Among the many reasons for non-response to rHuEPO, iron deficiency (absolute or functional), infections, and hyperparathyroidism are the most common in the pediatric renal patient. Hypertension is the most-frequent side effect of rHuEPO treatment and needs careful monitoring. Iron should be supplemented orally or IV. No significant beneficial effect of rHuEPO on growth has been demonstrated. However, the association with recombinant human growth hormone therapy is not detrimental in children.

Topics: Anemia; Child; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Approximately 50% of cancer patients develop anemia. In the past, the only available treatment option for these patients was transfusion. Since the late 1980s, recombinant human erythropoietin (rHuEPO, epoetin alfa [Epogen, Procrit]) has provided a treatment alternative. Controlled clinical trials have shown that rHuEPO increases hemoglobin and hematocrit levels and reduces the need for transfusions in patients with cancer-related anemia. These controlled trials have suggested (as larger, uncontrolled studies) that the improvements in hemoglobin are associated with increases in energy level, functional status, and overall quality of life. However, only about 50% of patients respond adequately to usual doses of rHuEPO. In the chronic renal failure population, functional iron deficiency is the most common cause of inadequate response to rHuEPO. It has been hypothesized that functional iron deficiency may also occur in cancer patients receiving rHuEPO and may account for the lack of response in up to half of those patients. Studies in renal failure patients have shown that administration of intravenous iron can correct functional iron deficiency more effectively than oral iron and may improve response to rHuEPO. Intravenous iron also reduces the total amount of rHuEPO needed to normalize hematocrit and hemoglobin levels, thereby reducing treatment costs. Ongoing clinical trials are evaluating whether IV iron can also improve rHuEPO responsiveness in patients with cancer-related anemia.

Topics: Anemia; Erythropoietin; Health Care Costs; Hematocrit; Hemoglobins; Humans; Iron; Iron Deficiencies; Kidney Failure, Chronic; Neoplasms; Recombinant Proteins

In patients with cardiovascular disease, partial correction of anaemia with epoetin improves quality of life and exercise capacity, and reduces left ventricular hypertrophy. The currently recommended haemoglobin in these patients is 11-12 g/dl. The optimal haemoglobin in patients with diabetes mellitus does not differ from that in non-diabetic patients; however, haemoglobin should be increased slowly. There is no difference in the recommended haemoglobin between children and adults. However, epoetin sensitivity is lower in children who, therefore, typically need the same absolute dose of epoetin as adults. Epoetin treatment may delay the progression of chronic renal failure (CRF) in paediatric patients. Elderly patients obtain similar benefits from epoetin as younger adults; moreover, there are no differences in the doses of epoetin required or the optimal haemoglobin. There are very few data available on the effects of epoetin in patients with CRF and chronic obstructive pulmonary disease. At present, a haemoglobin of 11 g/dl seems appropriate. In sickle-cell anaemia patients with CRF, a high haemoglobin could precipitate painful crises; consequently, the recommended haemoglobin is the pre-CRF concentration of 6-9 g/dl. There is no convincing evidence of any effect of previous epoetin treatment on the long-term outcome of renal transplantation. In patients with a failing or failed transplant, the required dose of epoetin may be higher than in pre-transplantation patients. In such cases, transplant nephrectomy might be considered.

Topics: Adult; Aged; Anemia; Anemia, Sickle Cell; Child; Diabetic Nephropathies; Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Lung Diseases, Obstructive

There is a clear relationship between anaemia and cardiovascular risk in chronic renal failure (CRF) patients. Left ventricular hypertrophy (LVH) is present in about three-quarters of patients starting dialysis, and is a strong predictor of mortality. Anaemia contributes to the development of LVH, mainly via increased cardiac output. In some patients, anaemia results in an increase in LV mass, while in others it also results in LV end-diastolic volume dilatation. These changes increase the risk of arrhythmias, myocardial infarction and myocardial fibrosis. The lower the haemoglobin, the more likely it is that LVH and heart failure will develop. Furthermore, a haemoglobin of < 11 g/dl is associated with increased morbidity and mortality. Partial correction of anaemia with epoetin leads to a partial, but not complete, reversal of LVH. One large prospective study (Lombardy Registry) found that epoetin treatment was accompanied by a 30% reduction in crude relative risk of mortality. A progressive reduction in the relative risk of general and cardiovascular mortality was found with increasing haematocrit, with and without adjustment for co-morbid conditions. Mean hospitalizations also decreased with increasing haematocrit. The long-term effects of normalized haematocrit/haemoglobin values in uraemic patients have not yet been evaluated exhaustively in prospective, randomized, multicentre studies. Epoetin treatment has been shown to induce lasting improvements in patients' sense of well-being, reduce fatigue, increase appetite and work capacity, and improve exercise tolerance, libido and work performance. Further studies are needed to demonstrate whether greater haemoglobin concentrations are associated with greater improvements in quality of life during epoetin treatment.

Topics: Anemia; Animals; Erythropoietin; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Quality of Life

Adjuvant therapy may allow patients being treated with epoetin to derive greater clinical benefits. Iron supplementation is currently the most widely used form of adjuvant therapy; intravenous (i.v.) iron is required by the majority of haemodialysis patients receiving epoetin. Measurement of hypochromic red blood cells is the most direct way of assessing iron supply to the bone marrow. During the correction phase, a dose of i.v. iron equivalent to 50 mg/day is recommended, with the total dose not exceeding 3 g. When subclinical vitamin C deficiency is suspected, ascorbic acid may be given orally (1-1.5 g/week) or i.v. (300 mg three times weekly at the end of dialysis). The active vitamin D metabolites alfacalcidol and calcitriol may, under some circumstances, improve anaemia and reduce epoetin dosage requirements. Vitamin B6 requirements are increased during epoetin therapy, and supplementation at a dose of 100-150 mg/week is recommended. Supplementation of vitamin B12 is optional. Folic acid is supplemented routinely in haemodialysis patients, though evidence that it increases the efficacy of epoetin is limited. Low doses (2-3 mg/week) should normally be sufficient to maintain optimal folic acid stores in epoetin-treated patients, although higher doses are necessary for patients with hyperhomocysteinaemia. L-Carnitine supplementation may be appropriate in some patients with anaemia of chronic renal failure (CRF) unresponsive to, or requiring large doses of, epoetin. Androgens potentially could reduce epoetin costs in countries with limited resources, but should only be used in men older than 50 years with a remnant kidney. Recent animal studies indicate that the combination of epoetin and insulin-like growth factor 1 might be beneficial in CRF patients. High doses of angiotensin-converting enzyme (ACE) inhibitors should be reserved for dialysis patients who have hypertension that cannot be controlled by other agents, or who require an ACE inhibitor for treatment of heart failure.

Topics: Androgens; Anemia; Angiotensin-Converting Enzyme Inhibitors; Ascorbic Acid; Carnitine; Cytokines; Erythropoietin; Humans; Iron; Kidney Failure, Chronic; Pyridoxine; Vitamin D

Cardiovascular disease is the leading cause of increased mortality in patients with renal failure and vigorous attention to cardiovascular risk factors is therefore required to improve patient outcome. The availability of recombinant human Epo has focused the interest on the role of chronic anaemia in the pathogenesis of cardiovascular disease. Severalfold evidence indicates that anaemia can contribute to cardiac volume overload and together with overhydration, fistula flow and the pressure overload secondary to arterial hypertension, it may play a significant role in the development of cardiac hypertrophy. As in the general population left ventricular hypertrophy is a severe adverse risk factor in renal patients. In addition, in the presence of ischaemic heart disease anaemia may further worsen cardiac oxygen supply. This dual effect of anaemia probably explains why epidemiological studies have shown that a 1 g/dl decrease in haemoglobin levels is an independent, statistically significant risk factor for the development of cardiac morbidity and mortality. Follow-up examinations have demonstrated that partial correction of anaemia with recombinant Epo can improve cardiac oxygen supply and partially reverse pathological changes in left ventricular geometry. However, although partial anaemia correction regularly reduces left ventricular volume, the effects on wall thickness are far less significant. Moreover, in patients with advanced cardiac disease it has recently not been possible to demonstrate that a normalization of haemoglobin levels provides further benefit. It is not unlikely therefore that the development of severe anaemia has to be prevented by early implementation of Epo therapy in order to achieve the maximum benefit with respect to the cardiovascular system.

Topics: Adaptation, Physiological; Adult; Aged; Anemia; Cardiovascular Diseases; Cardiovascular System; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins

Renal anaemia causes in patients with chronic renal failure numerous serious problems which can be favourably influenced by improvement of the anaemia. There is a number of known factors which cause deterioration of anaemia and make its treatment more difficult. For a long time it was not clear that these negatively acting factors included also insufficiently effective dialysis treatment. The authors of the submitted paper evaluate the relationship between anaemia and the effectiveness of dialysis based on new data reported in the literature and their own results. From this evaluation ensues that inadequate haemodialysis, assessed from the percentage reduction of urea in blood, is associated with a reduced response to recombinant human erythropoietin which is the basic remedy of renal anaemia. If the inadequate intensity of haemodialysis is increased, anaemia improves substantially. In patients on continuous ambulatory peritoneal dialysis (CAPD) there is a direct relationship between the effectiveness of blood purification expressed by the index KT/Vurea, i.e. the indicator of urea elimination, and the severity of anaemia. In patients treated by CAPD there is a significant association between the haematocrit and KT/Vurea supplied by the peritoneum as well as the kidneys. KT/Vurea supplied by the patient's own kidneys is from the aspect of anaemia more significant. Some facts regarding the relationship between anaemia and the effectiveness of dialysis treatment remain obscure so far. This however does not influence the fact that based on data available at present, effective dialysis must be included among basic prerequisites of effective treatment of renal anaemia in dialyzed patients.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis

Anemia in premature infants can be prevented by prophylactic treatment with recombinant human erythroprotein (r-huEPO). r-HuEPO as been used for a long time in patients with end-stage renal failure. The main factor which can limit r-HuEPO efficiency is limited iron bioavailability. Adapted iron supplementation is needed when preterm infants receive r-HuEPO in order to avoid the depletion of iron stores. Oral iron supplementation is simple but indigestibility is frequent. Furthermore, the intestinal absorption and utilization of oral iron is limited. Parenteral iron supplementation is possible in infants who are very pre-term as they are parenterally fed during the first weeks of life. There are various preparations of intravenous iron with different physicochemical properties. Toxicity and side-effects of parenteral iron preparations depend on these properties. Two parenteral iron preparations are available in France: iron-saccharate (Venofer) and iron-dextrin (Maltofer). Iron delivery and possible side-effects of these preparations are different and need to be considered before use in preterm infants.

Topics: Adult; Dietary Supplements; Erythropoietin; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hematinics; Humans; Infant, Newborn; Infant, Premature; Infusions, Intravenous; Kidney Failure, Chronic; Recombinant Proteins

About 50% of patients with multiple myeloma are older than 65 years and are not eligible for high-dose therapy, which has proved to be more efficacious than standard-dose chemotherapy in young patients.. Apart from high-dose therapy, no clear therapeutic advance has been achieved in the past 20 years, and melphalan-prednisone combinations remain reference treatments for many patients with multiple myeloma. Despite a great number of clinical trials, the use of interferon alpha is still controversial. The role of high-dose dexamethasone has been recently established and we are currently comparing dexamethasone alone, melphalan-dexamethasone and dexamethasone-interferon alpha treatments in a multicenter randomized trial (IFM 95-01). Bisphosphonates have also emerged as an efficacious and well tolerated adjuvant treatment. Optimal use of recently released bisphosphonates at various stages of the disease will possibly lead to a clear therapeutic advantage.. Other drugs, such as erythropoietin or interferon gamma require further evaluation. The recent implication of metalloproteinases in multiple myeloma and the efficacy of metalloproteinase inhibitors in animal models and phase I/II clinical studies in solid tumors provide a strong rationale for the clinical evaluation of these agents in multiple myeloma.

Topics: Anemia; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Humans; Interferon-alpha; Kidney Failure, Chronic; Multiple Myeloma

Topics: Anemia; Animals; Erythropoietin; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; Renal Dialysis

Recombinant epoetin therapy and correction of the chronic anemia of renal failure have greatly reduced the number of red cell transfusions and hence the propensity to iron overload. The majority of HD patients require intravenous iron therapy to achieve the hematocrit levels that correspond to improved outcome measures. Although the short-term benefits of intravenous iron have been clearly defined, the long-term risks of intravenous iron are less well-defined. Iron overload before the availability of epoetin constituted a serious problem; our review of the literature does not decisively conclude that these patients had more serious bacterial infections or increased mortality when compared with their non-iron overloaded counterparts, unless chronic transfusion-related hepatic disease was superimposed. Specifically, no data unequivocally confirm that iron overload from parenteral iron contributes to all-cause patient morbidity or mortality. Furthermore, therapy that maintains intravenous iron optimal iron stores and replaces iron losses associated with the dialytic procedure does not engender iron overload in the carefully monitored patient. Optimized anemia therapy in ESRD requires individualized and specific application of epoetin and iron for each patient, and significant cost savings can result from such a strategy. Prospective studies are clearly necessary to define those parameters that reflect adequacy of iron storage in renal failure patients. We should develop alternative means of iron delivery and develop monitors that accurately discriminate between patients who will respond to additional iron therapy and those who will not. Whether ferritin should be supplanted by another parameter and whether iron itself poses an increased risk to those patients it has so beneficially served are issues that must be resolved. Until these answers are known, the importance of carefully crafted iron therapy cannot be overstated.

Topics: Anemia; Coronary Disease; Erythropoietin; Female; Free Radicals; Humans; Infections; Injections, Intravenous; Iron; Iron Deficiencies; Kidney Failure, Chronic; Male; Recombinant Proteins; Risk Factors; Safety; Transferrin

Anemia, a decreased oxygen-carrying capacity of the blood, develops frequently in patients with end-stage renal disease (ESRD) or cancer. Given the wide variation in clinical response to erythropoietin in the treatment of anemia associated with these diseases, 2 meta-analyses of its effectiveness were undertaken. Databases (MEDLINE and International Pharmaceutical Abstracts) were searched to identify relevant articles. Search terms included erythropoietin, anemia, end-stage renal disease, cancer, multiple myeloma, and myelodysplastic syndrome. Searches were limited to human subjects and the English language. Reference lists of identified articles were reviewed for further articles of interest. The primary author (W.A.M.) selected the articles, and 2 researchers, working independently, extracted the necessary data. Articles had to meet the following criteria to be included in the meta-analyses: (1) Articles must have dealt with treatment of subjects with documented anemia. (2) Studies must have been original research with sample size > or =10. (3) Abstracts could be included if the full research manuscript was unavailable. (4) Patients could not be concurrently receiving other growth factors. (5) The quality of the selected articles must have been assessed by 2 independent researchers. A clinical response to erythropoietin was defined as a 0.06 increase in hematocrit or a 20 g/L increase in hemoglobin. Thirty-nine of the 76 identified articles were included in the meta-analyses. The effectiveness of erythropoietin was calculated at 87% for ESRD, 79% for multiple myeloma, 40% for solid tumor cancer, and 13% for myelodysplastic syndrome. Both subgroup and sensitivity analyses were performed.

Topics: Anemia; Clinical Trials as Topic; Erythropoietin; Humans; Kidney Failure, Chronic; Neoplasms

Topics: Anemia; Animals; Arginine; Bleeding Time; Blood Platelets; Endothelium, Vascular; Enzyme Inhibitors; Erythropoietin; Guanidines; Hemorrhage; History, 18th Century; History, 20th Century; Humans; Isoenzymes; Kidney Failure, Chronic; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; omega-N-Methylarginine; Rats; Succinates; Uremia

Topics: Anemia; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Drug Interactions; Drug Resistance; Drug Therapy, Combination; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Sensitivity and Specificity

Topics: Anemia; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; DNA-Binding Proteins; Erythropoietin; Event-Related Potentials, P300; Gene Expression Regulation; Genetic Therapy; Hepatocyte Nuclear Factor 4; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Failure, Chronic; Nuclear Proteins; omega-N-Methylarginine; Phosphoproteins; Transcription Factors; Transcription, Genetic

While oral iron can be used to manage iron stores in some hemodialysis patients, most require intravenous iron supplementation. Maintenance of iron balance in these patients is critical, since patients with end stage renal disease often suffer from anemia caused by inadequate production of red blood cells and iron deficiency resulting from chronic blood loss. Using guidelines that include maintenance dosing ensures sustained adequate iron stores and maximizes the effects of rHuEPO therapy. Easy-to-administer clinical practice guidelines for repletion and maintenance of iron stores are presented here.

Topics: Algorithms; Anemia, Iron-Deficiency; Decision Trees; Drug Monitoring; Erythropoietin; Ferritins; Humans; Injections, Intravenous; Iron-Dextran Complex; Kidney Failure, Chronic; Nursing Assessment; Practice Guidelines as Topic; Renal Dialysis; Transferrin

Anemia is equally devastating in children as in adults. Decreased energy levels from anemia can lead to deterioration in the ability to (a) exercise, (b) participate in the normal activities of childhood, and (c) learn. Moreover, these effects may make it difficult for children to engage in social interactions with their peers, thereby altering their development. Epoetin alfa therapy effectively ameliorates the anemia of end-stage renal disease in pediatric dialysis patients and thus minimizes many of these negative effects. This article examines the use of Epoetin alfa in the pediatric population, including the role of nurses in educating patients and ensuring prescribed outcomes.

Topics: Adolescent; Age Factors; Anemia, Iron-Deficiency; Child; Energy Metabolism; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Kidney Failure, Chronic; Patient Education as Topic; Play and Playthings; Recombinant Proteins; Renal Dialysis; Treatment Outcome

During the last decade, a considerable amount of new information has accumulated regarding therapy optimalization of renal anaemia with recombinant human erythropoietin (EPO). Key question involved is EPO hyporesponsiveness caused by absolute or functional iron deficiency. Most controversial issue in the treatment of renal anaemia in patients with chronic renal insufficiency is the definition of optimal target haemoglobin. Many questions about optimizing EPO therapy were considered at the 2nd European Epoetin Symposium which was held in April 1998 on Crete. Discussion was devoted also to revision of a draft version of the European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure. The presented review is on summary of new insights presented at the symposium. (Ref. 85.)

Topics: Anemia; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins

Proper management of the anemia of end-stage renal disease (ESRD) requires chronic monitoring of an interrelated set of variables that can affect the erythrokinetic response. In most cases, therapeutic interventions should be determined on the basis of serial trends in laboratory values, thereby providing a historical pattern of clinical response. This article reviews the rationale for using laboratory trend analysis to manage anemia. A methodology for categorizing patterns in hemoglobin and hematocrit response to identify probable causes of hypo- or hyper-response to Epoetin alfa therapy is provided.

Topics: Anemia, Iron-Deficiency; Data Interpretation, Statistical; Drug Monitoring; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic; Middle Aged; Nursing Assessment

Anemia management using erythropoietin and intravenous iron supplementation has improved the lives of many patients with end stage renal disease (ESRD). However, because iron is an essential nutrient for microorganisms, it is plausible that iron supplementation may promote infection. This review examines the literature on the connection between iron and infection, with a focus on the relevance of these data to hemodialysis patients treated according to the National Kidney Foundation--Dialysis Outcomes Quality Initiative (NKF-DOQI) Guidelines for Anemia Management. The current evidence does not show a cause-and-effect relationship between intravenous iron administration and an increased susceptibility to infection in hemodialysis patients. Therefore, the author does not recommend changing current iron management practices in ESRD patients because of concern about infectious risk.

Topics: Anemia, Iron-Deficiency; Bacterial Infections; Erythropoietin; Evidence-Based Medicine; Humans; Iron Compounds; Kidney Failure, Chronic; Practice Guidelines as Topic; Renal Dialysis; Research Design; Risk Factors

Hyporesponse to Epoetin alfa therapy can be minimized by categorizing patients on the basis of trends in hemoglobin/hematocrit levels and initiating a continuous quality improvement effort that focuses on subnormal outcomes. An algorithm is provided that clinicians can use to proactively assess common causes that contribute to hyporesponse and limit the effect on patient outcomes.

Topics: Algorithms; Anemia, Iron-Deficiency; Decision Trees; Drug Monitoring; Erythropoietin; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic; Nursing Assessment; Quality of Life; Total Quality Management

Topics: Anemia, Hypochromic; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Iron Compounds; Kidney Failure, Chronic; Male; Prognosis; Quality of Life; Renal Dialysis; Treatment Outcome

The hormonal aberrations that occur with end-stage renal disease (ESRD) are presented in this review in relation to fertility and conception among women on dialysis. The imbalance in gonadotropin production in dialysis-dependent men and women is characterized by elevations in luteinizing hormone (LH). In women dialysis patients, the normal estradiol-stimulated LH surge does not occur, resulting in anovulation. In men dialysis patients spermatogenesis is impaired, and low testosterone levels cause elevated LH. Infertility in those with ESRD is a culmination of many factors, including impotence and loss of libido, anovulation, and an altered hormonal milieu. Despite these inhibitors of conception, women on dialysis can conceive; pregnancy has been reported in 1% to 7% of women on dialysis in survey studies. The influence of dialysis mode (hemodialysis v peritoneal dialysis), recombinant human erythropoietin (EPO), and dialysis adequacy on the likelihood of conception among patients of either sex on dialysis is unknown. Reduced sexual activity and interest has consistently been reported in the ESRD population. The reasons for this are complex and likely involve the effects of comorbid illnesses, overall health status, body image factors, and hormonal alterations. Nephrologists rarely discuss conception and contraception with their women dialysis patients. Greater attention to these issues is needed.

Topics: Adult; Contraceptive Agents; Erythropoietin; Female; Fertilization; Humans; Infertility; Kidney Failure, Chronic; Male; Peritoneal Dialysis; Pregnancy; Recombinant Proteins; Renal Dialysis; Uremia

Topics: Diabetic Nephropathies; Erythropoietin; Glucose Intolerance; Humans; Insulin Resistance; Kidney Failure, Chronic; Renal Dialysis

The possibility of lower efficacy and the fear of an increased incidence of side effects may explain the reluctance to use recombinant human erythropoietin (r-HuEPO) in patients with impaired renal function who do not yet require dialysis, as well as in transplanted patients with a failing renal allograft. Several recent studies have clearly shown that r-HuEPO is effective in these patient populations and that the doses needed to control anaemia are comparable with or lower than those needed for dialysis patients. When started at a low dose, the risk of severe hypertension is minimal, although in a significant number of patients intensification of the antihypertensive regimen is needed. Moreover, there are no indications that the use of r-HuEPO accelerates the deterioration of residual renal function.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Recombinant Proteins; Renal Dialysis; Safety

Optimizing the use of recombinant human erythropoietin (r-HuEPO) involves choosing an appropriate dose regimen and target haemoglobin level, addressing factors that inhibit response, and considering appropriate adjuvant therapy. Subcutaneous administration of r-HuEPO two or three times weekly is optimal for most patients. Early detection and treatment of iron deficiency is mandatory. Measurement of the percentage of hypochromic red blood cells is a reliable marker of functional iron deficiency, and the treatment of choice is intravenous iron. Other factors that can affect the response to r-HuEPO include blood loss (sometimes occult), infection, inflammation, hyperparathyroidism with marrow fibrosis, aluminium toxicity, vitamin B12/folate deficiency, haemolysis, bone marrow disorders, haemoglobinopathies, under-dialysis and possibly angiotensin-converting enzyme inhibitors. These factors should be identified and corrected where possible. Ascorbic acid, vitamin D, folic acid, carnitine, other cytokines and growth factors have all been shown to augment the response to r-HuEPO in some patients. Further research is required before any of these adjuvant therapies can be incorporated into routine clinical practice. With regard to target haemoglobin value, the current practice is to aim for a level of 10-12 g/dl, but it may be argued that a higher target would achieve greater benefits in terms of physical performance, quality of life, and possibly cardiac morbidity and mortality. International multicentre trials are currently in progress to address this issue, as are studies on other substances that may be able to stimulate erythropoiesis.

Topics: Anemia; Ascorbic Acid; Carnitine; Clinical Trials as Topic; Cytokines; Drug Administration Schedule; Erythropoietin; Folic Acid; Growth Substances; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Iron; Iron Deficiencies; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Vitamin D

The improved outcomes recently experienced by children with chronic renal failure and end stage renal disease (ESRD) does not obviate the need to strive to better the quality of their physical, mental and emotional well-being. This article reviews some of the recent advances in the care of these children that are intended to achieve that goal. Dialysis topics include prescription, novel solutions, adequacy measures, management of anemia, and access. Transplantation areas covered include graft and patient survival, growth, organ availability, opportunistic infections and immunity, immunosuppressive agents, and transplant-related malignancies. The care of the pre-ESRD patient is discussed with a review of new data that are being compiled in this patient population.

Topics: Child; Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Topics: Anemia; Anemia, Hypochromic; Antihypertensive Agents; Blood Transfusion; Cardiovascular Diseases; Combined Modality Therapy; Erythropoietin; Hemoglobins; Humans; Hypertension; Immunocompromised Host; Immunosuppressive Agents; Iron; Iron Deficiencies; Kidney Failure, Chronic; Nutrition Disorders; Recombinant Proteins; Renal Dialysis

We investigated the in vitro erythroid progenitor growth and the effects of sera on normal-marrow CFU-E (colony-forming units - erythroid) growth in 2 patients with renal failure on regular hemodialysis following a prior history of polycythemia vera (PV). PV was diagnosed 3 and 11 years, respectively, before the development of terminal renal failure. One of the patients had entered a spent phase of PV as characterized by diffuse extensive myelofibrosis and anemia; the other also had mild myelofibrosis. The serum erythropoietin (EPO) levels were low or normal on serial measurements by radioimmunoassay. There was no correlation between the hematocrit values and serum EPO levels. EPO-independent erythroid colonies were present in the cultures of bone marrow and peripheral blood cells from both patients after renal failure in the anemic state. With the addition of various concentrations of EPO, the number of erythroid colonies increased as the concentrations of EPO increased which was in accordance with the clinical observation that 1 patient with postpolycythemic myeloid metaplasia partially responded to recombinant human EPO therapy. In the EPO-dependent CFU-E assay, normal-marrow CFU-E numbers supported by 10% of the patient sera were less than those by normal sera. In the absence of EPO in cultures, no erythropoietic activity was found in the patients' sera. Our study on uremic patients with underlying PV showed that the biologic characteristics of autonomous erythroid progenitor growth for PV persisted during the spent phase and after the development of terminal renal failure with anemia. The erythroid progenitors responded to EPO both in vitro and in vivo. Their sera exhibited an inhibiting effect on the growth of normal-marrow erythroid progenitors.

Topics: Adult; Anemia; Blood Proteins; Cell Division; Cells, Cultured; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hematopoietic Stem Cells; Humans; Kidney Failure, Chronic; Middle Aged; Polycythemia Vera; Recombinant Proteins; Renal Dialysis

Epoetin alfa is the cornerstone of anemia therapy in patients with end-stage renal disease. In addition to stimulating erythropoiesis, Epoetin alfa has been demonstrated to affect hemostasis. Such effects may be important because patients with chronic renal failure have a bleeding diathesis that is multifactorial in origin. Therefore, a computer literature search on the relationship between Epoetin alfa therapy for anemia in patients with end-stage renal disease and platelets, coagulation, coagulation inhibitors, and fibrinolysis was performed. All articles and abstracts reporting original data in the English language on Epoetin alfa and its effect on hemostasis were reviewed. The literature suggests that the effects of Epoetin alfa on the coagulation cascade are of minimal clinical importance. However, Epoetin alfa transiently increases the number of circulating platelets and improves platelet function, and these effects are associated with a return of the bleeding time towards normal.

Topics: Anemia; Epoetin Alfa; Erythropoietin; Fibrinolysis; Hematinics; Hemostasis; Humans; Kidney Failure, Chronic; Recombinant Proteins

The rationale for treatment with recombinant human erythropoietin (rHuEPO) in thalassemia came from studies in baboons, thalassemic mice and in erythroid cultures. The results demonstrated an increase in gamma globin synthesis and consequently in fetal Hb (Hb F) resulting in improvement in erythropoietic parameters. In addition, endogenous serum Epo levels in various forms of thalassemia were inconsistent and not related to the severity of the anemia. Therefore, several preliminary studies with rHuEPO were performed, mainly on patients with beta thalassemia intermedia. The results indicate: a) a significant, dose-related (500 u/kg to 1000 u/kg x 3/week) increase in thalassemia erythropoiesis without changes in % of Hb F, MCV and MCH, mainly in splenectomized patients; b) the minimum effective dose is 500 u/kg x 3/week; c) there were no major side effects during the continuous treatment period of 9 months. In order to improve both quantitative and qualitative thalassemia erythropoiesis, several trials were undertaken combining rHuEPO with hydroxyurea (HU), which is known to increase % Hb F, MCV and MCH without a major effect on Hb levels. The designed trial included 3 to 6 months of HU alone (20 mg/kg x 4/week), or with rHuEPO alone (500 u/kg x 3/week or 375 u/kg x 2/week) or a combination of the two drugs. The results show an additive effect of the two drugs, in some of the patients. It is not known whether the addition of oral iron to rHuEPO is warranted for maximal erythropoietic response. The major limiting factor in designing large scale clinical trials is the relatively high cost of the drug. Nevertheless rHuEPO alone or in combination with other Hb F modulating drugs may have a positive effect in thalassemia with resulting improvement in the quality of life.

Topics: Animals; beta-Thalassemia; Erythropoiesis; Erythropoietin; Fetal Hemoglobin; Globins; Humans; Kidney Failure, Chronic; Mice; Recombinant Proteins

Topics: Anemia; Cost-Benefit Analysis; Erythropoietin; Hematocrit; Humans; Iron; Kidney Failure, Chronic; Recombinant Proteins; Risk Factors; Treatment Outcome; United States

We experienced a patient on continuous ambulatory peritoneal dialysis (CAPD) who showed hypererythropoietinemia (Epo concentration: 86.7 mU/ml, normal range: 8-36 mU/ml), erythrocytosis, high renin concentration (26.5 pg/ml) and chronic hypotension. In this patient the erythrocytosis progressed along with exacerbation of the chronic severe hypotensive state. This patient had systemic circulatory insufficiency as suggested by the fact that he had a fibrous myocardium and an increased anion gap. We hypothesized that circulatory insufficiency due to chronic severe hypotension may lead to the stimulation of the Epo production, due to a decreased oxygen supply to peripheral tissues and/or to the stimulation of the renin angiotensin system even in patients with end-stage renal failure.

Topics: Aged; Chronic Disease; Erythropoietin; Fatal Outcome; Humans; Hypotension, Orthostatic; Kidney; Kidney Failure, Chronic; Male; Myocardium; Peritoneal Dialysis, Continuous Ambulatory; Renin

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Morbidity; Recombinant Proteins; Renal Replacement Therapy; Risk Factors

Topics: Adult; Age Factors; Aged; Cost-Benefit Analysis; Erythropoietin; Hemodialysis, Home; Humans; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Quality of Life; Quality-Adjusted Life Years; Recombinant Proteins; Renal Dialysis; Socioeconomic Factors; Surveys and Questionnaires; Terminal Care; Time Factors

Infectious and inflammatory disorders cause a disturbance in iron metabolism that leads to a sequestration of iron in the reticuloendothelial (R-E) system and a sometimes sharp and sudden decline in red blood cell indices. Underlying inflammatory conditions can decrease responsiveness to Epoetin alfa in dialysis patients and complicate anemia management. Understanding the possible infectious and inflammatory etiologies that can affect enemia management is essential to enhancing the nursing care of dialysis patients. Nurses caring for patients receiving Epoetin alfa must be aware of the possible effects of these conditions and know how to assess, detect, intervene, and evaluate factors that detract from an optimal erythropoietic response.

Topics: Aged; Anemia; Erythropoietin; Humans; Infections; Inflammation; Kidney Failure, Chronic; Male; Nursing Assessment; Renal Dialysis

At Winthrop-University Hospital, implementation of the National Kidney Foundation's Dialysis Outcome Quality Initiative (NKF-DOQI) is guided by the principles of reengineering. On the basis of this model, anemia management is entrusted to a process owner. This advanced practice nurse is empowered with the responsibility of managing anemia and evaluated on his/her success in attaining predetermined quality standards-including ongoing patient satisfaction. This article examines use of the process owner position to evaluate, implement, and proactively manage anemia-related outcomes.

Topics: Anemia, Iron-Deficiency; Erythropoietin; Humans; Infusions, Intravenous; Iron Compounds; Kidney Failure, Chronic; Renal Dialysis

Chronic renal failure, dialysis and transplantation have major effects on male reproductive health because of the impairment of spermatogenesis, steroidogenesis and sexual function. Hypothalamo-pituitary testicular dysfunction in uraemia is manifest clinically as delayed growth and puberty, sexual dysfunction, androgen deficiency, impaired spermatogenesis and infertility. Apart from renal anaemia, there are at present no proven indications for androgen therapy in chronic renal failure. This chapter reviews the basis and scope for various clinical applications of gonadotropin and androgen therapy as an adjunct to the standard medical care of chronic renal failure. The therapeutic possibilities implied by experimental and clinical findings suggesting that uraemic hypogonadism may be a functional state of gonadotropin deficiency are emphasized.

Topics: Anemia; Clinical Trials as Topic; Enuresis; Erythropoietin; Gonadotropins; Growth Disorders; Humans; Infertility, Male; Kidney Failure, Chronic; Male; Puberty, Delayed; Sleep Apnea Syndromes; Testosterone

One of the important components of successful anemia therapy in patients with end-stage renal disease (ESRD) treated with recombinant human erythropoietin is the maintenance of adequate available iron. To accomplish this task, iron status must be serially monitored and supplemental iron administered as required. Among nonuremic subjects, the body's iron supply is tightly conserved, and iron deficiency usually develops only when chronic blood loss occurs. In patients with ESRD, iron deficiency occurs more frequently, because of increased external losses of iron, decreased availability of the body's storage of iron, and perhaps a deficit in intestinal iron absorption. Detecting iron deficiency in these patients can be difficult because of the inaccuracy of available diagnostic tests. The goals of iron therapy in ESRD include the prevention of iron deficiency by chronically supplementing iron, and the prompt treatment of overt iron deficiency. Oral iron supplements are inexpensive and safe, but poor patient compliance and reduced intestinal absorption may limit their effectiveness. Intravenous iron supplements have a greater efficacy then oral iron, which must be weighed against the small risk of allergic reactions. We present strategies for using the various diagnostic tests and treatment modalities to effectively manage iron supply for predialysis, hemodialysis, and peritoneal dialysis patients.

Topics: Anemia, Iron-Deficiency; Erythropoietin; Ferritins; Humans; Iron; Kidney Failure, Chronic; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis; Transferrin

Topics: Amino Acid Sequence; Anemia; Animals; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Models, Biological; Molecular Sequence Data

Topics: Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Careful evaluation of iron status is of pivotal importance in end-stage renal disease patients before and during r-HuEPO therapy. Absolute (ferritin < 100 micrograms/l) and functional (ferritin normal or supranormal, transferrin saturation < 20%, hypochromic red blood cell [RBC] > 5%) iron deficiency are the main reasons for r-HuEPO hyporesponsiveness. Adequate iron supplementation allows significant reduction of r-HuEPO dosage and costs. Oral iron supplementation is recommended for predialysis and peritoneal dialysis patients with serum ferritin > 100 micrograms/l, whereas i.v. iron supplementation is the therapy of choice in hemodialysis patients. However, neutrophil impairment and other possible side-effects (e.g. cardiovascular complications, malignancy) as a result of i.v. iron therapy suggest that overtreatment with i.v. iron should be avoided.

Topics: Aluminum; Enzyme Inhibitors; Erythrocytes; Erythropoietin; Ferritins; Hemoglobins; Humans; Iron; Iron Deficiencies; Kidney Failure, Chronic; Protoporphyrins; Recombinant Proteins; Transferrin

The mechanism of resistance to recombinant human erythropoietin (EPO) in hemodialysis patients with hemoglobinopathy is not yet fully understood. Poor responses to EPO have been reported in anemic dialysis patients with sickle cell disease and thalassemia. We present the first case of a hemodialysis patient with EPO resistance and hemoglobin J-Meinung, which is initially found by hemoglobin electrophoresis and finally proven by molecular genetic analysis. Additionally, the patient was diagnosed as having chronic active hemolysis with hallmarks of splenomegaly, an increased serum bilirubin and reticulocyte index, and a reduced haptoglobin level. We discuss the possible mechanisms and proper treatment options in such patients with a poor response to EPO.

Topics: Adult; Base Sequence; Erythropoietin; Hemoglobin J; Hemoglobinopathies; Heterozygote; Humans; Kidney Failure, Chronic; Male; Molecular Sequence Data; Polymerase Chain Reaction; Recombinant Proteins; Renal Dialysis

Topics: Anemia; Animals; Erythropoietin; Hematocrit; Hemoglobins; Humans; Iron Deficiencies; Kidney; Kidney Failure, Chronic; Quality of Life; Receptors, Erythropoietin; Recombinant Proteins; Renal Replacement Therapy

Quality improvement techniques provide a scientific approach that allows nurses and other health care professionals to improve patient satisfaction and outcomes. Continuous quality improvement (CQI) encourages the health care team to move beyond minimum standards of care and create an environment in which all team members are continuously working to improve services. This article reviews the principles of CQI and discusses the nurses' role in implementing and maintaining a successful CQI program. Anemia management is used as an example to illustrate how CQI principles and tools can lead to improvements in patient outcomes.

Topics: Anemia; Critical Pathways; Erythropoietin; Humans; Kidney Failure, Chronic; Outcome and Process Assessment, Health Care; Renal Dialysis; Total Quality Management

Iron deficiency is common in patients with end stage renal disease (ESRD) receiving recombinant human erythropoietin (rHuEPO). Consequently, such patients require routine iron monitoring by measurement of serum ferritin and transferrin saturation, with interpretation of these values in light of the response to rHuEPO. This article will review issues related to iron metabolism, the causes and diagnosis of absolute and functional iron deficiency, and treatment options for iron deficiency. In addition, the role of the nurse in iron management will be identified.

Topics: Anemia, Iron-Deficiency; Drug Monitoring; Erythropoietin; Ferrous Compounds; Humans; Kidney Failure, Chronic; Nephrology; Specialties, Nursing

Impaired cognitive function, a common morbidity associated with end-stage renal disease (ESRD), can hinder a patient's ability to work with the dialysis team and live well. A combination of adequate dialysis and correction of anemia with Epoetin alfa can mitigate the neurobehavioral syndrome associated with ESRD and lead to improved cognition. In the presence of suspected cognitive impairment, nursing management should emphasize techniques that provide individualized, innovative, and ongoing reinforcement of treatment goals and outcomes to improve patients' overall quality of life.

Topics: Anemia; Cognition Disorders; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Middle Aged; Quality of Life; Renal Dialysis

Studies in rats with renal ablation indicate that anemia lessens, whereas its vigorous correction with recombinant human erythropoietin (r-HuEPO) worsens systemic and glomerular hypertension, factors known to promote progression of chronic renal failure (CRF). However, in human studies, use of r-HuEPO in predialysis patients has not been associated with worsening renal function, provided blood pressure control is achieved. Histological evidence of bone disease is common in early renal failure, and deficits in calcitriol synthesis seem to be an important factor in the pathogenesis of secondary hyperparathyroidism (HPTH) in early CRF. Reports to data, on the use of low dose active vitamin D metabolites in predialysis patients, indicate either a reversible decline or no decline in renal function. Adynamic bone disease, however, may ensure during such therapy if excessive reductions in serum intact parathyroid hormone concentrations occur. Recent data suggest that chronic metabolic acidosis decreases albumin synthesis, increases muscle proteolysis, and induces negative nitrogen balance in patients with CRF. Despite these experimental data, the clinical relevance of correction of metabolic acidosis in end-stage renal disease (ESRD) is still not defined. Even though therapy of metabolic acidosis in the adult patient with CRF remains conjectural at this time, reports indicate that its correction might lead to healing of osteomalacia and osteopenia, and possibly may decrease protein degradation and improve growth in children with CRF.

Topics: Acidosis; Adult; Anemia; Animals; Calcitriol; Calcium Compounds; Cholecalciferol; Chronic Kidney Disease-Mineral and Bone Disorder; Ergocalciferols; Erythropoietin; Humans; Kidney Failure, Chronic; Rats; Recombinant Proteins; Renal Dialysis

Much progress has been made in recent years in the management of anemia associated with chronic and renal failure with recombinant human erythropoietin (r-Hu EPO). However, there remains much debate surrounding the diagnosis and treatment of iron deficiency. To ensure that full benefit from erythropoietin therapy is received, most patients require iron supplement during treatment. There are, however, few guidelines for the use of iron therapy. Iron deficiency results in an inadequate response to r-Hu EPO and is the main cause of resistance to this treatment. Oral iron therapy is of limited value in patients receiving r-Hu EPO. Thus, intravenous iron supplementation should be administered only in patients who do not tolerate available intravenous iron preparations or who are on continuous ambulatory peritoneal dialysis with no evidence of functional iron deficiency. This article provides guidelines for the diagnosis of absolute or functional iron deficiency in patients with renal anemia and suggests treatment schedules for intravenous iron supplementation. We hope that all dialysis patients will be able on this basis to achieve a satisfactory iron status and benefit fully from r-Hu EPO therapy.

Topics: Anemia; Anemia, Iron-Deficiency; Erythropoietin; Ferritins; Humans; Infusions, Intravenous; Iron; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

To investigate an appropriate hematocrit (Hct) for managing renal anemia complicated by angina pectoris at rest.. Nonrandomized, retrospective and prospective observational study.. Sapporo Medical University Hospital, Sapporo, Japan.. Thirty-two anemic patients (aged 62 +/- 10 years, range 40 to 78) with rest angina in end-stage renal failure.. Serial changes of exercise tolerance (estimated metabolic equivalents [METs] on stress electrocardiography produced by improvement of patients' Hct, using recombinant human erythropoietin (rHuEPO). Adverse effects, such as deteriorating systemic hypertension, were investigated with regard to the severity of coronary arteriographic findings (Leaman's score) and cardiac events within a six-month period.. Higher Hct was clearly correlated with better estimated METs: when Hct was less than 20%, MET was 1.4 +/- 0.5; with 20% < or = Hct < 25% 2.1 +/- 1.4; with 25% < or = Hct < 30% 3.1 +/- 1.6; and with 30% < or = Hct < 35% 4.9 +/- 1.1. Patients with cardiac events (elective balloon angioplasty [n = 5], bypass surgery [n = 1], myocardial infarction [n = 2] and hospital death from congestive heart failure [n = 3]) had advanced coronary lesions compared with patients without coronary events (Leaman's score 15.9 +/- 9.3 versus 7.3 +/- 4.4, respectively, P < 0.01) and lower exercise capacity at 25% < or = Ht < 30% (estimated METs 2.4 +/- 1.2 versus 3.9 +/- 1.9, respectively, P < 0.05). Moreover, there was an inverse linear correlation between estimated METs and Leaman's score only when Hct was over 25%. In prospectively examined subjects (n = 16), Hct 35% or greater without systemic hypertension was obtained in only seven (44%), and no additional effect on exercise tolerance was expected when Hct was 35% or greater.. Managing renal anemia with 30% < or = Hct < 35% with rHuEPO is considered an appropriate therapy in patients with end-stage renal failure complicated by rest angina.

Topics: Adult; Aged; Anemia; Coronary Disease; Erythropoietin; Female; Hematocrit; Humans; Informed Consent; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Retrospective Studies

Topics: Cardiovascular System; Catheters, Indwelling; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Physical Endurance; Quality of Life; Recombinant Proteins; Thrombosis

Topics: Blood Pressure; Blood Volume; Cell Size; Controlled Clinical Trials as Topic; Erythrocyte Count; Erythrocytes; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Multicenter Studies as Topic; Renin-Angiotensin System; Vascular Resistance

Improving patient outcomes by achieving a stable Hct in the higher end of the target Hct range of 30% to 36% is the primary goal of anemia management and Epoetin alfa therapy. Recently, attention has been focused on the potential differences between subcutaneous (s.c.) and intravenous (i.v.) administration. Although some patients may require less Epoetin alfa when it is administered by the s.c. route, many patients require the same dose or more due to the significant heterogeneity in response. To ensure that therapeutic outcomes are maintained or improved, clinicians should evaluate both staff considerations and individual patient tolerance and response when determining the optimal route of administration.

Topics: Anemia; Education, Nursing, Continuing; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Molecular Biology; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction

Topics: Anemia; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; Toxins, Biological; Uremia

Absolute and functional iron deficiency is the most common cause of epoetin (recombinant human erythropoietin) hyporesponsiveness in renal failure patients. Diagnostic procedures for determining iron deficiency include measurement of serum iron levels, serum ferritin levels, saturation of transferrin and percentage of hypochromic red blood cells. Patients with iron deficiency should receive supplemental iron, either orally or intravenously. Adequate intravenous iron supplementation allows reduction of epoetin dosage by approximately 40%. Intravenous iron supplementation is recommended for all patients undergoing haemodialysis and for pre-dialysis and peritoneal dialysis patients with severe iron deficiency. During the maintenance phase (period of epoetin therapy after correction of iron deficiency), the use of low-dose intravenous iron supplementation (10 to 20 mg per haemodialysis treatment or 100 mg every second week) avoids iron overtreatment and minimises potential adverse effects. Depending on the degree of pre-existing iron deficiency, markedly higher iron doses are necessary during the correction phase (period of epoetin therapy after correction of iron deficiency) [e.g. intravenous iron 40 to 100 mg per haemodialysis session up to a total dose of 1000 mg]. The iron status should be monitored monthly during the correction phase and every 3 months during the maintenance phase to avoid overtreatment with intravenous iron.

Topics: Anemia, Iron-Deficiency; Citric Acid; Drug Combinations; Drug Monitoring; Erythropoietin; Ferric Compounds; Ferric Oxide, Saccharated; Ferrous Compounds; Glucaric Acid; Humans; Infusions, Intravenous; Injections, Intravenous; Iron Compounds; Iron Overload; Iron-Dextran Complex; Kidney Failure, Chronic; Sorbitol

Clinical evidence indicates that maintaining a stable hematocrit (Hct) higher in the target range of 30% to 36% can lead to improvement in overall patient outcomes. On the basis of these data, a recent analysis by the Dialysis Outcomes Quality Initiative Anemia Work Group has recommended a target Hct of 33% to 36% (hemoglobin 11 g/dl to 12 g/dl). Maintaining a stable Hct higher in the target range provides nurses and other dialysis clinicians with two benefits: improved patient care and decreased time and costs for patient management. This article focuses on the data supporting such a policy. Clinical practices from two prominent dialysis centers are presented as models of good anemia management.

Topics: Anemia; Body Weight; Epoetin Alfa; Erythropoietin; Health Status; Hematinics; Hematocrit; Humans; Kidney Failure, Chronic; Patient Care Planning; Recombinant Proteins; Survival Analysis

Topics: Anemia; Blood Pressure; Clinical Trials as Topic; Erythropoietin; Hemodynamics; Humans; Hypertension; Kidney Failure, Chronic; Male; Monitoring, Physiologic; Multicenter Studies as Topic; Recombinant Proteins; Renal Dialysis; Risk Factors; Vascular Resistance

Topics: Anemia; Chronic Disease; Erythrocyte Count; Erythropoiesis; Erythropoietin; Humans; Infections; Kidney Failure, Chronic; Neoplasms; Rheumatic Diseases

The addition of recombinant human erythropoietin (rHuEPO) to the therapeutic regimen for children with chronic renal failure (CRF) is one of the most important improvements in care in the last 20 years. Anemia had played an important role in the morbidity of chronic dialysis treatment. Before the availability of rHuEPO, repeated erythrocyte transfusions provided incomplete treatment and had significant long-term sequelae. Recombinant erythropoietin treatment resulted in the amelioration of anemia and marked reduction in transfusions. Additional benefits of the correction of anemia with rHuEPO include improvements in exercise tolerance and regression of ventricular hypertrophy. Many rHuEPO-treated patients have had subjective increases in appetite, but there has been no consistent improvement in dietary intake or anthropometric measures. Correction of anemia with rHuEPO has not been shown to improve the growth of children with CRF receiving dialysis. The most significant adverse effects of rHuEPO are the development of iron deficiency and the exacerbation or development de novo of hypertension. RHuEPO treatment has been shown to treat the anemia of CRF in children safely and effectively. In most cases, putative inhibitors of erythropoiesis and blood loss can be overcome. Many of the symptoms previously ascribed to "uremia" have improved with correction of anemia. The full implications of treatment of anemia with rHuEPO will be clearer when the health outcomes for children who never become severely anemic or require transfusions are more completely studied.

Topics: Anemia; Child; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Topics: Aluminum; Anemia; Bone Diseases; Erythropoietin; Humans; Hypoparathyroidism; Kidney Failure, Chronic; Models, Biological

Topics: Anemia; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Half-Life; Hemoglobinometry; Humans; Kidney Failure, Chronic; Metabolic Clearance Rate; Peritoneal Dialysis

Partial correction of renal anemia by the use of recombinant human erythropoietin is associated with various effects on cardiovascular performance parameters. A decrease in cardiac output as well as an increase in systemic peripheral resistance have been noted and the pathogenetic basis of these changes will be discussed. Furthermore this article will focus on the potential cardiovascular consequences of prolonged correction of anemia in patients with renal failure. The literature on the clinical implications, such as left ventricular hypertrophy, peripheral arterial occlusive disease and finally patient care costs, will be discussed.

Topics: Anemia; Cardiac Output; Erythropoietin; Hematocrit; Hemodynamics; Hemoglobins; Humans; Kidney Failure, Chronic; Vascular Resistance

Epoetin beta is a recombinant form of erythropoietin, the hormone responsible for the maintenance of erythropoiesis. The drug binds to and activates receptors on erythroid progenitor cells which then develop into mature erythrocytes. Epoetin beta increases reticulocyte counts, haemoglobin levels and haematocrit in a dose-proportional manner. These changes are accompanied by beneficial cardiovascular effects, including decreased cardiac output, resting heart rate and left ventricular hypertrophy in patients with chronic renal failure (CRF). Increases of 15 to 54% in haemoglobin levels and 17 to 60% in haematocrit were reported after subcutaneous or intravenous epoetin beta therapy in studies of 8 weeks' to 12 months' duration. Two multicentre clinical trials demonstrated clearly the superior efficacy of epoetin beta over placebo in 229 patients with CRF undergoing haemodialysis. Reduction or elimination of transfusion requirements was reported in studies where this parameter was measured. Comparative data indicate that dosage reductions of approximately 30% compared with intravenous therapy are possible when subcutaneous administration of epoetin beta is used. Haematocrit increased more rapidly in 5 multicentre studies in patients who received epoetin beta subcutaneously than in those who received the same dosage intravenously. Correction of anaemia with epoetin beta is associated with significant improvements in quality of life in patients with CRF. Available data indicate greatest cost-effectiveness in patients who are severely incapacitated by anaemia before treatment. The cost of administration of the drug may also be reduced by the use of the subcutaneous route. Hypertension may occur in patients who receive epoetin beta but may be minimised by avoiding rapid increases in haematocrit (> 0.5%/week), and is managed in most cases with control of fluid status and antihypertensive medication. Although clotting of the vascular access has not been conclusively linked to epoetin beta, caution is recommended in patients undergoing haemodialysis. Increased heparinisation is recommended to prevent clotting in dialysis equipment. Epoetin beta is more effective and/or better tolerated than alternative treatments (e.g. androgenic steroids) for anaemia associated with CRF. It also causes significant improvements in quality of life, exercise capacity and overall well-being. Results of clinical studies indicate that subcutaneous administration is desirable where possi

Topics: Anemia; Animals; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Aluminum; Bone and Bones; Deferoxamine; Erythropoietin; Humans; Iron; Kidney Failure, Chronic; Parathyroid Hormone

Topics: Anemia; Antibody Formation; Endothelium, Vascular; Erythropoietin; Glomerulonephritis, IGA; Humans; Immunity, Cellular; Kidney; Kidney Failure, Chronic; Research; Singapore

Topics: Erythropoietin; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins

Renal disease is characterized by failure of erythropoietin (Epo) production and low bone marrow sensitivity to Epo. The reticulocyte count is the best laboratory marker of erythropoiesis available, but reticulocytes have not been extensively studied in renal disease. Cluster analysis suggests that in non-haemodialysed renal patients the anaemia is associated with uraemia while the reticulocyte number and immature subclasses are correlated with the ineffective erythropoietic component of the anaemia. This emphasizes the importance of treating the renal disease in patients with the anaemia of end-stage renal failure. Human recombinant Epo therapy has been demonstrated to be effective in correcting anaemia in most cases of chronic renal insufficiency. In renal patients the reticulocyte count should only be monitored by automated methods to assure reliability at low counts.

Topics: Anemia; Cluster Analysis; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Reticulocyte Count

Erythropoietin, a glycoprotein, is synthesized mainly in the kidney. With the destruction of renal tissue, erythropoietin production decreases; this is a major factor in the development of anemia in patients with renal failure. For about ten years now, recombinant human erythropoietin has been available for the treatment of renal anemia. All patients with renal insufficiency, independent of their plan for future renal replacement therapy, may benefit from erythropoietin. At what extent of anemia erythropoietin therapy should be started is still discussed and is certainly dependent on the degree of the patient's impairment by his anemia. Before beginning a therapy with erythropoietin, other forms of anemia observed in patients with renal failure, i.e. mainly iron deficiency, have to be excluded. A strict monitoring of hematocrit during treatment with erythropoietin is mandatory. Hypertension, seizures and cardiovascular complications have been observed with overdosing of erythropoietin. Special emphasis of this review is therefore put on the discussion of the dynamics of the erythropoietin-red cell system.

Topics: Anemia, Hypochromic; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins

Splenic peliosis was identified at necropsy in a 62-year-old woman receiving continuous ambulatory peritoneal dialysis for end-stage renal failure, and erythropoietin therapy for uraemia and anaemia. The immediate cause of death was arrhythmia related to ischaemic heart disease, following an episode of intramuscular haematoma (secondary to platelet dysfunction). The unusual association between peliosis and renal failure, and possibly erythropoietin therapy, is discussed.

Topics: Anemia; Erythropoietin; Fatal Outcome; Female; Hematoma; Humans; Kidney Failure, Chronic; Middle Aged; Splenic Diseases; Uremia

Topics: Anemia; Electrolytes; Energy Metabolism; Erythropoietin; Exercise; Humans; Insulin Resistance; Kidney Failure, Chronic; Muscles; Proteins

Epoetin alfa is a recombinant form of erythropoietin, a glycoprotein hormone which stimulates red blood cell production by stimulating the activity of erythroid progenitor cells. This review discusses the use of the drug in the management of anaemia in diseases often associated with advancing age [renal failure, cancer, rheumatoid arthritis (RA) and other chronic diseases, and the myelodysplastic syndromes (MDS)] and in surgical patients. Intravenous and subcutaneous therapy with epoetin alfa raises haematocrit and haemoglobin levels, and reduces transfusion requirements, in anaemic patients with end-stage renal failure undergoing haemodialysis or peritoneal dialysis. The drug is also effective in the correction of anaemia in patients with chronic renal failure not yet requiring dialysis and does not appear to affect renal haemodynamics adversely or to precipitate the onset of end-stage renal failure. Response rates of 32 to 82% with epoetin alfa therapy have been reported in patients with anaemia associated with cancer or cytotoxic chemotherapy. Limited data in patients with anaemia associated with RA show correction of anaemia after epoetin alfa treatment. Response rates to the drug of 0 to 56% have been noted in patients with MDS. Epoetin alfa also reduces anaemia, increases the capacity for autologous blood donation and reduces the need for allogeneic blood transfusion in patients scheduled to undergo surgery. Hypertension occurs in 30 to 35% of patients with end-stage renal failure who receive epoetin alfa, but this can be managed successfully with correction of fluid status and antihypertensive medication where necessary, and is minimised by avoiding rapid increases in haematocrit. Although vascular access thrombosis has not been conclusively linked to therapy with the drug, increased heparinisation may be required when it is administered to patients on haemodialysis. Epoetin alfa does not appear to exert any direct cerebrovascular adverse effects. Thus, epoetin alfa is a well established and effective therapy for the management of anaemia associated with renal failure. It also improves haematocrit and quality of life in patients with anaemia associated with cancer or chemotherapy. Epoetin alfa increases the capacity for blood donation and reduces the decrease in haematocrit seen in patients donating autologous blood prior to surgery. It also reduces, but may not eliminate, the need for allogeneic blood transfusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adolescent; Adult; Aged; Anemia; Chronic Disease; Erythropoietin; Humans; Kidney Failure, Chronic; Middle Aged; Postoperative Complications; Recombinant Proteins

Recombinant human erythropoietin is increasingly used to treat anemia in predialysis patients. Approximately 33-40% of patients ultimately receiving dialysis or a transplant may be eligible for treatment, thus increasing the costs. Clinical trials demonstrate no significant alteration in the progression of renal disease, secondary to changes in systemic hemodynamics or blood volume, provided that blood pressure is controlled. Hypertension results from changes in viscosity and erythrocyte fluidity, loss of hypoxic vasodilatation, and changes in blood volume. The predialysis patient treated with recombinant human erythropoietin is likely to need aggressive antihypertensive therapy and vigorous diuresis. Cardiac output remains unchanged in the absence of blood volume expansion. The effects on left ventricular hypertrophy, left ventricular volume, or exercise-induced ischemic electrocardiographic changes in predialysis have not been studied systematically. Doses of recombinant human erythropoietin in predialysis patients tend to be lower when administered subcutaneously rather than intravenously, but the comparative cost-effectiveness of different dosing strategies is currently unknown. The dosing frequency can vary from three times a week to twice a month. The effect of anemia correction on the 'rehabilitation' of predialysis patients remains to be addressed.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Topics: Erythropoietin; Female; Graft Survival; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Quality of Life; Recombinant Proteins; Risk Factors; Survival Rate

A patient with advanced multiple myeloma (MM) and renal failure presented a severe chronic anemia requiring frequent blood transfusions. Treatment with recombinant human erythropoietin (rHuEPO) led to a rapid improvement of anemia, and further blood transfusions were not required. Pathophysiological studies about the erythropoiesis in patients with MM and trials with rHuEPO in myeloma-associated anemia are commented.

Topics: Aged; Anemia; Chronic Disease; Combined Modality Therapy; Erythropoietin; Fatal Outcome; Female; Humans; Immunoglobulin kappa-Chains; Kidney Failure, Chronic; Multiple Myeloma; Recombinant Proteins

The success of maintenance haemodialysis in the 1960s was blighted by the problem of anaemia. Treatment with iron, folic acid, androgens and transfusions did no more than minimize its effects. The need for a renewable source of erythropoietin was appreciated very early but the hope took 25 years to realize. Cloning and expression of the human gene was achieved in 1984 and clinical trials planned even before the descriptions of the recombinant hormone were published. The Amgen material was tested in parallel studies in Seattle and England and by the end of 1986 the efficacy of recombinant human erythropoietin (r-HuEPO) given in large intravenous bolus doses in reversing the anaemia of uraemia was established. The benefits were immediately obvious: relief from transfusion dependence was the unequivocal evidence but the effect on 'wellbeing' though subjective was remarkable. Large clinical trials were completed in Europe and the USA so that r-HuEPO was licensed as a therapeutic drug less than two years later. The pilot studies flagged a number of key issues: hypertension, sometimes with encephalopathy, occurred in patients whose blood pressure was labile before treatment; vascular access failure seemed more frequent and hyperkalaemia was thought to reflect less efficient dialysis. Failure to respond focused attention on iron balance as well as on factors such as infection, aluminium, and hyperparathyroidism. A more clear understanding of the pathogenesis of the anaemia of uraemia was made possible by dissection of the specific effects of the exogenous erythropoietin on erythroid function.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anemia; Drug Resistance; Erythropoietin; Humans; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins

Topics: Anemia; Erythropoietin; Humans; Injections, Intraperitoneal; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Recombinant Proteins

In an era of increasing scrutiny regarding use of health care resources, it is critical that physicians have rational, evidence-based guidelines for treatment decisions. This review of more than 200 published papers constitutes a comprehensive approach to evaluating the current evidence regarding the clinical use of recombinant human erythropoietin therapy in renal failure patients. After this review, specific recommendations are provided regarding who should receive r-HuEPO; what the target hemoglobin should be; the best route of administration of r-HuEPO; how iron status should be evaluated and managed; and monitoring and follow-up of patients taking r-HuEPO. Throughout the article, areas for important future research are also identified.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis

The induction or the aggravation of a hypertension is a side effect of recombinant human erythropoietin therapy in 30% of dialysed patients. Clinical manifestations can be severe. Pathogenesis of erythropoietin-induced hypertension is ill known. Peripheral vascular changes were found in most studies. Recently, it was demonstrated that erythropoietin increased endothelin-1 release by endothelial cells. Ambulatory blood pressure recording seems to be the best method for evaluating the modification of blood pressure profile during the interdialytic period. Erythropoietin-induced hypertension is easily controlled by drugs, but also by low dose of erythropoietin. Subcutaneous administration of erythropoietin is an approach to avoid the induction of hypertension. Furthermore economical advantages of subcutaneous administration are proven.

Topics: Anemia; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Renal Dialysis

Erythropoiesis is a highly dynamic process which may be monitored by quantitative reticulocyte counting. In chronic renal failure erythropoietin therapy can restore erythropoiesis to normal level. Occult infection and malignancy can limit this response and quantitative reticulocate counting can be used to identify this at an early stage. Iron supply may also be limiting and the measurement of percentage hypochromia is an effective means of detecting this. In pregnancy erythropoiesis is stimulated at a very early stage, direct measurement of red cell mass using a non-radioactive method has shown that half of the increase may occur within the first trimester. Recent studies suggest that erythropoiesis is stimulated very soon after conception.

Topics: Erythropoiesis; Erythropoietin; Female; Humans; Iron; Kidney Failure, Chronic; Pregnancy

End-stage renal disease complicates only a small percentage of pregnancies, but, of these, virtually all become anemic due to a deficiency in erythropoietin. Erythropoietin has been shown to correct anemia due to renal disease in nonpregnant patients. We report two cases of erythropoietin use during pregnancy complicated by severe anemia due to renal failure. No maternal or fetal side effects were noted. Our two cases exemplify that erythropoietin is an effective means of treating anemia due to renal disease in the gravid patient.

Topics: Adult; Anemia; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Pregnancy; Pregnancy Complications, Hematologic; Recombinant Proteins

Topics: Angiotensin-Converting Enzyme Inhibitors; Dietary Proteins; Energy Intake; Erythropoietin; Humans; Kidney Failure, Chronic; Renal Dialysis

Epoetin (recombinant human erythropoietin) is now a widely available though expensive treatment for the anaemia of chronic renal failure, and is effective in more than 95% of patients. Complications of epoetin in this context include hypertension in a third of cases, including hypertensive encephalopathy in a few, and thrombosis of shunts or vascular access devices. Fears that epoetin would cause progression of renal failure have not generally been confirmed, but hyperkalaemia may be a problem in the initial phase of treatment. Epoetin is up to twice as effective when administered subcutaneously rather than intravenously. Responding patients will normally do so within 3 months of starting epoetin. Failures to respond are usually due to iron deficiency or intercurrent disease. Other diseases associated with anaemia and an inappropriately low serum epoetin level include prematurity, the anaemia of cancer and rheumatoid arthritis. The baseline serum endogenous erythropoietin may provide a guide to response in some of these cases. Some encouraging results are being published. Situations where the serum erythropoietin levels are normal or elevated where epoetin has been employed include boosting of haematocrit presurgery as an adjunct to autologous blood donation, treatment of anaemic patients with myelodysplastic syndromes, and improvement of athletic performances.

Topics: Anemia; Dose-Response Relationship, Drug; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Injections, Intraperitoneal; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia; Erythropoietin; Hemodynamics; Humans; Hypertension; Iron Deficiencies; Kidney; Kidney Failure, Chronic; Physical Fitness; Quality of Life; Recombinant Proteins; Renal Dialysis

Topics: Activities of Daily Living; Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; Renal Dialysis

Recombinant human erythropoietin (r-HuEPO) effectively corrects the anemia of end stage renal disease (ESRD). Development or aggravation of hypertension has been the most commonly reported side-effect of r-HuEPO treatment. Placebo controlled trials have shown incidence rates ranging from 16-21%. Renal failure itself obviously is a prerequisite in the pathogenesis of r-HuEPO-induced hypertension, since it was never observed in anemic patients without renal disease. Increased whole blood viscosity and/or reduced hypoxic vasodilatation due to the rise in hematocrit may play a role in the development of hypertension at high concentrations of hematocrit. However, at hematocrit levels around 30% additional hypertensinogenic effects of r-HuEPO treatment seem likely. Endothelin and prostanoids are possible mediators of this effect. Left ventricular hypertrophy (concentric and eccentric), which can be due to hypertension and anemia, is commonly observed in ESRD patients and has been shown to be a predictor of cardiac morbidity and mortality in these patients. Following correction of anemia with r-HuEPO measures of left ventricular hypertrophy decrease by about 18% within a year. Normalization, though, is generally not achieved and in patients with r-HuEPO induced hypertension the increase of blood pressure may oppose the beneficial effects of r-HuEPO treatment on cardiac hypertrophy.

Topics: Anemia; Animals; Erythropoietin; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Recombinant Proteins

Although the benefits of rhGH and r-HuEPO therapy in children with CRF and on dialysis are already significant, further study of these new additions to the therapeutic arsenal remains necessary. Data on the final adult height achieved in patients who receive rhGH are extremely important information that is as yet unavailable. The risks and benefits of raising the target hematocrit to a "normal" value in patients receiving r-HuEPO remains under study. Only when these and other issues are soundly evaluated will the full impact of these medications be understood.

Topics: Animals; Child; Erythropoietin; Growth Hormone; Humans; Kidney Failure, Chronic

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic

Topics: Anemia; Erythropoietin; Hemoglobins; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins

Recombinant human erythropoietin has been available for clinical use since 1985. It was an immediate success in treating the anemia of chronic renal failure and has also enjoyed some objective success in the treatment of other anemias in either a therapeutic or prophylactic setting, but the issues of appropriate patient selection and cost-benefit ratios are still unresolved. This review discusses the most recent literature concerning the use of recombinant human erythropoietin for the anemia associated with cancer, HIV infection, myelodysplasia, prematurity, autologous blood transfusion, bone marrow transplantation, and chronic renal failure.

Topics: Anemia; Blood Transfusion, Autologous; Erythropoietin; HIV Infections; Humans; Infant, Newborn; Infant, Premature, Diseases; Kidney Failure, Chronic; Myelodysplastic Syndromes; Neoplasms; Recombinant Proteins

Peak oxygen uptake (VO2peak) of patients with end-stage renal failure treated with hemodialysis is very low. The improvement of anemia with recombinant human erythropoietin (rHuEPO) results in a very small change in VO2peak. This change is minimal compared with the magnitude of change in hematocrit, suggesting that other factors continue to limit exercise tolerance. This article reviews the physiology of oxygen transport and the determinants of VO2peak. Anemic hemodialysis patients are limited by a reduced cardiac output response to exercise and an inability to widen the arterio-venous oxygen difference. The lack of change in cardiac output and a remaining low arterio-venous oxygen difference following improvement of anemia with rHuEPO therapy suggest an underlying muscle limitation to exercise. Evidence for this muscle limitation is presented. Exercise training may improve the ability of muscle to use oxygen, thus optimizing the effect of the increased hematocrit resulting from rHuEPO therapy.

Topics: Anemia; Erythropoietin; Exercise; Hemodynamics; Humans; Kidney Failure, Chronic; Muscle, Skeletal; Oxygen; Recombinant Proteins; Renal Dialysis

Topics: Dietary Proteins; Erythropoietin; Humans; Kidney Failure, Chronic; Nutritional Status; Parenteral Nutrition; Recombinant Proteins; Renal Dialysis; Survival Analysis

The availability of recombinant EPO has greatly improved the lives of patients with end-stage renal disease. Knowledge is still accumulating regarding the use and effects of EPO in patients on PD, and several critical questions remain to be answered: 1. At what hematocrit level and when in the predialysis or dialysis course should EPO be started in PD patients? Recent studies by Golper suggest that the concomitant initiation of EPO and PD results in an increased hematocrit response compared to starting EPO after PD has been initiated for some time (63). 2. What is the best route of administration of EPO in PD patients? It is apparent that i.v., SC, and IP EPO can be effective in this population if utilized properly. The goal should be to tailor the route to the needs of the patient. Perhaps the daily SC route, for example, might be best for minimizing hypertension because of the slow, steady rise of hematocrit, while the IP route would be best tolerated by children (33,64). 3. What should the target hematocrit level be? This may vary depending on which organ function is being assessed. For the whole patient data are not currently available on appropriate hematocrit targets to maximize oxygen utilization, but near normal levels have recently been reported to be safe and beneficial (65-67). 4. What are the end-organ effects of anemia and its correction in PD patients? There is a dearth of information in this area for PD as well as HD patients. Additional research of this kind will increase our understanding of the pathophysiology of anemia as well as uremia.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anemia; Animals; Clinical Trials as Topic; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins

Knowledge continues to grow on the biology of endogenous erythropoietin (EPO), its effects on red blood cell physiology, and the use of the recombinant form of the hormone. In addition to oxygen delivery, oxygen consumption may be important in stimulating EPO production. This production is likely mediated by an intracellular messenger system other than cAMP. Once released, EPO prevents programmed cell death of BFU-E and CFU-E cells. Recent evidence suggests that lack of EPO, rather than the presence of EPO inhibitors, is the cause of the anemia seen in renal patients. Recombinant EPO has been available clinically since mid 1989. Nearly two thirds of dialysis patients are receiving this agent, although low doses are the rule, with the average hematocrit achieved of only 31%. EPO dosing has been subjected to kinetic modeling that has revealed a wide range in RBC half-life from patient to patient. This accounts in part for the varying maintenance dosing requirements. An additional modulating factor in the response to EPO is severe, secondary hyperparathyroidism with bone marrow fibrosis which may be reversible with medical or surgical parathyroidectomy. Hypertension continues to occur in 20-35% of patients given EPO. This effect may be mediated by endothelin which appears to be stimulated by EPO administration. Treatment of the anemia of renal failure leads to many organ system benefits including improved muscle metabolism, decreased left ventricular hypertrophy, enhanced immune responses to hepatitis vaccine, and improved brain electrophysiology. he optimal target hematocrit to achieve the greatest benefits for the patient at an acceptable cost remains to be determined.

Topics: Adult; Aged; Anemia; Child; Erythropoiesis; Erythropoietin; Female; Hematocrit; HIV Infections; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Pregnancy; Pregnancy Complications; Recombinant Proteins; Renal Dialysis

Plasma concentrations of IR endothelin are elevated in patients with chronic renal failure. But its exact causes have not been clarified. Hypertension may be one of the most important factors associated with elevated plasma IR endothelin concentrations, although it still remains to be determined whether hypertension is a result or a cause of the elevated plasma IR endothelin concentrations in patients with chronic renal failure. Elevation of plasma IR endothelin concentrations was found in hemodialysis patients with rHuEPO-induced blood pressure elevation. Endothelin may be one of the causes in rHuEPO-induced hypertension in some hemodialysis patients. Endothelin receptors have been cloned, and several endothelin antagonists have been reported. The studies using clinically useful endothelin antagonists will further clarify the pathophysiology of endothelin in patients with chronic renal failure.

Topics: Amino Acid Sequence; Anemia; Endothelins; Erythropoietin; Humans; Kidney Failure, Chronic; Molecular Sequence Data; Recombinant Proteins

The discovery of new drugs and their introduction into US markets will become an intense area of focus should health care reform result in Medicare insurance coverage for prescription drugs. Particular attention will be focused on high-cost drugs. Two high-cost drugs, cyclosporine and recombinant human erythropoietin (rHuEPO), introduced into the clinical management of patients with kidney disease during the past decade, provide some experience concerning the forces affecting the use of expensive drugs in a cost-conscious health care system. The decision to prescribe a drug will depend on provider's judgements of the drug's clinical benefits and costs compared with those of other possible therapies. It may also depend on payment policy. Both cyclosporine and rHuEPO were adopted rapidly and extensively by providers of end-stage renal disease care following US Food and Drug Administration approval, despite their high costs. Both drugs were remarkably effective, relatively safe, and able to be administered without great difficulty compared with the therapies they have replaced. There was no additional payment to hospitals for the initial use of cyclosporine, which was introduced in 1983 at the time when Medicare's prospective payment was established, since choice of immunosuppressive agent did not affect the fixed, per-admission payment determined by the diagnosis-related group for kidney transplantation. Medicare coverage for continuing outpatient use of cyclosporine was not initially provided, in contrast to rHuEPO, which was introduced in 1989 with Medicare outpatient coverage and payment of 80% of the allowed charge. Despite their high costs and different methods of insurance payment both drugs achieved a rather quick and high penetration rate into their respective populations.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Cyclosporine; Drug Costs; Drug Utilization; Erythropoietin; Humans; Insurance, Pharmaceutical Services; Kidney Failure, Chronic; Medicare; Recombinant Proteins; United States

Anemia is an inevitable and potentially serious complication of chronic renal failure and one of the most important limiting factors in patient rehabilitation. Although adequate dialysis can control many of the symptoms of uremia, dialysis does not reverse anemia-associated fatigue, and thus, many patients are not rehabilitated. Human recombinant erythropoietin (epoetin) therapy has proven to be effective in reversing anemia and increasing hematocrit levels in the majority of patients with chronic renal failure. Among this patient population, increases in hematocrit level have resulted in improvements in the symptomatology of organ hypoxia, neurobehavioral indices, anorexia, insomnia, depression, and sexual disinterest and dysfunction, as well as a reduction in cardiomegaly. However, despite the availability of epoetin and the dramatic improvements in the complications associated with the anemic state observed following therapy, it appears that patient rehabilitation remains a challenge. One aspect of the continuing problem of rehabilitation appears to be the reluctance of the medical community to increase hematocrit levels above 30%, despite the fact that higher hematocrit levels are associated with greater improvements and that potential adverse events related to hemodynamic adaptation are manageable. Indeed, a comparison of the results from two Epoetin alfa clinical trials, one in which hematocrit levels were maintained at 35% and a large phase IV study in which the target hematocrit level appears to have been approximately 30%, clearly demonstrate the benefits of optimizing hematocrit levels and thus improving the potential for rehabilitation.

Topics: Anemia, Hypochromic; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Quality of Life; Renal Dialysis

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Drug Therapy; Erythropoietin; Humans; Kidney Failure, Chronic; Pharmacokinetics; Recombinant Proteins; Renal Dialysis

The Health Care Financing Administration maintains a wide array of data systems that are essential to the functioning of the Medicare program. These data, collected and maintained for the purposes of ensuring entitlements and payment for services, also can be used to monitor programmatic changes and to define potential problem areas. The end-stage renal disease (ESRD) Program Management and Medical Information System (PMMIS) is a subset of the larger Medicare statistical system. It is a historic record of all Medicare ESRD beneficiaries dating back to 1978. Basic Medicare enrollment information on ESRD beneficiaries is enhanced with the addition of information on the cause of renal failure, type of dialysis therapy, transplantation history, and cause of death. The ESRD PMMIS has been put to a number of uses in the past decade or so, ranging from basic descriptive epidemiology to analyses of mortality rates to assessments of programmatic issues such as the composite rate and dialyzer reuse. Because of the limited clinical detail in the PMMIS, there are many specific questions that cannot be adequately addressed. With approval of the Food and Drug Administration and Medicare coverage of erythropoietin, a erythropoietin monitoring system was developed to assess utilization trends of this anemia control drug. Within a few months it became evident that dosing levels for erythropoietin were much lower than expected from the clinical trials. Following a change in the payment method from a fixed amount to one based on dose level, dosing has increased markedly. However, hematocrit levels still remain below optimal levels. This lack of hematocrit response has led the Health Care Financing Administration, in concert with the renal community, to target anemia control as a potential health care quality improvement project. This paper presents an example of the type of data presentation that can be derived from the current PMMIS. The Health Standards and Quality Bureau has made a commitment to a program of continuous quality improvement. Part of this process is the provision of descriptive data that can be the starting point for an iterative approach to quality improvement.

Topics: Anemia; Centers for Medicare and Medicaid Services, U.S.; Erythropoietin; Humans; Kidney Failure, Chronic; Medicare; Quality Assurance, Health Care; United States

Erythropoietin (EPO) is a glycoprotein produced primarily by the kidney in response to tissue hypoxia, and is the principal factor regulating red blood cell production. It stimulates erythroid precursors in the bone marrow to proliferate and mature into morphologically identifiable red blood cells. This hormone acts by binding to specific high-affinity receptor on erythroid precursors. Failure to produce adequate quantities of EPO leads to severe anemia, a situation most often encountered in patients with end stage renal disease. With the application of recombinant DNA technology, the gene for this hormone has been molecularly cloned, sequenced and expressed in a biologically active form in mammalian cells. The recombinant EPO has been demonstrated to correct anemia in patients with severe end stage renal disease and alleviate their transfusion requirements. It has also been studied for anemia associated with HIV infection/zidovudine therapy, in cancer, rheumatoid arthritis, and prematurity. In addition it has been studied as a facilitator of autologous blood predeposit in patients scheduled for elective surgery and as a perisurgical adjuvant to hasten hematologic recovery and possibly avoid the need for homologous transfusion after elective surgery. When administered with the current guidelines EPO appears to be safe drug with favorable risk/benefit ratio.

Topics: Acquired Immunodeficiency Syndrome; Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Myelodysplastic Syndromes; Neoplasms; Recombinant Proteins

The treatment of anemia in patients with renal failure has been dramatically changed with the development of recombinant human erythropoietin (r-HuEPO). This review discusses the pathogenesis of the anemia renal failure and the biology of erythropoietin. Causes of poor response to r-HuEPO therapy are outlined, and the importance of adequate available iron is highlighted. Parameters used to measure iron adequacy include serum iron levels, transferrin saturation, and ferritin levels. Other nutritional deficiencies, such as folic acid and vitamin B-12, can also impair r-HuEPO response. Clearly, the advent of r-HuEPO treatment for patients with renal failure and anemia has brought another dimension to the care of these patients. Optimal nutrition management is critical for the success of this new agent.

Topics: Anemia; Drug Therapy, Combination; Erythropoietin; Humans; Iron; Kidney Failure, Chronic; Nutritional Physiological Phenomena; Recombinant Proteins

Topics: Anemia; Animals; Erythropoietin; Humans; Kidney Failure, Chronic

The fact that a plasma factor was responsible for the stimulation of red cell production has been known for more than 35 years. However, it is only recently that the gene responsible for its production and its molecular structure has been identified. Furthermore, recombinant human erythropoietin is now available for clinical use. This article details the molecular biology and clinical pharmacology of this remarkable growth factor.

Topics: Anemia; Erythrocytes; Erythropoietin; Gene Expression Regulation; Hematocrit; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia; Cardiovascular Diseases; Chronic Kidney Disease-Mineral and Bone Disorder; Erythropoiesis; Erythropoietin; Glutathione; Hemolysis; Humans; Kidney Failure, Chronic; Nutrition Disorders; Oxidation-Reduction

Topics: Cardiac Surgical Procedures; Creatinine; Erythropoietin; Hemoglobins; Humans; Japan; Kidney Failure, Chronic; Metabolic Clearance Rate; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins

Decisions about epoetin (recombinant human erythropoetin) dosage and target haematocrit in dialysis patients have been determined largely by the high acquisition cost of epoetin, but are made with incomplete knowledge about which target haematocrit gives the optimum clinical benefit. Haematopoietic response to epoetin may be determined by pharmacodynamic factors such as rate and frequency of administration, as well as by individual patient characteristics such as ethnicity. Resistance to epoetin may be due to iron or vitamin deficiency, natural or exogenous inhibitors of erythropoiesis and bone marrow fibrosis. The high acquisition cost of epoetin must be considered along with a number of other factors that can influence the true cost of epoetin treatment. Hidden costs of epoetin treatment include administration costs, changes in other treatments, extra laboratory tests and adverse events. Administration costs and extra laboratory surveillance add little to overall cost. Depletion of iron stores, hypertension, increased blood coagulability and reduced dialyser efficiency resulting from epoetin treatment may all add a small additional component to the true cost. Severe complications with significant cost implications are rare. Amongst the various components of true cost, only the acquisition cost can definitely be reduced by low dosage treatment. Balanced against the true and potential costs of epoetin are a number of benefits which can result in potential savings. The need for blood transfusion is all but abolished, avoiding the cost of transfusion and its complications. Sensitisation against histocompatibility antigens is reduced by avoiding transfusion, and so the waiting time for cadaveric transplantation may be reduced. Rates of hospitalisation for all causes, especially those associated with anaemia, may be reduced by epoetin treatment. By improving well-being, epoetin may allow patients to be transferred to minimal-care units or home where dialysis can be performed much more cheaply. Amongst the various potential benefits of epoetin, the one with the greatest potential to save money for society is improved productivity. To date, productivity improvements with epoetin have been demonstrated only in small studies. If the acquisition costs of epoetin are reduced by low dosage therapy, these potential benefits can cover a large proportion of the total cost of epoetin. Epoetin undoubtedly improves quality of life and activity, but it is n

Topics: Costs and Cost Analysis; Erythropoietin; Humans; Kidney Failure, Chronic; Politics; Quality of Life; Renal Dialysis; Treatment Outcome

The anemia of chronic renal failure often contributes to the poor functional status in patients with renal insufficiency and results primarily from decreased erythropoietin production. Recombinant human erythropoietin (rHuEpo) results in clinical and symptomatic improvements in patients with anemia of chronic renal failure. Treatment with rHuEpo also improves the quality of life in these patients. Resistance to rHuEpo therapy is not uncommon, however, and often is related to iron deficiency resulting from rapid erythropoiesis during rHuEpo therapy. Interestingly, rHuEpo-treated patients may continue to develop iron deficiency while receiving oral iron. Alternatively, parenteral iron is effective in replenishing iron stores and sustaining erythropoiesis in patients treated with rHuEpo.

Topics: Erythropoietin; Humans; Iron; Iron Deficiencies; Kidney Failure, Chronic; Recombinant Proteins

Recombinant human erythropoietin is an efficacious therapy in treatment of the anemia of end-stage renal failure. However, the scale of impact on quality of life and medical care resources remains uncertain. By reviewing the literature we evaluate cost-effectiveness of recombinant human erythropoietin and show how previous studies may have implicitly overestimated cost-effectiveness.

Topics: Anemia, Hemolytic; Blood Transfusion; Cost-Benefit Analysis; Drug Costs; Erythropoietin; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins

The effectiveness of various recombinant human erythropoietin (epoetin) administration routes and dosage schedules in patients on dialysis was studied. The mean dose required to achieve and maintain a hematocrit level between 33% and 40% is 225 U/kg/wk when administered intravenously (i.v.) in three divided doses. A once-weekly i.v. schedule requires a dose of 429 U/kg/wk to maintain the same target hematocrit. In contrast, the required epoetin dose is reduced by an average of 25% to 50% when administered via the subcutaneous (SC) route. Analysis of data from 25 dialysis centers shows that SC epoetin administration resulted in higher normalized responses than i.v. administration. The hematocrit response in patients at these centers was proportional to the weekly dose, with a greater slope in those centers using predominantly SC as compared with i.v. dosing. Cost analysis indicates that the use of SC dosing two or three times weekly at an average total weekly dose of 120 U/kg is effective for the treatment of anemia in most patients on dialysis.

Topics: Anemia; Erythropoietin; Hematocrit; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Recombinant Proteins

We review data concerning site and regulation of erythropoietin (EPO) production, its effects on target tissue, routes of administration and clinical applications. In the anaemia of chronic renal failure (ACRF) treatment with recombinant human erythropoietin (r-Hu-EPO) has been shown to be effective in both improvement of the anaemia and increase in quality of life. In the anaemia of chronic disease (ACD), associated with various malignant, infectious and inflammatory disorders, many investigators have demonstrated an inappropriately low EPO response to anaemia. Therapeutic trials in patients with ACD mostly lacked sufficient numbers of patients for evaluation of the effects. The results obtained from some studies in AIDS and rheumatoid arthritis and the effect on the number of units of autologous blood obtained from patients planned for elective surgery are encouraging, however. Adverse reactions of r-Hu-EPO treatment are mainly confined to the ACRF population and include hypertension, shunt thrombosis and pain at the injection site. The exact mechanism of action of EPO is not yet fully understood. Large scale clinical trials are required to establish its effects on both the anaemia and quality of life in anaemias other than ACRF.

Topics: Anemia; Chronic Disease; Clinical Protocols; Clinical Trials as Topic; Drug Administration Schedule; Erythropoietin; Humans; Infections; Inflammation; Kidney Failure, Chronic; Neoplasms

It is indeed rare that a medication can do so much good and be associated with so few side effects and complications. The judicious use of Epo along with informed dosing practices will lead to an overwhelming favorable balance in the risk/benefit ratio of care. The move from a very specialized area of need into a more generic arena has done well for the development of drugs of this nature and may help stimulate further research in other "orphan" areas of drug need.

Topics: Amino Acid Sequence; Animals; Erythropoietin; Humans; Kidney Failure, Chronic; Molecular Sequence Data; Recombinant Proteins

Topics: Anemia; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Quality of Life; Renal Dialysis; Seizures; Thrombosis

Epoetin (recombinant human erythropoietin) is an effective treatment for the anaemia of patients with chronic renal failure. It is well tolerated, and the risk of adverse effects that are caused by too rapid a correction of anaemia, for example hypertension, can be reduced in most cases by lower starting dosage regimens. Epoetin improves the quality of life of anaemic patients with end-stage renal disease (ESRD), and significant improvements in most parameters of the Kidney Disease Questionnaire, the Sickness Impact Profile and the Nottingham Health Profile have been reported by patients. However, acquisition costs of epoetin are high, thereby adding a considerable cost to ESRD therapy despite a reduction in blood transfusion requirements. Notwithstanding, although cost-effectiveness studies have indicated that epoetin is associated with higher costs of therapy, cost-benefit analysis indicates that these costs can be reduced markedly with low-dose regimens and may be completely recovered if patients regain employment.

Topics: Adolescent; Adult; Aged; Androgens; Anemia; Blood Transfusion; Child; Child, Preschool; Cost of Illness; Cost Savings; Drug Costs; Drug Prescriptions; Drug Tolerance; Economics, Pharmaceutical; Erythropoietin; Formularies as Topic; Humans; Kidney Failure, Chronic; Middle Aged; Quality of Life; Renal Dialysis

Iron deficiency is the main reason for insufficient response to rEPO therapy. Serum ferritin and transferrin saturation give valuable information on storage iron and iron transport. Iron demand for correction of anemia can easily be estimated after HCT (vol%) x average blood volume (dl) = mg iron. Inadequate iron supply of the bone marrow in the presence of sufficient storage iron in the RES develops frequently under rEPO, possibly explaining the improvement of bone marrow response to rEPO by concomitant intravenous iron supply. The reasons of functional iron deficiency are still speculative.

Topics: Anemia; Bone Marrow; Erythrocyte Aging; Erythropoietin; Humans; Iron; Iron Deficiencies; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Fifty-five hemodialysis patients (pts) received rHuEpo for 3-5 years (51 +/- 11 months, hematocrit 32.5 +/- 3.7). BP medication was required in 42% of pts prior to rHuEpo (Hct 20.8 +/- 3.5) and 69% (38 patients) now require such therapy. BP was controlled with single therapy in 16 pts and only 8 required 3 or more different BP drugs. Vascular access clotting episodes were rare in pts with autologous fistula (17 of 24 pts had no clotting), whereas access clotting episodes were 10 times more common in pts with AV grafts, yet 20% had no clotting after 3-5 years of rHuEpo. Heart size decreased in most who initially had cardiomegaly. Cardiovascular related and other deaths were decreased in this selected group when compared to other dialysis pts matched for age, race and type of renal disease.

Topics: Anemia; Blood Coagulation; Cardiovascular System; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Seizures; Time Factors

It has been 6 years since the first reports of the use of recombinant human erythropoietin for the treatment of renal anemia appeared in the medical literature. During this period, erythropoietin has become established as a safe and highly effective therapy, and it is currently being evaluated for other nonrenal types of anemia. The initial clinical trials were in hemodialysis patients, followed by patients receiving continuous ambulatory peritoneal dialysis, and its use in predialysis and renal transplant patients is increasing. Various treatment schedules have been tried and compared; there are now reports of dosage frequencies varying from once daily to once weekly. Information has accumulated on the secondary effects of correction of renal anemia, particularly in relation to quality of life, exercise capacity, and cardiac function. Large multicenter trials have documented the safety profile of erythropoietin, whereas smaller studies have sought to elucidate the pathophysiology of its side effects, eg, hypertension and thrombotic events. This article reviews the latest developments in the use of erythropoietin in renal failure, concentrating particularly on those that have been published within the past year. Although there have been exciting advances in our understanding of the physiology and molecular biology of erythropoietin, these are amply described elsewhere and are beyond the scope of the present review.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Hypoproliferative anemia is a predictable and serious complication of progressive renal failure and contributes significantly to the overall morbidity of the uremic state. Until recently, there has been no satisfactory therapy to resolve the anemia. Now the anemia can be explicitly corrected with erythropoietin-replacement therapy, and the clinical debility generally attributable to renal insufficiency can be lessened and retarded. Anemia must no longer be regarded as an intractable consequence of the uremic syndrome and should be managed as conscientiously as the other polysystemic features of uremia.

Topics: Anemia; Animals; Cats; Dog Diseases; Dogs; Erythropoietin; Kidney Failure, Chronic; Recombinant Proteins

Symptomatic anemia is a common complication of chronic renal failure. Treatment is now possible with the availability of recombinant human erythropoietin (epoetin alfa). Previous experimental studies have suggested that correcting the anemia of chronic renal failure may be harmful in that renal failure may be accelerated. Although experience with this drug has been primarily restricted to its use in patients with end-stage renal disease, several recent trials have been reported in patients with varying degrees of chronic renal failure. We review these studies with particular reference to the progression of renal failure and the drug's reported side effects. We conclude that the use of epoetin is beneficial and well tolerated and that there is no compelling evidence for the acceleration of renal failure associated with its use in patients.

Topics: Anemia; Animals; Erythropoietin; Hematocrit; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Rats; Recombinant Proteins

Topics: Anemia; Erythrocyte Count; Erythroid Precursor Cells; Erythropoietin; Humans; Kidney; Kidney Failure, Chronic; Recombination, Genetic

Topics: Anemia; Animals; Blood Pressure; Disease Models, Animal; Double-Blind Method; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Hypertension, Renal; Kidney; Kidney Failure, Chronic; Rats; Recombination, Genetic

Recent studies showed that the blood BFU-E, when subtracted from the uremic milieu, normally responds to the stimulating factor produced by T lymphocytes. The serum of uremic patients inhibits the in vitro growth of normal BFU-E, however, the inhibition is almost completely reversed by hemodialysis. These data allow to understand why the therapy with erythropoietin relieves the anemia of CRF. Uremic T lymphocytes fail to stimulate the BFU-E growth. Normal T lymphocytes are inhibited by uremic serum and the hemodialysis does not correct the defect. Lymphopenia, decreased number of both T4 and T8 lymphocytes and low T4/T8 ratio were found in 50% of patients. Cimetidine was still able to increase the burst-stimulating activity of uremic T lymphocytes through inhibition of the suppressor T subset. In conclusion, one can say that in CRF T8 lymphocytes are normal and that uremic toxins decrease both number and function of T4 lymphocytes. The deficiency of BPA appears to significantly contribute to the pathogenesis of the anemia of CRF. The experience from our and other Institutions shows the effectiveness of the recombinant human erythropoietin in relieving the anemia of CRF, notwithstanding the hematological milieu is highly modified by uremia.

Topics: Anemia; Combined Modality Therapy; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Uremia

Topics: Anemia; Child; Erythropoietin; Growth Disorders; Growth Hormone; Humans; Kidney Failure, Chronic; Recombinant Proteins

Recombinant human erythropoietin (r-HuEPO) represents the therapy of choice in anaemia of chronic renal failure. A number of studies have analysed the relative effectiveness of r-HuEPO administered subcutaneously (s.c.) or intravenously (i.v.) in haemodialysis patients. The bioavailability of s.c. r-HuEPO appears to be low and the absorption of r-HuEPO variable. Nevertheless, s.c. administration of r-HuEPO is more efficacious than i.v. administration, probably due to the better time-averaged plasma concentrations. Patients on haemodialysis who were on i.v. r-HuEPO 3 times weekly for 9 months were subsequently successfully maintained on a self-administered s.c. dosage which was 50% of the i.v. maintenance dosage and which was later reduced further to 30% of the weekly i.v. maintenance dosage. An ongoing European multicentre study has confirmed these findings and demonstrated that s.c. administration 3 times weekly and once daily was as effective as i.v. administration 3 times weekly. Both these s.c. regimens resulted in a significant dosage reduction (30%) compared with the i.v. regimen. The study also found that once weekly s.c. dosing was as effective as 3 times weekly i.v. dosing but did not result in a dosage reduction. Other studies on the optimization of s.c. r-HuEPO in patients on continuous ambulatory peritoneal dialysis demonstrated that haemoglobin levels following s.c. r-HuEPO administration (60 U/kg twice weekly) can be further increased by 2 ml iron dextran (containing 50 mg/ml iron) administered i.v. 7-9 weeks after the start of therapy. Studies on the site of s.c. injection reveal that injection into the thigh results in more rapid absorption, higher peak concentrations and greater bioavailability than injection into the arm or abdomen. Data also demonstrate the economic advantage of s.c. r-HuEPO in high-risk patients.

Topics: Anemia; Biological Availability; Erythropoietin; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic

Chronic renal failure is almost invariably accompanied by symptomatic anemia. It has been demonstrated that the primary cause of this anemia is inadequate production of erythropoietin by the diseased kidneys. The isolation of erythropoietin, followed by the cloning and expression of the human erythropoietin gene, made possible clinical trials of rHuEPO in uremic patients. rHuEPO produced dramatic increases in the hematocrit in almost all patients treated and also ameliorated many symptoms, such as lethargy, dizziness, and poor appetite, that had long been attributed to the effect of uremic toxins. Adverse effects of treatment with rHuEPO noted in the early clinical trials included hypertension, seizures, arteriovenous fistula or shunt thrombosis, and hyperkalemia. Further study of rHuEPO has shown that many of these side effects may be no more frequent in patients receiving rHuEPO than in other uremic patients not receiving rHuEPO. Reduction of the rHuEPO dosage and subcutaneous administration produce less rapid increases in the hematocrit and may lessen the incidence and severity of these side effects. rHuEPO therapy places great demands on both the body's iron stores and the capacity to rapidly transfer iron from storage sites to the erythroid progenitor cells. Thus, almost all patients treated with rHuEPO become iron deficient and require oral or parenteral iron replacement. Response to rHuEPO in uremic patients is diminished if the anemia is complicated by iron deficiency, inflammatory disorders, aluminum overload, or deficiency of folate or vitamin B12. rHuEPO therapy is safe and effective in the treatment of the anemia of chronic renal failure. The use of rHuEPO leads to enhanced quality of life and eliminates the need for red cell transfusions. In addition to hemodialysis patients, predialysis patients and those on CAPD benefit from and are candidates for rHuEPO therapy.

Topics: Anemia; Drug Administration Schedule; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Adult; Anemia; Animals; Blood Transfusion; Erythropoietin; Humans; Infant, Newborn; Kidney Failure, Chronic; Prognosis; Renal Dialysis

Topics: Combined Modality Therapy; Diuretics; Erythropoietin; Humans; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Renal Dialysis; Sports

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic

The recent availability of Recombinant Human Erythropoietin (EPO) has radically stirred-up diagnosis and therapeutical approach of anemia in dialysis patients. By correcting anemia in a dose related manner in virtually all dialysis patients, clinical use of EPO has confirmed its remarkable efficiency. Correction of anemia marked by a rapid improvement in "well being" of patients is also objectively associated with the correction of most of the debilatating multiple organs dysfunction due to the uremic state. Hypertension is one of the more frequent and worrying complication associated with EPO therapy. Optimal use of EPO, integrating administration route and frequency of injections, will reduce the EPO doses needed and minimize cost and side-effects incidence. EPO represents a major advance in the treatment of chronic uremia. EPO opens a new therapeutic era offering for the first time a substitute to a kidney endocrine failure.

Topics: Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Uremia

As the anemia that accompanies chronic renal failure (CRF) is successfully treated with recombinant human erythropoietin (epoetin), striking improvements in overall quality of life have been noted in several clinical studies of patients receiving chronic hemodialysis. A review of available clinical data has shown that, following epoetin therapy, peak oxygen consumption, a principal indicator of exercise ability, increased by approximately 50% as the hematocrit level increased. Following epoetin therapy in pediatric patients with end-stage renal disease (ESRD), the ventilatory anaerobic threshold (VAT) increased significantly and correlated well with increases in hemoglobin concentrations. Increased exercise capacity associated with the reversal of anemia appeared to positively effect many quality-of-life parameters. Analysis of questionnaires incorporating both subjective and objective quality-of-life indicators showed significant improvements between baseline and follow-up periods. Many patients experienced relief from some of the debilitating symptoms of anemia and many had significantly improved functional ability. Higher activity and energy levels were reflected in enhanced emotional and social well-being, with improvements noted in appetite, sleeping behavior, and sexual function. There was no change in the employment status of most patients. The extent of improvement in overall quality of life may be a function of the baseline level of impairment and the potential for reversal. However, baseline capabilities at rest may not be appropriate for physiologic studies.

Topics: Anemia; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Quality of Life

The uremia of chronic renal failure (CRF) can alter brain electrophysiology and cognitive function, even in the well-dialyzed patient. The effect of uremia on brain function can be assessed by electrophysiologic techniques such as electroencephalogram (EEG), sensory-evoked potentials (EPs), and cognitive event-related potentials (ERPs), and through a series of neuropsychologic tests. Five tests have been used clinically to measure the speed and efficiency of cognitive functioning and include the following: Number Cancellation, Trailmaking Test, Symbol Digit Modalities Test, Rey Auditory Verbal Learning Test, and Controlled Oral Word Association Test. Test performance by patients with CRF is often below that of healthy controls. Auditory ERPs, a sensitive indicator of subtle changes in central nervous system (CNS) function in uremia, result in the generation of a P300 component wave that varies in amplitude and latency with patient variables such as attention and effort. Although dialysis tends to normalize P300 latencies, the waves remain somewhat prolonged in most patients. The anemia often observed in patients receiving chronic dialysis appears to aggravate uremic encephalopathy. This effect can be reversed when anemia is corrected following administration of recombinant human erythropoietin (epoetin). Improvement in P300 amplitudes, and, in some cases, decreases in P300 latencies correlated well with epoetin-induced increases in hematocrit levels. With the correction of anemia, that component of brain dysfunction not attributable to retention of uremic toxins can largely be reversed.

Topics: Anemia; Brain; Cognition Disorders; Erythropoietin; Humans; Kidney Failure, Chronic; Uremia

The renal glycoprotein hormone erythropoietin is an essential growth factor for the erythrocytic progenitors in the bone marrow. Erythropoietin deficiency is the main cause of the anemia in chronic renal failure. Genetical engineering has made it possible to produce recombinant human erythropoietin (rhu-Epo) in CHO cell cultures as a pharmaceutical compound. Endogenous and recombinant erythropoietin are similar with respect to their biological and chemical properties (M(r) 30,400 Da, protein content 60%, 165 amino acids, 4 carbohydrate side chains). With few side-effects, rhu-Epo corrects the anemia of predialysis and dialysis renal failure patients. In addition, rhu-Epo treatment may reduce the need for blood transfusion in other types of anemias, including those of rheumatoid arthritis, AIDS, malignant diseases and major surgical procedures. However, rhu-Epo has not been approved as yet for treatment of non-renal anemias in Germany.

Topics: Anemia; Biotechnology; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

The application of recombinant DNA technology to the field of hematology has contributed greatly to our understanding of Epo gene structure and regulation, cellular expression and regulation of hormone production, pharmacokinetics, receptor biology, and ultimately, the value of this hormone as a therapeutic treatment. Areas that will undoubtedly prove fruitful for future research include the mechanisms by which hypoxia influences gene expression, structure/function relationships of the Epo molecule, mechanisms of transmembrane signaling and nuclear activation, and the application of rHuEpo in the treatment of other anemias. Epo is but one example of the contribution that modern biology has made to the understanding of hematopoietic regulation and to the availability of these regulators for the treatment of human disease.

Topics: Amino Acid Sequence; Anemia; Animals; Blood Transfusion, Autologous; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Genes; Humans; Immunologic Factors; Kidney Failure, Chronic; Mice; Molecular Sequence Data; Recombinant Proteins; Renal Dialysis

Topics: Acquired Immunodeficiency Syndrome; Anemia; Antineoplastic Agents; Bone Marrow Transplantation; Drug Evaluation; Erythropoiesis; Erythropoietin; Forecasting; Hematopoietic Cell Growth Factors; Humans; Immunologic Factors; Kidney Failure, Chronic; Myelodysplastic Syndromes; Neutropenia; Radiation Injuries; Recombinant Fusion Proteins

A deficiency of erythropoietin is the major cause of anemia in patients with chronic renal failure. In 1984 Eschbach and co-workers (1) demonstrated that daily injections of erythropoietin-rich plasma corrected anemia in chronically uremic sheep. In the first studies of r-huEPO given to severely anemic hemodialysis patients, all patients showed increments of their reticulocyte counts and hemoglobin concentrations. The need for further blood transfusions was eliminated and hematocrits were restored to normal (2,3).

Topics: Anemia; Animals; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male

Topics: Anemia; Blood Transfusion; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Reference Values

Recombinant human erythropoietin (epoetin) is a remarkably safe and effective biological product. Many dialysis patients are benefiting from the use of this drug when administered intravenously (IV) or subcutaneously (SC) three times a week. However, many patients are not receiving optimal therapy. Optimal therapy requires an understanding of the principles of effective usage and a definition of an optimal hematocrit (Hct) level. These therapeutic principles include (1) the erythroid response to epoetin is dose-dependent, but variable within a given dose; (2) the SC route of injection is as effective, if not more so, than IV injections; (3) the frequency of administration is route-dependent; (4) adequate iron stores are necessary for optimal response; (5) blood pressure may increase as the Hct increases, but may improve with time due to hemodynamic adjustments; (6) the anemia is primarily a hormone-deficiency state and not due to uremia; and (7) infections and traumatic (ie, surgical) inflammation may blunt the response to epoetin. Many patients with the anemia of renal failure have yet to benefit from treatment. These include patients with progressive renal failure or chronic transplant rejection, and dialysis patients who have had incomplete correction of their anemia.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

This report reviews the author's experience and the results of a multicenter study with regard to the use of recombinant human erythropoietin (Epo) in predialysis patients. The data demonstrate that Epo corrects anemia and improves quality-of-life assessment and exercise capacity in patients who are not dialyzed, but who have renal insufficiency. The incidence of hypertension was 22% in the Epo-treated subjects and 19% in the placebo group. Within the Epo-treated group, there appears to be a greater frequency of hypertensive events in those subjects receiving the higher dosages. The concern that Epo might accelerate the deterioration of renal function is not substantiated by several clinical studies.

Topics: Anemia; Animals; Blood Pressure; Erythropoietin; Humans; Kidney; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins

Erythropoietin (Epo) is currently used less extensively in peritoneal dialysis (PD) patients than in hemodialysis (HD) patients. Early data suggest that Epo is equally effective in PD patients, and that the risk profile is similar. No adverse consequences to the dialysis procedure or peritonitis rates have been consistently noted. It has been suggested that PD patients may require less Epo than their HD counterparts, but this is unproven. Further research on the preferred route of administration and timing of the dosing is necessary.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis

Extensive clinical studies have documented the effectiveness of recombinant human erythropoietin (rHuEPO) in correcting the anemia of adult dialysis patients, but the safety and efficacy of rHuEPO in children with renal anemia cannot yet be confirmed, due to the relative deficiency of reported studies involving pediatric subjects. To date, published experience with rHuEPO therapy in children has totaled 257 patients, although the majority of these reports have appeared only as abstracts. Overall experience has been favorable, with renal anemia and transfusion dependency successfully resolved in almost all pediatric patients reported. However, controlled clinical trials have not been performed, so it is not yet possible to clearly define the risks associated with rHuEPO therapy in children. Hypertension appears to occur or become worse in up to one third of treated children, but it is unclear to what extent rHuEPO therapy is accompanied by an increased risk of seizures, thrombosis of vascular access, hyperkalemia, hyperphosphatemia, or peritonitis (when administered via the intraperitoneal route). Only preliminary and somewhat conjectural recommendations can be offered regarding pediatric rHuEPO dosing, route of administration, special precautions, and adjunctive monitoring and therapy. Fortunately, a multicenter controlled clinical trial is underway that is designed to address these issues. Because the harmful effects of renal anemia are typically more profound for children than they are for adults, the benefits of rHuEPO promise to be even greater among pediatric patients. Whether rHuEPO therapy will substantially improve growth and neurologic and psychosocial development remains to be seen, but the potential is there for rHuEPO to dramatically improve the lives of children who suffer from the effects of the anemia of chronic renal failure. Other non-renal anemias that afflict pediatric patients, such as the anemia of prematurity, also may be amenable to rHuEPO therapy.

Topics: Anemia; Child; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

In successful renal transplant recipients, transient and modest increases in endogenous erythropoietin (Epo) reverse anemia, whereas in dialysis patients, sustained administration of large doses of exogenous Epo is required for the correction of uremic anemia. Moreover, in transplant recipients, serum Epo returns to normal as the hematocrit level increases to greater than 32%. Thereafter, the hematocrit continues to increase to normal levels, while serum Epo remains in the normal range. Thus, the restoration of renal function may improve the erythropoietic response to Epo, and/or erythropoiesis in transplant patients may be stimulated by factors other than, or in addition to, Epo. In early posttransplant patients who develop erythrocytosis, serum Epo levels are often elevated, while in long-term transplant recipients, erythrocytotic patients (with normal serum ferritin) have normal serum Epo levels. On the other hand, in long-term transplant recipients with low serum ferritin, circulating Epo levels are elevated, even in patients with no overt anemia. This suggests a possible interaction between body iron store status and the synthesis of Epo.

Topics: Anemia; Anemia, Hypochromic; Animals; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation

Close on the heals of the first successful reports of recombinant human erythropoietin (rHuEPO) use in dialysis-associated anemia, concern surfaced that raising the hematocrit level could threaten both the safety and efficacy of hemodialysis. Theoretical considerations prompted the conclusion that by decreasing the plasma water space available for dialysis, removal of plasma solutes would decrease in direct proportion to the increase in hematocrit. Predictions of thrombotic disaster were also aired, citing the increase in blood viscosity expected after correction of anemia. After 18 months of widespread use of rHuEPO in the United States, clinical experience has shown that correction of anemia can be accomplished without serious impact on either safety or efficacy in both conventional and high efficiency/high dialysis. Although predialysis concentrations of creatinine, phosphate, and potassium may increase whenever the hematocrit increases substantially, the magnitude of the rise is limited. Increased predialysis solute concentrations, which may be caused by either decreased dialyzer efficiency or increased dietary intake due to improved appetite, are readily managed by increasing dialysis blood flow rate, dialyzer surface area, and dialysis time. Since these measures may have little effect on increased phosphate levels, increased administration of phosphate binders may be required. However, by way of caution, the ready dialyzability of urea renders the predialysis blood urea nitrogen (BUN), as well as urea kinetics, relatively unaffected by the change in hematocrit, thereby masking adverse effects on other solutes. Fortunately, serious thrombotic consequences have not been seen, probably because anticoagulation is adequately managed by routine increases in heparin utilization.

Topics: Anemia; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Increased blood pressure (BP) has been the most commonly reported side effect in trials of treatment of the anemia of chronic renal failure with recombinant human erythropoietin (rHuEPO). An increase in BP develops in one third of patients, in most cases necessitating initiation or increase of antihypertensive therapy. Elevated BP is not related to dose of rHuEPO, nor to the final hematocrit level achieved or the rate of increase of hematocrit. Increases in BP arise particularly during the first 4 months of therapy, and BP usually stabilizes thereafter. rHuEPO therapy does not appear to affect BP in patients with normal renal function. The mechanism of hypertension related to rHuEPO remains uncertain. An increase in systemic vascular resistance occurs in all patients, whether or not BP increases. This is due largely to increased blood viscosity and reversal of hypoxic vasodilatation, but other factors may also contribute. A lack of adequate reduction in cardiac output distinguishes patients in whom BP increases, and this in turn may be due to abnormal cardiovascular autoregulation in these patients. Acute elevation in BP during rHuEPO therapy occasionally results in hypertensive encephalopathy and seizures. This complication is unrelated to the extent or rate of increase in hematocrit, but is associated with a rapid increase in BP, and may occur in previously normotensive patients. Hypertension developing during rHuEPO therapy should be controlled by conventional antihypertensive therapy. If hypertension persists, the rHuEPO dose should be reduced or therapy temporarily discontinued. Frequent BP monitoring during the first 4 months of treatment is mandatory.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anemia; Blood Pressure; Brain Diseases; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins

The absence of any response to the administration of recombinant human erythropoietin (rHuEpo) is exceptional in uremic patients with anemia. Initial "nonresponders" generally respond to higher doses of the hormone. However, a small number of patients may remain unresponsive. The most common cause of limited response is mild to moderate iron deficiency, either at the start of treatment or secondary to enhanced iron utilization by newly formed erythrocytes. Another common cause of resistance is the presence of an overt or, more often, an unrecognized inflammatory state, including acute or chronic infection. Marked aluminum overload and severe hyperparathyroidism also have been shown to induce resistance in at least some patients. Other factors may contribute to the severity of anemia and hence increase rHuEpo requirements, such as acute or chronic hemolytic conditions or blood loss, folate deficiency, hemoglobinopathies, and still poorly defined uremic toxins. In patients who show a resistance to the effect of the recombinant hormone, these should be sought and eliminated, if possible.

Topics: Anemia; Drug Resistance; Erythropoietin; Hematopoiesis; Humans; Hyperparathyroidism; Inflammation; Kidney Failure, Chronic; Recombinant Proteins

Recombinant erythropoietin is usually associated with marked improvement in physiological and psychological well-being. Adverse effects are unusual. In this report, the unusual occurrence of seizures, increased clotting, and influenza-like syndromes is reviewed. Emphasis is given to adverse effects noted in the few available placebo-controlled studies.

Topics: Anemia; Blood Coagulation Disorders; Clinical Trials as Topic; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Seizures

The development of recombinant human erythropoietin (Epo), along with a sensitive and reproducible assay for plasma Epo, has resulted in new potential applications for the treatment of medical and surgical anemias. A series of studies have defined a role for Epo therapy in the perisurgical setting to include the facilitation of autologous blood procurement and to facilitate postoperative erythropoiesis in order to minimize homologous blood transfusion requirements. Other possible applications of Epo therapy include the treatment of medical illnesses. Clinical trials to date have demonstrated that Epo therapy can correct the anemias of renal insufficiency, of rheumatoid arthritis, and of acquired immunodeficiency syndrome (AIDS) patients undergoing antiviral therapy. Clinical trials investigating the application of Epo therapy in the oncologic setting are in progress. These developments herald a new age in transfusion medicine, which includes the use of pharmacologic therapies in blood conservation strategies.

Topics: Anemia; Blood Transfusion, Autologous; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Neoplasms; Recombinant Proteins; Surgical Procedures, Operative

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Anemia (hematocrit less than 25%) predictably accompanies chronic renal failure and is present in over 90% of patients on chronic dialysis. Relative erythropoietin deficiency is the proximate cause. Recombinant human erythropoietin recently became available for research and clinical use. Erythropoietin production is regulated by a single copy gene located on chromosome 7; its expression has been shown in the kidney, liver, and macrophages. It is glycosylated protein of 166 amino acids with a molecular weight of 34,000 D. When given to patients with the anemia of renal failure, erythropoietin causes a dose-dependent rise in hematocrit to the normal range within 8 to 14 weeks. Complications of this response are minimal except for a significant incidence of hypertension. When the anemia is corrected, the patient's quality of life, cognitive function, and brain electrophysiology improve dramatically. Recombinant human erythropoietin represents a major breakthrough in the treatment of patients with chronic renal failure. Current reimbursement constraints limit its full application.

Topics: Anemia; Animals; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

The hormone deficiency that underlies anemia in chronic kidney failure can now be corrected. Along with the primary benefit of raising the hematocrit and reversing anemia, dramatic secondary benefits can be achieved. Exercise capacity, neuropsychiatric and sexual function, and overall quality of life are enhanced. Guidelines for management are discussed.

Topics: Anemia; Erythropoietin; Female; Hematocrit; Humans; Kidney Failure, Chronic; Male; Quality of Life; Recombinant Proteins; Renal Dialysis

Topics: Anemia; Erythropoietin; Humans; Infant, Newborn; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia; Blood Pressure; Erythropoietin; Hematocrit; Hemodynamics; Humans; Kidney; Kidney Failure, Chronic; Recombinant Proteins; Renal Circulation; Renal Dialysis

Moderately increased blood levels of endogenous erythropoietin (Epo) usually induce complete restoration of renal anemia after successful kidney transplantation. With good graft function erythropoiesis is maintained by normal Epo serum levels. Persistent anemia can be related to iron deficiency, low excretory graft function, and high dosage of immunosuppressive agents leading to marrow suppression or nephrotoxicity. Acute early rejection is associated with a fall in serum Epo and abrogation of reticulocytosis. About 15% of recipients fail to exhibit the normal feedback regulation and develop a mostly transient posttransplant erythrocytosis. Both an increased sensitivity of erythrocytic progenitors to Epo and inappropriate Epo secretion by the native kidneys may account for this overshooting reaction.

Topics: Anemia; Erythropoiesis; Erythropoietin; Graft Rejection; Humans; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Postoperative Complications

The analysis of the hemodynamics accompanying correction of renal anemia by rhEPO shows that--although they behave qualitatively as in nonuremic anemic patients--cardiac output and peripheral resistance may change inadequately and thereby cause a rise of blood pressure. The underlying mechanisms are not yet fully understood but to a great part may be related to preexisting pathology due to a history of longlasting hypertension. In some patients the development of hypertension may only represent a temporary phenomenon of hemodynamic dysregulation. To avoid cardiovascular complications the following should be considered: Patients with a history of hypertension, even if they are normotensive in the anemic state, are at a higher risk of developing hypertension during therapy with rhEPO. Hypertensive complications may be rare events when anemia is corrected slowly. In case of the development or aggravation of hypertension a reduction of the target hematocrit is indicated.

Topics: Anemia; Cardiac Output; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins; Vascular Resistance

Topics: Animals; Erythropoietin; Humans; Hypoxia; Kidney; Kidney Failure, Chronic; Parathyroidectomy; Polycystic Kidney Diseases; Polycythemia

Topics: Anemia; Animals; Erythropoietin; Hematocrit; Hemodynamics; Humans; Kidney; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; Renal Dialysis

The treatment of renal anaemia by recombinant human erythropoietin (EPO) is now well established. Several studies have examined the pharmacokinetics and efficacy of the drug given intravenously, intraperitoneally and subcutaneously and there is increasing evidence that the subcutaneous route has several advantages including the requirement for a lower dose. It is also important to stress the need for careful determination of baseline iron status of all patients before commencing EPO therapy. In the long term the extremely high iron stores of transfusion dependent patients will disappear. In the short term, however, the majority of the patients whose serum ferritin is less than 100 micrograms/l will require iron supplementation to allow an appropriate haemoglobin response. Alternatively, a fall in transferrin saturation to less than 20% is certainly an indication for iron supplementation and if oral iron therapy is not adequate then intravenous preparations may have to be considered. Although the anaemia of renal failure can be fully corrected by EPO, partial correction may be sufficient to reverse the problems of reduced exercise capacity, myocardial ischaemia and cardiomegaly which are frequently associated with end-stage renal disease. Partial correction will also result in a lesser rise in whole blood viscosity and, in turn, possibly reduce hypertension, thrombosis and increased peripheral resistance and thus lessen the side effects of EPO therapy.

Topics: Anemia, Hypochromic; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Thrombosis

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

The analysis of the hemodynamic parameters involved in the regulation of blood pressure during correction of anemia shows - although peripheral resistance and cardiac output behave qualitatively as in the nonuremic patient - that the extent of change may be inadequate resulting in an increased blood pressure. The underlying mechanisms are not yet fully understood but to a greater part may be related to preexisting pathology due to a history of long-lasting hypertension. To avoid cardiovascular complications under rhEPO therapy the following should be considered: patients with a history of hypertension, even if they are normotensive in the anemic state, are at a higher risk for developing hypertension under rhEPO. Hypertensive complications may be rare events when anemia is corrected slowly. Further studies will demonstrate whether in addition to the benefit of a very low maintenance dose of rhEPO subcutaneous administration will also contribute to the reduction of the incidence of hypertension.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Humans; Kidney; Kidney Failure, Chronic; Liver; Recombinant Proteins; Uremia

Recombinant human erythropoietin represents a potential therapeutic alternative to red blood cell transfusions in a number of pediatric anemias. It is effective in correcting anemia associated with chronic renal failure and may significantly reduce the morbidity associated with childhood CRF. Most exposures to allogeneic blood products in pediatrics for treatment of anemia with blood transfusions occur in neonatal intensive care units. If proven effective in treating anemia in premature babies, r-HuEPO will be responsible for a major reduction in the use of blood transfusions in clinical neonatology. Carefully designed, placebo-controlled clinical trials will be required to establish the role of r-HuEPO in anemia of prematurity. Recombinant human erythropoietin also may be useful to increase the amount of blood that can be collected before elective surgical procedures. Another potential indication is to raise the hematocrits of infants with large intracardiac shunts who develop congestive heart failure coincident with the developmental fall in hemoglobin concentration after birth. Finally, r-HuEPO may one day play a role in modifying the expression of globin genes and, thereby, ameliorate the course of sickle cell disease and beta thalassemia. Many questions surrounding the use of r-HuEPO in infancy and childhood are being addressed in ongoing clinical trials.

Topics: Anemia; Anemia, Sickle Cell; Blood Transfusion, Autologous; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases; Kidney Failure, Chronic; Recombinant Proteins

The analysis of the structure of erythropoietin and the subsequent production of recombinant human erythropoietin opened a new era in the understanding of the pathogenesis and therapy of renal anaemia. From the diagnostic point of view sufficiently accurate radioimmunoassays are currently available to throw new light on the pathogenesis of renal anaemia, and enable pharmacokinetic studies of the recombinant hormone to be carried on. For the first time a causal therapy is available for renal anaemia. The following review summarizes the consequences of these innovations on the different aspects of nephrology.

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

The anemia of chronic renal failure can now be effectively treated with recombinant human erythropoietin when given in adequate doses. This hormone replacement therapy is associated with significant clinical benefits but it requires adequate iron stores for maximal effectiveness, it may result in elevation in diastolic blood pressure, and the response may be blunted by the presence of infection or inflammation.

Topics: Anemia; Erythropoietin; Humans; Inflammation; Iron; Kidney Failure, Chronic; Recombinant Proteins

Topics: Adult; Aged; Erythropoietin; Female; Hemodynamics; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Seizures

Topics: Anemia; Animals; Erythropoietin; Humans; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Rabbits; Recombinant Proteins

The remarkable capacity of the bone marrow to compensate for blood loss and for reduced atmospheric oxygen tension has been found to be mediated by a renal hormone, named erythropoietin. It is produced by peritubular interstitial cells in response to renal hypoxia, but molecular engineering has permitted large scale production of an identical recombinant erythropoietin in vitro. When used as a replacement hormone in patients with impaired endogenous production it has been found to be capable of improving or eliminating the anemia of chronic kidney disease and the anemia of prematurity. In the future it may also be used as a pharmacologic agent and possibly be able to control the anemia of patients with bone marrow failure and make them transfusion-independent.

Topics: Anemia; Bone Marrow; Erythropoiesis; Erythropoietin; Humans; Kidney; Kidney Failure, Chronic; Polycythemia Vera; Recombinant Proteins

Topics: Acquired Immunodeficiency Syndrome; Anemia; Arthritis, Rheumatoid; Blood Transfusion, Autologous; Erythropoietin; Humans; Hypertension; Inflammation; Iron; Kidney Failure, Chronic; Recombinant Proteins; Vascular Resistance

Topics: Anemia; Animals; Blood Platelets; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Quality of Life; Recombinant Proteins; Renal Dialysis

The authors reported on a three month long EPREX (human recombinant erythropoietin) therapy of 5 hemodialysis patients for the treatment of their anemia. The drug was administered in bolus form 2 or 3 times a week after dialysis in a dose of 50 to 150 IU/bodyweight increased gradually in every (or every second) week. Hgb ad Htk values were determined once a week while erythrocyte, leukocyte, thrombocyte and reticulocyte count once a month. Serum iron, TIBC, serum ferritin, BUN, serum creatinine, urea, serum ions, liver function assays, serum lipids and amylase were also established. Hgb, Htk levels and reticulocyte count have significantly increased in the 4th week of treatment already, severe anemia ceased with improved appetite, general condition and physical strength. Serum urea and LDH levels significantly increased while SGOT decreased. No significant change in leukocyte and thrombocyte count, serum Na, K, Ca, P, Cl, BUN, creatinine, total protein level, serum albumin, bilirubin, alkaline phosphatase, GGT, GPT, amylase and blood sugar as well as serum lipid level were observed. No adverse reactions occurred during the treatment. After the three gradually decreased and within 6 weeks they had to be transfused again. In three patients the need for transfusion has significantly grown after the treatment. The authors consider EPREX a highly efficient drug in the treatment of anemia in dialysis patients.

Topics: Anemia; Erythropoietin; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic; Renal Dialysis

Topics: Acute Kidney Injury; Aluminum; Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis

Recombinant human erythropoietin (rHuEpo) has now been in clinical trials for over four years. rHuEpo has been shown to be nearly uniformly effective in correcting the anaemia of patients on haemodialysis or patients with progressive chronic renal failure not yet on dialysis. rHuEpo has been shown to be effective in increasing the ability of individuals to donate blood for self-use and to increase the haematocrit in patients with rheumatoid arthritis. Preliminary results indicate that rHuEpo will decrease transfusion requirements of patients with the acquired immune deficiency syndrome who are anaemic. Trials in patients with anaemia associated with cancer or myelodysplastic syndromes are in early stages. rHuEpo will have a major impact as a therapeutic agent, particularly in patients with renal disease.

Topics: Acquired Immunodeficiency Syndrome; Anemia; Arthritis, Rheumatoid; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia; Anemia, Refractory; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Humans; Hypoxia; Kidney Failure, Chronic; Polycythemia; Recombinant Proteins

Topics: Erythropoietin; Female; Hormones; Humans; Hyperparathyroidism, Secondary; Kidney; Kidney Failure, Chronic; Male; Pancreatic Hormones; Pituitary-Adrenal System; Prostaglandins; Renin-Angiotensin System; Testosterone

Administration of recombinant erythropoietin constitutes a revolution in treatment of the anemia of chronic dialysis patients. Such treatment has been anxiously awaited. Its realization has been possible thanks to the spectacular progress allowed by the newly developed techniques of recombinant genetics. Correction of this type of anemia can be obtained rapidly and permanently if treatment is continued without interruption. It is followed by a remarkable transformation of the patient's physical and psychic status. The occurrence of certain side effects (e.g., elevation of blood pressure and an increased tendency toward vascular thrombosis), however, requires increased awareness in the follow-up of patients at risk and adaptation of erythropoietin administration to individual needs.

Topics: Adolescent; Adult; Anemia; Clinical Trials as Topic; Drug Evaluation; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins

Topics: Clinical Trials as Topic; Dose-Response Relationship, Drug; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Data presented in this study suggest existence of hyperendorphinism in uraemic patients. This hyperendorphinism may be regarded both as a primary beneficial compensatory mechanism counteracting disturbances of the internal environment, while causing secondary harmful side effects, which contribute to the uraemic state. Erythropoietin treatment of uraemic, haemodialyzed patients is followed by marked endocrine alterations (suppression of plasma levels of STH, ACTH, prolactin, glucagon, aldosterone, cortisol and plasma renin activity, elevation of plasma insulin and atrial natriuretic levels, lack of influence on plasma PTH, CT and AVP). It remains to be clarified whether the erythropoietin induced endocrine alterations are due to correction of the existing anaemia or reflect a specific effect of this hormone.

Topics: Endocrine System Diseases; Erythropoietin; Hormones; Humans; Kidney Failure, Chronic; Receptors, Opioid; Renal Dialysis

Red cell production in vertebrates is controlled by a glycoprotein hormone known as erythropoietin (Ep), which is produced by the kidney in response to hypoxia and acts on the marrow to selectively stimulate erythropoiesis. The gene for Ep has recently been cloned, and highly pure recombinant human Ep (rHuEp) is now available in considerable quantity. This has led to a better understanding of many aspects of Ep biology and to clinical trials in humans. The amino acid sequence of Ep is now completely known, and the protein portion of the natural hormone and the recombinant product are identical. Both the natural hormone and rHuEp produced in Chinese hamster ovary cells are heavily glycosylated in a very similar manner. This glycosylation is not necessary for in vitro activity but is required for activity in vivo. Radioimmunoassays (RIAs), which use labeled rHuEp, have been developed and are sufficiently sensitive to measure normal plasma levels. However, since Ep exists in plasma in several forms that vary in their immunologic and biologic activities, the ability of a RIA to provide information on the pathogenesis of clinical disease may be limited and should be referenced to the polycythemic mouse assay. The kidney's role in the production of Ep has been greatly clarified. Studies using probes to Ep mRNA have shown that Ep is primarily made in the kidney and secreted as the intact hormone. Moreover, renal secretion appears to be regulated by the rate of synthesis of the hormone, which in turn is dependent on the rate of synthesis of Ep mRNA. The cells that produce Ep have been identified as peritubular interstitial cells that may be endothelial in origin. The initiating mechanism for hormone production appears primarily to involve recruitment of additional cells rather than increased production by individual cells. Ep primarily acts on the marrow to stimulate the growth and maturation of early cells in the erythroid lineage that are known as the burst-forming unit-erythroid (BFU-E) and colony-forming unit-erythroid (CFU-E). The BFU-E is a very early cell closely related to the pluripotent stem cell, while the CFU-E is a later cell close to the first recognizable erythroblast.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Anemia; Animals; Blood Transfusion, Autologous; Erythropoiesis; Erythropoietin; Feedback; Humans; Kidney Failure, Chronic; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Receptors, Cell Surface; Receptors, Erythropoietin; Recombinant Proteins; Second Messenger Systems

Topics: Erythropoietin; Humans; Infant, Newborn; Kidney Failure, Chronic; Pharmacies; Recombinant Proteins; Renal Dialysis

Several factors contribute to the pathogenesis of anemia due to renal failure. Hypoproliferation of red cell progenitors may be caused partially by an inhibitory effect of some 'uremic toxins' whose existence certainly is very controversial. Iron deficiency due to gastrointestinal and dialysis-related blood losses and occasionally aluminum intoxication may interfere with the maturation of the erythron. Moderate hemolysis with shortening of red cell survival to some 50% of normal may be an additional factor. The main cause of anemia is, however, inadequate production of erythropoietin by the diseased kidney. This latter factor has now become amenable to treatment.

Topics: Anemia; Erythropoiesis; Erythropoietin; Hemolysis; Humans; Kidney Failure, Chronic; Renal Dialysis; Uremia

The anemia associated with end-stage renal disease (ESRD) is primarily due to a deficiency in renal-derived erythropoietin. Through advances in genetic engineering, the gene for erythropoietin has been isolated and cloned, and recombinant human erythropoietin (r-HuEPO; EPOGEN, AMGEN Inc, Thousand Oaks, CA) is now available for clinical use. Study results indicate that r-HuEPO is highly effective in ameliorating symptomatic anemia in patients with chronic renal failure. Sustained dose-dependent increases in hematocrit values are achieved in at least 97% of patients, with improvement in quality of life, exercise tolerance, decrease in total body iron stores, and virtual elimination (40-fold reduction) of transfusion requirements. Hypertension is the most common side effect, but is easily controlled. To date, anti-erythropoietin antibodies have not been detected in patients treated with this product. Doses between 100 and 150 U/kg body weight are sufficient to increase hematocrit levels to normal in 2 months or less, with iron replacement therapy needed in most patients. The correction of anemia in ESRD patients promotes an increase in appetite, causing ingestion of more protein, potassium, and sodium. The resulting need for increased dialysis may burden existing dialysis facilities. Experience with 36 patients receiving r-Hu-EPO demonstrates that high-flux short-time hemodialysis is as effective as conventional hemodialysis. There were no significant differences between the groups in laboratory parameters including blood urea nitrogen, creatinine, potassium, phosphate, mean arterial pressure, and weight loss, although hematocrit values were slightly higher in the high-flux dialysis patients. Adverse effects resulting from r-HuEPO treatment were minor and were not more common in the group receiving high-flux short-time hemodialysis.

Topics: Anemia; Clinical Trials as Topic; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

The debilitating symptoms of the anemia associated with end-stage renal disease (ESRD) may have a profound effect on patients' quality of life. Until now it has been difficult to differentiate symptoms caused by the anemia from those caused by uncleared uremic toxins and other concomitant diseases. Treatment with recombinant human erythropoietin (EPOGEN, AMGEN Inc, Thousand Oaks, CA) largely eliminates the anemia associated with ESRD; it therefore offers a means of improving patients' quality of life while also clarifying the possible causes of the various symptoms. However, because quality of life involves many factors, such as self-concept, interpersonal relations, and work identity, an improvement in the anemia will have a varying impact on different individuals.

Topics: Anemia; Clinical Trials as Topic; Erythropoietin; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; Renal Dialysis

The development of hypoproliferative anemia with generally normocytic red blood cells in most patients with chronic renal failure impairs the success of maintenance dialysis therapy, particularly hemodialysis. Anemia can be a complication of the hemodialysis procedure itself, with its associated blood losses and mild effect on oxygen transport functioning. However, the primary cause of anemia in the chronic dialysis patient is decreased erythropoiesis. The most important mechanism leading to decreased erythropoiesis involves the production of subnormal levels of erythropoietin (EPO). Insufficient nephric output of EPO or, possibly, suppression of the effect of EPO by uremic inhibitors may cause this decreased erythropoiesis. Other factors, such as iron deficiency, hyperparathyroidism, systemic infections, and aluminum toxicity may contribute to anemia in some patients. Increased hemolysis, a comparatively mild factor in the anemia of chronic dialysis patients, may be related to retention of protein metabolism products, hypersplenism, hypophosphatemia, drugs, or other conditions in affected patients. There are several traditional treatment options for anemia: transfusions; iron, vitamin B12, or folic acid supplementation when indicated; a change to peritoneal dialysis; parathyroidectomy; and administration of androgens. None of these treatments have proved satisfactory, and some, such as transfusions and androgen therapy, pose risks and have serious side effects. A comparatively new approach, administration of genetically engineered erythropoietin (r-HuEPO; EPOGEN, AMGEN inc, Thousand Oaks, CA), has been found effective in treating anemia in clinical trials. Patients have shown improved cardiac performance as well as enhanced quality of life, and hypertension appears to be the most serious side effect of r-HuEPO therapy.

Topics: Anemia; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Renal Dialysis

The traditional options available for the correction of hemodialysis-related anemia are blood transfusions and androgen therapy to stimulate erythropoiesis. A new therapeutic option, recombinant human erythropoietin (r-HuEPO; EPOGEN, AMGEN Inc, Thousand Oaks, CA), is currently undergoing clinical trials. Each treatment alternative has certain attendant adverse effects. The adverse effects of transfusion include transmission of infections such as hepatitis or acquired immunodeficiency syndrome, iron overload, and sensitization to histocompatibility antigens. Androgen therapy can cause masculinization of women and children and, in some forms, is associated with a high incidence of abnormal liver function. Treatment with r-HuEPO has some potential adverse effects, including hypertension, thrombosis of arteriovenous fistulae, prolonged duration of dialysis, hyperkalemia, and iron deficiency. Gradual and careful introduction of r-HuEPO should prevent hypertension from becoming problematic.

Topics: Androgens; Anemia; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis; Transfusion Reaction

A number of conditions can contribute to the development of the anemia that inevitably occurs with end-stage renal disease. The primary ones are decreased production of erythropoietin (EPO), decreased response to EPO by the bone marrow, and shortened red cell survival. Dialysis improves hematocrit levels by reducing plasma volume and by increasing red cell mass as a result of clearing some of the middle molecule uremic toxins that affect EPO efficiency and red cell survival time. Patients undergoing continuous ambulatory peritoneal dialysis generally show higher hematocrits and lower transfusion dependencies than hemodialysis patients. The development of recombinant human EPO (EPOGEN, AMGEN Inc, Thousand Oaks, CA) largely ends the transfusion dependence of hemodialysis patients and may prove efficacious in those patients who are not transfusion dependent but whose low hematocrit levels may cause debilitating symptoms.

Topics: Anemia; Blood Transfusion; Erythropoietin; Humans; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis

Topics: Adult; Anemia; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins

Topics: Anemia; Drug Evaluation; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia; Chemical Phenomena; Chemistry; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia; Cells, Cultured; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia; Blood Viscosity; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Extensive testing has proven that recombinant human erythropoietin (r-HuEPO; EPOGEN [epoetin alfa], AMGEN Inc, Thousand Oaks, CA) corrects the anemia of end-stage renal disease and eliminates the need for transfusions in virtually all patients. Patients whose hematocrit levels are less than 0.30 or who are transfusion dependent are candidates for therapy. A dosage of 50 to 150 U/kg body weight intravenously three times a week produces an increase in hematocrit by approximately 0.01 to 0.02 per week. Once the hematocrit reaches 0.30 the dose is adjusted so that a target hematocrit of 0.32 to 0.38 is maintained. Eighty percent of patients need maintenance doses of r-HuEPO of less than or equal to 150 U/kg; the other 20% of patients require larger doses. Reasons for poor responses include iron deficiency, inflammation due to surgery or infection, and osteitis fibrosa. Most patients require iron supplementation to prevent functional iron deficiency. BP increased in one third of patients, and in 3% seizures occurred during the initial phase of therapy, often associated with a sudden increase in BP. This hypertension can be controlled with medication. Increased dialyzer clotting may occur, which is prevented when heparin doses are adjusted, and dialyzer solute clearances may decrease slightly. Treatment with r-HuEPO does not elicit an antibody response. The mechanism of action of r-HuEPO is identical to that of natural erythropoietin, and therefore is an appropriate therapy for the long-term management of anemia in chronic renal failure.

Topics: Anemia; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Recombinant Proteins

Effective monitoring of chronic hemodialysis patients treated with recombinant human erythropoietin (r-HuEPO; EPOGEN [epoetin alfa], AMGEN Inc, Thousand Oaks, CA) includes an initial evaluation of the patient, the patient's anemia, and the patient's iron stores. Assessment of iron stores includes obtaining hematocrit and hemoglobin levels, reticulocyte count, red cell indices, serum ferritin level, transferrin percent saturation, and the patient's transfusion history. If iron stores are inadequate to support the increased erythropoiesis induced by the therapy, appropriate iron replacement therapy should be provided. Monitoring also involves assessment of BP (and its control), because development or exacerbation of hypertension is the most significant side effect associated with this treatment. Because the dose-response relationship for r-HuEPO therapy has been clearly documented, a target hematocrit and target rate of increase in hematocrit can be established. As anemia improves, continued monitoring of hematocrit, hemoglobin, red cell indices, serum ferritin level, and transferrin percent saturation will ensure that depleted iron stores are noted and treated as necessary. Heparin requirements during dialysis, blood chemistries, and blood access problems should also be monitored. No data currently exist suggesting that dialyzer reuse is compromised by r-HuEPO therapy. Quality-of-life surveys show improvement with r-HuEPO treatment and effective reduction of anemia. There is also some indication that morbidity is lessened and survival improved when anemia is treated with r-HuEPO therapy.

Topics: Anemia; Blood Pressure Determination; Erythropoietin; Hematocrit; Humans; Iron; Kidney Failure, Chronic; Monitoring, Physiologic; Quality of Life; Recombinant Proteins; Renal Dialysis

Onset or exacerbation of hypertension has been observed as a possible complication of recombinant human erythropoietin (r-HuEPO; EPOGEN [epoetin alfa], AMGEN Inc, Thousand Oaks, CA) therapy for the anemia of end-stage renal disease. This effect is attributed to an overly rapid rise in the hematocrit level and the accompanying consequences, which include increased hemoglobin, blood viscosity, and red cell mass, as well as normalization of the cardiac index of anemia. The sluggish response to these changes by compensatory mechanisms, resulting in increased peripheral vascular resistance, may be the means by which BP becomes elevated during therapy. Although more than one third of patients receiving r-HuEPO therapy have developed sustained increases in diastolic pressure of 10 mmHg or more, this potential problem is controllable. Prevention or correction of hypertension is accomplished by initiating therapy with a low-dose regimen that is slowly increased, thereby preventing a rapid rise in the hematocrit level. Drug intervention, together with dialysis prescription modification and restriction of dietary salt and fluid to regulate weight, can effectively control BP. Discontinuation of therapy for severe and uncontrollable hypertension rarely becomes necessary.

Topics: Anemia; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Iron deficiency frequently complicates both acute and chronic phases of recombinant human erythropoietin (r-HuEPO; EPOGEN [epoetin alfa], AMGEN Inc, Thousand Oaks, CA) therapy for dialysis-associated anemia. During acute correction of anemia, iron needed for new hemoglobin production may outstrip available body iron stores. During maintenance r-HuEPO therapy, blood lost both through the dialysis process and the uremic predisposition to gastrointestinal bleeding promotes ongoing negative iron balance. Failure to recognize and treat iron deficiency may lead to impaired efficacy of r-HuEPO in the anemic patient by converting the anemia associated with chronic renal failure to the anemia associated with iron deficiency. The risk of iron deficiency is assessed by weighing available iron stores, as reflected by the level of serum ferritin, against anticipated iron needs for new hemoglobin synthesis, as measured by the difference between the current and target hemoglobin. Using this approach, body iron reserves can be determined, iron deficits predicted, and appropriate iron replacement therapy planned. Once patients are identified as being at risk for iron deficiency, they are treated prophylactically with oral iron supplements. Parenteral iron therapy is reserved for those at greatest risk for iron deficiency during acute r-HuEPO treatment and those intolerant or unresponsive to oral iron supplements during chronic r-HuEPO treatment. Although no dose-response relationship has been observed in the restoration of iron balance with oral iron supplements, those taking supplements show distinctly higher projected iron stores and daily iron balance than those not given supplements.

Topics: Anemia; Anemia, Hypochromic; Erythropoietin; Humans; Iron; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

The clinical manifestations of uremia are only incompletely reversed by chronic hemodialysis. Signs and symptoms can include abnormalities in electrophysiologic indices, clinical mental status, and neuropsychological test performance, as well as decreases in exercise tolerance, sexual potency, and general quality of life. Though retention of uremic toxins is responsible for many of these symptom complexes, some may be caused, or substantially aggravated, by the anemia that almost invariably accompanies chronic renal failure. Treatment with recombinant human erythropoietin (r-HuEPO; EPOGEN [epoetin alfa], AMGEN Inc, Thousand Oaks, CA) increases hematocrit values and thus reduces the anemia, in turn improving brain and cognitive function, exercise tolerance, sexual potency, and quality of life.

Topics: Anemia; Cognition; Erythropoietin; Exercise; Humans; Kidney Failure, Chronic; Quality of Life; Recombinant Proteins; Renal Dialysis; Sex

Recombinant human erythropoietin (r-HuEPO; EPOGEN [epoetin alfa], AMGEN Inc, Thousand Oaks, CA) has proven to be an effective agent in treating the anemia of chronic renal failure. Of patients enrolled in recent phase III trials in the United States, 97% have responded with near normalization of hematocrit within 12 weeks of therapy. Small numbers of patients, however, may exhibit sluggish or minimal responsiveness to treatment. In these patients, loss of responsiveness due to red cell substrate depletion (in particular, iron deficiency) or underlying inflammatory disease may occur at any time during the treatment calendar, whether at induction of therapy or during maintenance treatment. Primary unresponsiveness at initiation of treatment may also result from such potentially reversible abnormalities as aluminum intoxication, poorly controlled hyperparathyroidism, and, possibly, severe azotemia. These abnormalities can be investigated in a systemic fashion and frequently corrected so that successful treatment can resume.

Topics: Anemia; Clinical Trials as Topic; Drug Resistance; Erythropoietin; Hematocrit; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia; Erythropoietin; Ferritins; Hematocrit; Humans; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis; Transferrin

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic

Renal dysfunction gives rise to a variety of hematologic disturbances, including anemia, leukocyte dysfunction, and coagulopathy. The anemia of renal failure has been attributed to a relative deficiency of erythropoietin, but contributing factors include an absolute deficiency of iron or folate. Other contributing factors include heavy metal toxicity, blood loss, and hemolysis. The treatment of the anemia of renal disease has advanced with the development of recombinant human erythropoietin. At doses from 15-500 micrograms/kg triweekly in selected patients, normalization of hemoglobin is presently possible. Transfusion may still have a role in patients with renal disease, although more as preconditioning for renal transplantation. In non-HLA matched transplantation, donor-specific transfusion, as well as immunosuppressives, may exert some benefit in graft survival. The coagulopathy of renal disease consists of an acquired qualitative platelet defect best remedied by dialysis but also treated successfully by cryoprecipitate or DDAVP. Infectious complications of uremia include diminished leukocyte chemotaxis, phagocytosis, and bactericidal activity. Cell-mediated immune defects and hypogammaglobulinemia have also been described. The pathophysiology involved in the protean hematologic manifestations of uremia are discussed; additionally, we describe therapeutic recommendations to deal with anemia, bleeding and infectious complications of renal failure.

Topics: Anemia; Blood Platelet Disorders; Blood Transfusion; Erythropoiesis; Erythropoietin; Humans; Infections; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis

The chemistry, pharmacology, pharmacokinetics, clinical uses and efficacy, adverse effects, drug interactions, dosage and administration, and formulary considerations of epoetin are described. Erythropoietin, a glycoprotein hormone primarily synthesized in the kidney, is the chief regulator of red blood cell production. Erythropoietin concentrations increase in response to a hypoxic state, resulting in increased red blood cell formation, accelerated hemoglobin production, and premature movement of reticulocytes into the circulation. The human gene responsible for the production of erythropoietin recently was cloned, and the recombinant product--epoetin--has been made available through mass production. The apparent volume of distribution of i.v. epoetin approximates the assumed plasma volume both in healthy volunteers and in patients with chronic renal failure. Little is known about the metabolism and route of elimination of epoetin and erythropoietin. Epoetin recently was approved by the FDA for treatment of anemia associated with chronic renal failure. Clinical trials in patients receiving hemodialysis or peritoneal dialysis and in predialysis patients with renal dysfunction demonstrate epoetin's efficacy. Other potential indications include augmentation of blood production in patients enrolled in autologous blood donation programs and treatment of anemias associated with rheumatoid arthritis, sickle cell disease, acquired immunodeficiency syndrome, cancer, and premature birth. The most frequent adverse effect associated with epoetin therapy is the worsening or development of hypertension. Other adverse effects include thrombocytosis, hyperkalemia, rise in serum urea concentration, iron deficiency, and flu-like symptoms. No drug interactions with epoetin have been reported in humans. The recommended starting epoetin dosage in patients with chronic renal failure is 50-100 IU/kg three times weekly. Epoetin is available only as an injection for i.v. or s.c. administration. Epoetin provides a new therapeutic approach to the treatment of anemia associated with chronic renal failure in hemodialysis, peritoneal dialysis, and predialysis patients. Benefits of epoetin therapy include reduced need for blood transfusions, the amelioration of anemic symptoms, and an improved quality of life.

Topics: Anemia; Blood Transfusion, Autologous; Chemical Phenomena; Chemistry; Drug Interactions; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Combined Modality Therapy; Erythropoietin; Hemoglobins; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Renal Dialysis

The available data from experimental and clinical studies suggest that in the development of hypertension following correction of renal anemia under rhEPO three mechanisms are operative: (1) an increase in whole blood viscosity; (2) possible also a reduction of hypoxic vasodilatation, and (3) at least in some patients an inadequate reduction of cardiac output. To avoid cardiovascular complications under rhEPO therapy, the following should be considered: Patients that were hypertensive before the start of renal replacement therapy, even if they were normotensive in the anemic state - because of morphological alterations of their peripheral vascular bed-may run a higher risk for developing hypertension under rhEPO. As patients with undetected volume contraction may be more endangered by cardiovascular complications, the hematocrit should be monitored before and after dialysis, especially in patients with high weight gain and in children. Patients who are hypertensive under rhEPO therapy should be treated by antihypertensive drugs as appropriate. Drugs of the first choice are beta-blockers and vasodilating agents. Volume removal should not be the sole measure for blood pressure control and should be applied carefully. To avoid hypertensive and rheological complications, the target hematocrit should not exceed 30 vol%.

Topics: Anemia; Blood Viscosity; Cardiac Output; Erythropoietin; Hemodynamics; Humans; Hypertension; Kidney Failure, Chronic; Renal Dialysis; Vasodilation

Erythropoietin mRNA is detected primarily in kidney peritubular cells in response to hypoxia, and this tissue is the major adult source of the hormone. Erythropoietin can be assayed by in vivo or in vitro biological methods, or by radioimmunoassay, but only the in vivo assay can distinguish the most biologically active forms. The mature hormone consists of 166 amino acids and approximately 50% of the mature molecule (Mr 39,000) consists of carbohydrate. The gene is highly conserved among species studied, and is located on human chromosome 7, region q11-q22. Recombinant erythropoietin has been administered to haemodialysis patients and shown to increase haemoglobin levels, reticulocyte numbers and haematocrit. In transfusion-dependent patients, the need for regular transfusions was abrogated. Problems with hypertension have been noted in previously hypertensive patients, but the results of clinical trials with erythropoietin suggest that it will provide a valuable alternative therapy, for correcting some disorders of erythropoiesis.

Topics: Anemia, Hemolytic; Animals; Cloning, Molecular; Erythropoietin; Humans; Kidney Failure, Chronic; Rats

Topics: Anemia; Clinical Trials as Topic; Drug Administration Schedule; Erythropoietin; Humans; Iron; Kidney Failure, Chronic; Mononuclear Phagocyte System; Multicenter Studies as Topic; Recombinant Proteins

Recombinant human erythropoietin is a major advance in the management of patients with chronic renal failure. The sustained dose-dependent rise in haematocrit which it produces effectively abolishes symptoms of anaemia, but at the cost of an increase in blood viscosity. This in turn predisposes to increased vascular resistance and the development of hypertension. Over half of all deaths of patients with end-stage renal failure are from cardiovascular disease, notably myocardial infarction, heart failure, and stroke, for which hypertension is a known risk factor. Erythropoietin-related increases in blood pressure are therefore of particular concern, and seem to be most severe in previously hypertensive patients. There is now a need to establish the optimum rate and extent of rise of haematocrit required to alleviate symptoms without incurring undue risk.

Topics: Blood Viscosity; Cardiovascular Diseases; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Recombinant Proteins; Risk Factors

In summary, the anemia of CRF results from several interactive processes, chief among these inadequate Ep production relative to the degree of anemia. The anemia of renal failure can be regarded as an endocrine deficiency state, which is corrected by the specific replacement therapy. The advances of molecular biology have provided a biosynthetic Ep, a potent tool for correction and prevention of the anemia of renal failure. However, new problems often arise as new treatments become available. The rapid improvement in hematocrit and the resultant lowering in plasma volume may affect dialysis clearances in hemodialysis patients. Since the well-being and appetite of the patients improves as the hematocrit rises, newer methods to increase the weekly dialysis clearances will be needed to prevent the complication of underdialysis in these patients.

Topics: Anemia; Erythropoiesis; Erythropoietin; Humans; Kidney; Kidney Failure, Chronic; Renal Dialysis

Topics: Aluminum; Angiotensin II; Chronic Kidney Disease-Mineral and Bone Disorder; Communicable Diseases; Erythropoietin; History, 20th Century; Humans; Insulin; Kidney Failure, Chronic; Renal Dialysis; Renin; Uremia; Vitamin D

Topics: Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Amino Acid Sequence; Anemia; Animals; Erythropoietin; Humans; Kidney Failure, Chronic; Molecular Sequence Data; Rats; Recombinant Proteins

The pathophysiology of the anemia of chronic renal failure (CRF), erythropoietin physiology, the characteristics of recombinant human erythropoietin, and the results of nearly 2 years of therapy with this product in hemodialysis patients are detailed in this review. This anemia is primarily an endocrine deficiency state corrected by the hormone erythropoietin. Correction of the anemia eliminates transfusions and their associated risks, improves physical endurance, and results in healthier patients beginning dialysis. Adequate support services will be necessary to maximize patient rehabilitation and employment potential. Further research is needed to better understand erythropoietin physiology and metabolism, and the impact of uremia on end organ function in the absence of anemia.

Topics: Anemia; Animals; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Recombinant human erythropoietin raises serum erythropoietin concentrations to adequate levels and restores the hematocrit to normal values in the vast majority of anemic, end stage renal disease patients undergoing regular hemodialysis. It can eliminate the need for transfusions and thus the risk of immunologic sensitization, infection and iron overload. Erythropoietin not only alters laboratory findings but improves the well being and performance of patients on hemodialysis as well. Side effects are minimal and neither antibodies nor resistance to the recombinant hormone have been observed so far. Along with the rise in hematocrit and blood viscosity some patients developed increased blood pressure and a few hypertensive encephalopathy, but after brief interruption of therapy erythropoietin treatment could be continued in combination with antihypertensive drugs. The pathophysiology of the increase in blood pressure, the risk of encephalopathy and the possibly somewhat higher risk of thrombosis remain to be elucidated. Nevertheless, the first recombinant hematopoietic hormone has passed its first clinical trials with success.

Topics: Anemia; Antihypertensive Agents; Blood Transfusion; Blood Viscosity; Clinical Trials as Topic; Drug Evaluation; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Renal Dialysis

Topics: Anemia; Erythropoietin; Hematopoietic Stem Cells; Humans; Kidney Failure, Chronic; Uremia

Topics: Anemia; Erythrocyte Aging; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia; Child; Erythropoietin; Humans; Kidney Failure, Chronic

Topics: Anemia, Refractory; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Half-Life; Hematopoietic Stem Cells; Hormones; Humans; Kidney; Kidney Diseases; Kidney Failure, Chronic; Oxygen Consumption

Topics: Anemia; Bone Marrow; Erythrocytes; Erythropoiesis; Erythropoietin; Ferritins; Folic Acid; Hemoglobins; Hemorrhage; Hemostasis; Humans; Hypersplenism; Iron; Kidney Failure, Chronic; Kidney Transplantation; Renal Dialysis; Uremia; Vitamin B 12

Topics: Anemia; Animals; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Humans; Kidney; Kidney Failure, Chronic; Renal Dialysis; Sheep

Topics: Anemia; Anemia, Hemolytic; Anemia, Hypochromic; Anemia, Sideroblastic; Animals; Erythrocytes; Erythropoietin; Humans; Kidney Failure, Chronic; Rats; Renal Dialysis

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Hemolysis; Hemorrhage; Humans; Kidney Failure, Chronic

Topics: Anemia; Animals; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Hematopoietic Stem Cells; Heme; Humans; Kidney; Kidney Failure, Chronic; Methylguanidine; Models, Biological; Rabbits

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Humans; Kidney; Kidney Failure, Chronic; Kidney Neoplasms; Rats

Topics: Aging; Androgens; Anemia; Animals; Erythropoietin; Humans; Kidney; Kidney Failure, Chronic; Liver; Nephrectomy

A review is given of clinical studies performed by use of a highly sensitive in-vitro erythropoietin assay (fetal mouse livercell culture) in large patients' populations to clarify the controversial role of erythropoietin deficiency in the pathogenesis of renal anemia. Studies involved a.) patients with chronic renal disease and varying degree of renal insufficiency in the predialysis phase b.) non-nephrectomized and anephric patients on regular hemodialysis treatment. The data available demonstrate that the initial phase of renal anemia is accompanied by a compensatory increase of serumerythropoietin concentration and therefore erythropoietin deficiency has to be excluded as a primary cause of the anemia of renal failure; merely a relative lack of erythropoietin seems to exist. In the terminal phase of renal failure, erythropoietin deficiency becomes absolute, such in 50% of the investigated non-nephrectomized hemodialysis patients and in all anephric patients. However in individual patients even in terminal renal failure a sustained regulatory feedback mechanism between serumerythropoietin concentration and hematocrit, probably working at lower hematocrit level, could be demonstrated.

Topics: Anemia; Animals; Cells, Cultured; Erythropoietin; Hematocrit; Humans; In Vitro Techniques; Kidney Failure, Chronic; Liver; Mice; Uremia

Uremia interferes with erythropoiesis, granulocyte, platelet, and immune functions. As a result, uremic patients are almost invariably anemic, and have a high incidence of infections and hemorrhagic complications. The anemia of renal failure, which is caused primarily by damage to the site of erythropoietin production is often complex, and complicated by hemolysis from a variety of mechanisms, iron deficiency, and so forth. Although hemodialysis ameliorates some of the hematologic complications to a variable degree, they remain a serious hinderance to the well being of this group of patients. Progress in understanding the mechanism of these problems and their therapy has been reviewed here.

Topics: Anemia; Anemia, Hemolytic; Anemia, Hypochromic; Blood Transfusion; Erythrocytes; Erythropoiesis; Erythropoietin; Folic Acid Deficiency; Hemorrhage; Humans; Kidney; Kidney Failure, Chronic; Renal Dialysis; Testosterone; Testosterone Congeners

Recent work from our laboratory on the mechanism of polypeptide hormone handling by the normal kidney and the pathogenesis of altered hormonal metabolism in renal failure is reviewed. The kidney extracts substantial amounts of low - and medium - molecular weight polypeptide hormones from the renal circulation by a process which probably involves both glomerular filtration plus luminal reabsorption and direct peritubular uptake, although the relative contribution of the two mechanisms under physiologic conditions is not known. The bulk of the extracted hormone is catabolized in the renal parenchyma since urinary excretion is negligible. Renal catabolism contributes an important fraction of the total metabolic clearance of polypeptide hormones, which accounts in part for their increased circulating levels in renal failure. Since certain hormones are heterogenous and a large proportion of their plasma immunoreactivity may consist of components of uncertain biologic activity, simple correlations between circulating hormone levels and endocrine abnormalities in uremia are hazardous.

Topics: Animals; Antigens; C-Peptide; Erythropoietin; Glucagon; Gonadotropins, Pituitary; Humans; Insulin; Kidney; Kidney Failure, Chronic; Luteinizing Hormone; Metabolic Clearance Rate; Molecular Weight; Pancreatic Hormones; Proinsulin; Prolactin; Uremia

Topics: Acute Kidney Injury; Anemia; Anemia, Hemolytic; Blood Viscosity; Bone Marrow; Diphosphoglyceric Acids; Erythrocytes; Erythropoietin; Half-Life; Hematocrit; Hemoglobins; Hemolysis; Humans; Kidney Failure, Chronic; Oxygen Consumption; Pyelonephritis; Renal Dialysis; Transfusion Reaction

The effects of removal of all renal tissue on hematopoiesis, osteodystrophy, blood pressure regulation and metabolic functions are reviewed; and, the indications for, and results of, bilateral nephrectomy are discussed. Nephrectomy results in a more severe anemia in dialysis patients which is poorly responsive to androgen therapy. No differences were detected in the severity of osteodystrophy between nephric and anephric patients. However, bilateral nephrectomy can occasionally result in the acute onset of hypocalcemia. Blood pressure regulation must be accomplished in the absence of a functioning renin-angiotensin system. This is largely on the basis of volume, but changes in vascular tone may also be significant. Little is known about the metabolic consequences of nephrectomies. The effect on substances metabolized by the kidney is an area for further investigation. Kidney tissue should be preserved, if at all possible, and nephrectomy performed only for specific indications.

Topics: Adult; Anemia; Angiotensin II; Blood Pressure; Chronic Kidney Disease-Mineral and Bone Disorder; Dihydroxycholecalciferols; Erythropoietin; Female; Hematocrit; Hematopoiesis; Humans; Hypocalcemia; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Nandrolone; Nephrectomy; Renal Dialysis; Renin; Testosterone; Vitamin D

Anemia is a frequent complication of renal failure. As in anemias of other origin, the resulting tissular hypoxia is partially compensated by an increased production of 2,3-diphosphoglycerate in red cells and a shift to the right of the oxygen hemoglobin dissociation curve. Two mechanisms are implicated in this anemia: increased hemolysis and depressed production of red cells. Decreased production of erythropoietin is probably the cause of reduced erythropoiesis, but the role of uremic intoxication has not been unequivocally excluded. In the course of chronic hemodialysis, iron deficiency anemia and occasionally hypersplenism develop. It is noteworthy that blood requirements in anephric patients are two to three times greater than those of nonanephric hemodialyzed patients. Accordingly, bilateral nephrectomy should be restricted to carefully selected cases. At the present time, androgens seem to be the best treatment of renal anemia. Qualitative anomalies of platelets are the main factor responsible for uremic bleeding and are corrected by hemodialysis.

Topics: Anemia; Animals; Cell Survival; Erythrocytes; Erythropoiesis; Erythropoietin; Hematologic Diseases; Hemolysis; Hemorrhagic Disorders; Humans; Kidney Failure, Chronic; Kidney Transplantation; Renal Dialysis; Transplantation, Homologous; Uremia

Erythropoietin is a polypeptide hormone, which is produced in response to a deficit in the delivery of oxygen to the tissues relative to their oxygen needs; although other feedback mechanisms also modulate its production. The kidneys play a major role in the elaboration of this hormone. However, the precise action of the kidney is not yet known. Diseases of the kidneys cause profound alteration in the normal regulation of erythropoiesis. Some of these are reviewed here.

Topics: Anemia; Animals; Cobalt; Dactinomycin; Erythropoiesis; Erythropoietin; Hormones; Humans; Kidney; Kidney Failure, Chronic; Mice; Oxygen Consumption; Polycythemia; Rats

Topics: Angiotensin II; Animals; Calcium; Dihydroxycholecalciferols; Erythropoietin; Hormones; Humans; Hypocalcemia; Kallidin; Kallikreins; Kidney; Kidney Failure, Chronic; Natriuresis; Parathyroid Hormone; Phosphates; Prostaglandins; Renin; Urokinase-Type Plasminogen Activator

Topics: Adolescent; Adult; Anabolic Agents; Androgens; Anemia; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Transplantation, Homologous

Topics: Acute Kidney Injury; Androgens; Anemia; Blood Transfusion; Cobalt; Erythropoietin; Female; Humans; Iron; Kidney; Kidney Failure, Chronic; Male; Nephrectomy; Renal Dialysis; Sex Factors

Topics: Anemia; Erythrocytes; Erythropoiesis; Erythropoietin; Hematocrit; Hemolysis; Humans; Iron; Kidney Failure, Chronic; Oxygen; Renal Dialysis

Topics: Adrenal Glands; Aldosterone; Anemia; Biopsy, Needle; Cholinesterases; Erythropoietin; Fibrin; Graft Rejection; Humans; Hyperparathyroidism; Hypertension; Juxtaglomerular Apparatus; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Polycythemia; Proteinuria; Radioisotope Renography; Renin; Transplantation, Homologous; Ultrasonography

Topics: Anemia; Animals; Chemical Phenomena; Chemistry; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Humans; Hypoxia; Kidney Failure, Chronic; Neoplasms; Oxygen Consumption; Polycythemia Vera

Topics: Anemia; Bone Marrow; Dextrans; Erythrocytes; Erythropoiesis; Erythropoietin; Ferritins; Hemosiderin; Histiocytes; Humans; Intestinal Absorption; Iron; Iron Radioisotopes; Kidney Failure, Chronic; Liver; Metabolic Diseases; Molecular Weight; Mononuclear Phagocyte System; Polycythemia; Spleen; Transferrin

Topics: Adult; Anemia; Anemia, Hemolytic; Anemia, Hypochromic; Blood Platelets; Blood Urea Nitrogen; Bone Marrow Cells; Chronic Disease; Erythrocytes; Erythrocytes, Abnormal; Erythropoiesis; Erythropoietin; Feedback; Female; Hemolysis; Hemostasis; Humans; Hypertension, Malignant; Iron; Kidney; Kidney Concentrating Ability; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Oxygen Consumption; Plasma Volume; Uremia

Topics: Animals; Calcium; Erythropoietin; Humans; Hyperparathyroidism; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Phosphorus; Rats

To determine whether or not Darbepoetin alpha (DA) was non-inferior to recombinant human erythropoietin (rHuEPO) in the treatment of anemia in children with chronic kidney disease (CKD) stage 3-5 (on or not on dialysis). This was a randomized, open-label, two-arm, parallel group, active-controlled, non-inferiority trial conducted at a tertiary care center in New Delhi, India. Fifty patients of either gender (aged 1-18 years) with CKD stage 3-5 (on or not on dialysis) who had baseline hemoglobin (Hb) between 9 and 12 g/dL and were on stable erythropoietin therapy for at least 8 weeks were randomized (1:1) to either continue rHuEPO or switch to DA therapy for a period of 28 weeks. Doses were titrated in the initial 23 weeks to maintain the Hb between 11 and 12 g/dL, and efficacy was assessed between weeks 24 and 28. The primary efficacy outcome was the mean change in Hb between baseline and the evaluation period. In the intention-to-treat population (n = 50), the adjusted between-group difference in mean Hb change between the baseline and the evaluation period was 0.131 g/dL (95% CI: - 0.439 to 0.719, p = 0.629). The lower limit of the two-sided 95% CI for the difference in the mean change in Hb between the two treatment groups was well above the pre-specified non-inferiority margin of - 1.0 g/dL. Similar pattern of non-inferiority was seen for per protocol population. The safety profile of DA and rHuEPO was also comparable (injection site pain:rHuEPO-3, DA-7; p-0.296).   Conclusion: DA is non-inferior to rHuEPO for the treatment of anemia of CKD (stage 3-5) in pediatric population with a comparable safety profile.   Trial registration: ClinicalTrials.gov Identifier: NCT04959578 (retrospectively registered), Date: July 13, 2021. What is Known: • Limited studies showing darbepoetin alpha is effective in children as an erythropoiesis stimulating agent. • No RCT from Indian subcontinent addressing this topic. What is New: • Darbepoetin alpha is non inferior to recombinant human erythropoietin for treatment of anemia in children with CKD stage 3-5 (on or not on dialysis) with safety comparable to recombinant human erythropoietin. • A cost reduction of approximately 8.6% per patient by shifting to darbepoetin alpha.

Topics: Adolescent; Anemia; Child; Child, Preschool; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; India; Infant; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Treatment Outcome

Anemia is one of the most common complications of Chronic Kidney Disease (CKD). The vast majority of Egyptian CKD patients are interchangeably treated with Darbepoetin Alfa (DPA) and Epoetin Alfa (EPA) to achieve and maintain target hemoglobin levels. Our study aimed to compare the efficacy and safety of DPA versus EPA for managing anemia amongst Egyptian patients with CKD undergoing dialysis.. A multicenter, open label, randomized, prospective, parallel study was conducted. Patients with CKD undergoing dialysis with Hb level < 10 g/dl were enrolled. The primary efficacy endpoint was the change in hemoglobin concentration at the evaluation period (weeks 20-24). Prespecified adverse events of interest following administration, including blood transfusions requirement, blood pressure and hemoglobin excursions, the relationship between C - Reactive Protein (CRP) and hemoglobin, were assessed.. Only 98 of 104 enrolled patients completed the study, fifty patients received EPA, and 48 patients received DPA. Our results showed that a significantly higher percentage of patients who achieved target Hb level ≥ 11 g/dL in DPA treated group vs. EPA as well as the meantime to achieve Hb level ≥ 10 g/dL was shorter in DPA treated group. Safety profiles of both treatments were similar. A negative correlation was observed between serum CRP and hemoglobin level in hemodialysis patients.. Our study showed that DPA was more effective and well tolerated in achieving and maintaining Hb levels with lower dosing frequency compared to EPA. Furthermore, CRP is recommended to be routinely measured where patients with higher CRP require high ESA doses.

Topics: Anemia; Darbepoetin alfa; Egypt; Epoetin Alfa; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Prospective Studies; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Administration of intravenous vitamin C in hemodialysis patients can reduce their ferritin levels. Nevertheless, little research has been carried out in this regard. Hence, this study aimed to determine the effect of intravenous vitamin C on ferritin levels in a group of hemodialysis patients.. The study population included 32 patients with chronic renal failure undergoing hemodialysis who had been referred to Qazvin Hospital. These patients had functional iron deficiency (IDA) and high levels of serum ferritin. Patients were randomly allocated into intervention group A (n = 16) and control group B (n = 16). Group A was given intravenous ascorbic acid, while group B was given the same amount of distilled water as a placebo three times a week after each dialysis session for three months along with erythropoietin. Laboratory parameters were assessed at the beginning and the end in an interval of three months.. In patients who received vitamin C injections, the mean ferritin level decreased at the end of the study (P < .05). But vitamin C intake did not affect BUN, creatinine, sodium, potassium, TIBC, hemoglobin, platelets count, and the length and number of dialysis sessions.. Results of our study showed that vitamin C can reduce serum ferritin levels in hemodialysis patients. Therefore, it can be used as an adjunct in the treatment of anemia in patients.  DOI: 10.52547/ijkd.6531.

Topics: Anemia; Ascorbic Acid; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Renal Dialysis; Vitamins

(1) Background: Chronic Kidney Disease (CKD) induces metabolic derangement of amino acid (AA) kinetics, eliciting severe damage to the protein anabolism. This damage is further intensified by a significant loss of AAs through hemodialysis (HD), affecting all tissues with a high metabolic turnover, such as the myocardium and body muscle mass. (2) Aim: to illustrate the effects of a novel AA mixture in boosting mitochondrial energy production. (3) Methods: A strict selection of 164 dialysis patients was carried out, allowing us to finally identify 22 compliant patients who had not used any form of supplements over the previous year. The study design envisaged a 6-month randomized, double-blind trial for the comparison of two groups of hemodialysis patients: eleven patients (67.2 ± 9.5 years) received the novel AA mix (TRG), whilst the other eleven (68.2 ± 10.5 years) were given a placebo mix that was indistinguishable from the treatment mix (PLG). (4) Results: Despite the 6-month observation period, the following were observed: maintenance of target hemoglobin values with a reduced need for erythropoiesis-stimulating agents in TRG > 36% compared to PLG (p < 0.02), improved phase angle (PhA) accompanied by an increase in muscle mass solely in the TRG group (p < 0.05), improved Left Ventricular Ejection Fraction (LVEF > 67%) in the TRG versus PLG group (p < 0.05) with early but marked signs of improved diastolic function. Increased sensitivity to insulin with greater control of glycemic levels in TRG versus PLG (p = 0.016). (5) Conclusions: the new AA mix seemed to be effective, showing a positive result on nutritional metabolism and cardiac performance, stable hemoglobin levels with the need for lower doses of erythropoietin (EPO), insulin increased cell sensitivity, better muscle metabolism with less loss of mass.

Topics: Amino Acids; Anemia; Erythropoietin; Hemoglobins; Humans; Insulins; Kidney Failure, Chronic; Myocardium; Pilot Projects; Renal Dialysis; Stroke Volume; Ventricular Function, Left

EPREX®/ERYPO®/PROCRIT® (epoetin alfa, Janssen-Cilag GmbH) was the first available recombinant human erythropoietin (rHuEPO) and was universally reference product as per the recommendation provided by European Medicines Agency. EPIAO® is a biosimilar formulation of EPREX®, and making it a 1:1 dose conversion from EPREX® according to recommendation of European Medicines Agency. This study evaluated the clinical efficacy and safety of EPIAO® in subjects with end-stage renal disease receiving hemodialysis after intravenous administration.. This study was a multicenter, prospective, randomized, double-blind, parallel-group, 2-cohort, maintenance phase, therapeutic equivalence study to evaluate a 1:1 dose conversion from EPREX® to EPIAO® in terms of clinical efficacy and safety that was conducted at 20 sites in 2 countries in patients with end-stage renal disease on hemodialysis. Eligible subjects were treated with EPREX® (reference product of epoetin) for a period of at least 3 months before the treatment period, and then were randomly assigned to the group of EPREX® or EPIAO®. Primary endpoints were mean absolute change in hemoglobin level and mean absolute change in weekly epoetin dosage from baseline to 6 months after treatment with EPIAO®/EPREX® in parallel groups.. A total of 200 people received the random intervention and were included in the safety set. After 6, 9, and 12 months of treatment with EPIAO® or EPREX®, there were no significant differences in the hemoglobin levels of the 2 groups compared with baseline. The 95% confidence interval for the treatment difference was within the predetermined acceptable range: ±0.5 g/dL. There were no significant differences in the epoetin dosage of the 2 groups compared with the baseline. The 95% confidence interval for the treatment difference was within the predetermined acceptable range: ± 45 IU/kg. There were no significant differences in the incidence of adverse events between the EPIAO® and EPREX® groups. Most adverse events were mild to moderate and were reverted/resolved.. EPIAO® demonstrated promising effectiveness and manageable safety in patients with end-stage renal disease on hemodialysis.

Topics: Anemia; Biosimilar Pharmaceuticals; Epoetin Alfa; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Prospective Studies; Renal Dialysis; Translocation, Genetic; Treatment Outcome

Topics: Aged; Erythropoietin; Ferritins; Ferrous Compounds; Hemoglobins; Hepcidins; Humans; Inflammation; Iron; Kidney Failure, Chronic; Middle Aged; Resistance Training

This study was carried out to evaluate the effect of pegylated erythropoietin and to compare its effects with the effects of darbepoetin alfa on anemia of chronic kidney patients on maintenance hemodialysis having erythropoietin hyporesponsiveness.. Forty adult patients of chronic kidney disease(CKD) with erythropoietin hyporesponsiveness undergoing maintenance hemodialysis were included in the study. These patients were randomly divided into two groups, Group A consisting of 20 patients who received Subcutaneous Pegylated erythropoietin at a dose of 0.6 mcg/kg body weight, once in every two weeks along with intravenous iron 100 mg/week for 3 months. Group B patients received subcutaneous darbepoietin alfa at a dose of 0.45 mcg/kg body weight once weekly along with iv iron 100mg /week for 3 months. Hematological, renal and inflammatory parameters such as erythrocyte sedimentation rate, C reactive protein, serum ferritin and transferrin saturation were measured at monthly intervals for three months, compiled and analyzed statistically.. At the end of the study, in group A there was a significant rise in the hemoglobin, haematocrit and transferrin saturation (p < 0.001 for each of them) while there was a significant decrease in serum ferritin levels (p<0.001). In group &B the increase in hemoglobin, haematocrit and transferrin saturation were not statistically significant (p>0.05), and also there was a significant rise in the serum ferritin levels at the end of the study (p< 0.05). The mean rise in hemoglobin between subsequent months was higher in group A as compared to group B which was statistically significant.. Pegylated erythropoietin is better than darbepoetin alfa in overcoming erythropoietin hyporesponsiveness and maintaining stable hemoglobin levels in CKD patients on maintenance hemodialysis.

Topics: Adult; Anemia; Darbepoetin alfa; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

We evaluated the efficacy and safety of roxadustat versus epoetin alfa for the treatment of chronic kidney disease-related anemia in patients new to dialysis.. HIMALAYAS was a Phase 3, open-label, epoetin alfa-controlled trial. Eligible adults were incident to hemodialysis/peritoneal dialysis for 2 weeks to ≤4 months prior to randomization and had mean hemoglobin (Hb) ≤10.0 g/dL. Primary endpoints were mean Hb (g/dL) change from baseline averaged over Weeks 28-52 regardless of rescue therapy [non-inferiority criterion: lower limit of 95% confidence interval (CI) for treatment difference >-0.75] and percentage of patients achieving an Hb response between Weeks 1 and 24 censored for rescue therapy (non-inferiority margin for between-group difference -15%). Adverse events were monitored.. The intent-to-treat population included patients randomized to roxadustat (n = 522) or epoetin alfa (n = 521). Mean (standard deviation) Hb changes from baseline averaged over Weeks 28-52 were 2.57 (1.27) and 2.36 (1.21) in the roxadustat and epoetin alfa groups. Roxadustat was non-inferior [least squares mean difference: 0.18 (95% CI 0.08, 0.29)] to epoetin alfa. Percentages of patients with an Hb response were 88.2% and 84.4% in the roxadustat and epoetin alfa groups, respectively. Roxadustat was non-inferior to epoetin alfa [treatment-group difference 3.5% (95% CI -0.7%, 7.7%)]. Adverse event rates were comparable between treatment groups.. Roxadustat was efficacious for correcting and maintaining Hb levels compared with epoetin alfa. Roxadustat had an acceptable safety profile.

Topics: Anemia; Epoetin Alfa; Erythropoietin; Glycine; Hematinics; Hemoglobins; Humans; Isoquinolines; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Anemia is one of the most common complications of chronic kidney disease (CKD). As a result of the side effects of high doses of recombinant human erythropoietin (rhEPO) and the differences in the standard dose of the injectable iron, this study aimed to evaluate the effect of high and low intravenous iron supplementation on hematinic parameters and EPO requirements in patients under hemodialysis.. This multicenter, randomized, double-blind clinical trial was conducted on 60 patients with CKD admitted to Sina and 29 Bahman hospitals in Tabriz, Iran in 2019-2020 to undergo hemodialysis. In the two studied groups, low (100 mg/week) and high (400 mg/week) doses of iron were administered and subjects were followed up for 6 months. The incidence of acute myocardial ischemia, stroke, and mortality during 6 months was recorded.. The required rhEPO dosage (mg/week) to maintain hemoglobin levels between 10 and 12 g/dL in the high-dose iron group was significantly decreased during the follow-up period (52,129.03 ± 23,810 vs. 45,760 ± 20,978.71, P ≤ 0.028). Transferrin saturation (TSAT) index had a significant upward trend after iron injection and significant correlations with the serum levels of Fe (r ≥ 0.353, P ≤ 0.007), ferritin (r ≥ 0.315, P ≤ 0.016), and total iron binding capacity (r ≥ 0.219, P < 0.050) during the follow-up period in the studied groups.. High-dose intravenous iron (400 mg/week) can reduce the mean dose of rhEPO requirements and increase the TSAT index over a period of 6 months in hemodialysis patients. High-dose IV iron administration can decrease cardiovascular events in hemodialysis patients with iron deficiency anemia.

Topics: Dietary Supplements; Erythropoietin; Hematinics; Hemoglobins; Humans; Injections, Intravenous; Iron; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, was evaluated in a phase 1b study in patients with end-stage renal disease with anemia on hemodialysis. Seventeen patients, on epoetin-alfa maintenance therapy with stable hemoglobin levels ≥10 g/dL, had epoetin-alfa discontinued on day 3 and were enrolled in this double-blind placebo-controlled study. Two cohorts were randomized 3:1 (roxadustat: placebo). Patients received single doses of roxadustat (1 or 2 mg/kg) or placebo 1 hour after hemodialysis on day 1 and 2 hours before dialysis on day 8. Maximum plasma concentration and area under the plasma concentration-time curve for patients receiving roxadustat were slightly more than dose proportional and elimination half-life ranged from 14.7 to 19.4 hours. Roxadustat was highly protein bound (99%) in plasma, and dialysis contributed a small fraction of the total clearance: only 4.56% and 3.04% of roxadustat recovered from the 1 and 2 mg/kg dose groups, respectively. Roxadustat induced transient elevations of endogenous erythropoietin that peaked between 7 and 14 hours after dosing and returned to baseline by 48 hours after dosing. Peak median endogenous erythropoietin levels were 96 mIU/mL and 268 mIU/mL for the 1- and 2-mg/kg doses, respectively, within physiologic range of endogenous erythropoietin responses to hypoxia at high altitude or after blood loss. No serious adverse events were reported, and there were no treatment- or dose-related trends in adverse event incidence.

Topics: Administration, Oral; Adult; Aged; Anemia; Area Under Curve; Dose-Response Relationship, Drug; Double-Blind Method; Erythropoiesis; Erythropoietin; Female; Glycine; Humans; Hypoxia; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Kidney Failure, Chronic; Male; Middle Aged; Prolyl-Hydroxylase Inhibitors; Renal Dialysis; Treatment Outcome

The response to erythropoiesis stimulating agents (ESAs) is affected by inflammation linked to middle molecules in hemodialysis (HD) patients. We evaluated the effect of a medium cut-off (MCO) dialyzer on ESA resistance in maintenance HD patients. Forty-nine patients who underwent high-flux HD were randomly allocated to the MCO or high-flux group. The primary outcome was the changes of erythropoietin resistance index (ERI; U/kg/wk/g/dL) between baseline and 12 weeks. The MCO group showed significant decrease in the ESA dose, weight-adjusted ESA dose, and ERI compared to the high-flux group at 12 weeks (p < 0.05). The generalized estimating equation models revealed significant interactions between groups and time for the ESA dose, weight-adjusted ESA dose, and ERI (p < 0.05). Serum iron and transferrin saturation were higher in the MCO group at 12 weeks (p < 0.05). The MCO group showed a greater reduction in TNF-α and lower serum TNF-α level at 12 weeks compared to the high-flux group (p < 0.05), whereas no differences were found in the reduction ratio of hepcidin and serum levels of erythropoietin, erythroferrone, soluble transferrin receptor and hepcidin between groups. HD with MCO dialyzer improves ESA resistance over time compared to high-flux HD in maintenance HD patients. The MCO dialyzer provides superior removal of the inflammatory cytokine and thus improves iron metabolism in a hepcidin-independent manner.

Topics: Aged; Anemia; C-Reactive Protein; Erythropoiesis; Erythropoietin; Female; Hematinics; Hepcidins; Humans; Inflammation; Iron; Kidney Failure, Chronic; Male; Middle Aged; Receptors, Transferrin; Renal Dialysis; Tumor Necrosis Factor-alpha

Posttransplant anemia may be a major determinant of chronic allograft nephropathy. However, the impact of correcting anemia on graft function remains controversial.. A 3-year follow-up of an open-label, multicenter, randomized controlled trial involving kidney transplantation recipients examined whether sustained maintenance of target hemoglobin (Hb) concentrations at a high level (12.5-13.5 g/dL, n = 64) with either darbepoetin alfa or epoetin beta pegol would slow the graft function decline rate as the primary efficacy endpoint, compared with maintenance of a low Hb concentration (10.5-11.5 g/dL, n = 63).. The mean blood pressures in the two groups were well controlled throughout the study. In the high Hb group, mean Hb concentrations increased to >12 g/dL at 3 months, reaching the target range at 18 months. At the end of this study (36 months), the mean Hb concentration was 12.8 ± 0.7 g/dL in the high Hb group and 11.5 ± 1.2 g/dL in the low Hb group. The decline rate of the estimated glomerular filtration (eGFR) rate was considerably greater in the low Hb group (ΔeGFR, -5.1 ± 9.5 mL/min/1.73 m2) than in the high Hb group (-1.0 ± 8.4 mL/min/1.73 m2) (P = 0.02). Of note, only a few high Hb patients developed cardiovascular events and returned to hemodialysis, but the low Hb patients did not.. This prospective study suggests that correcting anemia to the target Hb level range (12.5-13.5 g/dL) slows renal function deterioration by >3 years in the chronic phase of allograft nephropathy.

Topics: Adult; Allografts; Anemia; Blood Pressure; Disease Progression; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hemoglobins; Humans; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Renal Dialysis; Treatment Outcome

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Anemia is one of the most prevalent complications in patients with chronic kidney disease, which is believed to be caused by the insufficient synthesis of erythropoietin by the kidney. This phase III study aimed to compare the efficacy and safety of CinnaPoietin® (epoetin beta, CinnaGen) with Eprex® (epoetin alfa, Janssen Cilag) in the treatment of anemia in ESRD hemodialysis patients.. In this randomized, active-controlled, double-blind, parallel, and non-inferiority trial, patients were randomized to receive either CinnaPoietin® or Eprex® for a 26-week period. The primary endpoints of this study were to assess the mean hemoglobin (Hb) change during the last 4 weeks of treatment from baseline along with the evaluation of the mean weekly epoetin dosage per kilogram of body weight that was necessary to maintain the Hb level within 10-12 g/dL during the last 4 weeks of treatment. As the secondary objective, safety was assessed along with other efficacy endpoints.. A total of 156 patients were included in this clinical trial. There was no statistically significant difference between treatment groups regarding the mean Hb change (p = 0.21). In addition, the mean weekly epoetin dosage per kg of body weight for maintaining the Hb level within 10-12 g/dL showed no statistically significant difference between treatment arms (p = 0.63). Moreover, both products had comparable safety profiles. However, the incidence of Hb levels above 13 g/dL was significantly lower in the CinnaPoietin® group.. CinnaPoietin® was proved to be non-inferior to Eprex® in the treatment of anemia in ESRD hemodialysis patients. The trial was registered in Clinicaltrials.gov (NCT03408639).

Topics: Adult; Aged; Anemia; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Anemia is common among end-stage renal disease (ESRD) patients who undergone hemodialysis. The total reduction of red blood cell (RBC) count is associated with poor prognosis in these patients. Although erythropoietin (EPO) has been used as an effective treatment for ESRD patients with anemia, a large number of patients still present poor responses to EPO treatment.. We measured T-cell receptor sequencing profiles, including length of complementarity-deteremining region 3 (CDR3), intra- and inter-group (EPO resistant vs. responsive) clonotype diversity, V(D)J usage profiles and V-J combinations from ESRD patients and to investigate the correlation between these features and EPO treatment efficacy.. Our results revealed statistical significance in the top 3 ~ 15 most abundant joint distributions of Vβ/Jβ among the two groups, suggesting the importance of V or J gene utilization in the EPO response of ESRD patients.. In summary, we provided evidence addressing the potential correlation between the immune repertoire and EPO response in ESRD patients.. TMU-JIRB 201309026. Registered 16 October 2013.

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Treatment Outcome

Hemodialysis (HD) patients often show impaired response to erythropoiesis-stimulating agents (ESAs). Extended HD membrane permeability may potentially improve ESA response.. Twenty-four prevalent HD patients were randomly assigned to 12 weeks use of high cut-off (HCO) membrane (in every second dialysis treatment) or continued treatment with high-flux membrane. We monitored changes in hemoglobin (Hb), ESA dose, and key biochemical markers.. The Hb level increased in the study group (from 11.6 ± 1.0 to 12.5 ± 1.5 g/dl; p = 0.038) but was stable in the control group. Variation over time in ESA dose and ESA resistance index did not differ between groups. HCO membrane usage for 12 weeks led to decreased hepcidin level, from 303 ± 189 to 157 ± 83 ng/ml (p = 0.024); serum albumin level decreased and stabilized 15 ± 6% below baseline.. These results indicate that use of a more permeable dialysis membrane may improve ESA responsiveness in iron-replete HD patients. Extensive albumin removal may preclude long-term use of the HCO membrane.

Topics: Aged; Anemia; C-Reactive Protein; Drug Resistance; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Hepcidins; Humans; Interleukin-6; Kidney Failure, Chronic; Male; Membranes, Artificial; Middle Aged; Permeability; Pilot Projects; Recombinant Proteins; Renal Dialysis; Serum Albumin

This study aimed to evaluate the effect of different timings of iron administration during erythropoiesis activated by continuous erythropoietin receptor activator (CERA) on reticulocyte iron uptake in hemodialysis patients. In total, 110 patients were randomized to receive 40 mg intravenous elemental iron doses at all three hemodialysis sessions in the first week (IW1 group: n = 57) or in the third week (IW3 group: n = 53) after CERA administration. Following CERA administration at day 0, reticulocyte count increased, peaking at day 7. At days 7 and 14, the observed changes in Ret-He were higher in the IW1 group than in the IW3 group. Increases in total reticulocyte hemoglobin at day 7 were higher in the IW1 group than in the IW3 group. In contrast, there was only tendency toward greater total reticulocyte hemoglobin after iron administration in the third week in the IW3 group. Intravenous iron supplementation in the first week of CERA administration increases reticulocyte iron uptake; however, iron supplementation in the third week does not. The findings indicate that iron should be intravenously administered to increase the efficacy of CERA within 1 week of CERA administration during highly active erythropoiesis.

Topics: Administration, Intravenous; Aged; Erythropoiesis; Erythropoietin; Female; Follow-Up Studies; Hematologic Tests; Humans; Iron; Kidney Failure, Chronic; Male; Polyethylene Glycols; Renal Dialysis; Reticulocytes

In hemodialysis (HD) patients, zinc depletion caused by inadequate intake, malabsorption, and removal by HD treatment leads to erythropoiesis-stimulating agent (ESA) hyporesponsiveness. This study investigated the effects of zinc supplementation in HD patients with zinc deficiency on changes in the erythropoietin responsiveness index (ERI).. Patients on HD with low serum zinc levels (<65 μg/dL) were randomly assigned to two groups: The polaprezinc group (who received daily polaprezinc, containing 34 mg/day of zinc) (n = 35) and the control group (no supplementation) (n = 35) for 12 months. All the 70 patients had been taking epoetin alpha as treatment for renal anemia. ERI was measured with the following equation: Weekly ESA dose (units)/dry weight (kg)/hemoglobin (g/dL).. There were no significant changes in hemoglobin levels within groups or between the control and polaprezinc groups during the study period. Although reticulocyte counts were increased immediately after zinc supplementation, this change was transient. Serum zinc levels were significantly increased and serum copper levels were significantly decreased in the polaprezinc group after three months; this persisted throughout the study period. Although there was no significant change in the serum iron or transferrin saturation levels in the polaprezinc group during the study period, serum ferritin levels significantly decreased following polaprezinc treatment. Further, in the polaprezinc group, ESA dosage and ERI were significantly decreased at 10 months and nine months, respectively, as compared with the baseline value. Multiple stepwise regression analysis revealed that the change in the serum zinc level was an independent predictor of lowered ERI.. Zinc supplementation reduces ERI in patients undergoing HD and may be a novel therapeutic strategy for patients with renal anemia and low serum zinc levels.

Topics: Administration, Oral; Aged; Anemia; Carnosine; Copper; Dietary Supplements; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Multivariate Analysis; Organometallic Compounds; Regression Analysis; Renal Dialysis; Trace Elements; Zinc; Zinc Compounds

The incidence of end-stage renal disease (ESRD) has been consistently shown to be higher among blacks and Hispanics compared to whites with unmeasured risk factors and access to care as suggested explanations. In a high-risk cohort with frequent protocol-directed follow-up, we evaluated the influence of race on cardiovascular (CV) outcomes and incidence of ESRD.. TREAT was a randomized, double-blind, placebo-controlled study. This secondary analysis focused on role of race on outcomes. TREAT enrolled 4,038 patients with type 2 diabetes, chronic kidney disease (estimated glomerular filtration rate 20-60 mL/min per 1.73 m(2)), and anemia (hemoglobin level ≤11 g/dL) treated with either darbepoetin alfa or placebo. We compared self-described black and Hispanic patients to white patients with regard to baseline characteristics and outcomes, including mortality, CV outcomes (myocardial infarction, stroke, heart failure, resuscitated sudden death, and coronary revascularization), and incident ESRD. Multivariate adjusted Cox models were developed for these outcomes.. Black and Hispanic patients were younger, more likely women, had less prior CV disease, and higher blood pressure. During a mean follow-up of 2.4 years with comparable access to care, blacks and Hispanics had a greater risk of ESRD but a significant lower risk of myocardial infarction and coronary revascularization than whites. After adjusting for confounders, blacks remained at significantly greater risk of ESRD than whites (hazard ratio 1.53, 95% CI 1.26-1.85, P < .001), whereas this ESRD risk did not persist among Hispanics.. Despite similar access to care and lower CV event rates, the risk of ESRD was higher among blacks and Hispanics than whites. For blacks, but not Hispanics, this increase was independent of known attributable risk factors.

Topics: Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Double-Blind Method; Erythropoietin; Ethnicity; Follow-Up Studies; Global Health; Glomerular Filtration Rate; Hematinics; Humans; Incidence; Kidney Failure, Chronic; Prognosis; Prospective Studies; Racial Groups; Survival Rate; Time Factors

Vitamin E (VE) bonded polysulfone dialysis membranes have putative erythropoiesis stimulating agent (ESA)-sparing and anti-inflammatory properties based on data from a small number of studies. We sought to investigate this in a large, prospective 12-month randomized controlled trial.. Two-hundred and sixty prevalent haemodialysis (HD) patients were randomized to dialysis with VE-bonded polysulfone membranes or non-VE-bonded equivalents. All ESA-dosing was performed by means of a computer-based anaemia management decision support system. Monthly data were used to calculate the ESA resistance index (ERI) and blood tests were performed at baseline, 6 and 12 months for measurement of C-reactive protein (CRP) levels.. Of the 260 patients, 123 were randomized to dialysis with the VE-membrane and 12-month data was available for 220 patients. At the study population level, no beneficial effect of the VE membranes on the ERI or CRP levels was observed. Post hoc analyses indicated that there was a significant fall in ERI for patients with the highest baseline ESA resistance dialysed with the VE (9.28 [7.70-12.5] versus 7.70 [5.34-12.7] IU/week/kg/g/dL Hb, P = 0.01) but not the control membranes (9.45 [7.62-12.3] versus 8.14 [4.44-15.6] IU/week/kg/g/dL Hb, P = 0.41); this was not attributable to changes in CRP levels.. Wholesale switching of all chronic HD patients to dialysis with VE-bonded polysulfone membranes appears not to be associated with improvements in ESA-responsiveness or CRP. These membranes may have utility in patients with heightened ESA resistance.

Topics: Aged; C-Reactive Protein; Darbepoetin alfa; Drug Resistance; Erythropoietin; Female; Hematinics; Humans; Kidney Failure, Chronic; Male; Membranes, Artificial; Middle Aged; Polymers; Prospective Studies; Renal Dialysis; Sulfones; Vitamin E

Use of recombinant human erythropoietin (rh-Epo) improves hemoglobin (Hgb) in 90-95% of the cases of anemia of chronic kidney disease (CKD). However, it is known that pro-inflammatory cytokines such as interferon-gamma (IFN-γ), tumor necrosis factor-alfa (TNF-α) and interleukin-1 (IL-1) suppress erythropoiesis, resulting in inadequate response to rh-Epo. Pentoxifylline has been shown to have modulatory effects on the immune system. This prospective study to evaluate the effect of pentoxyphylline on erythropoeisis was performed on 15 (eight males, seven females) clinically stable patients who had been on hemodialysis for at least six months with anemia (Hgb of <10.7 g/dL) unresponsive to rh-Epo despite high doses. They were treated with 400 mg pentoxifylline tablets once daily for 12 weeks. Hgb increased after one and two months of drug administration, but significant changes were observed in eight (53%) patients after three months (P <0.05). Our study illustrates a probable new use for an old medicine. Three months treatment with pentoxifylline was seen to increase Hgb significantly in rh-Epo-resistant patients. More prospective studies with a larger sample size are needed to determine the inhibitory role of cytokines on hematopoiesis and exploring new drugs or new drug indications to overcome anemia in advanced renal failure.

Topics: Adult; Anemia; Biomarkers; Drug Resistance; Drug Substitution; Erythropoiesis; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Iran; Kidney Failure, Chronic; Male; Middle Aged; Pentoxifylline; Prospective Studies; Recombinant Proteins; Renal Dialysis; Time Factors; Treatment Failure; Tumor Necrosis Factor-alpha; Up-Regulation

Randomized trials found that use of erythropoiesis-stimulating agents to target normal hematocrit (Hct) levels (>39%) compared with 27%-34.5% increases cardiovascular risk and mortality among chronic kidney disease patients. However, the effects of the most widely used Hct target in the past 2 decades, 34.5%-39%, have never been examined.. To compare the effects of 2 Hct target strategies-30.0%-34.5% (low) and 34.5%-39.0% (mid) in a high-risk population: elderly dialysis patients with significant comorbidities.. Observational data from the US Renal Data System were used to emulate a randomized trial in which patients were assigned to either Hct strategy. Follow-up started after completing 3 months of hemodialysis and ended 6 months later. We conducted the observational analogs of intention-to-treat and per-protocol analyses. Inverse-probability weighting was used to adjust for measured time-dependent confounding by indication.. A total of 22,474 elderly patients with both diabetes and cardiovascular disease who initiated hemodialysis in 2006-2008.. Hazard ratios (HRs) and survival probabilities for all-cause mortality and a composite cardiovascular and mortality endpoint.. The intention-to-treat HR (95% confidence interval) for mid versus low Hct strategy was 1.05 (0.99-1.11) for all-cause mortality and 1.03 (0.98-1.08) for the composite endpoint. The per-protocol HR (95% confidence interval) for mid versus low Hct strategy was 0.98 (0.78-1.24) for all-cause mortality and 1.00 (0.81-1.24) for the composite outcome.. Among hemodialysis patients, we did not find differences in 6-month survival or cardiovascular risk between clinical strategies that target Hct at 30.0%-34.5% versus 34.5%-39.0%.

Topics: Aged; Anemia, Iron-Deficiency; Cardiovascular Diseases; Comorbidity; Dose-Response Relationship, Drug; Drug Dosage Calculations; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis; Risk Factors; Survival Analysis; Treatment Outcome; United States

Indoxyl sulfate (IS) suppresses erythropoietin (EPO) activity and exerts renal damage. The oral adsorbent AST-120 reduces IS load and has antioxidant and renoprotective properties; however, its roles in the treatment of anemia remain unclear in chronic kidney disease (CKD) patients.. Fifty-one Stage 5 predialysis CKD patients with hemoglobin <10 g/dL were randomly assigned to receive two period treatments with AST-120 plus once-monthly administration of continuous EPO receptor activator (CERA, A) and CERA alone (B), with a 4-week washout period in between. Mean changes of serum creatinine, estimated glomerular filtration rate (eGFR) and hemoglobin levels from the baseline were compared between two treatments.. The baseline and postintervention mean creatinine levels were 5.48 and 5.36 mg/dL in the Treatment A, and 5.14 mg/dL and 5.61 g/dL in the Treatment B group, respectively (treatment effect P = 0.025, period effect P = 0.467, carryover effect P = 0.384). The baseline and postintervention mean hemoglobin levels were 9.27 and 10.47 g/dL in the Treatment A, and 9.63 g/dL and 9.54 g/dL in the Treatment B group, respectively (treatment effect P = 0.039, period effect P = 0.001, carryover effect P = 0.060). Use of AST-120 significantly reduced IS and p-cresyl sulfate (PCS) levels. Hierarchical regression showed that eGFR was an independent predictor for hemoglobin after adjustment of serum free IS and PCS levels (B = 0.049, P = 0.005).. Use of adjuvant AST-120 may improve renal function and hemoglobin levels than use of CERA alone in late-stage CKD patients. The change of eGFR might play an intermediate role between serum IS/PCS and improve hemoglobin levels. The finding offered insight into novel therapeutic strategies of anemia for late-stage CKD patients.

Topics: Adult; Aged; Anemia; Carbon; Cross-Over Studies; Drug Synergism; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Indican; Kidney; Kidney Failure, Chronic; Male; Microspheres; Middle Aged; Oxides; Polyethylene Glycols; Recombinant Proteins

A short-term open prospective study examined 62 patients at the terminal stage of chronic renal failure. The experimental group received erythropoietin in a total dose of about 40,000 U. The expression of glycoproteins IIb-IIIa, IIb, and Ib was enhanced, the content of LPO products was elevated, and SOD and catalase activities were reduced in platelets from patients with chronic renal failure. Administration of erythropoietin partially restored free radical oxidation and expression of glycoproteins IIb-IIIa, IIb, and Ib in platelets. A significant correlation was revealed between the expression of platelet receptors on the one hand, and content of LPO products and SOD and catalase activities, on the other hand.

Topics: Blood Platelets; Catalase; Drug Administration Schedule; Erythropoietin; Female; Free Radicals; Gene Expression; Humans; Kidney; Kidney Failure, Chronic; Lipid Peroxidation; Male; Middle Aged; Oxidation-Reduction; Platelet Glycoprotein GPIb-IX Complex; Platelet Glycoprotein GPIIb-IIIa Complex; Platelet Membrane Glycoprotein IIb; Prospective Studies; Superoxide Dismutase

We evaluate the effect of the protoconized anemia therapy on adverse events using the Hb and ferritin levels of individual patients undergoing maintenance hemodialysis (MHD).. Design: A randomized, parallel group, multi-center study.. Two hundred sixty-six MHD patients. Intervention group: The doses of erythropoietin, iron, and vitamin C were adjusted every month based on the ferritin and hemoglobin (Hb) levels according to the protocol. Non-intervention group: The attending physician determined the doses of erythropoietin and iron.. The maintenance rate of target Hb and ferritin levels were significantly higher in the Intervention group than in the Non-intervention group. The frequency of hospitalization was significantly lower for patients with a higher maintenance rate of target Hb levels than for those with a lower maintenance rate.. Using an anemia treatment protocol according to the individual Hb and ferritin levels of hemodialysis patients might stabilize the Hb and ferritin levels, which in turn could contribute to the lower frequency of adverse events in MHD patients.

Topics: Adult; Aged; Anemia; Ascorbic Acid; Biomarkers; Drug Dosage Calculations; Drug Monitoring; Drug Therapy, Combination; Erythropoietin; Female; Ferritins; Hematinics; Hemoglobins; Hospitalization; Humans; Iron; Japan; Kidney Failure, Chronic; Male; Middle Aged; Predictive Value of Tests; Renal Dialysis; Time Factors; Treatment Outcome

We investigated the method of switching EPO to CERA that does not cause a decrease in the Hb level.. Fifty EPO-treated patients were randomly divided into two groups in which CERA was administered every two weeks (Q2W) or every four weeks (Q4W). After 8 weeks of treatment, the frequency of administration was changed to Q4W in the former. Follow-up was performed for 24 weeks.. There was no difference in the Hb level between the two groups until 6 weeks. In the Q2W group, the Hb maintained a stable level throughout a study period. However, in the Q4W group, the Hb level was significantly lower than in the Q2W group at weeks 9, 11, and 13.. EPO switching to CERA without a decrease in the Hb level could be achieved by administering CERA every two weeks, but not every four weeks, for a specific period after switching.

Topics: Aged; Anemia; Drug Administration Schedule; Drug Substitution; Erythropoiesis; Erythropoietin; Female; Ferritins; Hematinics; Hemoglobins; Hepcidins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis; Transferrin

Insufficient production oferythropoietin (EPO) is the primary cause ofanemia in patients with chronic kidney disease (CKD). The EPO treatment is an established treatment for renal anemia. The study investigated the therapeutic outcome between lyophilized powder and liquid form of EPO alpha by intravenous (IV) administration in hemoglobin maintenance of anemic treatment for CKD patients receiving hemodialysis.. Forty patients were randomly assigned to either lyophilized powder of EPO alpha (treatment, n = 21) or liquidform of EPO alpha (control, n = 19) for 12 weeks by lVadministration. The hemoglobin was maintained within the target range of 10. 0 to 12.0 g/dL by adjusting the dosage of EPO. The clinical and biochemical profiles including transferrin saturation andferritin were measured. Adverse events were documented.. The mean hemoglobin ofboth groups at baseline was 11.2±0.6 g/dL. Mean hemoglobin and mean hematocrit levels at baseline, and follow-up data of both groups were not statistically different. The mean weekly dosage of EPO in the treatment and control groups had no statistical significance within the same group and between groups as well. Stable hemoglobin levels were maintained without EPO dosage adjustment in the majority ofpatients in both groups (treatment group, 90.5%, control group, 94.7%). During the 12-week study period, no serious side effect was detected. The present study demonstrated that the lyophilizedpowder ofEPO alpha was effective and safe as the standard liquid form of EPO alpha when it was administered by IV route in hemoglobin maintenance of anemia treatment.

Topics: Anemia; Chemistry, Pharmaceutical; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Female; Freeze Drying; Hemoglobins; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Powders; Renal Dialysis; Treatment Outcome

To study the specific features of diastolic dysfunction (DD) in different types of left ventricular (LV) hypertrophy (LVH) in patients with end-stage renal failure (ESRF) and to estimate the cardioprotective effect of erythropoietin.. 107 patients (57 women and 50 men) aged 22 to 63 years with ESRF were examined. The follow-up was 18 months. LV ejection fraction, peak early diastolic filling rate, peak late diastolic filling rate, their ratio, LV isovolumic relaxation time, LV end-diastolic diameter, LV end-diastolic volume, LV end-diastolic diameter index (EDDI), LV posterior wall and ventricular septal thickness, and LV mass index were determined. J. Gottdiener's classification based on the calculation of EDDI and LV relative wall thickness was used to estimate LV geometry. Erythropoietin was given to patients with the baseline level of hemoglobin (Hb) < 110 g/l or hematocrit (Ht) < 33%; and iron (III) hydroxide sucrose complex was used to those with ferritin < 100 microg/l or transferrin saturation < 20%. The target level of blood pressure was 130/80 mm Hg; Hb was less than 110 g/l for women and 120 g/l for men; Ht, > 33%.. The patients with ESRF were found to have different types of DD and LVH, the severity of which correlated with the magnitude of renal anemia and arterial hypertension (AH). Adequate correction of anemia and AH promoted the transition of more to less severe DD and LVH and in a number of cases the recovery of LV structure and function.. ESRF is characterized by different types of DD, which are pathogenetically closely related to different types of LVH. Adequate correction of renal anemia and AH may cause a significant reduction and, in a number of cases, alleviate VLH, and normalize LV systolic and diastolic functional values.

Topics: Adult; Cardiotonic Agents; Diastole; Echocardiography; Epoetin Alfa; Erythropoietin; Female; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Treatment Outcome; Ventricular Function, Left; Young Adult

Hepatitis C virus (HCV) infection is a global health problem, common worldwide, leading to acute and chronic hepatitis and its consequences of hepatic cirrhosis and hepatocellular carcinoma. Antiviral therapy of HCV+ in dialysis patients with interferon-α (INF-α) gives slightly better results than in the general population, but is poorly tolerated and associated with side effects. Although, Ribavirin in not recommended for dialysis patients, the addition of small doses of this medication to pegylated INF is discussed.. The aim of this study is to assess the efficacy and safety of peginterferon alfa-2b (12 kDa) plus Ribavirin in hemodialysis chronic HCV patients.. Fourteen end-stage renal disease patients (ESRD) on regular hemodialysis (HD) in Prince Salman Center for Kidney Diseases (PSCKD), ten males (71.4%) and four females (28.6) were enrolled in a prospective study. All the patients have Hepatitis C Virus infection; were treated by pegylated interferon alpha-2b (peginterferon alfa-2b) 1 mcg/kg/week subcutaneously with Ribavirin 200 mg three times weekly; for 48 weeks. Two patients were non responsive to previous course of 24 weeks peginterferon alfa-2a. HCV -RNA PCR qualitative and quantitative were tested before, 12, 48 weeks of treatment and 24 weeks after for sustained virologic response (SVR) results. α-fetoprotein level was measured in all the 14 patients before starting treatment to exclude any evidence of hepatocellular carcinoma.. One patient (7.1%) refused to complete the treatment because he could not tolerate the side effects and treatment was stopped after the third dose. After 12 weeks, three of 14 patients (21.4%) were still HCV-RNA PCR positive and there were not two log decrees in quantitative PCR, so treatment was stopped in this group of patients. One patient of the remaining had more than two log decrees in quantitative PCR, while nine were seroconverted to HCV-RNA PCR negative, so the treatment was completed for 48 weeks in 10 patients. After 48 weeks of treatment, qualitative and quantitative HCV-RNA PCR were done for 10 patients and the results were still negative (71.4%). Results of qualitative and quantitative HCV-RNA PCR done 24 weeks later showed that 10 patients still negative and SVR was (64%). Their mean ALT and AST dropped from 54.36 ± 36.79 IU/dL and 31.52 ± 17.02 IU/dL before starting therapy to 37.26 ± 36.53 IU/dL and 25.37 ± 23.72 IU/dL, respectively, after termination. Their mean hemoglobin (Hb) level dropped from 11.31 ± 0.86 to 10.06 ± 1.06 g/dL; (p < 0.001), and white blood cell count (WBC) dropped from 6.14 ± 0.65 × 10(3)/mm(3) to 4.51 ± 0.95 × 10(3)/mm(3); (p < 0.001). Platelet count fell from 130.11 ± 48.06 × 10(3)/mm(3) to 63.03 ± 23.19 × 10(3)/mm(3); (p < 0.001), also erythropoietin dose increased from 182.14 ± 39.30 IU/kg/w to 253.93 ± 83.07 IU/kg/w, (p = 0.776).. Peginterferon alfa-2b (12 kDa) plus Ribavirin therapy in hemodialysis chronic HCV patients is safe, well tolerated and effective with accepted rates of sustained virological response up to 64%.

Topics: Adult; Antiviral Agents; Erythropoietin; Female; Hemoglobins; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Kidney Failure, Chronic; Male; Middle Aged; Polyethylene Glycols; Prospective Studies; Recombinant Proteins; Renal Dialysis; Ribavirin; Saudi Arabia

Increased viscosity may increase the risk of thrombosis or thromboembolic events. Recombinant human erythropoietin (rHuEPO) is the key stone treatment in anemic ESRD patients with the thrombotic limiting side effect. We evaluated the influence of clinical and laboratory findings on plasma viscosity in MHD patients in the present study.. After applying exclusion criteria 84 eligible MHD patients were included (30 female, age: 54.7 ± 13.7 years).. Patients with high viscosity had longer MHD history, calcium × phosphorus product, and higher rHuEPO requirement (356.4 versus 204.2 U/kg/week, P: 0.006). rHuEPO hyporesponsiveness was also more common in hyperviscosity group. According to HD duration, no rHuEPO group had the longest and the low rHuEPO dosage group had the shortest duration. Despite similar Hb levels, 68% of patients in high rHuEPO dosage group; and 38.7% of patients in low rHuEPO dosage group had higher plasma viscosity (P: 0.001). Patients with hyperviscosity had higher rHuEPO/Hb levels (P: 0.021). Binary logistic regression analyses revealed that rHuEPO hyporesponsiveness was the major determinant of hyperviscosity.. We suggest that the hyperviscous state of the hemodialysis patients may arise from the inflammatory situation of long term HD, the calcium-phosphorus mineral abnormalities, rHuEPO hyporesponsiveness, and related high dosage requirements.

Topics: Adult; Aged; Anemia; Arteriovenous Shunt, Surgical; Blood Viscosity; Calcium; Drug Resistance; Erythropoietin; Female; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Phosphorus; Prospective Studies; Recombinant Proteins; Renal Dialysis; Thromboembolism

Darbepoetin alfa (DA) is an attractive alternative to recombinant human erythropoietin (rHuEPO) in managing renal anemia. Since DA has not been approved by the appropriate Japanese drug regulatory agencies for the indication of renal anemia in children in Japan, we have conducted a multicenter prospective study to determine the efficacy and safety of DA in Japanese children undergoing peritoneal dialysis (PD).. Pediatric patients subcutaneously receiving rHuEPO were switched to DA treatment for a period of 28 weeks. The conversion to the initial dose of DA was calculated as 1 μg DA for 200 IU rHuEPO, and DA was administered intravenously once every 2 weeks. The target hemoglobin (Hb) concentration was defined as 11.0 to ≤13.0 g/dL. In some patients, the dose of DA was adjusted appropriately to achieve this target level, and/or the dosing frequency changed to once every 4 weeks.. In the 25 patients switched from rHuEPO to DA the mean Hb concentration increased from 9.9 ± 1.0 to 11.1 ± 1.0 g/dL at 8 weeks following commencement of the DA treatment. The target Hb concentration was achieved in 88 % of these patients, and 60 % maintained this target value on completion of the study. The dosing frequency was extended to once every 4 weeks in 60 % of patients. Twenty-four adverse events were noted in 11 of 25 patients (44 %); however, there was no causality between DA and adverse events.. The results of this study suggest that intravenous administration of DA once every 2 or 4 weeks is an effective and safe treatment for renal anemia in Japanese children undergoing PD.

Topics: Adolescent; Anemia; Child; Child, Preschool; Darbepoetin alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Peritoneal Dialysis; Prospective Studies

Peginesatide (Omontys) is a novel, synthetic, PEGylated, peptide-based erythropoiesis-stimulating agent (ESA) that is designed to specifically stimulate the erythropoietin receptor. This study evaluated maintenance of hemoglobin levels in patients after conversion from darbepoetin alfa to once-monthly peginesatide.. This open-label, multicenter study included 101 CKD patients, 52 of whom were receiving dialysis. The duration of the study was 24 weeks. The primary endpoint was the mean change in hemoglobin from baseline to the evaluation period (weeks 19-24). The study was conducted during the period from September 22, 2008 to December 24, 2009.. The mean change among hemodialysis patients was -0.42 g/dl (95% confidence interval, -0.65 to -0.19) and the mean change among CKD nondialysis patients was 0.49 g/dl (95% confidence interval, 0.26-0.71). The percentages of patients who maintained hemoglobin levels within ±1.0 g/dl of baseline values were as follows: 80.0% for hemodialysis and 68.1% for nondialysis, and73.3% for hemodialysis and 68.1% for nondialysis within the target range of 10.0-12.0 g/dl. Few patients received red blood cell transfusions (hemodialysis, 5.8%; nondialysis, 2.0%). Seventy-nine patients experienced adverse events, the majority of which were mild or moderate in severity. There were 40 serious adverse events and 2 deaths reported.. In this study, once-monthly peginesatide resulted in a slight decrease in mean hemoglobin levels in individuals on hemodialysis and a small increase in individuals with CKD who were not on dialysis.

Topics: Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peptides; Renal Dialysis; Treatment Outcome

Dialysis patients, receiving erythropoiesis stimulating agents, typically show signs of hemoglobin variability as a consequence of their dosing patterns, bleeding, infection, etc., which is commonly managed adjusting the dose regimen of the erythropoiesis stimulating agent. However, information on dosing strategies used in daily clinical practice and their outcomes in relation to hemoglobin variability is limited.. To investigate clinical practice in Austria in relation with the management of hemoglobin variability, defined as a decrease of ³ 1 g/dL within 4 weeks from ³ 11 g/dL to £ 11 g/dL during maintenance therapy with darbepoetin alfa. The nature and incidence of clinical events related to the hemoglobin drop were also assessed.. The MAINTAIN non-interventional study was conducted in hemodialysis patients, receiving darbepoetin alfa in accordance to the label approved in the European Union at that time. Patient data were documented retrospectively for the 3 months prior to the hemoglobin drop. Data for the 6 months post hemoglobin drop were collected retrospectively or prospectively, depending on the time of patient inclusion respective to the Hb drop.. A hundred thirty six of 154 patients fulfilled all inclusion/exclusion criteria and had prospective documentation of 6 months. The main causes for the hemoglobin drop included surgical and medical procedures (36.1 %), and infections or infestations (24.4 %). The median treatment period was 273 days. The mean hemoglobin drop was - 1.74 g/dL (95 % confidence interval (CI): - 1.60 to - 1.87). Consequently, 81 % of the patients had their dose of darbepoetin alfa increased within a median Kaplan-Meier time to dose increase of 12.5 days (95 % CI: 6-22). The geometric mean weekly darbepoetin alfa dose increased by a factor of 1.1 from 29.1 mg (95 % CI: 24.6-34.4) in the 3 months before hemoglobin drop to 32.4 (95 % CI: 27.2-38.6) in months 4-6 post hemoglobin drop. Three patients had red blood cell transfusions before hemoglobin drop and nine patients after hemoglobin drop. The mean hemoglobin increase was 0.43 g/dL (95 % CI: 0.24-0.62) from immediately prior to 2 weeks after dose increase. The median Kaplan-Meier time to achieve a hemoglobin ³ 11 g/dL after hemoglobin drop was 36 days (95 % CI: 32-45). Frequent darbepoetin alfa dose adjustments were necessary to sustain maintenance levels. No drug-related adverse events were reported.. This observational study describes physicians' reactions to a drop in hemoglobin in clinical practice. Using darbepoetin alfa, the drop was generally compensated without leading to overcorrection.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Austria; Comorbidity; Darbepoetin alfa; Erythrocyte Indices; Erythropoietin; Female; Hematinics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prevalence; Renal Dialysis; Treatment Outcome; Young Adult

The extent to which anemia management is facilitated by more frequent hemodialysis (HD) is controversial. We hypothesized as a preselected outcome that patients receiving HD six times (6×) compared with three times (3×) per week would require lower doses of erythropoietin-stimulating agents (ESA) and/or achieve higher blood hemoglobin (Hb) concentrations.. Subjects enrolled in the Frequent Hemodialysis Network (FHN) daily and nocturnal trials were studied. As the primary outcome for anemia, the dose of ESAs was recorded at 4-month intervals and the monthly dose of intravenous iron (IV Fe) was reported. Serum iron, transferrin saturation and ferritin were measured at baseline and then at 4-month intervals, whereas Hb concentration was measured monthly.. There was no significant treatment effect in the 6× versus 3× treatment groups on logESA dose or the ratio of log of ESA dose to Hb concentration in either trial. In the daily trial, Hb concentrations increased significantly in the 6× versus 3× group, at Month 12 compared with baseline (0.3 g/dL; 95% CI: 0.05-0.58, P<0.021), but both groups had Hb concentrations in the usual target range. In the daily trial, the weekly logESA dose and the logESA dose to Hb concentration ratio tended to decline more in the 6× versus 3× group. This trend was not observed in the nocturnal trial. IV Fe doses were significantly lower in the 6× compared with the 3× group by Month 12 in the nocturnal trial, but not different in the daily trial.. In the FHN Daily and Nocturnal Trials, more frequent HD did not have a significant or clinically important effect on anemia management.

Topics: Anemia; Combined Modality Therapy; Erythropoietin; Female; Follow-Up Studies; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prognosis; Prospective Studies; Renal Dialysis; Risk Factors

Anemia is a well-documented consequence of chronic kidney disease, its frequency increases with the progression of renal failure and occurs in up to 95% of patients with end stage renal disease (ESRD). Erythropoietin stimulating agents (ESAs) have become the standard of care in the treatment of renal anemia. The use of methoxy polyethylene glycol-epoetin beta, continuous erythropoietin receptor activator, represents an important benefit in clinical practice.. The aim of the OPATIJA study was to compare the efficacy and safety of maintaining hemoglobin levels in dialysis patients and to assess its variability in a parallel-group design. Patients were randomly assigned to receive methoxy polyethylene glycolepoetin beta once monthly in "normal" dose conversion according to the label of record or "low" or "alternative" dose conversion widely spread according to previous ESA doses.. A total of 79 patients were included in the study. The patients who had undergone continuous maintenance intravenous ESA therapy were divided into two parallel groups: group 1 including 36 patients directly switched to CERA according to the manufacturer recommended dosage; and group 2 including 43 patients that were switched by using "low" or "alternative" dose conversion widely spread according to previous ESA doses. During the 18-month period, each patient's anemia parameters, i.e. hemoglobin level, serum iron concentration, TSAT and ferritin, were monitored at intervals not longer than two months. According to hemoglobin levels, the dosage of CERA was adjusted if needed along with iron supplementation.. At the end of the study, the two groups consisted of 51 patients: 26 of those treated with the recommended dose of CERA and 25 treated with the alternative dose. In the normal conversion group, the mean hemoglobin level during the course of the study was 104.41 g/L with the mean monthly dose of 104.33 mcg CERA. In the alternative conversion group, the mean hemoglobin level during the course of the study was 105.33 g/L with the mean monthly dose'of 113.08 mcg CERA. In the alternative conversion group, 33% of patients had Hb levels in the tight recommended range of 110-120 g/L. In 30% of patients, Hb levels were 100-110 g/L, in 29% less than 100 g/L, and in 8% more than 120 g/L. The mean Hb levels at the beginning and the end of the study did not differ significantly, except for the patient group with Hb levels >120 g/L, where 7% of patients with recommended dosing and none of the patients from the alternative dosing group had such levels (P=0.017). Hemoglobin variability higher than 10 and 20 g/L was recorded in both groups, but less frequently in the alternative CERA dosing group.. Both treatments with the recommended and alternative conversion dosing achieved and maintained target hemoglobin level. Study results confirmed the need of individualized approach in the treatment of anemia in ESRD patients receiving hemodialysis, resulting in less potentially harmful hemoglobin variability.

Topics: Anemia; Drug Substitution; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Polyethylene Glycols; Renal Dialysis

To evaluate the safety and efficacy of epoetin alfa administered in extended-dosing intervals to a target hemoglobin (Hb) level not exceeding 12.0 g/dL for the treatment of anemia in subjects with chronic kidney disease (CKD) not on dialysis.. An open-label, randomized, multicenter, controlled study consisting of a 1-week screening phase and a 26-week open-label treatment phase.. Twenty-seven long term care (LTC) facilities in the United States.. Subjects with CKD who were not receiving dialysis, who had not received an erythropoiesis-stimulating agent for 8 weeks before screening, and whose Hb levels were lower than 11.0 g/dL at screening were eligible.. In the epoetin alfa group, subjects were administered 20,000 international units epoetin alfa subcutaneously every 2 weeks (Q2W). Dosing was based on the Hb concentration measurement obtained by HemoCue Hb201+System (Quest Diagnostics; Madison, NJ) at the time of the scheduled dose. When the Hb concentration was 11.0 to 11.5 g/dL on 2 consecutive biweekly measurements, the dose was doubled and administered on the day that the second consecutive measurement was obtained. The dosing interval was then extended to every 4 weeks (Q4W). Subjects in the standard of care (SOC) group received treatment for their anemia according to the practice of the LTC facility.. Study visits were every 2 weeks, at which time blood was drawn and used for efficacy analysis. Measurements included: the Hb concentration change from baseline to the end of the study; the proportion of subjects who achieved an Hb response (defined as 2 consecutive Hb measurements at least 1.0 g/dL greater than baseline or 2 consecutive Hb measurements ≥11.0 g/dL at any time during the study); the time to the Hb response; the proportion of subjects who received a transfusion and the number of units of transfused; the proportion of epoetin alfa-treated subjects converting to Q4W dosing; and the proportion of subjects who converted to Q4W dosing and remained on Q4W dosing through the end of the study.. A total of 157 subjects were randomized: 118 subjects to the epoetin alfa group and 39 to the SOC group. The mean change in Hb was significantly greater in the epoetin alfa group (0.9 g/dL) compared with the SOC group (0.3 g/dL) (P = .006). A significantly greater percentage of subjects achieved a Hb response in the epoetin alfa group (85.1%) compared with the SOC group (53.8%) (P < .001). The time to achieve a Hb response was significantly shorter in the epoetin alfa group (41 days) than in the SOC group (114 days) (P < .0001). There were no transfusions in the SOC group, whereas 4 subjects (3.5%) required transfusions in the epoetin alfa group. Of the 114 subjects receiving epoetin alfa, 33 (28.9%) subjects were converted to Q4W dosing, and all subjects who converted were able to be maintained on this schedule.. The administration of epoetin alfa in extended-dosing intervals of Q2W followed by Q4W was safe and effective in the treatment of anemia in subjects with CKD who reside in LTC facilities.

Topics: Aged; Aged, 80 and over; Anemia; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Long-Term Care; Male; Outcome Assessment, Health Care; Recombinant Proteins; Residential Facilities; United States

In the last years, the number of hemodialysis (HD) patients with erythropoietin (rHuEPO) resistance is increasing. Probably, central venous catheters (CVCs) contribute to this resistance by inducing inflammation and oxidative stress. This study was aimed to compare vitamin E-bonded dialyzer (PSVE) versus polyethersulfone membrane. Sixteen subjects with CVCs were included in a prospective two-arm crossover 12-month study. The primary endpoints were the rHuEPO requirement and the erythropoiesis-stimulating agents (ESA) index, which was defined by the ratio between weekly EPO dosage (IU/kg/week) and Hb levels (g/dl). The mean dosages of rHuEPO to maintain hemoglobin between 10.5 and 12 g/dl were 135 ± 59 and 101 ± 57 IU/kg/week with polysulfone and PSVE, respectively (P = 0.14). The ESA indexes were 12.1 ± 5.2 and 8.7 ± 5.2 (P < 0.0001) with polysulfone and PSVE, respectively. A trend towards consensual changes in protein glycoxidation, antioxidant, and inflammatory markers was observed. In conclusion, the study suggests a role for PSVE in the reduction of ESA index in HD patients with CVCs.

Topics: Aged; Aged, 80 and over; Anemia; Antioxidants; C-Reactive Protein; Central Venous Catheters; Coated Materials, Biocompatible; Cross-Over Studies; Erythropoietin; Glycation End Products, Advanced; Hematinics; Hemoglobins; Humans; Interleukin-1; Kidney Failure, Chronic; Membranes, Artificial; Oxidative Stress; Pilot Projects; Polymers; Recombinant Proteins; Renal Dialysis; Sulfones; Vitamin E

Retrospective studies suggest that chronic allograft nephropathy might progress more rapidly in patients with post-transplant anemia, but whether correction of anemia improves renal outcomes is unknown. An open-label, multicenter, randomized controlled trial investigated the effect of epoetin-β to normalize hemoglobin values (13.0-15.0 g/dl, n=63) compared with partial correction of anemia (10.5-11.5 g/dl, n=62) on progression of nephropathy in transplant recipients with hemoglobin <11.5 g/dl and an estimated creatinine clearance (eCrCl) <50 ml/min per 1.73 m(2). After 2 years, the mean hemoglobin was 12.9 and 11.3 g/dl in the normalization and partial correction groups, respectively (P<0.001). From baseline to year 2, the eCrCl decreased by a mean 2.4 ml/min per 1.73 m(2) in the normalization group compared with 5.9 ml/min per 1.73 m(2) in the partial correction group (P=0.03). Furthermore, fewer patients in the normalization group progressed to ESRD (3 versus 13, P<0.01). Cumulative death-censored graft survival was 95% and 80% in the normalization and partial correction groups, respectively (P<0.01). Complete correction was associated with a significant improvement in quality of life at 6 and 12 months. The number of cardiovascular events was low and similar between groups. In conclusion, this prospective study suggests that targeting hemoglobin values ≥13 g/dl reduces progression of chronic allograft nephropathy in kidney transplant recipients.

Topics: Adult; Aged; Anemia; Antihypertensive Agents; Disease Progression; Erythropoietin; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Quality of Life; Recombinant Proteins; Transplantation, Homologous

Erythropoiesis-stimulating agent (ESA) resistance remains incompletely understood among hemodialysis (HD) patients.. A retrospective, multicenter study was designed to analyze data from 1,934 patients followed for up to two years. The outcome measure was the erythropoietin resistance index (ERI), defined as erythropoietin dosage over a week divided by the post-HD weight and hemoglobin value.. Multivariate analysis revealed albumin, Kt/V, transferrin saturation, statin use and male gender to be inversely related to ERI, whereas parathyroid hormone and angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) use were associated with higher ESA resistance. ERI was statistically lower in patients with higher levels of albumin (p < 0.001) and with higher transferrin saturation levels (p < 0.05).. The results allow for a better understanding of predictors of erythropoietin resistance among HD patients including not extensively studied factors such as statin and ACEI/ARB use.

Topics: Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Drug Resistance; Erythropoietin; Female; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Renal Dialysis; Retrospective Studies; Serum Albumin; Sex Factors; Transferrin; Treatment Outcome

To compare the efficacy and safety of epoetin theta and epoetin beta in anemic patients with chronic kidney disease (CKD) not yet receiving dialysis and previously on stable maintenance therapy with epoetin beta.. In this multicenter, randomized, controlled, double-blind, non-inferiority study, 288 patients were treated subcutaneously (s.c.) for 24 weeks with epoetin theta (n = 193) or epoetin beta (n = 95). The primary efficacy endpoint was change in hemoglobin (Hb) from a 2-week baseline period to end of treatment (12-week efficacy evaluation period [EEP], weeks 15-26). The non-inferiority limit was 1.0 g/dL (2-sided alpha = 0.05). Weekly doses of epoetin required to maintain Hb levels, dose changes, safety, tolerability, and immunogenicity were also evaluated.. EudraCT No. 2005-000142-37.. Mean Hb values were comparable in both groups at baseline and during the 24-week treatment period. The estimated treatment difference between groups from baseline to EEP was 0.01 g/dL (95% confidence interval: -0.20, 0.22; p = 0.9207 (ANCOVA)), indicating that epoetin theta was non-inferior to epoetin beta. The weekly doses of epoetin theta or epoetin beta were nearly the same and the change from baseline to EEP in patients who switched to epoetin theta (36.6 to 30.0 IU/kg(BW)) was comparable to those continuing epoetin beta therapy (37.7 to 28.3 IU/kg(BW)). The profile and the frequency of adverse drug reactions (ADRs) were comparable in both groups (17.1% epoetin theta; 14.7% epoetin beta). The most common ADR was hypertension. No patient developed anti-erythropoietin antibodies.. Epoetin theta (s.c.) has efficacy comparable with epoetin beta (s.c.) in pre-dialysis patients with renal anemia based on Hb changes from baseline to end of treatment (non-inferiority). The safety profile was also comparable. Patients could be switched from maintenance treatment with epoetin beta to epoetin theta without relevant dose changes.

Topics: Aged; Anemia; Double-Blind Method; Erythropoietin; Female; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis

Reticuloendothelial blockade in hemodialysis patients prevents optimal intravenous (IV) iron utilization. Vitamin C has emerged as a potential therapy to improve anemia treatment by enhancing iron mobilization. However, Vitamin C can act as a pro-oxidant in the presence of iron. This was a prospective, open-label, crossover study. Thirteen patients with end-stage renal disease on hemodialysis and four healthy controls were assigned to receive 100 mg of IV iron sucrose (IS) or 100 mg of IV IS co-administered with 300 mg of IV Vitamin C (IS + C) in random sequence. Serum samples for IL-1, IL-6, TNF-α and IL-10 and non-transferrin bound iron were obtained at baseline, 45 min and 105 min post study medication administration. Peripheral blood mononuclear cells were isolated at the same time points and stained with fluorescent probes to identify intracellular reactive oxygen species and mitochondrial membrane potential (Δψm) by flow cytometry. Lipid peroxidation was assessed by plasma F2-isoprosatane concentration. Both IS and IS + C were associated with increased plasma F2-isoprostanes concentrations post-infusion. Maximal plasma F2-isoprostane concentrations after IS + C were significantly elevated from baseline (234 ± 0.04 vs. 0.198 ± 0.028 ng/mL, p = 0.02). After IS + C, IL-1, IL-6, IL-10, and TNF-alpha were significantly elevated compared to baseline. After IS alone only IL-6 was noted to be elevated. Intracellular production of H(2)O(2) and loss of mitochondrial membrane potential (Δψm) was observed after IS while IS + C was associated with increased O (2) (·-) production. Both IS and IS + C induced serum cytokine activation accompanied by lipid peroxidation, however, IS + C induced higher plasma concentrations of F2-isoprostanes, IL-1, IL-10, and TNF-α post-infusion. Long-term safety studies of IV iron co-administered with Vitamin C are warranted.

Topics: Adult; Ascorbic Acid; Cross-Over Studies; Cytokines; Epoetin Alfa; Erythropoietin; F2-Isoprostanes; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Lipid Peroxidation; Male; Membrane Potential, Mitochondrial; Middle Aged; Oxidative Stress; Prospective Studies; Reactive Oxygen Species; Recombinant Proteins; Systems Biology

Hepcidin-25, the bioactive form of hepcidin, is a key regulator of iron homeostasis as it induces internalization and degradation of ferroportin, a cellular iron exporter on enterocytes, macrophages and hepatocytes. Hepcidin levels are increased in chronic hemodialysis (HD) patients, but as of yet, limited information on factors associated with hepcidin-25 in these patients is available. In the current cross-sectional study, potential patient-, laboratory- and treatment-related determinants of serum hepcidin-20 and -25, were assessed in a large cohort of stable, prevalent HD patients. Baseline data from 405 patients (62% male; age 63.7 ± 13.9 [mean SD]) enrolled in the CONvective TRAnsport STudy (CONTRAST; NCT00205556) were studied. Predialysis hepcidin concentrations were measured centrally with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Patient-, laboratory- and treatment related characteristics were entered in a backward multivariable linear regression model. Hepcidin-25 levels were independently and positively associated with ferritin (p<0.001), hsCRP (p<0.001) and the presence of diabetes (p = 0.02) and inversely with the estimated glomerular filtration rate (p = 0.01), absolute reticulocyte count (p = 0.02) and soluble transferrin receptor (p<0.001). Men had lower hepcidin-25 levels as compared to women (p = 0.03). Hepcidin-25 was not associated with the maintenance dose of erythropoiesis stimulating agents (ESA) or iron therapy. In conclusion, in the currently studied cohort of chronic HD patients, hepcidin-25 was a marker for iron stores and erythropoiesis and was associated with inflammation. Furthermore, hepcidin-25 levels were influenced by residual kidney function. Hepcidin-25 did not reflect ESA or iron dose in chronic stable HD patients on maintenance therapy. These results suggest that hepcidin is involved in the pathophysiological pathway of renal anemia and iron availability in these patients, but challenges its function as a clinical parameter for ESA resistance.

Topics: Aged; Antimicrobial Cationic Peptides; Biomarkers; C-Reactive Protein; Cross-Sectional Studies; Erythropoiesis; Erythropoietin; Female; Ferritins; Glomerular Filtration Rate; Hematinics; Hepcidins; Humans; Iron; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Peptide Fragments; Renal Dialysis

To evaluate the efficacy and safety of continuous erythropoietin receptor activator (C.E.R.A.) once every 4 weeks by subcutaneous administration on hemoglobin (Hb) maintenance in dialytic patients with chronic renal anemia who had been treated with stable dose of erythropoietin (EPO).. This was an open, randomized, controlled, multi-center trial. All the hemodialysis or peritoneal dialytic patients in EPO maintenance treatment received subcutaneous EPO-β during the 6-week pre-treatment period to maintain Hb level between 100 g/L and 120 g/L. Eligible patients were randomized (2:1) to accept either C.E.R.A. once every 4 weeks by subcutaneous administration (C.E.R.A. group, n = 187) or subcutaneous EPO-β 1-3 times weekly (EPO group, n = 94) for 28 weeks (including 20-week dose titration period and 8-week efficacy evaluation period). The starting dose of C.E.R.A. was converted according to the dose of EPO-β administered in the week preceding the first study drug administration. The primary outcome was the change of Hb level between the baseline and that in the efficacy evaluation period.. Totally 253 patients completed the whole 28-week treatment. The change of baseline-adjusted mean Hb was +2.57 g/L for C.E.R.A. group and +1.23 g/L for EPO group, resulting in a treatment difference of 1.34 g/L (95%CI -1.11 - 3.78 g/L). Since the lower limit of 95%CI was greater than the pre-defined non-inferiority margin -7.5 g/L (P < 0.0001), C.E.R.A. once every 4 weeks by subcutaneous administration was clinically non-inferior to EPO regarding the maintenance of stable Hb level. The proportion of patients maintaining Hb level within the range of 100-120 g/L through efficacy evaluation period was similar between the two groups (69.0% for C.E.R.A. group vs 68.9% for EPO group, P > 0.05). The overall incidence of adverse events was similar between the C.E.R.A.(41.7%) and EPO (46.2%) groups (P > 0.05). The safety findings were in accordance with the patients' primary diseases rather than the administration.. Conversion from EPO to C.E.R.A. once every 4 weeks by subcutaneous injection could maintain the Hb in target level in dialytic patients with renal anemia, and it was non-inferior to EPO. In general, subcutaneous administration of C.E.R.A. is well tolerated in dialytic patients with chronic renal anemia.

Topics: Adult; Aged; Anemia; Erythropoietin; Humans; Kidney Failure, Chronic; Middle Aged; Polyethylene Glycols; Renal Dialysis; Treatment Outcome

Preliminary clinical evidence suggests that heme iron polypeptide (HIP) might represent a promising, novel oral iron supplementation strategy in chronic kidney disease. The aim of this multi-centre randomized controlled trial was to determine the ability of HIP administration to augment iron stores in darbepoetin (DPO)-treated patients compared with conventional oral iron supplementation.. Adult peritoneal dialysis (PD) patients treated with DPO were randomized 1:1 to receive two capsules daily of either HIP or ferrous sulphate per os for 6 months. The primary outcome measure was transferrin saturation (TSAT). Secondary outcomes comprised serum ferritin, haemoglobin, DPO dose and responsiveness, and adverse events.. Sixty-two patients were randomized to HIP (n = 32) or ferrous sulphate (n = 30). On intention-to-treat analysis, the median (inter-quartile range) TSAT was 22% (16-29) in the HIP group compared with 20% (17-26) in controls (P = 0.65). HIP treatment was not significantly associated with TSAT at 6 months on multivariable analysis (P = 0.95). Similar results were found on per-protocol analysis and subgroup analysis in iron-deficient patients. Serum ferritin levels at 6 months were significantly lower in the HIP group (P = 0.003), while the cost of HIP was 7-fold higher than that of ferrous sulphate. No other differences in secondary outcomes were observed.. HIP showed no clear safety or efficacy benefit in PD patients compared with conventional oral iron supplements. The reduction in serum ferritin levels and high costs associated with HIP therapy suggest that this agent is unlikely to have a significant role in iron supplementation in PD patients.

Topics: Administration, Oral; Adult; Aged; Anemia, Iron-Deficiency; Darbepoetin alfa; Dietary Supplements; Erythropoietin; Female; Ferritins; Ferrous Compounds; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peptide Fragments; Peritoneal Dialysis; Treatment Outcome

Recombinant human erythropoietin (rHuEPO) is the cornerstone therapy for anemia associated with chronic kidney disease. However, not all patients with renal anemia receive sufficient doses of rHuEPO due to its high cost. The present trial aimed to evaluate the efficacy of Epolyrec, a biogeneric rHuEPO, in the management of renal anemia in patients on hemodialysis.. Seventy-two patients with end stage renal disease (ESRD) who were receiving hemodialysis were assigned to receive Epolyrec subcutaneously at a dose of 40-80 IU/Kg in 2-3 divided doses after each dialysis session for 12 weeks. Hemoglobin, hematocrit, and CBC/DIFF together with biomarkers of iron status, renal function, and trace elements were evaluated at baseline and during the course of trial.. Hemoglobin concentrations and hematocrit progressively increased from baseline (8.45 +/- 1.42 mg/dL and 27.05 +/- 4.64% for hemoglobin and hematocrit, respectively) to the end of trial (10.56 +/- 1.93 and 34.06 +/- 6.70) (p < 0.001). RBC count (p = 0.026), reticulocyte count (p = 0.045), and MCV (p < 0.001) were also significantly increased at the end of trial (3.86 +/- 0.91x10(6)/microL, 0.78 +/- 0.31%, and 93.50 +/- 10.90 fL for RBC count, reticulocyte count, and MCV, respectively) compared to baseline (0.98 +/- 3.38, 0.18 +/- 0.63, and 89.75 +/- 9.35). Serum iron and ferritin were decreased while creatinine and phosphorous increased by the end of trial. No significant change was observed in WBC count, RDW, MCH, MCHC, BUN, PTH, Na, Ca, K, and Mg (p > 0.05). The frequencies of evaluated side effects were generally low and < 10%.. Epolyrec is clinically efficacious in the elevation of hemoglobin and hematocrit in anemic ESRD patients receiving hemodialysis. Future comparative trials are warranted to compare the efficacy and safety of Epolyrec to those of innovator products.

Topics: Anemia; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis

Recent retrospective studies suggest an association of therapy with erythropoiesis-stimulating agents (ESAs) and increased mortality in renal transplant recipients (RTR). Large artery structure and function are significantly impaired in RTR which contributes to their high cardiovascular morbidity and could be altered by erythropoietin. We aimed to examine the influence of ESA therapy on large artery stiffness and endothelial function in RTR.. 63 RTR with chronic allograft dysfunction and renal anemia were randomized to a group receiving darbepoetin alfa (Dar) and a control group (Co). At baseline and after 8 months of treatment (cumulative Dar dose 11.1 µg/kg b.w.) brachial and common carotid artery distensibility coefficients, aortic pulse wave velocity, brachial artery flow-mediated and nitroglycerin-mediated vasodilation were measured as well as the following biomarkers of vascular function: vWF, sVCAM, sICAM, E-selectin, t-PA and PAI-1.. 23 patients in the Dar group and 17 patients in the Co group were available for per-protocol analysis. Hemoglobin increased significantly from 10.9 to 12.6 g/dl after 8 months in the Dar group, whereas it remained stable at 11.3 g/dl in the Co group. Effects on large artery stiffness, endothelial function and biomarkers of vascular function did not differ significantly between the two groups.. Therapy with Dar during 8 months did not significantly impact parameters of large artery stiffness and endothelial function in RTR. These data suggest that therapy with erythropoietin does not deteriorate arterial stiffness and endothelial function in RTR.

Topics: Anemia; Brachial Artery; Darbepoetin alfa; Endothelium, Vascular; Erythropoietin; Female; Hematinics; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Primary Graft Dysfunction; Risk Factors; Transplantation, Homologous; Treatment Outcome; Vascular Stiffness; Vasodilation

We investigated the long-term effects of maintaining high hemoglobin (Hb) on renal function in patients with chronic kidney disease not on dialysis. Subjects (Hb < 10 g/dL and serum creatinine (Cr) 2-6 mg/dL) were randomized to either a high Hb group (N = 161, 11.0 ≤ Hb < 13.0 g/dL) receiving darbepoetin alfa or to a low Hb group (N = 160, 9.0 ≤ Hb < 11.0 g/dL) with epoetin alfa, stratified according to baseline Hb and serum Cr levels, comorbidity of diabetes, and study centers. Primary endpoints were composites of the following events: doubling of serum Cr, initiation of dialysis, renal transplantation, or death. Three-year cumulative renal survival rates (95% CI) were 39.9% (30.7-49.1%) and 32.4% (24.0-40.8%) in the high and low Hb groups, respectively (log-rank test; P = 0.111). A Cox proportional-hazards model adjusted by age, sex and the randomization factors showed a significantly lower event rate in the high Hb group (P = 0.035). The estimated hazard ratio (95% CI) for the high versus the low Hb group was 0.71 (0.52-0.98), the risk reduction was 29% in the high Hb group. Incidences of serious adverse cardiovascular events did not differ significantly between the high and low Hb groups (3.1% and 4.4%, respectively). No safety issues were noted in either group. Maintaining higher Hb levels with darbepoetin alfa better preserved renal function in patients with chronic kidney disease not on dialysis.

Topics: Aged; Creatinine; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Incidence; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Proportional Hazards Models; Recombinant Proteins; Treatment Outcome

Patients with cardiorenal syndrome (CRS) have high cardiovascular morbidity. Endothelial progenitor cells (EPC) constitute an endogenous vascular repairsystem, protecting against atherosclerosis development. Erythropoietin (EPO) treatment may have beneficial effects by mobilizing EPC from the bonemarrow. Our objective is to determine EPC levels and effects of EPO therapy on EPC levels in CRS patients.. Open-label randomized trial.. Part of the EPOCARES-trial, conducted in Utrecht (Netherlands).. Patients with CRS and anaemia and healthy controls were included. Interventions Patients were randomized to receive EPO therapy (50 IU/kg/wk) for 52 weeks or no EPO therapy.. CD34(+)KDR(+)-EPC, cultured EPC outgrowth and function at baseline, after 18 days and after 52 weeks.. Patients showed lower CD34(+)KDR(+)-cell numbers compared to controls (6(12) vs. 19(19) cells/10(5) granulocytes; p = 0.010), despite increased levels of stromal cell-derived factor-1α; (3.1(0.8) vs 2.6(0.3) ng/ml; p = 0.001). EPC outgrowth and function were not different between patients and controls. EPC levels did not change after 18 days with or without EPO treatment. CD34(+)KDR(+)-cells significantly declined after 52 weeks in the non-treated group (p = 0.028). Long-term EPO therapy did not significantly affect this reduction in CD34(+)KDR(+)-EPC levels.. CRS patients showed reduced CD34(+)KDR(+)-EPC levels compared to controls, consistent with a reduced vascular regenerative potential and despite upregulated SDF-1α levels. Over a one-year follow-up period a marked 68% further reduction in EPC levels was observed in the patient group without EPO treatment. In spite of promising experimental studies, our longitudinal, randomized study did not show significant influence of either short- or long-term EPO therapy on reduced EPC levels in CRS patients.

Topics: Anemia; Antigens, CD34; Cell Count; Cell Proliferation; Chemokine CXCL12; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Heart Failure; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Long-Term Care; Male; Recombinant Proteins; Stem Cells; Syndrome

Oxidative stress is prevalent in dialysis patients and has been implicated in the pathogenesis of cardiovascular disease and anemia. Vitamin E is a fat-soluble antioxidant that plays a central role in reducing lipid peroxidation and inhibiting the generation of reactive oxygen species. The aim of this cross-over randomized study was to compare the effects of a vitamin E-coated polysulfone (Vit E PS) membrane and a non-vitamin E-coated polysulfone (PS) membrane on inflammatory markers and resistance to erythropoietin-stimulating agents (ESAs).. After a 1-month run-in period of standard bicarbonate dialysis with a synthetic membrane, 62 patients of both genders, and older than 18 years, dialysis vintage 48 ± 27 months, BMI 22 ± 3 (from 13 different dialysis units) were randomized (A-B or B-A) in a cross-over design to Vit E PS (treatment A) and to PS (treatment B) both for 6 months. C-reactive protein (CRP) and interleukin-6 (IL-6) concentrations were determined by a sandwich enzyme immunoassay at baseline and every 2 months; red blood cell count, ESA dose and ESA resistance index (ERI) were assessed monthly.. Hemoglobin (Hb) levels significantly increased in the Vit E PS group from 11.1 ± 0.6 g/dl at baseline to 11.5 ± 0.7 at 6 months (p < 0.001) and remained unchanged in the PS group. Although ESA dosage remained stable during the observation periods in both groups, ERI was significantly reduced in the Vit E PS group from 10.3 ± 2.2 IU-dl/kg/g Hb week at baseline to 9.2 ± 1.7 at 6 months (p < 0.001). No significant variation of ERI was observed in the PS group. A significant reduction in plasma CRP and IL-6 levels was observed in the Vit E PS group: CRP from 6.7 ± 4.8 to 4.8 ± 2.2 mg/l (p < 0.001) and IL-6 from 12.1 ± 1.4 to 7.5 ± 0.4 pg/ml (p < 0.05). In the PS group, CRP varied from 6.2 ± 4.0 to 6.4 ± 3.7, and IL-6 from 10.6 ± 2.1 to 9.6 ± 3.5 (p = n.s.).. Treatment with Vit E PS membranes seems to lead to a reduction in ESA dosage in HD patients; in addition, a low chronic inflammatory response may contribute to a sparing effect on exogenous ESA requirements.

Topics: Aged; Aged, 80 and over; Antioxidants; Biomarkers; C-Reactive Protein; Coated Materials, Biocompatible; Cross-Over Studies; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hemoglobins; Humans; Interleukin-6; Italy; Kidney Failure, Chronic; Lipid Peroxidation; Male; Middle Aged; Oxidative Stress; Polymers; Renal Dialysis; Single-Blind Method; Sulfones; Vitamin E

The short half-life of erythropoietin (rHuEPO) leads to repeated fluctuations in hemoglobin levels and the need for frequent administration. Continuous erythropoietin receptor activator (CERA) therapy has been approved for once or twice a month in adult dialysis patients. To evaluate the efficacy and safety of CERA therapy in the management of anemia in pediatric peritoneal dialysis (PD) stable PD children under twice-a-week EPO were converted to a subcutaneous CERA, scheduled every 2 weeks. The follow-up was 6 months. The primary efficacy parameter was hemoglobin > 11 g/dL. The exclusion criteria were ferritin <100 ng/ml and Hb saturation <20%. Sixteen children, aged 9.75 ± 3.6 years, including 11 boys, participated in the study. Mean Hb level at month 0 was 10.8 ± 1.9 g/dL. A decrease in hemoglobin to 10.38 ± 1 g/dL at month 2 was observed. The CERA dose was increased from 0.86 ± 0.33 to 1.67 ± 0.4 μg/kg at month 3. The target Hb level was reached by the 3rd month. The Hb level and CERA dose were 12.2 ± 1.2 and 1.6 ± 0.67 μg/kg respectively at the end of the study. No adverse events were observed during the protocol. CERA is an effective and safe therapy for maintaining hemoglobin levels when administered twice, up to once a month, in PD children. Doses required to reach target Hb were higher than published experiences in adult populations.

Topics: Anemia; Child; Dose-Response Relationship, Drug; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Peritoneal Dialysis; Polyethylene Glycols

Although originally described in dialysis patients treated with recombinant human erythropoietin (rHuEPO), haemoglobin variability has recently also been noted to be increased in patients who have chronic kidney disease (CKD) without dialysis. In our country, pre-dialysis CKD patients generally would not receive rHuEPO treatment. We studied the degree of haemoglobin variability and its prognostic implication in this group of patients.. We reviewed 332 patients with Stages 3 through 5 CKD; patients with overt iron deficiency or requiring blood transfusion were excluded. Patients were followed for up to 5 years. End points include all-cause mortality, progression to dialysis-dependent renal failure and hospitalization.. The average haemoglobin level was 11.4 ± 2.8 g/dL; intra-individual SD of haemoglobin was 0.76 ± 0.61 g/dL. Haemoglobin variability, as represented by intra-individual SD of haemoglobin, was significantly associated with the average haemoglobin level (r = -0.130, P = 0.017), Charlson's comorbidity score (r = 0.113, P = 0.040) and proteinuria (r = 0.151, P = 0.044). Univariate analysis showed that patients with high haemoglobin variability had a significantly higher all-cause mortality (log-rank test, P = 0.030) and risk of progression to end-stage renal disease (log-rank test, P = 0.021) and was associated with the adjusted duration of hospitalization (r = 0.134, P = 0.015). However, all associations become statistically insignificant after multivariate analysis to control for confounding factors.. Fluctuation of haemoglobin level is common and substantial in Chinese pre-dialysis CKD patients. Our results suggests that the observed clinical effect of haemoglobin variability in this patient population is an epiphenomenon secondary to the association between haemoglobin variability and other clinical factors.

Topics: Aged; Asian People; Creatinine; Disease Progression; Erythropoietin; Female; Follow-Up Studies; Glomerular Filtration Rate; Hemoglobins; Hospitalization; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prognosis; Renal Dialysis; Survival Rate

The quality of the water used for dialysis has been suggested as a factor causing inflammation in patients on hemodialysis (HD). We therefore conducted this study to identify the effect of quality of the water on nutritional state, inflammation and need for human recombinant erythropoietin (EPO) in patients undergoing HD at Agadir, Morocco. This prospective study included patients on HD for at least one year. The water treatment was done according to the standard protocol, which was followed by additional enhancement of ultrafiltration using an additional polysulfone filter (diasafe, Fresenius, Bad Homburg, Germany) before the dialyser. Water was monitored regularly during the study period to ensure acceptable levels of bacterial count as well as endotoxin levels. Various parameters including dry weight, systolic and diastolic blood pressure (PA) before and after an HD session, need for human recombinant EPO, levels of hemoglobin (Hb), albumin, ferritin, C-reactive protein (CRP), and the dose of dialysis delivered (Kt/V) were measured first at the beginning of the study and thereafter, in the third, sixth and 12 th months of the study. The study involved 47 patients, and after 12 months of the study, an improvement in median dry weight (1.2 kg, P = 0017) and a simultaneous median reduction of 20.7 IU/kg/week of EPO, with an in-crease of the median level of Hb, was noted. The results of our study suggest that by improving the biocompatibility of HD with the use of good quality water, patients acquire a better nutritional, inflammatory and hematologic status.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analysis of Variance; Bacterial Load; Body Weight; C-Reactive Protein; Endotoxins; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Morocco; Nutritional Status; Prospective Studies; Renal Dialysis; Ultrafiltration; Water Microbiology; Water Supply; Young Adult

Studies have shown that red cell distribution width (RDW) is related to outcome in chronic heart failure (CHF). The pathophysiological process is unknown. We studied the relationship between RDW and erythropoietin (EPO) resistance, and related factors such as erythropoietic activity, functional iron availability and hepcidin.. In the Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome (EPOCARES) study, which investigates the role of EPO in 54 iron-supplemented anemic patients with CHF and chronic kidney disease (CKD) (n = 35 treated with 50 IU/kg/wk Epopoetin beta, n = 19 control), RDW was not associated with EPO resistance. We defined EPO resistance by EPO levels (r = 0.12, P = .42), the observed/predicted log EPO ratio (r = 0.12, P = .42), the increase in reticulocytes after 2 weeks of EPO treatment (r = -0.18, P = .31), and the increase of hemoglobin after 6 months of EPO treatment (r = 0.26, P = .35). However, RDW was negatively correlated with functional iron availability (reticulocyte hemoglobin content, r = -0.48, P < .001, and transferrin saturation, r = -0.39, P = .005) and positively with erythropoietic activity (soluble transferrin receptor, r = 0.48, P < .001, immature reticulocyte fraction, r = 0.36, P = .01) and positively with interleukin-6 (r = 0.48, P < .001). No correlation existed between hepcidin-25 and RDW.. EPO resistance was not associated with RDW. RDW was associated with functional iron availability, erythropoietic activity, and interleukin-6 in anemic patients with CHF and CKD.

Topics: Aged; Aged, 80 and over; Anemia; Cell Size; Drug Resistance; Erythrocyte Indices; Erythrocytes; Erythropoietin; Female; Heart Failure; Humans; Kidney Failure, Chronic; Male; Prospective Studies

Lipid abnormalities, especially high serum lipoprotein (a) [Lp (a)] concentration, and anemia are two major causes of cardiovascular diseases (CVDs) in hemodialysis patients. Therefore, this study was designed to investigate the effects of marine omega-3 fatty acids on serum lipids, Lp (a), and hematologic factors in hemodialysis patients.. Thirty-four hemodialysis patients were randomly assigned to either omega-3 fatty acid supplement or placebo group. Patients in the omega-3 fatty acids group received 2080 mg marine omega-3 fatty acids, daily for 10 weeks, whereas the placebo group received a corresponding placebo. At baseline and the end of week 10, 7 mL blood was collected after a 12- to 14-h fast and serum triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), Lp (a), blood hemoglobin, hematocrit, red blood cells (RBCs), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) were measured.. Serum triglyceride decreased significantly in the omega-3 fatty acids group at the end of week 10 compared with baseline (p < 0.05) and this reduction was significant in comparison with the placebo group (p < 0.01). No significant differences were observed between the two groups in mean changes of serum total cholesterol, LDL-C, HDL-C, Lp (a), blood hemoglobin, hematocrit, RBC, MCV, MCH, and MCHC.. The results of our study indicate that marine omega-3 fatty acids can reduce serum triglyceride, as a risk factor for CVD, but it does not affect other serum lipids, Lp (a), and hematologic factors in hemodialysis patients.

Topics: Administration, Oral; Adult; Aged; Cholesterol; Dietary Supplements; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Fatty Acids, Omega-3; Female; Folic Acid; Follow-Up Studies; Humans; Iron Compounds; Kidney Failure, Chronic; Lipids; Lipoprotein(a); Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Prospective Studies; Reference Values; Renal Dialysis; Risk Assessment; Treatment Outcome; Young Adult

Erythropoietin (EPO) has been widely used for the treatment of anemia in chronic kidney disease (CKD). A growing body of evidence indicates that the therapeutic benefits of EPO could extend beyond the improvement of anemia. The aim of the present study was to determine whether EPO affects renovascular and oxidative stress biomarkers in pre-dialysis CKD patients with anemia.. The study was a single-arm prospective study. Fifteen CKD patients (9 males and 6 females, mean age 63 years) with anemia (mean Hb: 8.1 g/dL) were treated with recombinant human EPO; 12,000 U administered subcutaneously once every 2 weeks. Various parameters were measured before and 6 months after treatment. These included serum hemoglobin (Hb), creatinine, estimated glomerular filtration rate (eGFR), proteinuria, urinary liver-type fatty acid binding protein (L-FABP--a biomarker of renal injury), urinary 8-hydroxydeoxyguanosine (8-OHdG--a marker of oxidative stress), serum asymmetrical dimethylarginine (ADMA), carotid artery intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) as vascular markers and plasma brain natriuretic peptide (BNP) levels and left ventricular ejection fraction (LVEF) as cardiac function markers and cardio-thoracic ratio (CTR) and inferior vena cava dimension (IVCS) as extra fluid retention markers.. After 6 months, serum Hb was significantly increased (p<0.001) and urinary levels of protein, L-FABP and 8-OHdG, carotid IMT, baPWV, plasma BNP and serum ADMA levels were significantly decreased (p<0.001). Serum creatinine, eGFR, LVEF, CTR and IVCS showed little difference throughout the experimental period.. These data suggest that recombinant human EPO may ameliorate renal injury, oxidative stress and progression of atherosclerosis in addition to improving anemia in CKD patients.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Acute Kidney Injury; Aged; Arginine; Atherosclerosis; Biomarkers; Cardiovascular System; Carotid Intima-Media Thickness; Deoxyguanosine; Dose-Response Relationship, Drug; Erythropoietin; Fatty Acid-Binding Proteins; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Oxidative Stress; Prospective Studies; Recombinant Proteins; Treatment Outcome

Correcting anemia in patients with chronic kidney disease (CKD) to higher hemoglobin (Hb) levels may be associated with increased risk. No optimal target for Hb has been established. This controlled study examined 321 patients with CKD who were not on dialysis, had a Hb level of <10g/dL, and a serum creatinine of 2.0 to 6.0mg/dL. They were randomized into two target Hb groups: 161 to high Hb (11.0-13.0g/dL) to receive darbepoetin alfa and low Hb to 160 (9.0-11.0g/dL) to receive recombinant erythropoietin. The study lasted 48weeks. Of 154 and 153 patients with adverse events, cardiovascular adverse events developed in 42 and 51 patients in the high and low Hb groups, respectively, with no significant difference in the incidence. All quality of life scores improved in the high Hb group and vitality improved significantly more with high Hb (P=0.025). The left ventricular mass index (LVMI) remained stable in the low Hb group, but there was a significant decrease in LVMI in the high group (P<0.001). There were no safety concerns with targeting a higher Hb level during the 48weeks of this study. Patients with a higher Hb target had comparatively better outcomes with respect to quality of life and LVMI.

Topics: Aged; Anemia; Cardiovascular Diseases; Creatinine; Darbepoetin alfa; Erythropoietin; Female; Heart Ventricles; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Quality of Life; Treatment Outcome

There is no consensus about the toxicity of erythropoiesis-stimulating agents among hemodialysis patients. We aimed to calculate the risk of death according to anemia control and erythropoietin (EPO) dosing among end-stage renal disease patients undergoing hemodialysis. We retrospectively studied 156 end-stage renal disease patients on hemodialysis from a single renal unit during 12 months. Participants were classified according to anemia control into four groups: excellent (A), good (B), moderate (C) and bad (D) control. They were also classified according to EPO dosing into two groups: usual and high EPO dosing. The Cox proportional hazards regression model, adjusted for the difference in age, sex, time on dialysis, comorbidity, albumin, and Kt/V index, was performed to calculate the risk of death according to anemia control and EPO dosing profiles. Multivariate analysis by backward stepwise logistic regression was used to calculate the risk of death according to the variables that differed in the comparison between survivors and nonsurvivors. The hazard ratio of death was not significant according to anemia control profile C/D vs. A/B, but hazard ratio was 2.967 (95% confidence interval [CI] = 1.132-7.777; P = 0.027) for high EPO dosing profile patients. The multivariate analysis showed comorbidity (odds ratio [OR] = 8.958; 95% CI = 2.843-26.223; P < 0.001], high EPO dosing profile (OR = 5.172; 95% CI = 1.663-16,081; P = 0.005), age (OR = 1.056; 95% CI = 1.020-1.094; P = 0.002), and mean hemoglobin (OR = 0.435; 95% CI = 0.267-0.709; P = 0.001) to be predictive of death. Even though we cannot conclude that mortality risk is due to EPO toxicity, hemodialysis patients using high EPO dosing must be seen as at risk.

Topics: Adolescent; Adult; Anemia; Disease-Free Survival; Erythropoietin; Female; Humans; In Vitro Techniques; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Retrospective Studies; Risk Factors; Survival Rate

To assess the prevalence of Restless Legs Syndrome (RLS) in anemic patients with Congestive Heart Failure (CHF) and Chronic Renal Failure (CRF) and to evaluate the effect of anemia treatment on RLS.. 38 anemic CHF-CRF patients were treated with subcutaneous Erythropoietin (EPO) and intravenous (IV) iron over 1 year. They were questioned initially and at 3 months post treatment about symptoms of RLS according to standard criteria. They were also contacted by telephone about RLS symptoms 12 months after onset of anemia treatment.. RLS was found in 15 (39.5%) of the 38 patients. In 10 (66.7%) patients it was present at least 6 days a week. The prevalence of the RLS initially was not related to Hb, to serum iron or % Transferrin Saturation. Diabetes and lower serum ferritin were more common in the RLS group (p<0.05). After 3 months of treatment, Hb increased from 10.4+/-0.8 to 12.3+/-1.2 g/dl, but RLS symptoms did not change. By 12 months the prevalence and frequency of RLS complaints was similar to what it had been initially.. RLS is common and often undiagnosed and untreated in anemic CHF-CRF patients. Unfortunately, successful treatment of anemia with EPO and IV iron did not improve this condition.

Topics: Aged; Anemia; Erythropoietin; Female; Heart Failure; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Prevalence; Restless Legs Syndrome

L-carnitine supplementation has been the subject of heated discussion in the context of the treatment of pediatric hemodialysis patients. The aim of this study was to analyze the effect of intravenous L-carnitine supplementation on the erythropoetin (EPO) requirement in six pediatric hemodialysis patients. All patients were on intravenous L-carnitine (2.5 g per session for patients >30 kg and 1 g for those <30 kg) for 9 months. The EPO dose was adapted monthly to maintain a target hemoglobin (Hb) level of 11-13 g/dl. Prior to the initiation of L-carnitine supplementation, the EPO requirement was 1.15 +/- 0.22 (range 0.37-1.75) microg/kg darbepoetin alpha. Free carnitine (FC) levels were measured before (40.4 +/- 4.9 micromol/l), immediately after the 9-month L-carnitine supplementation period (378.5 +/- 77.3 micromol/l), and 4 months after withdrawal of L-carnitine (95.6 +/- 4.0 micromol/l). After 9 months, the EPO dose was 0.47 +/- 0.10 microg/kg (p < 0.002). The Hb levels increased from 12.2 +/- 0.97 to 14.0 +/- 0.54 g/dl (p < 0.05) within the first 2 months, and the EPO dose was then decreased in a stepwise manner. In conclusion, following intravenous carnitine supplementation, FC levels were higher and persisted longer than expected. This rise was associated with increased Hb levels and decreased EPO requirement. Since controls were missing for this study, prospective long-term multi-center studies on a large number of patients are required to provide solid answers to the controversial question of L-carnitine supplementation in hemodialyzed children.

Topics: Adolescent; Carnitine; Child; Erythropoietin; Female; Hemoglobins; Humans; Injections, Intravenous; Kidney Failure, Chronic; Male; Prospective Studies; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Anemia is common among patients with chronic kidney disease (CKD). The introduction of erythropoietin treatment has changed anemia management, but the therapeutic hemoglobin (Hb) target is still under debate, and clinical evidence for its effect on cardiac functions and QOL is sparse.. A 16-week dose-response study and a 32-week follow-Up study were combined. After correcting anemia of less than 10 g/dl in pre-dialysis Japanese CKD patients, a higher Hb target (12-13 g/dl) by darbepoetin alfa (DPO) was compared with the conventional Hb target by epoetin alfa (EPO). Outcomes were anemia correction, management of the left ventricular mass index (LVMI) and QOL scores.. No significant difference was seen in Hb at baseline and week 16, but a significant difference was recorded at week 34 (12.34 +/- 0.93 g/dl for DPO and 10.43 +/- 0.90 g/dl for EPO). In both groups, LVMI decreased similarly until week 16, but the decrease of EPO was retarded, and a significant difference between LVMI was seen only in DPO at week 34 (100.7 +/- 16.6 g/m(2) for DPO and 110.9 +/- 25.2 g/m(2) for EPO). Relationships between Hb and LVMI change at week 34 were examined by stratifying Hb into four groups (Hb <10 g/dl, 10 g/dl < or = Hb <11 g/dl, 11 g/dl < or = Hb <12 g/dl and 12 g/dl < or = Hb), and a decrease of LVMI was prominent in the 12 g/dl < or = Hb group. Correction of anemia to 11 g/dl or more led to improved QOL scores. No safety difference was observed among the treatments.. Targeting a higher Hb around 12 g/dl was more beneficial than targeting conventional Hb in terms of reduction of LVMI and QOL. Further studies to determine the appropriate Hb target are necessary.

Topics: Adult; Aged; Asian People; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Heart Ventricles; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Japan; Kidney Failure, Chronic; Male; Middle Aged; Quality of Life; Recombinant Proteins

C.E.R.A., a continuous erythropoietin receptor activator, is a long-acting erythropoiesis-stimulating agent (ESA) that is approved for the treatment of renal anemia. This analysis evaluated the safety profile of C.E.R.A. in comparison to that of other ESAs in patients with chronic kidney disease (CKD).. Safety parameters were analyzed in a pooled population comprising all patients with CKD on dialysis and not on dialysis from the completed Phase II and Phase III studies in the C.E.R.A. clinical program (Phase II/III population); patients were treated with either C.E.R.A. (n = 1,789) or comparator ESA (n = 948). Differences between treatment groups in safety parameters were identified by either a 2% difference in incidence between groups, or a statistically significant difference between groups (p < or = 0.05 with the Fisher's exact test, which was used as a conservative screening tool). To assess changes in safety findings over time, long-term safety data were analyzed from patients who were given the option to enter long-term safety studies upon completing their initial Phase II/III study (safety extension population).. Compared with the C.E.R.A. group, the incidence of adverse events (AEs) was higher in the comparator ESA group in the Phase II/III population (C.E.R.A. vs. comparator ESA, 89.5% vs. 91.8%, p = 0.067), and significantly so in the safety extension population (93.0% vs. 95.8%, p = 0.003). The incidence of serious AEs was significantly higher in the comparator ESA group than in the C.E.R.A. group in both analysis populations (Phase II/III population, 37.8% vs. 42.4%, p = 0.021; safety extension population, 53.3% vs. 59.7%, p = 0.001). However, there was no consistent pattern of clinical events that could explain these differences between the treatment groups.. Analysis of safety events in patients with renal anemia receiving long-term treatment with C.E.R.A. shows a safety profile comparable to that of other ESAs.

Topics: Anemia; Dose-Response Relationship, Drug; Erythropoietin; Follow-Up Studies; Humans; Incidence; Kidney Failure, Chronic; Polyethylene Glycols; Prospective Studies; Recombinant Proteins; Renal Dialysis; Time Factors; Treatment Outcome

Variable hemoglobin (Hb) response to erythropoiesis stimulating agents may result in adverse outcomes. The utility of model predictive control for drug dosing was previously demonstrated.. This was a double-blinded, randomized, controlled trial to test model predictive control for dosing erythropoietin in ESRD patients. The trial included 60 hemodialysis patients who were randomized into a treatment arm (30 subjects) that received erythropoietin doses on the basis of the computer recommendations or a control arm (30 subjects) that received erythropoietin doses on the basis of recommendations from a standard anemia management protocol (control). The subjects were followed for 8 months, and the proportions of measured Hb within the target of 11 to 12 g/dl and outside 9 to 13 g/dl were measured. Variability of the Hb level was measured by the absolute difference between the achieved Hb and the target Hb of 11.5 g/dl as well as the area under the Hb curve.. Model predictive control resulted in 15 observations >13 or <9 g/dl (outliers), a mean absolute difference between achieved Hb and 11.5 g/dl of 0.98 +/- 0.08 g/dl, and an area under the Hb curve of 2.86 +/- 1.46. The control group algorithm resulted in 30 Hb outliers (P = 0.051), produced a mean absolute difference between achieved Hb and 11.5 g/dl of 1.18 +/- 0.18 g/dl (P < 0.001 difference in variance), and an area under the Hb curve of 3.38 +/- 2.69 (P = 0.025 difference in variance).. Model predictive control of erythropoietin administration improves anemia management.

Topics: Aged; Algorithms; Anemia; Biomarkers; Clinical Protocols; Double-Blind Method; Drug Dosage Calculations; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Models, Biological; Nurse Practitioners; Renal Dialysis; Time Factors; Treatment Outcome

The primary objective of the trial was to prove the therapeutic equivalence of epoetin zeta to epoetin alfa when administered subcutaneously for maintaining target hemoglobin (Hb) in patients with renal anemia on chronic hemodialysis. Additional information was provided on the safety and tolerability of epoetin zeta with particular focus on the formation of anti-erythropoietin antibodies.. A total of 462 patients were randomized to either epoetin zeta or alfa for 28 weeks after an open period of dose adjustment of 12-16 weeks with only epoetin zeta. The aim of treatment was to maintain Hb between 10.0-12.0 g/dL with constant epoetin dosage. Primary endpoints were the mean Hb level and the mean weekly epoetin dosage during the last 4 weeks of treatment. Safety endpoints were the occurrence of anti-erythropoietin antibodies, incidence of Hb levels above 13 g/dL, ratings of tolerability, and adverse events (AEs).. The mean Hb level (+/-SD) during the last 4 weeks of treatment was 10.94+/-0.84 g/dL (epoetin zeta) and 11.02+/-0.94 g/dL (epoetin alfa). The 95% confidence interval (CI) (''C0.28 g/dL to 0.12 g/dL) was entirely within the predefined equivalence range (+/-0.5 g/dL). The mean weekly epoetin dosage per body weight over the last 4 weeks of treatment was 97.0+/-94.3 IU/kg/week (epoetin zeta) and 86.0+/-78.0 IU/kg/week (epoetin alfa). The 95% CI (''C8.06 IU/kg/week to 29.96 IU/kg/week) was also within the predefined equivalence range of +/-45 IU/kg/week. The most common AEs were infections and infestations (15.1% of patients on epoetin zeta and 14.8% of patients on epoetin alfa). None of the patients developed anti-erythropoietin antibodies.. Epoetin zeta, administered subcutaneously, is equivalent to epoetin alfa in respect of its clinical efficacy. The safety profile of both products is similar: no unexpected AEs were observed, no patients developed anti-erythropoietin antibodies, and both epoetin preparations were well tolerated.

Topics: Adult; Aged; Anemia; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Single-Blind Method; Therapeutic Equivalency

Although left ventricular hypertrophy (LVH) is a characteristic finding in hemodialysis (HD) populations, few risk factors for progressive LVH have been identified.. As part of a multinational, blinded, randomized, controlled trial that demonstrated no effect of hemoglobin targets on LV size, 596 incident HD patients, without symptomatic cardiac disease or cardiac dilation, had baseline echocardiograms within 18 months of starting dialysis and subsequently at 24, 48, and 96 weeks later. A wide array of baseline risk factors were assessed, as were BP and hemoglobin levels during the trial.. The median age and duration of dialysis were 51.5 years and 9 months, respectively. LV mass index (LVMI) rose substantially during follow-up (114.2 g/m(2) at baseline, 121 at week 48, 123.4 at week 48, and 128.3 at week 96), as did fractional shortening, whereas LV volume (68.7, 70.1, 68.7, and 68.1 ml/m(2)) and E/A ratio remained unchanged. At baseline, the only multivariate associations of LVMI were gender and N terminal pro-B type natriuretic peptide. Comparing first and last echocardiograms in those without LVH at baseline, independent predictors of increase in LVMI were higher time-integrated systolic BP and cause of ESRD. An unadjusted association between baseline LVMI and subsequent cardiovascular events or death was eliminated by adjusting for age, diabetes, systolic BP, and N terminal pro-B type natriuretic peptide.. Progressive concentric LVH and hyperkinesis occur in HD patients, which is partly explained by hypertension but not by a wide array of potential risk factors, including anemia.

Topics: Anemia; Canada; Disease Progression; England; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Linear Models; Logistic Models; Male; Middle Aged; Odds Ratio; Proportional Hazards Models; Prospective Studies; Recombinant Proteins; Renal Dialysis; Risk Factors; Time Factors; Ultrasonography

Anemia is an early sign of chronic kidney dysfunction, caused by many different factors, but the insufficient erythropoietin synthesis is the crucial factor in its development.. The objective of our study was to compare effectiveness of epoietin alpha and beta application in the treatment of renal anemia in chronic hemodialyzed patients.. The group included 60 patients of both sexes, randomly chosen. Criteria for including patients into the study were: older than 18 years, haemodialyzed longer than three months and treated by epoietin beta, stable level of hemoglobin, between 9 and 11 g/dL at least two successive measurements and no malignant disease present. The patients were then randomized into groups: 20 patients were administered epoietin alpha intravenously instead of epoietin beta subcutaneously (experimental group); 20 patients were administered intravenously epoietin beta instead of epoietin beta subcutaneously (control group A), the rest of 20 patients were administered epoietin beta subcutaneously (control group B). All the testees were administered epoietin alpha or beta three times weekly after haemodialysis, intravenously or subcutaneously.. Comparison among mean values of hematological and biochemical parameters before starting the treatment by erythropoietin, and third and sixth months after therapy in the studied groups, no significant difference was found (p > 0.05).. Epoietin alpha and beta showed approximate degree of efficacy in renal anemia treatment of hemodialysis patients. The way of erythropoetin administration did not significantly effect the level of hemoglobin and hematocrit in six months research period.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Anemia is a risk factor for death, adverse cardiovascular outcomes and poor quality of life in patients with chronic kidney disease (CKD). Erythropoietin Stimulating Agents (ESA) are commonly used to increase hemoglobin levels in this population. In observational studies, higher hemoglobin levels (around 11-13 g/dL) are associated with improved survival and quality of life compared to hemoglobin levels around 9-10 g/dL. A systematic review of randomized trials found that targeting higher hemoglobin levels with ESA causes an increased risk of adverse vascular outcomes. It is possible, but has never been formally tested in a randomized trial, that ESA dose rather than targeted hemoglobin concentration itself mediates the increased risk of adverse vascular outcomes. The Clinical Evaluation of the DOSe of Erythropoietins (C.E. DOSE) trial will assess the benefits and harms of a high versus a low fixed ESA dose for the management of anemia in patients with end stage kidney disease.. This is a randomized, prospective open label blinded end-point (PROBE) trial due to enrol 2204 hemodialysis patients in Italy. Patients will be randomized 1:1 to 4000 IU/week versus 18000 IU/week of intravenous epoietin alfa or beta, or any other ESA in equivalent doses. The dose will be adjusted only if hemoglobin levels fall outside the 9.5-12.5 g/dL range. The primary outcome will be a composite of all-cause mortality, non fatal stroke, non fatal myocardial infarction and hospitalization for cardiovascular causes. Quality of life and costs will also be assessed.. The C.E.DOSE study will help inform the optimal therapeutic strategy for the management of anemia of hemodialysis patients, improving clinical outcomes, quality of life and costs, by ascertaining the potential benefits and harms of different fixed ESA doses.. Clinicaltrials.gov NCT00827021.

Topics: Adult; Anemia; Cardiovascular Diseases; Cost-Benefit Analysis; Epoetin Alfa; Erythropoietin; Female; Health Care Costs; Hematinics; Hemoglobins; Hospitalization; Humans; Kidney Failure, Chronic; Male; Outcome Assessment, Health Care; Quality of Life; Recombinant Proteins; Renal Dialysis

In patients on long-term hemodialysis, high lipoprotein(a) [Lp(a)] levels are difficult to lower with medications, although they remain a risk factor for cardiovascular disease. We investigated whether ultrapure dialysate (UPD) could lower Lp(a).. We randomly assigned patients stabilized on long-term dialysis to either a low-flux synthetic polysulphone membrane (the UPD group; n=14) or to a conventional dialysate (the CD group; n=13). Blood samples were collected 1 week before dialysis and 1 week, 1 month, 6 months and 12 months after dialysis; Lp(a) was measured by the immunoturbidimetry method. Hemoglobin, interleukin-6, hypersensitive C-reactive protein, beta(2) microglobulin and albumin were also measured. The erythropoietin dosage, Kt/V, and normalized protein catabolic rate were recorded monthly.. At 12 months, mean (SD) serum levels of Lp(a) in the CD patients increased from 143.46 (125.11) to 283.89 (145.81) mg/L (p<0.01), whereas levels in the UPD group remained unchanged: 131.38 (201.45) to 120.90 (122.11) mg/L. Endotoxin levels in the 10 CD patients who completed the study ranged from 0.116 to 0.349 EU/mL and were undetectable in the 11 UPD patients who completed the study. The cultures were less than 200 CFU/mL in CD patients and negative all the time for all UPD patients. Changes in Lp(a) from baseline values were lower in the UPD group than in the CD group (p<0.05). However, changes in other variables did not differ between groups.. Ultrapure dialysate can prevent the rise of Lp(a), potentially decreasing the risk of cardiovascular disease in hemodialysis patients.

Topics: Aged; beta 2-Microglobulin; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Down-Regulation; Endotoxins; Erythropoietin; Female; Hematinics; Hemodialysis Solutions; Hemoglobins; Humans; Inflammation Mediators; Interleukin-6; Kidney Failure, Chronic; Lipoprotein(a); Male; Membranes, Artificial; Middle Aged; Nephelometry and Turbidimetry; Polymers; Recombinant Proteins; Renal Dialysis; Serum Albumin; Sulfones; Time Factors; Treatment Outcome

Erythropoietin (EPO) resistance, an important cause of anaemia in patients with heart and renal failure, is associated with increased mortality. The hypothesis of the present study was that exogenous EPO decreases hepcidin levels and that the decrease in hepcidin levels upon EPO treatment is related to the bone marrow response.. In the EPOCARES trial, patients with renal failure (glomerular filtration rate 20-70 mL/min), heart failure, and anaemia were randomized to receive 50 IU/kg/week EPO (n = 20) or not (n = 13). Haemoglobin (Hb), hepcidin-25, ferritin, reticulocytes, serum transferrin receptor (sTfR), IL-6, and high-sensitivity C-reactive protein were measured at baseline and during treatment. Hepcidin-25 was measured by weak cation exchange chromatography/matrix assisted laser desorption ionization time-of-flight mass spectrometry. Baseline hepcidin levels were increased compared with a healthy reference population and were inversely correlated with Hb (r(2) = 0.18, P = 0.02), and positively with ferritin (r(2) = 0.51, P < 0.001), but not with renal function, high-sensitivity C-reactive protein or IL-6. Erythropoietin treatment increased reticulocytes (P < 0.001) and sTfR (P < 0.001), and decreased hepcidin (P < 0.001). Baseline hepcidin levels and the magnitude of the decrease in hepcidin correlated with the increase in reticulocytes (r(2) = 0.23, P = 0.03) and sTfR (r(2) = 0.23, P = 0.03) and also with the Hb response after 6 months (r(2) = 0.49, P = 0.001).. In this group of patients with combined heart and renal failure and anaemia, increased hepcidin levels were associated with markers of iron load and not with markers of inflammation. The (change in) hepcidin levels predicted early and long-term bone marrow response to exogenous EPO. In our group hepcidin seems to reflect iron load and response to EPO rather than inflammation and EPO resistance.

Topics: Aged; Aged, 80 and over; Anemia; Antimicrobial Cationic Peptides; Biomarkers; Drug Resistance; Erythropoietin; Female; Follow-Up Studies; Heart Failure; Hemoglobins; Hepcidins; Humans; Kidney Failure, Chronic; Male; Mass Spectrometry; Middle Aged; Prognosis; Recombinant Proteins

European guidelines stress that iron status should be regularly assessed for the optimal management of renal anemia. These guidelines include the hemoglobin content of reticulocytes and the percentage of hypochromic RBC as markers for functional iron deficiency. Recently, equivalents of these indices have become available on the automated hematology analyzer Sysmex XE-2100, these being reticulocyte hemoglobin equivalent (Ret-He) and DF-HYPO XE, respectively.. In a prospective study, we closely monitored these parameters in dialysis-dependent patients with end-stage renal disease during the switch from a first-generation epoetin (EPO) once weekly to a third-generation EPO [continuous erythropoietin receptor activator (CERA)] once monthly. As a control, patients staying on EPO beta were monitored.. During follow-up, no changes in erythrocyte indices were noticed in the EPO beta group. By contrast, in the CERA group, a decrease in Ret-He and an increase in DF-HYPO XE were transiently found 7-10 days after administration. The transient state of functional iron deficiency could not be prevented by extra intravenous iron.. Fluctuations in Ret-He and DF-HYPO XE have to be taken into account when these parameters are used for the assessment of iron-deficient states. We suggest that a fixed time point in the CERA schedule should be chosen for iron monitoring.

Topics: Drug Monitoring; Erythrocyte Indices; Erythropoietin; Hematologic Tests; Humans; Iron; Iron Deficiencies; Kidney Failure, Chronic; Polyethylene Glycols; Practice Guidelines as Topic; Prospective Studies; Recombinant Proteins; Renal Dialysis

To explore the efficacy of oral N-acetylcysteine (NAC) supplementation for anemia and oxidative stress in hemodialysis (HD) patients.. Of the eligible patients (n = 325) in an outpatient HD unit, 49 received NAC 200 mg orally thrice a day during the first 3 months, while the other 276 patients not receiving NAC were observed.. During the 4-month study, 11 patients receiving NAC withdrew but had no severe adverse effects, while 49 patients not receiving NAC had negative confounding events. Thus only the data of the remaining patients, 38 taking NAC and 227 not taking NAC, were analyzed for efficacy. The demographic and laboratory data of both groups were similar at baseline. When the erythropoietin dosage was stable throughout, only the NAC group had a significant increase in hematocrit, accompanied with a decrease in plasma levels of 8-isoprostane and oxidized low-density lipoprotein. Analyzed as a nested case-control study, NAC supplementation was also found to be a significant predictor of positive outcomes in uremic anemia.. Oral NAC supplementation may be a promising therapy for uremic anemia and oxidative stress in HD patients.

Topics: Acetylcysteine; Administration, Oral; Adult; Aged; Aged, 80 and over; Anemia; Antioxidants; Case-Control Studies; Chlorides; Dinoprost; Erythropoietin; Female; Ferric Compounds; Hematocrit; Humans; Kidney Failure, Chronic; Lipoproteins, LDL; Male; Middle Aged; Oxidative Stress; Recombinant Proteins; Renal Dialysis

Treatment of anaemia in renal-insufficient patients relies on the use of an erythropoiesis-stimulating agent (ESA). This study aimed to compare the impact of two different strategies of ESA prescribing on variation in haemoglobin (Hb) concentration in end-stage renal disease (ESRD) patients.. Patients with ESRD, on haemodialysis, and who had received ESA for >3 months were recruited. Different parameters were analysed: demographics, Hb level the last day of the year before dialysis, the most recent weekly ESA dose, risk factors for resistance and cost. Each institution continued its local practice for achieving the desired Hb level: increasing the ESA dose to overcome resistance in one centre and defining an upper ESA-dose limit in the other.. A total of 185 patients were recruited. No significant differences in the biological parameters were found between the two populations. In both centres, Hb levels were comparable and mean levels exceeded 11 g/dL, despite the higher ESA doses given in one centre to achieve this target. This finding also held true for the subgroups with greater than or equal to two resistance factors. These two strategies led to large between-centre differences in treatment costs.. The ESA-use strategy difference probably indicates that erythropoietin-resistance was not overcome with increased dosing. The Hb concentrations remained stable even when ESA doses were increased. On current evidence, the cheaper ESA-dose limitation strategy is preferable but randomized controlled studies, including comparisons of alternative ESA formulations are necessary.

Topics: Aged; Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; France; Hematinics; Humans; Inpatients; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Treatment Outcome

Non–placebo-controlled trials of erythropoiesis-stimulating agents (ESAs) comparing lower and higher hemoglobin targets in patients with chronic kidney disease indicate that targeting of a lower hemoglobin range may avoid ESA-associated risks. However, target-based strategies are confounded by each patient's individual hematopoietic response.. We assessed the relationship among the initial hemoglobin response to darbepoetin alfa after two weight-based doses, the hemoglobin level achieved after 4 weeks, the subsequent darbepoetin alfa dose, and outcomes in 1872 patients with chronic kidney disease and type 2 diabetes mellitus who were not receiving dialysis. We defined a poor initial response to darbepoetin alfa (which occurred in 471 patients) as the lowest quartile of percent change in hemoglobin level (<2%) after the first two standardized doses of the drug.. Patients who had a poor initial response to darbepoetin alfa had a lower average hemoglobin level at 12 weeks and during follow-up than did patients with a better hemoglobin response (a change in hemoglobin level ranging from 2 to 15% or more) (P<0.001 for both comparisons), despite receiving higher doses of darbepoetin alfa (median dose, 232 μg vs. 167 μg; P<0.001). Patients with a poor response, as compared with those with a better response, had higher rates of the composite cardiovascular end point (adjusted hazard ratio, 1.31; 95% confidence interval [CI], 1.09 to 1.59) or death (adjusted hazard ratio, 1.41; 95% CI, 1.12 to 1.78).. A poor initial hematopoietic response to darbepoetin alfa was associated with an increased subsequent risk of death or cardiovascular events as doses were escalated to meet target hemoglobin levels. Although the mechanism of this differential effect is not known, these findings raise concern about current target-based strategies for treating anemia in patients with chronic kidney disease. (Funded by Amgen; ClinicalTrials.gov number, NCT00093015.)

Topics: Aged; Anemia; Cardiovascular Diseases; Chi-Square Distribution; Darbepoetin alfa; Diabetes Mellitus, Type 2; Double-Blind Method; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Proportional Hazards Models; Risk; Stroke

Finding the lowest effective dose of erythropoietin-stimulating agents is critical in the management of renal anemia. We evaluated the efficacy of converting darbepoetin to CERA at doses lower than those usually recommended.. We selected consecutive non-dialysis chronic kidney disease patients treated with darbepoetin doses ≤40 μg/week in absence of iron deficiency, recent blood transfusion, bleeding, neoplasia, myocardial infarction/stroke in the last 3 months. Darbepoetin ≤20 μg/week was shifted to CERA 75 μg/month, while darbepoetin 21-40 μg/week to CERA 100 μg/month. Primary endpoint was the change in hemoglobin (Hb goal, 11-13 g/dl) at month 3, 6, 9 and 12.. Studied patients (n = 37) were aged 70 ± 13 years and GFR was 30 ± 12 ml/min/1.73 m(2); prevalence of males, diabetes and prior cardiovascular disease was 43, 45 and 40%, respectively. Before switching, efficacy population received darbepoetin 18 ± 10 μg/week with 28 patients receiving ≤20 μg/week. Prevalence of Hb goal at baseline was 75.7% and did not change at months 3 (70.3%), 6 (70.3%), 9 (72.2%), and 12 (80.0%). CERA dose remained unchanged during the study (81 ± 11, 82 ± 16, 91 ± 30, 90 ± 54 and 88 ± 61 μg/month). Out of the 438 visits performed, CERA dose was increased in 52 (11.9%) and reduced in 36 (8.2%) visits. Blood pressure, Hb, GFR, transferrin saturation and ferritin did not change.. In chronic kidney disease patients treated with darbepoetin doses ≤40 μg/week, CERA can be efficaciously used at doses lower than those recommended.

Topics: Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Erythropoietin; Female; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins

The reasons for inadequate production of erythropoietin (EPO) in patients with ESRD are poorly understood. A better understanding of EPO regulation, namely oxygen-dependent hydroxylation of the hypoxia-inducible transcription factor (HIF), may enable targeted pharmacological intervention. Here, we tested the ability of fibrotic kidneys and extrarenal tissues to produce EPO. In this phase 1 study, we used an orally active prolyl-hydroxylase inhibitor, FG-2216, to stabilize HIF independent of oxygen availability in 12 hemodialysis (HD) patients, six of whom were anephric, and in six healthy volunteers. FG-2216 increased plasma EPO levels 30.8-fold in HD patients with kidneys, 14.5-fold in anephric HD patients, and 12.7-fold in healthy volunteers. These data demonstrate that pharmacologic manipulation of the HIF system can stimulate endogenous EPO production. Furthermore, the data indicate that deranged oxygen sensing--not a loss of EPO production capacity--causes renal anemia.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Follow-Up Studies; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney Failure, Chronic; Male; Middle Aged; Nephrectomy; Procollagen-Proline Dioxygenase; Reference Values; Renal Dialysis; Risk Assessment; Treatment Outcome

To compare the effect on erythropoietin (Epo) resistance between acupoint injection and subcutaneous injection of rHuEpo in patients with chronic renal failure (CRF).. Thirty-eight cases were randomly divided into two groups, 19 cases in each one. In subcutaneous injection group (control group), subcutaneous injection of rHuEpo was administered, 3 times a week, lasting 2 months. In acupoint group (observation group), rHuEpo was injected on unilateral Shenshu (BL 23) and Zusanli (ST 36), one point was chosen each time, the bilateral acupoints were injected alternatively, 3 times a week, for 2 months. Meanwhile, a normal control group of 19 healthy persons was set up. The levels of CRP, IL-6, TNF-alpha, Scr, BUN, Hb, Hct and SF were observed.. Before treatment, the values of CRP, IL-6 and TNF-alpha in two groups were all higher than those in normal control group (all P < 0.01). After treatment for 2 months, the values of CRP, IL-6,TNF-alpha, Scr and BUN in two groups decreased apparently and those of Hb, Hct and SF increased obviously, indicating statistic significant differences as compared with the values before treatment separately (P < 0.05, P < 0.01). In comparison between two groups after treatment, every index above in observation group was improved much significantly (P < 0.05, P < 0.01).. Acupoint injection of rHuEpo at Zusanli (ST 36) and Shenshu (BL 23) increases significantly the values of Hb, Hct and SF, and decreases apparently the values of BUN, Scr and inflammatory factors, such as CRP, IL-6 and TNF-alpha as compared with subcutaneous injection. Acupoint injection improves Epo resistance and enhances Epo efficacy via alleviating micro-inflammatory state of the body.

Topics: Acupuncture Points; Adult; Aged; Drug Resistance; Erythropoietin; Female; Humans; Inflammation Mediators; Injections, Subcutaneous; Interleukin-6; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Tumor Necrosis Factor-alpha

To characterize the pharmacokinetics of darbepoetin alpha and covariate relationships in chronic kidney disease (CKD) patients after a single subcutaneous administration.. A total of 989 serum concentration recordings from 64 patients were analyzed using NONMEM with a model including endogenous erythropoietin production. The basic and final models were evaluated for stability using bootstrapping.. The selected basic model had one-compartment with a combination of the additive and constant coefficient of variation error models for residual variability. The significant covariate was weight for apparent clearance (CL/f) and apparent volume of central compartment (V(1)/f). The typical values of CL/f, V(1)/f, and absorption rate constant were 0.158 l/h, 13.7 l, and 0.0376/h, respectively. Evaluation by bootstrapping showed that the final model was stable.. The present analysis indicated that weight is a significant covariate for CL/f and V(1)/f. However, dosage adjustment according to weight is not necessary for subcutaneous administration of darbepoetin alpha in CKD patients.

Topics: Absorption; Adult; Aged; Algorithms; Asian People; Computer Simulation; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Female; Hematinics; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Serum; Software

Erythropoietin-stimulating agent (ESA) hyporesponsiveness is aggravated by chronic inflammation in maintenance hemodialysis (MHD) patients. Dyslipidemia is prevalent in MHD patients. Statin therapy has been demonstrated to not only be effective in lowering lipid levels, but also numerous pleiotropic effects including anti-inflammatory, anti-fibrotic and endothelial function improvement. Recently, a retrospective study has shown that statin therapy decreases ESA requirements in MHD patients. We conducted a prospective study to analyze the effect of statin therapy on ESA hyporesponsiveness, and especially emphasized its anti-inflammatory benefits in MHD patients. This prospective study enrolled 30 patients with baseline cholesterol >220 mg/dl. Low-dose atorvastatin (10 mg/day) was prescribed for 12 weeks. We prospectively recorded patients' biochemistry and hematological profiles, ESA prescription and some inflammatory markers at baseline, 4 weeks and 12 weeks. Statistically significant changes were noted after 4 and 12 weeks of statin therapy for cholesterol (272.5 +/- 41.1 to 184.4 +/- 37.6 and 196.4 +/- 40.2 mg/dl, p < 0.05) and ESA hyporesponsiveness, which demonstrated as erythropoietin to hematocrit ratio (EHR) (129.3 +/- 58.2 to 122.3 +/- 53.5 and 121.0 +/- 53.3 EPO U/Hct/week, p < 0.05). Mean values for proinflammatory cytokines included interleukin-6 and tumor necrotic factor-alpha levels decreased by 30.8 and 10.6%, respectively. Thus, these data suggest that statin therapy may improve ESA hyporesponsiveness in dialysis patients. This improvement in ESA hyporesponsiveness is associated with the effects of statins on inflammation.

Topics: Aged; Anemia; Atorvastatin; Drug Synergism; Erythropoietin; Female; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Interleukin-6; Kidney Failure, Chronic; Lipids; Male; Middle Aged; Prospective Studies; Pyrroles; Recombinant Proteins; Renal Dialysis; Tumor Necrosis Factor-alpha

French and international clinical practice guidelines recommend a minimum hemoglobin level of 11 g/dl in patients with chronic kidney disease. Previous studies implemented between 1996 and 2003 showed that only 35 to 55% the patients reach this target. Dialysis NeoRecormon Epidemiology (DiaNE) is a one-year French multicentric observational study designed to follow a cohort of 1200 patients with ESRD treated with epoetin beta to assess the management of anemia in routine nephrologic practice. From December 2003 to September 2004, 1241 hemodialysis patients were recruited by 229 centers. At baseline, 64.4% of patients had hemoglobin levels greater than 11 g/dl. The proportion of patients with hemoglobin levels greater than 11 g/dl at the end of the study was 71.6%. These results could be partly explained by iron deficiency: 46% of patients had a serum ferritin between 200 and 500 microg/l and about one third of patients had a transferrin-iron saturation percentage greater or equal to 30% at baseline and at the end of the study. Epoetin beta was administrated by subcutaneous route in 65.5% of patients with similar efficacy and with less mean doses than intravenous route (114.6+/-81.5 IU/kg versus 146.5+/-124.3 IU/kg at the end of the study). In conclusion, the management of anemia in hemodialysis patients is not optimal but is slightly better than the management observed between 1996 and 2003. Iron and inflammatory status should be taken into account to improve the efficacy of anemia therapy using erythropoietin-stimulating agents.

Topics: Aged; Anemia; Anemia, Iron-Deficiency; Biomarkers; Comorbidity; Disease Management; Erythropoietin; Female; Follow-Up Studies; France; Humans; Inflammation; Injections, Intravenous; Injections, Subcutaneous; Iron; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis

To evaluate the efficacy and safety of darbepoetin alfa dosed every-other-week (Q2W) to treat anemia in subjects with chronic kidney disease (CKD), not receiving dialysis, who were naïve to erythropoiesis-stimulating agent (ESA) therapy.. This was an open-label, multicenter, single-arm study enrolling ESA-naïve CKD subjects with baseline hemoglobin (Hb) < 11.0 g/dL. Q2W darbepoetin alfa treatment was initiated at a dose of 0.75 microg/kg and titrated to achieve and maintain Hb levels at 11.0-13.0 g/dL. Treatment was administered from week 1 to week 19.. The primary endpoint was the proportion of subjects who achieved Hb > or = 11 g/dL at any study visit, except in week 1. Hb levels, darbepoetin alfa dose, and safety were also assessed.. Of the 128 subjects who received at least one dose of darbepoetin alfa and of the subjects who completed the study, 118 (92%) and 112 (97%), respectively, achieved a Hb > or = 11 g/dL in a median time of 5 weeks. Median darbepoetin alfa dose at week 1 and at the time of achieving a Hb > or = 11 g/dL were 60 and 80 microg, respectively. Darbepoetin alfa was well-tolerated, and short-term adverse events were consistent with those expected in CKD subjects.. This study demonstrates that de novo Q2W darbepoetin alfa was effective in correcting and maintaining Hb levels in ESA-naïve subjects with CKD who were not receiving dialysis. Study limitations, including lack of a control arm for the study and multiple race information for subjects, must be considered in interpreting the results.. ClinicalTrials.gov, NCT00112008.

Topics: Aged; Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythrocyte Transfusion; Erythropoietin; Female; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged

Vascular access failure is a major cause of morbidity and hospitalization in hemodialysis populations worldwide. Erythropoietin (EPO) potentially can contribute to vascular access stenosis and occlusion by promoting intimal hyperplasia and thrombosis. Intravenous administration of EPO results in a severe, but transient, increase in drug concentration within the vascular access, whereas subcutaneous administration leads to a mild, but sustained, increase in the systemic circulation. The effect of route of administration of EPO on vascular access outcomes is uncertain.. Randomized controlled trial.. 78 Korean hemodialysis patients were randomly assigned to receive either intravenous (n = 40) or subcutaneous (n = 38) EPO.. EPO was administered during dialysis, and the dose was titrated to maintain hemoglobin levels between 9 to 12 g/dL. All patients received EPO 2 or 3 times/wk. Study duration was 4 to 77 months.. The primary end point was time to vascular access failure. Analysis was performed using Cox regression analysis.. The incidence of access failure was 4.7%/patient-year in the intravenous-therapy group and 12.0%/patient-year in the subcutaneous-therapy group, with an unadjusted hazard ratio of 3.24 (95% confidence interval, 1.31 to 8.00; P = 0.01). After adjustment for dialysis access type, vascular access age, previous intervention, serum phosphorus level, and diabetes mellitus, subcutaneous EPO administration was independently associated with increased vascular access failure (hazard ratio, 3.56; 95% confidence interval, 1.20 to 10.58; P = 0.02). There were no significant differences in either hemoglobin concentration or EPO dosage between the 2 groups during the study period.. Relatively small sample size and lack of complete symmetry between the 2 groups with respect to some baseline characteristics.. This study suggests that the risk of vascular access failure may be greater with subcutaneous compared with intravenous administration of EPO in hemodialysis patients.

Topics: Catheters, Indwelling; Drug Administration Routes; Equipment Failure; Erythropoietin; Female; Follow-Up Studies; Humans; Injections, Intravenous; Injections, Subcutaneous; Inpatients; Kidney Failure, Chronic; Korea; Male; Middle Aged; Morbidity; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Risk Factors; Thrombosis; Time Factors; Treatment Outcome

The effects of different hemoglobin targets when using erythropoiesis-stimulating agents on quality of life are somewhat controversial, and predictors of change in quality of life in endstage renal disease have not been well characterized.. Five hundred ninety-six incident hemodialysis patients without symptomatic cardiac disease were randomly assigned to hemoglobin targets of 9.5 to 11.5 g/dl or 13.5 to 14.5 g/dl for 96 weeks, using epoetin_alfa as primary therapy. Patients and attending physicians were masked to treatment assignment. Quality of life, a secondary outcome, was prospectively recorded using the Kidney Disease Quality of Life (KDQoL) questionnaire at weeks 0, 24, 36, 48, 60, 72, 84, and 96, with prespecified outcomes being fatigue and quality of social interaction.. The mean age and prior duration of dialysis therapy of the study population were 50.8 and 0.8 yr. Mortality was low, reflecting the relatively healthy group enrolled. Of 20 domains within the KDQoL only the prespecified domain of fatigue showed significant change over time between the two groups. Improvement in fatigue scores in the high-target group ranged from 3.2 to 7.9 over time (P = 0.007) compared with change in the low-target group. Higher body mass index and lower erythropoietin dose at baseline were independent predictors of improvement in multiple KDQoL domains.. In relatively healthy hemodialysis patients, normal hemoglobin targets may have beneficial effects on fatigue. Improvement in multiple domains of quality of life is associated with higher body mass index and lower erythropoietin requirements.

Topics: Anemia; Body Mass Index; Canada; Epoetin Alfa; Erythropoietin; Europe; Fatigue; Female; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Quality of Life; Recombinant Proteins; Renal Dialysis; Social Behavior; Surveys and Questionnaires; Time Factors; Treatment Outcome

To help identify factors contributing to intra-patient Hb variability, pooled records were analyzed from 5,592 patients undergoing hemodialysis (HD) in European, multicenter, open-label, single-arm Phase 3b trials.. Patients previously treated with recombinant human erythropoietin (rHuEPO) were switched to darbepoietin-alpha administered once a week (QW) or once every 2 weeks (Q2W), maintaining the same dosing schedule and route of ESA administration (intravenous or subcutaneous) up to and through the evaluation period. Patients were treated with darbepoietin-alpha to maintain Hb levels between 10 and 13 g/dl. Intrapatient variability was calculated using the SD model, taking all of an individual patient's Hb values during the evaluation period (Weeks 21 - 24 after conversion) and calculating the SD of these Hb values. Adverse events (AE) of infection or inflammation were recorded.. Smaller variability was seen for patients 65 years of age or older compared with younger patients (p = 0.0044) and greater variability for patients less than 40 years of age compared with older patients (p < 0.01). Little difference in variability was seen in relation to sex overall or to the presence or absence of diabetes. Intra-patient Hb variability was greater in the presence of intercurrent conditions, including infection or inflammation (p = 0.0032), blood transfusion (p < 0.0001), hospitalization (p < 0.0001), or hospitalization for cardiovascular (CV) causes (p = 0.0012), than in their absence. Iron status differences had little detectable effect on intra-patient Hb variability. A larger number of changes made to the ESA dose during the evaluation period was also associated with greater Hb variability compared with fewer dose changes, but this association could not be proved as being causative. Although p values were calculated for some comparisons, statistical significance might not indicate clinical significance because of the large sample size. Multivariable analysis to assess the association between AE status and intra-patient Hb variability, adjusting for age, sex, diabetes status, number of dose changes and iron status showed that AE status was significantly associated with Hb variability.. Additional studies would be needed to further investigate causes and effects of Hb variability and intercurrent events.

Topics: Adult; Age Factors; Aged; Anemia; Blood Transfusion; Comorbidity; Dose-Response Relationship, Drug; Erythropoietin; Europe; Female; Hemoglobins; Hospitalization; Humans; Inflammation; Kidney Failure, Chronic; Linear Models; Male; Middle Aged; Pilot Projects; Recombinant Proteins; Renal Dialysis; Risk Factors

Less frequent dosing regimens during anemia treatment could benefit Peritoneal Dialysis (PD) patients. We investigated the effectiveness of darbepoetin alfa dosed every-other-week (Q2W) for maintaining hemoglobin (Hb) levels (11-13 g/dL).. One hundred and nine PD patients from 14 centers participated in an 8-month observational, prospective study. Patients (Hb 11-13 g/dL) receiving weekly (QW) darbepoetin alfa switched to Q2W dosing at the investigator's discretion. Doses were adjusted according to published guidelines.. Sixty-nine percent (75 out of 109) of patients switched to Q2W dosing. Thirty-three percent maintained the g/week, equivalent to twice the previous mean weekly dose (26.1-25.8 g/week, QW dose). Forty-seven percent received a dose reduction (35.8-20.2 equivalent to the previous QW dose). More patients in the maintenance dose group 11 g/dL than those receiving a reduced weekly dose (80% vs. had Hb levels 51.4%, respectively, p = 0.0236). During the Q2W phase, the mean Hb level ranged from 12.0-12.5 g/dL for the maintenance dose group and 11.5-12.0 g/dL for the reduced dose group. From the switch to the end of the study, the mean (SD) change in Hb was -0.7 g/dL (0.98 g/dL, p = 0.0557) and -0.6 g/dL (1.6 g/dL, p = 0.1296) for the maintenance and reduced dose groups, respectively. The Q2W darbepoetin alfa was well tolerated. Only a single treatment-related adverse event (polycythemia) occurred.. The majority of PD patients receiving QW darbepoetin alfa can be effectively switched to Q2W and still maintain their Hb level.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Polycythemia; Prospective Studies; Young Adult

Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA) used either intravenously or subcutaneously with no dose penalty; however, the direct switch from subcutaneous recombinant human erythropoietin (rHuEPO) to intravenous darbepoetin has barely been studied.. To establish the equivalence of a direct switch from subcutaneous rHuEPO to intravenous darbepoetin versus an indirect switch from subcutaneous rHuEPO to intravenous darbepoetin after 2 months of subcutaneous darbepoetin in patients undergoing hemodialysis.. In this open, randomized, 6-month, prospective study, patients with end-stage kidney disease who were on hemodialysis were randomized into 2 groups: direct switch from subcutaneous rHuEPO to intravenous darbepoetin (group 1) and indirect switch from subcutaneous rHuEPO to intravenous darbepoetin after 2 months of subcutaneous darbepoetin (group 2). A third, nonrandomized group (control), consisting of patients treated with intravenous rHuEPO who were switched to intravenous darbepoetin, was also studied to reflect possible variations of hemoglobin (Hb) levels due to change from one type of ESA to the other. The primary outcome was the proportion of patients with stable Hb levels at month 6. Secondary endpoints included Hb stability at month 3, dosage requirements for darbepoetin, and safety of the administration route.. Among 154 randomized patients, the percentages with stable Hb levels were equivalent in groups 1 and 2, respectively, at month 3 (86.0% vs 91.3%) and month 6 (82.1% vs 81.6%; difference -0.5 [90% CI -12.8 to 11.8]). Mean Hb levels between baseline and month 6 remained stable in both groups, with no variation in mean darbepoetin dose. Mean ferritin levels remained above 100 microg/L in the 3 groups during the whole study, and darbepoetin was well tolerated.. This study has shown equivalent efficacy on Hb stability without the need for dosage increase in patients switched directly from subcutaneous rHuEPO to intravenous darbepoetin.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Erythropoietin; Female; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Therapeutic Equivalency

To document the feasibility and report the results of dosing darbepoetin-alpha at extended intervals up to once monthly (QM) in a large dialysis patient population.. 175 adult patients treated, at 23 Swiss hemodialysis centres, with stable doses of any erythropoiesis-stimulating agent who were switched by their physicians to darbepoetin-alpha treatment at prolonged dosing intervals (every 2 weeks [Q2W] or QM).. Multicentre, prospective, observational study. Patients' hemoglobin (Hb) levels and other data were recorded 1 month before conversion (baseline) to an extended darbepoetin-alpha dosing interval, at the time of conversion, and once monthly thereafter up to the evaluation point (maximum of 12 months or until loss to follow-up).. Data for 161 evaluable patients from 23 sites were included in the final analysis. At 1 month prior to conversion, 73% of these patients were receiving darbepoetin-alpha weekly (QW) and 27% of the patients biweekly (Q2W). After a mean follow-up of 9.5 months, 34% received a monthly (QM) dosing regimen, 52% of the patients were receiving darbepoetin-alpha Q2W, and 14% QW. The mean (SD) Hb concentration at baseline was 12.3 +/- 1.2 g/dl, compared to 11.9 +/- 1.2 g/dl at the evaluation point. The corresponding mean weekly darbepoetin-alpha dose was 44.3 +/- 33.4 microg at baseline and 37.7 +/- 30.8 microg at the evaluation point.. Conversion to extended darbepoetin-alpha dosing intervals of up to QM, with maintenance of initial Hb concentrations, was successful for the majority of stable dialysis patients.

Topics: Aged; Algorithms; Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Monitoring; Erythropoietin; Feasibility Studies; Female; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis; Treatment Outcome

Quantitative adjuvant zinc therapy using polaprezinc was performed to examine the correlation between zinc concentration and anemia in maintenance hemodialysis patients to propose appropriate treatment. Anemia and serum zinc concentration were measured in 117 patients with chronic renal failure receiving outpatient maintenance hemodialysis at Tsuyama Chuo Kinen Hospital. Two bags of polaprezinc (containing zinc 34 mg/day) were administered to 58 patients with lower than normal zinc levels (Zn < 80 mg/dl) as adjuvant zinc therapy to assess anemia improvement. Zinc concentration and all anemia parameters showed significant positive correlation, indicating that anemia improves in patients with high serum zinc levels. Regarding the effects of adjuvant zinc therapy for improving anemia, hemoglobin levels were found to increase significantly to the highest value at 3 weeks. During treatment, the dosage of erythropoietin was reduced significantly from baseline at all assessment points. No zinc poisoning from therapy was seen, but two patients had diarrhea (1.9%). Zinc-treated patients required iron therapy due to the development of iron deficiency. Most maintenance hemodialysis patients suffer from zinc deficiency anemia, and zinc-based polaprezinc has been confirmed to be an effective and safe adjuvant zinc treatment. Most patients diagnosed as refractory anemia with no response to erythropoietin also suffer from zinc deficiency anemia, many of whom are expected to benefit from zinc therapy to improve their anemia. Possible zinc deficiency anemia should be considered in the treatment of refractory anemia with no response to erythropoietin.

Topics: Aged; Anemia; Anemia, Iron-Deficiency; Carnosine; Diarrhea; Dose-Response Relationship, Drug; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Iron Compounds; Japan; Kidney Failure, Chronic; Male; Middle Aged; Organometallic Compounds; Recombinant Proteins; Renal Dialysis; Zinc; Zinc Compounds

PDpoietin is a recombinant erythropoietin alfa that has been introduced by a manufacturer in Iran. We assessed the effectiveness and complications of PDpoietin in comparison with Eprex in anemic patients on hemodialysis.. This clinical trial was performed in a multicenter setting. Patients with a hemoglobin level less than 12 g/dL were assigned into 2 groups in order to receive either Eprex (Janssen Cilag) or PDpoietin (Pooyesh Darou) for 3 months.. Forty-one and 34 patients completed the study in the PDpoietin and Eprex groups, respectively. The mean hemoglobin levels at baseline were not significantly different between the two groups of patients with PDpoietin and Eprex. In both groups, hemoglobin levels increased significantly, but there were no significant differences between the two groups at months 1, 2, and 3. At the end of the study, the mean hemoglobin levels reached 11.6 +/- 1.7 g/dL and 11.8 +/- 1.9 g/dL, respectively (P = .002; P = .01). The mean hemoglobin per cumulative of drug dose index (hemoglobin/[erythropoietin dose/1000 x injections per month]) was not significantly different between the two groups at different treatment stages, and it did not change significantly in each group during the course of the study. No serious complications were reported.. Eprex and PDpoietin could equally increase the hemoglobin levels with no significant complication. Therefore, PD can be used for treatment of anemia in patients on dialysis, and the patients will have the advantages of its availability and low price.

Topics: Adult; Aged; Anemia; Cost-Benefit Analysis; Drug Costs; Epoetin Alfa; Erythropoietin; Feeding Behavior; Female; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

In clinical practice, physicians often use once-weekly (QW) and biweekly (Q2W) dosing of epoetin alfa to treat anemia in patients with chronic kidney disease (CKD). Although the literature supports this practice, previous studies were limited by short treatment duration, lack of randomization, or absence of the approved three times per week (TIW) dosing arm. This randomized trial evaluated extended dosing regimens of epoetin alfa, comparing QW and Q2W to TIW dosing in anemic CKD subjects. The primary objective was to show that treatment with epoetin alfa at QW and Q2W intervals was not inferior to TIW dosing.. 375 subjects with stage 3 to 4 CKD were randomized equally to the three groups and treated for 44 wk; to explore the impact of changing from TIW to QW administration on hemoglobin (Hb) control and adverse events, subjects on TIW switched to QW after 22 wk. The Hb was measured weekly, and the dose of epoetin alfa was adjusted to achieve and maintain an Hb level of 11.0 to 11.9 g/dl.. Both the QW and Q2W regimens met the primary efficacy endpoint. More subjects in the TIW group than in the QW and Q2W groups exceeded the Hb ceiling. Adverse events were similar across treatment groups and consistent with the morbidities of CKD patients.. Administration of epoetin alfa at QW and Q2W intervals are potential alternatives to TIW dosing for the treatment of anemia in stage 3 to 4 CKD subjects.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Dose-Response Relationship, Drug; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Hypertension, Renal; Incidence; Iron; Kidney Failure, Chronic; Male; Middle Aged; Morbidity; Recombinant Proteins; Renal Dialysis; Thromboembolism; Treatment Outcome

The Italian and European Best Practice Guidelines (EBPG) recommend a target haemoglobin value greater than 11 g/dl in most patients with Chronic Kidney Diseases. However, it is still difficult to maintain these values at a steady rate. Thus, the main aim of the study was to evaluate, throughout 2005, how many patients steadily maintained the performance targets related to anaemia treatment.. The survey was conducted on 3283 patients on haemodialysis (HD) and peritoneal dialysis (PD) at 20 Italian dialysis centres. 540 patients were randomly selected; each centre provided a statistically significant sample proportional to its total number of patients. Maintenance of the following target levels was assessed over time: Haemoglobin (HB) 11-12 gr/dl; Iron: 60-160 mcg/dl; Ferritin: 30-400 mcg/l; Transferrin: 200-360 mg/dl; Transferrin saturation percentage (TSAT %):> 25 <50; Dialysis doses (KT/V): >1.2 <2.0 for non-diabetic HD patients; >1.5 <2.2 for diabetic HD patients; DP: >1.8 <2.5.Outcome included:1- Percentage of target maintenance for each parameter.2- Erythropoietin dose in relation to dialysis techniques, presence of cancer or myeloma, diabetic status, Vitamin B therapy.3- Erythropoietin dose (International Units/kg/week) (IU/kg/wk) depending on: haemoglobin values, hospitalization of more than 3 days.. Mean age was 65.1; mean haemoglobin concentration over the whole population was 11.3 gr/dl (Standard Deviation (SD): 0.91). The clinical performance targets were maintained over time as follows: HB: 4.3% (Mean 11.43 gr/dl) (SD: 0.42); Ferritin: 71.1% (Mean: 250.23 mcg/L (SD:104.07); Iron: 95.0% (Mean 59.79 mcg/dl)(SD:16.76); Transferrin: 44.8% (Mean 216.83 mg/dl) (SD: 19,50); TSAT %: in 8.4% (Mean: 34.33% (SD: 6.56); HD KT/V: 61.0% (Mean:1.46) (SD: 0.7); PD KT/V:31.4% (Mean: 2.10) (SD: 0.02). The average weekly dose of Erythropoietin (IU/Kg/Wk) was significantly lower for the peritoneal dialysis technique; the higher haemoglobin values, the lower the Erythropoietin dose (IU/Kg/Wk).. A very low percentage of patients maintained haemoglobin target values over time. We need to identify precise criteria to evaluate the stability over time of clinical performance targets proposed by the guidelines.

Topics: Aged; Anemia; Clinical Audit; Erythropoietin; Female; Humans; Italy; Kidney Failure, Chronic; Male; Renal Dialysis; Retrospective Studies; Time Factors; Treatment Outcome

A long-acting erythropoiesis-stimulating agent named "darbepoetin alfa" (CAS 11096-26-7) was recently developed. Though it is already in use worldwide, especially in western countries, its efficacy and safety for Asian patients have not been well evaluated yet. The purpose of this study was to evaluate the efficacy and safety of short-term darbepoetin alfa administration for Japanese hemodialysis patients.. Patients who had undergone maintenance hemodialysis were enrolled in this study. The erythropoiesis-stimulating agent was switched from epoetin alfa (CAS 113427-24-0) to darbepoetin alfa so as to control the hemoglobin (Hgb) value between 10 and 12 g/dl. The initial conversion ratio was made according to the manufacturer's recommendations. The factors relevant to the responsiveness to erythropoiesis were analyzed.. One hundred and fifty-nine patients with a mean age of 67.6 years were enrolled. Two months after switching to darbepoetin alfa, the Hgb value had increased significantly (10.3 +/- 1.2 to 10.6 +/- 1.4 g/dl). Only iron supplementation correlated positively with the change of Hgb. In addition, 14.3% of patients had excess Hgb (Hgb > 12 g/dl) at the end of the study period, but only 5.6% patients at the run-in. Serious cardiovascular disease did not occur during the study period; however, the mean systolic blood pressure at the start of hemodialysis increased significantly and there was no correlation between the change of Hgb value and blood pressure.. Darbepoetin alfa increases the Hgb value effectively in Japanese hemodialysis patients. Although no serious adverse events were apparent in our short-term analysis, the incidence of hypertension and excessive increase of the Hgb value must be noted.

Topics: Aged; Anemia; Blood Pressure; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

The recombinant human epoetin-a HX575 (Sandoz Pharmaceuticals GmbH/Hexal AG, Holzkirchen, Germany) is the first biosimilar erythropoiesis-stimulating agent (ESA) with marketing authorization in Europe. The primary objective of the study was the evaluation of therapeutic equivalence in terms of hemoglobin (Hb) response of HX575 compared with the comparator product (EPREX/ ERYPO, Janssen-Cilag/Ortho Biotech, Neuss, Germany) in the long-term intravenous (i.v.) treatment of anemia in chronic renal failure patients on hemodialysis following a 1 : 1 dose conversion from the comparator product to HX575.. Hemodialysis patients with Hb levels of 10.0 - 13.0 g/dl were randomized to either continue their current i.v. epoetin-a treatment or switch to HX575. During treatment, epoetin dosages were titrated to maintain Hb values. The primary endpoint was the difference between treatment groups in the mean absolute change of Hb levels between baseline and evaluation period (Weeks 25 - 28).. Therapeutic equivalence of HX575 and the comparator epoetin-alpha, assessed during the evaluation period, was statistically confirmed: mean changes in Hb levels were 0.15 +/- 0.09 g/dl in the HX575 and 0.06 +/- 0.12 g/dl in the comparator epoetin-a group, with a difference between groups of 0.08 g/dl (95% confidence interval: -0.17; 0.34). Hb levels and epoetin dosages remained stable throughout the entire study period of 56 weeks. The long-term safety profile of HX575 was similar to that of the comparator epoetin-alpha. No antibody formation was detected.. The study demonstrated therapeutic equivalence of biosimilar HX575 to the comparator epoetin-a, together with a comparable safety profile.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Therapeutic Equivalency; Young Adult

Anemia is a common finding in dialysis patients. Recent evidence has accrued that hepcidin, an iron regulatory peptide, may play a crucial role in the pathophysiology of this condition. This study investigated the effect of erythropoietin (EPO) therapy on serum levels of prohepcidin, the pro-hormone of hepcidin, in patients with end-stage renal disease (ESRD) undergoing chronic dialysis treatment.. A total of 40 ESRD patients with renal anemia receiving either hemodialysis or peritoneal dialysis were included in this study. The patients were randomly allocated to EPO (subcutaneous 2000 microg three times weekly) plus parenteral iron (n=23) or parental iron only (n=17). Serum prohepcidin levels were measured before and at the end of the study.. The two groups were comparable in their demographic and laboratory characteristics. No significant differences were found in hemoglobin, hematocrit, iron store indices, or serum levels of prohepcidin at study entry. Significant increases in both hemoglobin and hematocrit as well as a decrease in serum prohepcidin level were evident in the EPO group at the end of the 6-month follow-up in comparison with their values at study entry compared with the control group (P<0.01).. It is concluded that EPO therapy, besides enhancing erythropoiesis, modulates serum prohepcidin levels in dialysis patients.

Topics: Antimicrobial Cationic Peptides; Erythropoietin; Female; Follow-Up Studies; Hepcidins; Humans; Infusions, Parenteral; Iron; Kidney Failure, Chronic; Male; Middle Aged; Protein Precursors; Recombinant Proteins; Renal Dialysis; Time Factors

Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested.. In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease.. Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group.. The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015.)

Topics: Aged; Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetes Mellitus, Type 2; Double-Blind Method; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Middle Aged; Neoplasms; Renal Insufficiency, Chronic; Stroke

Polymorphonuclear leukocyte priming and low grade inflammation are related to severity of kidney disease. Erythropoietin-receptor is present on PMNLs. OBJECTIVESxi: To evaluate the effect of 20 weeks of epoetin-alpha treatment on PMNL characteristics in relation to the rate of kidney function deterioration in patients with chronic kidney disease.. Forty anemic chronic kidney disease patients, stage 4-5, were assigned to EPO and non-EPO treatment for 20 weeks. A group of 20 healthy controls was also studied. PMNL priming and PMNL-derived low grade inflammation were estimated, in vivo and ex vivo, before and after EPO treatment: The rate of superoxide release, white blood cells and PMNL counts, serum alkaline phosphatase and PMNL viability were measured. EPO-receptor on PMNLs was assayed by flow cytometry. The effect of 20 weeks of EPO treatment on kidney function was related to the estimated glomerular filtration rate. esults: EPO treatment attenuated superoxide release ex vivo and in vivo and promoted PMNL survival ex vivo. Decreased low grade inflammation was reflected by reduced WBC and PMNL counts and ALP activity following treatment. EPO retarded the deterioration in GFR. The percent of PMNLs expressing EPO-R was higher before EPO treatment and correlated positively with the rate of superoxide release. After 20 weeks of EPO treatment the percent of PMNLs expressing EPO-R was down-regulated.. These non-erythropoietic properties of EPO are mediated by EPO-R on PMNLs, not related to the anemia correction. A new renal protection effect of EPO via attenuation of PMNL priming that decreases systemic low grade inflammation and oxidative stress is suggested.

Topics: Aged; Anemia; Epoetin Alfa; Erythropoietin; Female; Glomerular Filtration Rate; Hematinics; Humans; Kidney Failure, Chronic; Male; Neutrophils; Oxidative Stress; Receptors, Erythropoietin; Recombinant Proteins; Severity of Illness Index; Superoxide Dismutase

To compare injection site pain of subcutaneous (sc) epoetin beta and darbepoetin alfa in adult patients with chronic kidney disease.. This was a multi-centre, randomised, two-arm, single-blind, cross-over study. Patients were randomised to receive weekly sc darbepoetin alfa 30 mug or weekly sc epoetin beta 6000 IU for 2 weeks and were then crossed over to the alternative treatment for 2 weeks. Injection site pain was assessed using a 10 cm ungraduated visual analogue scale (0 = no pain, 10 = worst pain) and a six-point verbal rating scale. Patient preference for treatment was also assessed.. http://clinicaltrials. gov/(NCT00377481).. All randomised patients (N = 48) completed the study. The sample comprised 29 chronic kidney disease patients (Stage 3 or Stage 4), 11 peritoneal dialysis patients and 8 renal transplant patients. Patients perceived significantly less pain with epoetin beta than darbepoetin alfa, using the visual analogue scale (relative pain score = 2.75, darbepoetin alfa:epoetin beta, 95% CI: 1.85, 4.07; p < 0.0001) and the verbal rating scale (median: 0.5, 95% CI: 0.5, 1.0 vs. median: 1.5, 95% CI: 1.0, 2.0; p < 0.0001). Epoetin beta was preferred by significantly more patients (65%) than darbepoetin alfa (10%) (p < 0.001); 25% of patients reported no preference.. Limitations included lack of an epoetin alfa comparator and limited blinding (patients were blinded to treatment, however, an unblinded nurse administered treatment). We show that sc injection of epoetin beta is significantly less painful than darbepoetin alfa and patient preference for epoetin beta confirms that the difference is clinically meaningful.

Topics: Aged; Darbepoetin alfa; Erythropoietin; Female; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Pain; Pain Measurement; Recombinant Proteins

In the face of non fully correctable renal anemia in patients on continuous ambulatory peritoneal dialysis (CAPD) injecting erythropoetin subcutaneously by themselves, we compared the effectiveness of renal anemia compensation as well as potentially positive influence on the clinical course of CAPD erythropoietin alpha (EPOalpha) given intravenously 1 or 2 times weekly, by PD-nurse at patients home with the same protocol of erythropoietin beta (EPObeta) given subcutaneously by patient himself or by family helper.. There were 2 groups of CAPD patients qualified in years 2003-2005 to the 6 months study. Group 1 consisted of 12 patients who were receiving EPOalpha intravenously (7 women and 5 men; aged 57.8 +/- 14.0 years) and group 2 consisted of 12 patients who were given EPObeta subcutaneously by themselves (7 women and 5 men; age 58.0 +/- 12.5 years). In the course of home visits the nurses supervised the correctness of CAPD program performed by patient or family helper.. The results were as follows: we observed significant increase of the Hgb level in the group 1 between 3-rd and 6-th month of the study without significant increase of EPO dose. With respect to the course of CAPD program we found significantly higher frequency of peritonitis (1/11 vs 1/68 patient months; p < 0.05) and longer mean time of hospitalization (2.33 +/- 1.97 vs 1.17 +/- 1.03 days/pt; p < 0.05) in the group 2 in comparison with group 1. Mean peritonitis-free survival time was significantly longer in the group 1 in comparison with the group 2 (22.14 +/- 6.41 vs 16.51 +/- 9.70 weeks; p < 0.05).. We conclude that EPOalpha given intravenously by PD-nurse in patient home enabled maintenance of recommended Hgb level. The additional benefit from nurse assisted PD was reduction of peritonitis rate as well as duration of hospitalization from various reasons.

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Treatment Outcome

The main hypothesis of this study is that Oxpentifylline administration will effectively treat erythropoietin- or darbepoietin-resistant anaemia in chronic kidney disease patients.. Inclusion criteria are adult patients with stage 4 or 5 chronic kidney disease (including dialysis patients) with significant anaemia (haemoglobin or= 200 IU/kg/week) or darbepoetin (>or= 1 microg/kg/week). Patients will be randomized 1:1 to receive either placebo (1 tablet daily) or oxpentifylline (400 mg daily) per os for a period of 4 months. During this 4 month study period, haemoglobin measurements will be performed monthly. The primary outcome measure will be the difference in haemoglobin level between the 2 groups at the end of the 4 month study period, adjusted for baseline values. Secondary outcome measures will include erythropoiesis stimulating agent dosage, Key's index (erythropoiesis stimulating agent dosage divided by haemoglobin concentration), and blood transfusion requirement.. This investigator-initiated multicentre study has been designed to provide evidence to help nephrologists and their chronic kidney disease patients determine whether oxpentifylline represents a safe and effective strategy for treating erythropoiesis stimulating agent resistance in chronic kidney disease.

Topics: Adult; Anemia; Blood Cell Count; Blood Transfusion; Darbepoetin alfa; Double-Blind Method; Drug Resistance; Erythropoiesis; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Outcome Assessment, Health Care; Patient Selection; Pentoxifylline; Research Design; Sample Size

The anemia of chronic kidney disease (CKD) is associated with increased hospitalizations, increased cardiovascular morbidity and mortality, and diminished quality of life in the elderly. Darbepoetin alfa is an erythropoiesis-stimulating agent that has been shown to be effective in treating anemia in patients with CKD (but not on dialysis) when administered using extended-dosing regimens.. The purpose of this post hoc analysis was to examine the efficacy and safety profile of once-monthly (QM) darbepoetin alfa in study patients stratified according to age (ie, <65, 65-74, and > or =75 years).. Patients with CKD but not on dialysis, receiving darbepoetin alfa every other week (Q2W), and with stable hemoglobin (Hb) levels between 11 and 13 g/dL, inclusive, were enrolled in this 33-week, multicenter, open-label, single-arm study. The study was carried out at 36 US centers and consisted of a 24-week QM darbepoetin alfa dose-titration period followed by an 8-week evaluation period. Hb levels were measured Q2W. Study results were stratified according to patient age (<65, 65-74, and > or =75 years).. A total of 152 patients (79 women, 73 men) were enrolled; 55 patients (36%) were <65 years of age, 46 (30%) were 65 to 74 years of age, and 51 (34%) were > or =75 years of age. In patients who received > or =1 dose of darbepoetin alfa, Hb levels > or =11 g/dL were maintained in 76%, 80%, and 71% of patients aged <65, 65 to 74, and > or =75 years, respectively. For patients who completed the study, the proportions who maintained Hb levels > or =11 g/dL were 83%, 88%, and 85%, respectively, for the 3 age groups. The safety profile of QM darbepoetin alfa in this study was consistent with that expected in patients with CKD not receiving dialysis.. Darbepoetin alfa administered QM maintained Hb levels > or =11 g/dL in patients with CKD (not on dialysis) aged <65, 65 to 74, and > or =75 years. This treatment regimen may help optimize anemia management for older community-dwelling and long-term care patients.

Topics: Age Factors; Aged; Anemia; Darbepoetin alfa; Drug Administration Schedule; Drug Monitoring; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Long-Term Care; Male; Middle Aged; Residence Characteristics

The different efficacy of subcutaneous and intravenous rHuEPO results in higher doses and costs in intravenously treated patients. Darbepoetin alfa has a different pharmacokinetic profile compared to rHuEPO, and previous clinical experience suggests that subcutaneous and intravenous darbepoetin alfa may have similar efficacy. Objective. The aim of this study was to compare the efficacy of intravenous and subcutaneous darbepoetin alfa regarding haemoglobin levels and doses.. Patients treated with subcutaneous darbepoetin alfa for at least 6 months were randomized 1:1 to continue with subcutaneous treatment of darbepoetin alfa or to switch to the intravenous administration route. The application frequency was not altered. Darbepoetin alfa dose as well as haemoglobin concentrations were evaluated as per patient average at baseline (Week -3 +/- 1), Week 24 +/- 3 and Week 48 +/- 3.. One hundred fourteen patients in 9 German dialysis centres were included. Fifty-three patients were treated intravenously and 61 patients continued the subcutaneous therapy. Mean haemoglobin levels and mean weekly darbepoetin alfa dose did not change significantly in either treatment group.. Our data suggest that the darbepoetin alfa dose can be kept constant if patients are switched from subcutaneous to intravenous treatment.

Topics: Aged; Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Tolerance; Erythropoietin; Female; Germany; Hematinics; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis

Anaemia is a common in chronic kidney disease. Although erythropoietin and iron supplementation are established treatments, knowledge on the use of IV iron alone in patients not on dialysis or erythropoietin is incomplete. The responses of 82 patients referred to the renal anaemia service with haemoglobin of 11.5 g/dl or less were assessed 1 week after completing four once weekly doses of 200 mg of venofer. No patients were on dialysis or erythropoietin. The haemoglobin rise 1 week after treatment was 0.53 g/dl. Ferritin levels improved from 110.8 to 410.2 ng/l and transferrin saturation from 17.7 to 27.3%. Ferritin levels remained below our target range (200-500 ng/l) in 7.7% while 25.6% had levels above this. Ferritin levels remained less than 800 ng/l in nearly all patients. Intravenous iron is cost effective and should be considered for use in patients with renal anaemia. Patients with CKD stage 5 appeared to respond less well.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Iron-Deficiency; Cost-Benefit Analysis; Drug Administration Schedule; Drug Monitoring; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Glomerular Filtration Rate; Glucaric Acid; Hemoglobins; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Severity of Illness Index; Sucrose; Transferrin; Treatment Outcome

Maintenance of the red blood cell volume is a fundamental aspect of ensuring oxygen supply to the tissue. Recombinant human erythropoietin (rHuEPO) was approved for marketing in Japan in 1990 for the treatment of anemia in patients on dialysis. Recombinant human erythropoietin caused a significant increase in hemoglobin (Hb) levels in patients on dialysis. However, not all have a good response to rHuEPO therapy; the causes of rHuEPO failure include iron deficiency, infection, uremia, and interaction of some drugs. Juzen-taiho-to (TJ-48), a mixture of extracts from 10 medicinal herbs, has been used traditionally to treat patients with anemia, anorexia, or fatigue. To clarify the effect of TJ-48 on erythropoietin-resistant anemia, we studied the effect of TJ-48 in patients on hemodialysis with erythropoietin-resistant anemia. We divided 42 end-stage renal disease patients on hemodialysis with erythropoietin-resistant anemia (Hb<10.0 g/dL with rHuEPO 9000 U/wk or 15 U/kg/wk treatment) into 2 groups as follows: a TJ-48-treated group (TJ-48 group, 7.5 g/d, n=22) and a TJ-48 nontreated (control group, n=20). At the beginning of this study, there was no significant difference between the groups in age, sex, serum creatinine, blood urea nitrogen, serum iron, and ferritin. After 12 weeks of treatment, the Hb level had significantly increased from 8.4 +/- 1.1 to 9.5 +/- 1.3 g/dL (P=0.0272) in the TJ-48 group. C-reactive protein (CRP) had significantly decreased from 1.4 +/- 1.7 to 0.6 +/- 0.8 mg/dL (P=0.0438). There was a significant negative correlation between Hb and CRP in the TJ-48 group (r(2)=0.121, P=0.0066). In contrast, in the control group, Hb and CRP showed no significant changes throughout this study. Nor was there a significant correlation between Hb and CRP in the control group. In conclusion, TJ-48 was effective in improving erythropoietin-resistant anemia in end-stage renal disease patients. This effect was, at least in part, due to the anti-inflammatory effect of TJ-48 in patients on hemodialysis.

Topics: Administration, Oral; Aged; Anemia; Drug Resistance; Drug Therapy, Combination; Drugs, Chinese Herbal; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Mitogens; Recombinant Proteins; Renal Dialysis; Treatment Outcome

The aim of this trial was to gather data on the long-term safety of a new erythropoietin preparation (epoetin zeta), focusing on the formation of anti-erythropoietin antibodies, when administered intravenously for maintenance of target hemoglobin concentration in anemic patients with end-stage renal failure receiving chronic hemodialysis. In addition, we aimed to provide information on the efficacy of epoetin zeta under open, noncontrolled conditions.. Patients received epoetin zeta intravenously, 1-3 times/week for 56 weeks (overall patient group, n=745) or 108 weeks (Bulgarian subgroup, n=164). The aim of treatment was to maintain hemoglobin values between 10.5 and 12.5 g/dL with constant epoetin dosage. Primary (safety) endpoints were the occurrence of anti-erythropoietin antibodies and the evaluation of adverse events (AEs). Secondary (efficacy) endpoints included the mean weekly dose of epoetin per kg of body weight and mean hemoglobin concentrations.. No patients developed neutralizing anti-erythropoietin antibodies. The most commonly reported AEs were infections and infestations (34.1%); followed by injury, poisoning, and procedural complications (25.8%); and gastrointestinal disorders (21.9%); 37.3% of patients reported serious AEs. The hemoglobin values remained stable, with mean values after 56 weeks of 11.3-11.6 g/dL for the overall group and 11.1-11.6 g/dL for the Bulgarian subgroup. The dosage of epoetin zeta was stable throughout the course of the trial. No cases of lack of (or loss of ) efficacy were observed in the course of the trial.. The evaluation of the primary endpoints provided data supporting the intravenous administration of epoetin zeta in patients with chronic renal failure. Neutralizing antibodies against erythropoietin were not detected, and there were no reports of patients with increasing erythropoietin resistance. Our results suggest that intravenous administration of epoetin zeta is effective regarding its ability to maintain stabilized hemoglobin levels within the target range of 10.5-12.5 g/dL.

Topics: Anemia; Blood Transfusion; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis

Darbepoetin alfa can be administered less frequently than recombinant human erythropoietin (r-HuEPO) for the treatment of anemia in chronic renal failure (CRF) patients. We aimed to confirm that darbepoetin alfa at a reduced dosing schedule can safely maintain a target hemoglobin level in CRF patients undergoing peritoneal dialysis.. Forty-five PD patients receiving r-HuEPO were randomized in a 1:1 ratio to continue r-HuEPO or to change to darbepoetin alfa (open-label). Patients were maintained within a target range of haemoglobin for 5.5 months by adjusting the dose and then the frequency of darbepoetin alfa and r-HuEPO over the initial 4 months. The evaluation period was the final 1.5 months. A total of 37 patients completed the study.. During the evaluation period, the hemoglobin of the darbepoetin alfa group was higher than that in the baseline period (10.46 +/- 0.22 g/dL vs. 9.98 +/- 0.18 g/dL, p < 0.05). Hemoglobin remained similar in the r-HuEPO group. The average dose in the darbepoetin alfa group was 93.0 microg/month, while the average dose in the r-HuEPO group was 18,339.9 units/month. The dosing frequency was less in the darbepoetin alfa group (3.9 times/month vs. 9.2 times/month). We divided the darbepoetin alfa group into low-dose (< 70 microg/month) and high-dose (> or = 70 microg/month) subgroups. The body weight in the high-dose group was higher than that in the low-dose group (66 +/- 11 kg vs. 52 +/- 4.4 kg, p < 0.01).. Both darbepoetin alfa and r-HuEPO safely maintain hemoglobin levels within the target range in peritoneal dialysis patients.

Topics: Adult; Anemia; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Treatment Outcome

Hepcidin is a key regulator of iron metabolism. In this study, we examined whether measurement of hepcidin is useful in assessing recombinant human erythropoietin (rHuEPO) responsiveness in regular hemodialysis (HD) patients in a cross-sectional fashion. We examined the association between serum prohepcidin, a prohormone of hepcidin, and rHuEPO dosage and the rHuEPO/hemoglobin (Hb) ratio in 75 HD patients. We also semiquantatively measured the peak intensity of serum hepcidin-25, the major form of mature hepcidin, in 24 HD patients by using surface-enhanced laser desorption ionization time of flight time mass spectrometry, and compared those between rHuEPO-hyporesponsive (rHuEPO 192 +/- 10 [126-252] IU/kg/week, n = 15) and responsive patients (rHuEPO 40 +/- 9 [0-81] U/kg/week, n = 9). A significant but weak relationship was found between serum prohepcidin and rHuEPO dosage (r = 0.24, p < 0.05) and rHuEPO/Hb ratio (r = 0.22, p = 0.06). However, prohepcidin did not become an indicator of hematopoietic parameters by multiple regression analysis. Serum hepcidin-25 intensity was significantly and positively correlated with ferritin (r = 0.51, p < 0.01) but not with log-transformed C-reactive protein. There was no difference in the intensities of serum hepcidin-25 between rHuEPO-hyporesponsive and responsive patients (64 +/- 10 vs. 52 +/- 16 AU, p = NS). It follows from these findings that the assessment of serum hepcidin using currently available assays was not valid in predicting rHuEPO responsiveness in chronic HD patients.

Topics: Aged; Anemia, Iron-Deficiency; Antimicrobial Cationic Peptides; Biomarkers; Cross-Sectional Studies; Drug Monitoring; Erythropoietin; Female; Ferritins; Hepcidins; Humans; Kidney Failure, Chronic; Male; Protein Precursors; Recombinant Proteins; Renal Dialysis; Reproducibility of Results

This Phase III study examined the efficacy and safety of C.E.R.A., a continuous erythropoietin receptor activator, given once every 2 weeks (Q2W) via subcutaneous or intravenous injection using pre-filled syringes, for maintaining hemoglobin (Hb) levels in patients with chronic kidney disease (CKD) on dialysis who converted directly from epoetin therapy.. Patients (n = 336) were randomized 1:1 to continue epoetin at their current dose, route and administration interval (once to three times weekly (QW-TIW)), or receive C.E.R.A. Q2W by the same route as previous epoetin treatment for 36 weeks. Dosage was adjusted to maintain patients' Hb within +/-1.0 g/dl of baseline value and within 10.0-13.5 g/dl. Primary endpoint was mean change in Hb between baseline and the evaluation period (weeks 29-36).. Mean change in Hb for C.E.R.A. and epoetin was 0.088 and -0.030 g/dl, respectively (endpoint Hb 11.93 and 11.86 g/dl, respectively). Analysis showed that C.E.R.A. was as effective as epoetin in maintaining Hb (p < 0.0001), and was well tolerated. The administration route had no impact on primary endpoint.. Q2W C.E.R.A. administered using pre-filled syringes effectively maintains stable control of Hb in patients on dialysis who convert directly from epoetin QW-TIW.

Topics: Adult; Aged; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis; Syringes; Treatment Outcome

In hemodialysis patients, the hematological response to erythropoietin (epo) is variable and clinical factors that explain this variability are incompletely understood. We tested the hypothesis that the variability in hemoglobin (Hgb) response (epo sensitivity) is determined by key nutritional, inflammation, and oxidative stress markers.. Eighty-two consecutive patients on hemodialysis had 3 consecutive monthly predialysis evaluations of Hgb, total white blood cell (WBC) count, serum albumin, malondialdehyde (MDA), and monocyte chemoattractant protein-1 (MCP1). We analyzed the time course of Hgb in relationship to serum albumin, WBC, MDA, MCP1, epo and iron administration, and tests of iron sufficiency in a linear growth curve model.. Subjects with higher Hgb had a fall in Hgb and vice versa, regressing to a mean Hgb (SD) of 11.8 g/dl (1.8 g/dl). Whereas the average slope of Hgb was flat, the SD of slopes was 0.63 g/dl, which explained 39% of the variance in Hgb. Nonuse of epo was associated with a mean Hgb change of -0.18 g/dl (95% confidence interval [CI] -0.26 to -0.10) per 10,000 IU epo/mo (P < 0.05). Epo use was associated with steeper rate of change at 0.04 g/dl per mo per 10,000 IU (95% CI 0.01 to 0.07) (P < 0.01). Hgb at baseline was 0.73 g/dl higher for each 1-g/dl increase in albumin, and the rate of change increased by 0.49 g/dl per mo for each 1-g/dl increase in albumin concentration. WBC, MDA, or MCP1 had no role in predicting the baseline Hgb or its change over time.. Serum albumin concentration is an important predictor of both baseline Hgb and epo sensitivity in chronic hemodialysis patients. Factors that improve serum albumin may also improve Hgb in hemodialysis patients.

Topics: Adult; Aged; Anemia; Biomarkers; Chemokine CCL2; Erythropoietin; Female; Hemoglobins; Humans; Inflammation; Kidney Failure, Chronic; Leukocyte Count; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Predictive Value of Tests; Prospective Studies; Renal Dialysis; Serum Albumin; Treatment Outcome

It is not clear whether the correction of anemia with erythropoietin (rhuEpo) in patients with chronic kidney disease (CKD) has any benefit on cardiac function and geometry. Most studies are based on indices of systolic function and left ventricular mass (LVM) and the results are conflicting.. We sought to investigate the effect of rhuEpo on LV systolic and diastolic performance using conventional and novel echocardiographic indices. Thirty one patients with CKD (stage 3 or 4) were included. Fifteen patients (group I) treated with rhuEpo targeting at Hb >or=13.0 g/dL, while the remaining (group II) were not treated. Clinical and laboratory parameters were recorded at baseline and 1 year later. Ejection fraction (EF) and LVM were carefully determined. Diastolic function was assessed by mitral inflow indices (E and A wave velocities, Edt deceleration time and E/A) and novel indices of mitral annulus motion using Tissue Doppler Imaging (Em, Am, and E/Em). An index of global cardiac function (Tei) was also calculated.. At baseline, the 2 groups had comparable clinical and laboratory characteristics. After 1 year, a significant improvement in Hb levels (13.6 +/- 1.2 vs 10.3 +/- 1.2 g/dL, p < 0.05) as well as in systolic and diastolic function indexes was observed in group I compared to group II patients: EF (70.5 +/- 7.6 vs 63.4 +/- 9.3%, p < 0.05), LVM (116.5 +/- 34.9 vs 155.6 +/- 51.6 g/m(2), p < 0.05), Edt (233.9 +/- 98.6 vs 166.9 +/- 45.1 ms, p < 0.05), Tei index (0.35 +/- 0.12 vs 0.51 +/- 0.17, p < 0.01) and E/Em (9.7 +/- 2.4 vs 14.8 +/- 5.2, p < 0.05), respectively. Blood pressure and heart rate did not show significant changes.. Correction of anemia with rhuEpo in patients with CKD seems to improve cardiac performance and geometry.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Blood Pressure; Echocardiography, Doppler; Erythropoietin; Female; Follow-Up Studies; Heart Rate; Hematinics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Ventricular Function, Left

Confounding-by-indication is a bias in nonexperimental studies that occurs when outcomes are compared for treated and untreated patients and the treatment or medication dose is related to predictors of the outcome. Two recent publications reported that greater epoetin alfa (EPO) doses were associated with increased mortality rates. We assessed whether confounding-by-indication might account for these results.. We used a retrospective cohort study design.. Hemodialysis patients were randomly selected from a large dialysis organization from July 2000 to June 2002 and were required to have completed a 9-month baseline period.. EPO dose assessed during months 7 to 9 of the baseline period and monthly throughout the follow-up period. Hemoglobin (Hb) was assessed as average value during months 4 to 6 of the baseline period and monthly throughout the follow-up period. All other covariates were assessed during months 1 to 6 of the baseline period.. All-cause mortality during the 1 year of follow-up. Baseline Cox models were fitted with log EPO and Hb with and without adjustment for baseline patient characteristics. Time-dependent models were fitted with time-varying log EPO and Hb and, separately, lagged log EPO and Hb, with adjustment for baseline patient characteristics.. 22,955 patients met our inclusion criteria. In the unadjusted model, we observed increased mortality risk with increasing EPO dose (hazard ratio [HR], 1.31 per log unit increase; 95% confidence interval [CI], 1.26 to 1.36). Adjustment for baseline patient characteristics resulted in an appreciably decreased HR (HR, 1.21; 95% CI, 1.15 to 1.28). In the lagged time-dependent analyses, estimates ranged from HR of 0.93 (95% CI, 0.92 to 0.95) to HR of 1.01 (95% CI, 0.99 to 1.03) for the 1- and 2-month lagged models, respectively.. This analysis was limited to prevalent hemodialysis patients, and inhospital EPO dosing information was unavailable.. The observed mortality risk estimates associated with EPO dose in nonexperimental studies in dialysis patients may be highly sensitive to the analytic method used. This highlights the complexity of evaluating the association between EPO dose, Hb level, and mortality in these studies.

Topics: Adult; Aged; Cohort Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Retrospective Studies

To evaluate the therapeutic efficacy and safety of epoetin zeta, compared with epoetin alfa, in maintaining target haemoglobin (Hb) concentrations in patients with anaemia and chronic kidney disease (CKD) maintained on haemodialysis.. Patients received epoetin zeta or epoetin alfa intravenously, 1-3 times/week for 12 weeks, then the alternative treatment for 12 weeks, in this double-blind, crossover, phase III trial. Eligible patients were 18-75 years old with CKD stage 5 maintained on haemodialysis. Patients had received epoetin for > or = 3 months upon study entry and had achieved a target Hb level of 10.5-12.5 g/dL with a stable epoetin dose.. Primary efficacy endpoints were intra-individual differences (test-reference) in mean Hb levels and mean weekly dose/kg of body weight. Safety endpoints included occurrence of neutralizing anti-erythro poietin antibodies, tolerability, and adverse events (AEs).. In total, 313 patients were randomized to receive epoetin zeta (n = 155) or epoetin alfa (n = 158); 146 and 145 patients (respectively) switched treatment after 12 weeks. Mean (range) Hb levels were 11.35 (8.96-14.22) g/dL and 11.54 (8.74-13.84) g/dL for patients receiving epoetin zeta and epoetin alfa, respectively (95% confidence interval [CI] [test-reference]: 0.09-0.28 g/dL, within the predefined equivalence range of +/-0.6 g/dL). Mean (range) weekly doses were 92.68 (12.74-398.41) IU/kg/wk and 92.58 (10.53-393.07) IU/kg/wk for patients receiving epoetin zeta and epoetin alfa, respectively (95% CI [test-reference]: -4.67 and 4.29 IU/kg/wk, within the equivalence range of +/-45.00 IU/kg/wk). Patients underwent minor nominal dose adjustments during treatment crossover. AE profile was similar for both products; the most commonly reported AEs were infections and infestations (in 26.5% of patients receiving epoetin zeta and 23.6% receiving epoetin alfa). No patients developed neutralizing anti-erythropoietin antibodies.. Epoetin zeta is therapeutically equivalent to epoetin alfa in the maintenance of target Hb levels in patients with renal anaemia. No unexpected AEs were seen.

Topics: Adult; Aged; Anemia; Cross-Over Studies; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Therapeutic Equivalency

Renal anemia is one of the commonest complications of chronic renal failure. Iron deficiency is the most common factor which affects the efficacy of recombinant human erythropoietin (EPO) therapy. Intravenous (i.v.) iron preparations are commonly used in Western countries, but iron sucrose is seldom used in Chinese patients on maintenance hemodialysis. The aim of the present study was to explore the safety and efficacy of i.v. iron sucrose in Chinese patients on maintenance hemodialysis and to explore the optimal administration frequency.. One hundred and thirty-six patients on maintenance hemodialysis were involved in this randomized, controlled, parallel-group, single-center trial. Seventy patients received i.v. iron sucrose (Venofer(R), delivering 100 mg iron) twice a week for 8 weeks, then once a week for another 4 weeks. The other 66 patients received oral (p.o.) ferrous succinate 200 mg t.i.d. for 12 weeks. Levels of serum ferritin (SF), transferrin saturation (TSAT), hemoglobin (Hb) and hematocrit (Hct) were assessed at baseline and then again after 4, 8 and 12 weeks of treatment.. There were no differences between i.v. and p.o. groups in terms of sex, age, duration of hemodialysis, dialysis frequency per week, EPO dosage per week, the level of intact parathyroid hormone, serum creatinine, blood urea nitrogen, or hematological parameters at baseline. After 8 and 12 weeks of treatment, mean Hb concentration and Hct were significantly increased in the i.v. group, and were also significantly higher than those in the p.o. group. Levels of SF and TSAT were also significantly increased in the i.v. group, and significantly higher than in the p.o. group. After 8 weeks, the response rate in the i.v. group was 88.6%, which was significantly higher than that in the p.o. group. The mean EPO dose was significantly lower in the i.v. group than the p.o. group. Hb, Hct, SF and TSAT levels were maintained between 8 and 12 weeks in the i.v. group despite the decrease in dose frequency. There were no adverse events related to i.v. iron administration. Twenty-two patients in the p.o. group had adverse gastrointestinal effects. After 12 weeks, the cost of EPO + i.v. iron was significantly higher than the cost of EPO + p.o. iron.. Intravenous iron sucrose can effectively increase serum iron parameters and Hb levels in Chinese patients on maintenance hemodialysis and is well tolerated. Infusion of i.v. iron sucrose 100 mg per week can maintain serum iron parameters and Hb levels in Chinese patients on maintenance hemodialysis and can permit reductions in the required dose of EPO. However, the total cost of i.v. iron is relatively high.

Topics: Adult; Aged; Anemia; China; Drug Therapy, Combination; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferrous Compounds; Glucaric Acid; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Treatment Outcome

The Dialysis Patients Response to IV Iron with Elevated Ferritin (DRIVE) study demonstrated the efficacy of intravenous ferric gluconate to improve hemoglobin levels in anemic hemodialysis patients who were receiving adequate epoetin doses and who had ferritin levels between 500 and 1200 ng/ml and transferrin saturation (TSAT) < or = 25%. The DRIVE-II study reported here was a 6-wk observational extension designed to investigate how ferric gluconate impacted epoetin dosage after DRIVE. During DRIVE-II, treating nephrologists and anemia managers adjusted doses of epoetin and intravenous iron as clinically indicated. By the end of observation, patients in the ferric gluconate group required significantly less epoetin than their DRIVE dose (mean change of -7527 +/- 18,021 IU/wk, P = 0.003), whereas the epoetin dose essentially did not change for patients in the control group (mean change of 649 +/- 19,987 IU/wk, P = 0.809). Mean hemoglobin, TSAT, and serum ferritin levels remained higher in the ferric gluconate group than in the control group (P = 0.062, P < 0.001, and P = 0.014, respectively). Over the entire 12-wk study period (DRIVE plus DRIVE-II), the control group experienced significantly more serious adverse events than the ferric gluconate group (incidence rate ratio = 1.73, P = 0.041). In conclusion, ferric gluconate maintains hemoglobin and allows lower epoetin doses in anemic hemodialysis patients with low TSAT and ferritin levels up to 1200 ng/ml.

Topics: Adult; Aged; Anemia; Drug Interactions; Drug Therapy, Combination; Erythropoietin; Female; Ferric Compounds; Ferritins; Hematinics; Hemoglobins; Humans; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Transferrin

Darbepoetin alfa (KRN321) is a novel molecule that stimulates erythropoiesis by the same mechanism as endogenous erythropoietin. Due to its longer half-life and greater biological activity than recombinant human erythropoietin (rHuEPO), KRN321 maintains an effective hemoglobin (Hb) level at extended dose intervals compared with rHuEPO. This multicenter, open-label, single-arm study of 72 patients with end stage renal failure on peritoneal dialysis (PD) evaluated the efficacy and safety of KRN321 administered intravenously with the dosing intervals extended to monthly. PD patients that were either rHuEPO-naïve or rHuEPO-receiving were enrolled. In rHuEPO-naïve patients, the initial dose of KRN321 was 40 mug weekly by intravenous administration. For rHuEPO-receiving patients, an initial regimen of fortnightly intravenous administration was given and the initial dose was based on the dose of rHuEPO used before switching to KRN321. After starting the study medication, the Hb concentration was maintained between 10.0 g/dL and 13.0 g/dL. In those patients whose Hb concentrations showed a stable time-course, the dosing intervals of KRN321 were extended. The results suggest that it may be feasible to reduce the frequency of treatment to a monthly schedule, with an associated adjustment of dose, in most patients. Adverse events were observed in 67 of the 72 patients (93.1%, 267 events). Most of all the adverse events were reported in patients with chronic renal failure receiving conventional rHuEPO. No safety problems specific to KRN321 were noted. These results suggest that KRN321 could reduce of frequency of hospital visits for PD patients receiving erythropoietic therapy for renal anemia.

Topics: Adult; Aged; Aged, 80 and over; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Recombinant Proteins

Short-acting hematopoietic agents can improve the quality of life (QOL) of hemodialysis patients, but questions remain regarding the domains of QOL affected, the relative importance of initial and final hemoglobin (Hb) concentrations, and the use of long-acting hematopoietic agents. We measured Hb concentrations and QOL in 487 hemodialysis patients who were switched from treatment with recombinant human erythropoietin to treatment with darbepoetin alfa. QOL was measured with the Japanese-language version of the SF-36, at the start of therapy with darbepoetin alfa and again 7-14 weeks later. We examined changes in QOL over time in the group as a whole, and in subgroups stratified by the change in Hb concentration. We also studied relationships between the final Hb concentration achieved and the magnitude of change in QOL. QOL scores increased significantly in all SF-36 domains except Social Functioning. The greatest increases were in vitality and in the two role-functioning domains. The magnitude of the increase in Hb concentration was related to the magnitude of the increase in QOL for only one subscale: Vitality. Patients with higher final Hb concentrations also had greater increases in Vitality scores. Hematopoiesis induced by darbepoetin alfa is associated with increased vitality and may also be associated with improved role functioning. Vitality increased significantly only in those patients with the greatest increases in Hb concentration and in those with higher final Hb concentrations.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Erythropoietin; Female; Health Surveys; Hematinics; Hemoglobins; Humans; Japan; Kidney Failure, Chronic; Male; Middle Aged; Psychometrics; Quality of Life; Renal Dialysis; Time Factors

Anemia of chronic kidney disease (CKD) decreases patients' health-related quality of life (HRQoL). The objective of this subanalysis was to determine the effect of every-other-week (Q2W) darbepoetin alfa on hemoglobin (Hb) levels and HRQoL measures in subjects with CKD who are naïve to erythropoiesis-stimulating agents (ESAs).. STAAR was a 52-week, multicenter, single-arm study. Subject inclusion criteria included: > or = 18 years of age and creatinine clearance < or = 70 mL/min or estimated glomerular filtration rate < or = 60 mL/min/1.73 m(2) but not receiving dialysis. Subjects included in this subanalysis were previously naïve to ESAs, had Hb < 11 g/dL, were initiated on subcutaneous Q2W darbepoetin alfa to achieve a Hb level not to exceed 12 g/dL, and had responses to at least one question on the KDQOL-CRI forms administered at baseline, week 12, and week 52.. Of 911 ESA-naïve subjects enrolled in the study, 277 (30.4%) were included in this subanalysis. The majority of subanalysis subjects were Caucasian (63.2%) and/or women (54.5%). Mean Hb concentrations and all KDQOL-CRI scores improved significantly between baseline and week 12 (p < 0.0001), and were maintained until week 52. Darbepoetin alfa was well tolerated.. Darbepoetin alfa initiated Q2W achieved and maintained Hb targets, and significantly improved and maintained HRQoL in study subjects with CKD. Limitations of the study must be considered when extrapolating these results to assess the benefits of treatment on HRQoL in the general CKD population.

Topics: Aged; Anemia; Creatinine; Darbepoetin alfa; Erythropoietin; Female; Glomerular Filtration Rate; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Quality of Life; Renal Dialysis

To assess the therapeutic equivalence of epoetin zeta and epoetin alpha for correction of haemoglobin (Hb) concentration in patients with anaemia and chronic kidney disease (CKD) stage 5 maintained on haemodialysis.. In total, 609 patients with CKD and anaemia (Hb < 9 g/dL) were randomly assigned to receive either epoetin zeta or epoetin alpha intravenously, one to three times per week for 24 weeks. Dosing was titrated individually to achieve a stable, target Hb concentration of 11-12 g/dL. Primary endpoints were the mean weekly dose of epoetin per kilogram of body weight and mean Hb concentration during the last 4 weeks of treatment. Safety endpoints were the occurrence of anti-erythropoietin antibodies, ratings of tolerability and adverse events (AEs).. Mean (+/- standard deviation [SD]) Hb concentration over the last 4 weeks of treatment was 11.61 +/- 1.27 g/dL for patients receiving epoetin zeta, compared with 11.63 +/- 1.37 g/dL for patients receiving epoetin alpha (95% confidence interval [CI]: -0.25 to 0.20 g/dL). Mean (+/- SD) epoetin zeta weekly dose over the last 4 weeks of treatment was 182.20 +/- 118.11 IU/kg/wk, compared with 166.14 +/- 109.85 IU/kg/wk for epoetin alpha (95% CI: -3.21 to 35.34 IU/kg/wk). The most commonly reported AEs (> 5% of patients) were infections and infestations (12.5% and 12.8% of patients treated with epoetin zeta and epoetin alpha, respectively) and vascular disorders (8.5% and 8.9%, respectively). No patients developed neutralizing anti-erythropoietin antibodies.. Epoetin zeta, administered intravenously, is therapeutically equivalent to epoetin alpha in the correction of low Hb concentration in patients with CKD undergoing haemodialysis. No unexpected AEs were seen and both epoetin zeta and epoetin alpha were well tolerated.

Topics: Adolescent; Adult; Aged; Anemia; Confidence Intervals; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Risk Assessment; Severity of Illness Index; Therapeutic Equivalency; Treatment Outcome

In patients with chronic renal failure, the ability to reduce the administration frequency of subcutaneous (SC) erythropoietin (epoetin) could provide benefits and may improve compliance. The study investigated whether once-weekly SC epoetin alfa was equivalent to twice- or thrice-weekly SC administration in maintaining anaemia correction in haemodialysis patients.. Eighty-three patients were randomly assigned to either once-weekly epoetin alfa (n = 44) or their original dose twice- or thrice-weekly regimen (control, n = 39) for 12 weeks. The haemoglobin concentration was maintained within the target range of 9.0-12.0 g/dL by adjusting the dose of epoetin alfa. All patients received intravenous iron supplementation, as required.. Stable haemoglobin levels were maintained without epoetin dose increases in the majority of patients in both groups (once-weekly group, 95.0%, control group, 91.4%). The mean haemoglobin levels at randomization at weeks 4, 8 and 12 were 10.7, 11.1, 11.3 and 11.0 g/dL, respectively, in the once-weekly group, and 10.5, 11.3, 11.5 and 11.3 g/dL, respectively, in the control group. The mean weekly dose of epoetin alfa at randomization at weeks 4, 8 and 12 was 142.8, 114.5, 108.6 and 104.5 IU/kg, respectively, in the once-weekly group, and 128.4, 116.0, 101.0 and 96.1 IU/kg/week, respectively, in the control group. No statistically significant between-group differences were apparent for changes in haemoglobin levels or epoetin alfa dosages at week 12.. This study demonstrates that once-weekly SC administration of epoetin alfa is as effective and safe as two or three times weekly administration in maintaining haemoglobin levels. Therefore, the once-weekly therapy using high dose of epoetin alfa is considered to be an efficient method in stable haemodialysis patients.

Topics: Aged; Anemia; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

This multicentre, open-label prospective, randomized, comparative-group study evaluated the effects of maintaining haemoglobin (Hb) in pre-dialysis chronic kidney disease (CKD) patients.. A total of 197 patients were randomized to start subcutaneous epoetin-alpha (SC-EPO; EPREX; 1000 U twice weekly) at an early stage of anaemia to maintain Hb at 11.0 +/- 1.0 g/dl (group A, n = 65), or to allow Hb to fall to < or =9.0 g/dl before starting SC-EPO (group B, n = 132) (2000 U three times weekly); and subsequently maintaining Hb at 11.0 +/- 1.0 g/dl.. Of 132 patients randomized to group B, 55 progressed to treatment (-trigger). The study was prematurely terminated due to contraindication of the subcutaneous administration route. Mean weekly EPO doses at 1 year were 1471 U for group A; 820 U for group B; final doses were 2281 U for group A; 2099 U for group B. There was no significant difference between groups A and B with regard to left ventricular mass (-12.5 vs -9.7%; P = 0.82). In groups A and B, 48% and 52%, respectively, terminated the study because of dialysis/death, after a median of 36.3 and 27.3 months, respectively.. Early intervention to correct anaemia in CKD patients did not have a significant impact on LVM, the primary efficacy variable. Time to dialysis/death was not significantly different between groups A and B.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Time Factors; Treatment Outcome

The required erythropoiesis-stimulating agent (ESA) dose varies when correcting anaemia in chronic kidney disease (CKD) patients. This analysis was performed to identify the prevalence of and factors associated with ESA hyporesponsiveness.. This analysis was a post hoc evaluation of epoetin alfa dosage requirements in a subgroup of patients from the Effect of early Correction of Anemia on the Progression of CKD study. The patients in this subgroup were randomly assigned to the high haemoglobin target group (14-15 g/dl for men and 13-14 g/dl for women) and completed a 4-month haemoglobin stabilization phase with complete epoetin dosage data. The relationship of demographics, disease characteristics and laboratory measures with epoetin dosage were evaluated using Pearson's correlation, association measures and analysis of covariance (ANCOVA) models.. Of the 93 patients evaluated in this subgroup analysis, 14 (15%) were hyporesponsive to epoetin (maximum dosage >100 IU/kg/week during stabilization). An ANCOVA analysis showed that 52% of the observed variability in epoetin dosage at completion of the stabilization phase could be accounted for by diabetes as the primary cause of kidney disease, angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) use, proteinuria, transferrin saturation, age, pre-treatment haemoglobin, geographical region, serum iron and body mass index (BMI). Unidentified patient characteristics accounted for an additional 16% of the dosage variance.. Older age, higher BMI, anaemia, ACE inhibitor/ARB use and diabetes as the primary cause of kidney disease are associated with increased epoetin requirements when normalizing haemoglobin in anaemic CKD patients.

Topics: Adolescent; Adult; Aged; Anemia; Australia; Canada; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Europe; Female; Follow-Up Studies; Glomerular Filtration Rate; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Treatment Outcome

Darbepoetin alpha (DA) is a unique long-acting treatment for anaemia in patients with chronic renal failure (CRF). This study assessed the mean dose of DA to achieve and maintain haemoglobin (Hb) levels between 11 g/dl and 13 g/dl in CRF children aged 11 years to 18 years. This observational, prospective study was conducted in 39 patients treated with DA. Twenty-nine patients were switched from recombinant human erythropoietin (r-HuEPO), and ten patients were naive to r-HuEPO. Naive patients received initial doses of 0.45 microg/kg of DA. Switched patients received a dose adjusted to the prior dose of r-HuEPO (200 IU r-HuEPO:1 microg DA). Among the switched patients, 79.3% received dialysis. No naive patients underwent dialysis. Overall, 74% of patients showed increased Hb level, with a mean value of 11.6 +/- 1.6 g/dl, using a mean DA dose of 0.63 +/- 0.48 microg/kg per week, and 66.7% patients reached the target Hb level. Hb increased in naive patients from 9.5 (95% CI: 7.7, 11.4) to 11.7 (95% CI: 10.9, 12.6) g/dl and in switched patients from 11.1 (95% CI: 10.6, 11.5) to 11.5 (95% CI: 10.8, 12.2) g/dl). Higher doses of DA were needed in the "switched" than in the "naive" patients to maintain Hb levels over 11 g/dl, respectively 0.73 (95% CI: 0.54, 0.92) and 0.34 (95% CI: 0.16, 0.52) microg/kg per week. Our results indicate the doses of DA necessary to treat CRF patients aged 11 years to 18 years. DA was an effective treatment to stabilise CRF patients at extended dosing intervals.

Topics: Adolescent; Anemia; Child; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Ferritins; Hematinics; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Peritoneal Dialysis; Prospective Studies; Renal Dialysis; Safety

The percentage of hypochromic red blood cells (RBCs) (%HYPO) has been demonstrated as the best predictor of response to iron loading in haemodialysis patients treated with recombinant human erythropoietin (rHuEPO). However, we have previously shown that this parameter is positively influenced by erythropoietic activity since reticulocytes are considered hypochromic by cell counters. New cell counters are able to determine cell volume and haemoglobin (Hb) concentration separately on reticulocytes and mature erythrocytes. The aim of this study was to assess the sensitivity and specificity of mature erythrocyte parameters in detecting functional iron deficiency (FID).. A total of 32 stable chronic haemodialysis patients in the maintenance phase of rHuEPO therapy were included. Classical parameters of iron monitoring and mature erythrocyte parameters were measured after a 4-week iron-free period. Patients were classified as responders (R) or non-responders (NR) to an iron load of 100 mg iron sucrose at each dialysis session for 4 weeks, according to whether their Hb increased by >1 g/dl at the end of iron loading.. Twelve patients were identified as responders. Receiver operating characteristic (ROC) curve analysis demonstrated %HYPO and its corresponding parameter on mature erythrocyte, %HYPOm, as the best predictors of FID. The other parameters were ordered as follows: tranferrin saturation (TSAT), ferritin (FRT), mature RBC Hb content (CHm), mean corpuscular Hb concentration (MCHC), percentage of mature erythrocytes with a low CHm (%lowCHm), mean content in Hb (MCH) and reticulocyte Hb content CHr. Comparing the parameters at different cut-offs, the best sensitivity, specificity and efficiency were demonstrated for %HYPOm> 6%.. The best efficiency to predict FID was found for %HYPOm> 6%. The predictive value of %HYPO was quite similar. The clinical impact of %HYPOm in iron monitoring should also be tested in the induction phase of rHuEPO treatment because of its independence from erythropoietic activity.

Topics: Aged; Aged, 80 and over; Anemia, Hypochromic; Anemia, Iron-Deficiency; Biomarkers; Erythrocyte Count; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Predictive Value of Tests; Renal Dialysis; Sensitivity and Specificity

Iron supplementation is a mainstay for management of renal anaemia in patients receiving haemodialysis (HD). Although it is well known that a single intravenous iron (IVIR) administration transiently enhances oxidative stress in HD patients, the consequence of repeated IVIR administration is still unknown. This study aims to clarify the time course of changes in serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of DNA oxidative injury, during a period of repeated IVIR administration in HD patients.. Twenty-seven patients (62+/-14 years and 23 males) on long-term HD participated in this study. All patients had been on HD more than 6 months and none had received a blood transfusion or iron therapy in previous 6 months. The patients were divided into three groups according to the baseline haematocrit (Ht) and serum ferritin (FTN) levels as a marker of body iron stores: IVIR group (Ht<30% and FTN<100 ng/ml; n=7); High FTN group (Ht>or=30% and FTN>or=100 ng/ml; n=11); and low FTN group (Ht>or=30% and FTN<100 ng/ml; n=9). The IVIR group patients received 40 mg of ferric saccharate i.v. after each HD session until Ht increased by 5%. Serum 8-OHdG and other parameters were prospectively monitored for 10 weeks.. At baseline, the serum ferritin level was independently associated with 8-OHdG in a multiple regression model (total adjusted R2=0.47, P<0.01). All patients in the IVIR group achieved the target Ht level during the study. IVIR administration resulted in significant increases in 8-OHdG levels (0.22+/-0.07-0.50+/-0.16 ng/ml: baseline to 10 week) as compared with both the high FTN group (0.52+/-0.20-0.58+/-0.28 ng/ml) and the low FTN group (0.39+/-0.11-0.36+/-0.11 ng/ml) (ANOVA for repeated measures P<0.01). Additionally, serum 8-OHdG and serum ferritin changed in the same manner.. Repeated IVIR administration for HD patients was associated with signs of increased oxidative DNA injury, as reflected by increased serum levels of 8-OHdG. As these changes were accompanied by increased serum ferritin levels, excess body iron stores might play an important role in oxidative stress.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Anemia, Iron-Deficiency; Deoxyguanosine; DNA Damage; Dose-Response Relationship, Drug; Erythropoietin; Female; Ferritins; Hematocrit; Humans; Infusions, Intravenous; Iron; Kidney Failure, Chronic; Male; Middle Aged; Oxidative Stress; Prospective Studies; Recombinant Proteins; Regression Analysis; Renal Dialysis

To investigate the effects of angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARBs) and other anti-hypertensive agents on recombinant human erythropoietin (rHuEPO) in chronic renal failure (CRF) patients.. The present study was conducted at the Nephrology Department, Khan Research Laboratories Hospital and Quaid-i-Azam University, Islamabad, Pakistan during March 2004 to February 2005. One hundred patients, 55 males and 45 females (age range 13-78 years) were divided into 2 groups. Group-I patients received rHuEPO and ACE inhibitors/ARBs while Group-II patients received rHuEPO with other antihypertensives such as calcium channel blockers or beta-adrenergic receptor blockers. Monthly increment in hematocrit (HCT%) was monitored in both groups for 4 continuous months. One-way ANOVA on Dunn's, univariate and multivariate analyses were carried out to determine any significant improvement in erythropoiesis between the 2 treatment groups.. Monthly increase in HCT% was significantly greater in the group that was treated with rHuEPO and antihypertensives other than ACE inhibitors/ARBs compared with that treated with ACE inhibitors/ARBs, an effect observed even at a higher dose of rHuEPO, and the patients were iron replete.. The present data from our population confirms that ACE inhibitors/ARBs interfere with rHuEPO therapy for treatment of anemia in CRF. The ACE inhibitors/ARBs inhibit erythropoiesis induced by rHuEPO in CRF patients, therefore, simultaneous use of ACE inhibitors/ARBs and rHuEPO should be carried out with caution.

Topics: Adolescent; Adult; Aged; Analysis of Variance; Anemia; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Erythropoiesis; Erythropoietin; Female; Follow-Up Studies; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Multivariate Analysis; Probability; Recombinant Proteins; Renal Dialysis; Risk Assessment; Treatment Outcome

To evaluate the efficacy of once-monthly darbepoetin alfa in maintaining hemoglobin (Hb) levels between 10 and 12 g/dL in older subjects receiving darbepoetin alfa every 2 weeks.. A secondary analysis of a 29-week multicenter, open-label, single-arm study with an initial 2-week screening/baseline period, followed by a 20-week once-monthly darbepoetin alfa dose titration period and an 8-week evaluation period.. Twenty treatment centers in the United States.. Subjects with CKD who were not receiving dialysis and whose hemoglobin levels were > or =10 g/dL with darbepoetin alfa every 2 weeks.. Darbepoetin alfa administered once monthly and titrated to maintain Hb level between 10 and 12 g/dL, inclusive.. The proportion of subjects maintaining a mean Hb concentration of 10 to 12 g/dL, inclusive, while receiving once-monthly darbepoetin alfa during the evaluation period (weeks 21 to 29); the mean change in Hb levels and darbepoetin alfa doses between baseline and the evaluation period; and the treatment relationship, frequency, severity, and outcomes of all adverse events. Analyses were stratified by age (<65, > or =65, and > or =75 years).. Seventy-nine percent of subjects aged > or =65 years and 80% of subjects aged > or =75 years maintained their Hb levels within the specified target range, compared with 80% of subjects aged <65 years who maintained their Hb levels within the specified target range. Hemoglobin levels and darbepoetin alfa doses did not change significantly from baseline to the evaluation period. Darbepoetin alfa administered once monthly was well tolerated in all age groups.. Darbepoetin alfa administered once monthly effectively maintained target Hb levels in older subjects with CKD (not receiving dialysis) who were maintained previously with an every 2 weeks darbepoetin alfa regimen.

Topics: Age Factors; Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Drug Administration Schedule; Drug Monitoring; Erythropoietin; Female; Geriatrics; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Mass Screening; Middle Aged; Safety; Severity of Illness Index; Treatment Outcome; United States

1. Patients with advanced chronic renal disease and anaemia have decreased serum paraoxonase-1 (PON1) activity and an increased degree of oxidative stress compared with normal subjects. The present study investigated the effects of treatment of anaemia with exogenous recombinant erythropoietin (EPO) beta and iron on levels of antibodies against oxidized low-density lipoproteins (ox-LDL), as well as on serum PON1 activity and concentration, in predialysis patients with chronic renal disease. 2. Forty-nine patients with chronic renal failure and haemoglobin (Hb) < 11 g/dL were treated over a period of 6 months with EPObeta (80-120 U/kg per week, s.c.) and variable doses of iron. Selected biochemical variables were determined before and after treatment. 3. Treatment with EPObeta and iron was associated with a significant increase in mean (+/-SD) blood Hb concentration compared with pretreatment values (12.8 +/- 1.5 vs 9.9 +/- 0.6 g/dL, respectively; P < 0.001). The average dose of EPObeta was 6160 +/- 3000 U/week. After 6 months of treatment, compared with pretreatment values, the median levels (95% confidence intervals) of antibodies against ox-LDL were decreased (17.5 (10.6-24.4) vs 24.8 (11.5-38.1) U/mL, respectively; P < 0.001), serum PON1 activity was slightly but significantly increased (123.6 (76.1-343.6) vs 101.0 (50.0-332.5) U/L, respectively; P = 0.016) and the concentration of PON1 was significantly decreased (37.3 (11.8-76.2) vs 46.7 (24.6-98.0) mg/L, respectively; P < 0.001). There were no significant changes in total cholesterol, triglycerides or cholesterol fraction concentrations before and after treatment. 4. We suggest that EPObeta and iron treatment of anaemia promotes significant changes in serum PON1 activity and concentration and has a beneficial effect on oxidative stress in predialysis patients with chronic renal disease.

Topics: Aged; Anemia; Antibodies; Aryldialkylphosphatase; Dose-Response Relationship, Drug; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Lipid Peroxidation; Lipoproteins, LDL; Male; Middle Aged; Oxidative Stress; Recombinant Proteins; Renal Dialysis; Treatment Outcome

The residual uraemic syndrome that is inadequately cleared by diffusion is thought to contribute to the poor outcome of maintenance dialysis patients. Haemodiafiltration combines diffusion and convection in a single therapy, conferring theoretical benefits over haemodialysis. However, only few randomised comparisons have been carried out.. The prospective crossover clinical evaluation of high-flux ultrapure haemodialysis and online haemodiafiltration included 76 clinically stable patients on low-flux conventional bicarbonate buffered haemodialysis. They were randomized to high-flux haemodialysis or online haemodiafiltration (24 months) and switched to the alternative treatment (24 months).. Removal of urea (Kt/V) and phosphate was significantly greater for online haemodiafiltration than for haemodialysis. Both high-flux haemodialysis and haemodiafiltration were associated with sustained reductions of pretreatment beta 2 microglobulin levels, however, the decrease was greater with haemodiafiltration. Both modes of renal replacement therapy significantly improved nutritional status and the haematopoietic response to rHu EPO. Under unmatched conditions (sodium and energy balance) haemodiafiltration was associated with a lower number of hypotensive episodes and partial improvement of quality of life. The incidence of death was low in both groups and did not differ among the two modes of renal replacement therapy.. Online haemodiafiltration is a safe, effective and well tolerated therapy for end-stage renal disease patients even in the long run. Whether the dismal mortality rates of unselected end-stage renal disease patients can be changed by online haemodiafiltration remains to be shown in large scale long-term trials.

Topics: Adult; Aged; Calcium; Cross-Over Studies; Erythropoietin; Female; Hemodiafiltration; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nutritional Status; Phosphates; Prospective Studies; Quality of Life; Renal Dialysis; Statistics, Nonparametric; Surveys and Questionnaires; Treatment Outcome; Urea

Darbepoetin alfa has a longer half-life than epoetin-(EPO) alfa or beta, allowing administration at less frequent intervals for the treatment of renal anemia. The aim of the present analysis was to evaluate the efficacy and tolerability of an every-2-week (Q2W) schedule of darbepoetin alfa in a large cohort of dialysis patients.. Data were combined from eight similarly designed 24-week phase 3b European studies, in which patients receiving EPO alfa or beta once-weekly were converted to Q2W darbepoetin alfa. Darbepoetin alfa dosage was titrated to maintain hemoglobin (Hb) between 10 and 13 g/dl and efficacy was evaluated during a 4-week evaluation period.. In the 1,101 patients assigned to Q2W darbepoetin alfa (i.v., n = 196, s.c., n = 905), mean (SD) Hb levels were 11.53 (0.77) g/dl at baseline and 11.35 (1.04) g/dl at evaluation (mean change in Hb -0.27 g/dl, 95% confidence interval 0.34, -0.20). Hb levels were maintained between 10 and 13 g/dl during evaluation in 85% of patients. Darbepoetin alfa doses were similar at baseline and evaluation, and the i.v. and s.c. routes were associated with similar efficacy and dose requirements. Darbepoetin alfa was well-tolerated.. Q2W darbepoetin alfa is effective in maintaining Hb levels in dialysis patients switched from weekly rHuEPO, regardless of the route of administration and with no notable increase in the weekly equivalent dose.

Topics: Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Routes; Drug Administration Schedule; Erythropoietin; Europe; Female; Follow-Up Studies; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis; Single-Blind Method; Treatment Outcome

Although the general improvement caused by recombinant human erythropoietin (rHuEPO) in the correction of uraemic anaemia cannot be questioned, some data suggest that the changes in the haemostasis, endothelial function and oxidative stress (SOX) are induced. The aim of the present study was to investigate the effect of one-year rHuEPO therapy on the coagulation activation, endothelial injury markers and SOX in haemodialysis (HD) patients.. Assessment of coagulation activation pathway: tissue factor (TF), its inhibitor (TFPI) and prothrombin fragment 1+2 (F1+2); endothelial injury markers: von Willebrand factor antigen (vWF:Ag) and thrombomodulin (TM); and several parameters related to SOX: total peroxide, Cu/Zn superoxide dismutase (Cu/Zn SOD) and autoantibodies to oxidized LDL (OxLDL-Ab) levels were performed in stable HD patients, treated for 12 months with rHuEPO (n=18; mean dose 113.5+/-41 U/kg/week) or not (with Hg<10 g/dl, n=8 and with Hg>10 g/dl, n=12), none of them on iron therapy.. Patients with Hg<10 g/dl had a significantly lower erythrocytes count, Ht and Hg levels than those with Hg>10 g/dl and those on rHuEPO therapy. Long-term rHuEPO therapy does not affect coagulation pathway and SOX markers. Treatment with this hormone resulted in a tendency to decrease TM and vWF:Ag concentrations, however these changes did not reach a statistical significance.. These results suggest that one-year rHuEPO therapy seems to exert no additional influence on coagulation activation, endothelial cell damage/activation markers and oxidative stress in patients undergoing regular HD in the absence of concomitant iron supplementation and irrespective from haemoglobin levels.

Topics: Adult; Aged; Anemia; Biomarkers; Blood Coagulation; Endothelium, Vascular; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Oxidative Stress; Recombinant Proteins; Renal Dialysis; Time Factors; Uremia

Anaemia in diabetes mellitus (DM) and/or chronic renal failure (CRF) may be caused by a decreased production of erythropoietin (EPO), EPO resistance, and by the lysis of the young circulating red blood cells (neocytolysis) induced by subclinical inflammation and low EPO level. Aims of this study were to detect EPO resistance in patients with DM and/or CRF and to prove, that acetylsalicylic acid (ASA) is able to improve the haemopoietic status by decreasing neocytolysis.. In a cross-sectional study, three groups of selected patients (patients with DM; patients with DM+CRF; patients with CRF without DM, n=15 each) and a group of controls (non-diabetic, nonazotemic subjects, n = 10) were compared. In the intervention part of the study, the effect of a single dose of 1 gram ASA on neocytolysis was investigated in a subgroup of these patients.. Despite the similar EPO level (p = 1.000), all three patient groups had lower haemoglobin and haematocrit than control persons (p < 0.05 in all cases). Patients with DM+CRF had lower haemoglobin than patients with DM or CRF alone (p < 0.05). Single dose of ASA induced a fast increase in serum EPO level, a concomitant rise of the Rtc number and rate, red blood cell count, haematocrit and haemoglobin p < 0.01 for each). These changes were accompanied by a marked decrease in serum lactate dehydrogenase activity (p < 0.01).. DM and CRF may induce erythropoietin resistance. In these patients, ASA treatment increases serum EPO level. The higher EPO level and the anti-inflammatory effect of ASA may decrease neocytolysis.

Topics: Aged; Anemia; Aspirin; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Erythropoietin; Female; Hemolysis; Humans; Kidney Failure, Chronic; L-Lactate Dehydrogenase; Male; Middle Aged

This study was designed to assess the potential of the continuous erythropoietin receptor activator (C.E.R.A.) to correct anemia at extended administration intervals in erythropoiesis-stimulating agent-naīve patients with chronic kidney disease (CKD) not on dialysis and to determine its optimal starting dose.. Patients were assigned to subcutaneous C.E.R.A. at 3 doses: 0.15, 0.30 and 0.60 microg/kg/wk. During the first 6 weeks, dose adjustments for efficacy were not permitted in order to assess dose response. Within each of the 3 dose groups, patients were randomized to receive C.E.R.A. QW, Q2W or Q3W; the total dose during the first 6 weeks was the same for a particular dose group across the frequency subgroups. During the next 12 weeks, dose was adjusted according to predefined hemoglobin (Hb) criteria. The primary efficacy parameter was change in Hb over 6 weeks, estimated from regression analysis between baseline and the point at which the patient received a dose change or blood transfusion. It therefore provided an estimate of Hb increase based on starting dose. Other endpoints included Hb response rate (proportion of patients with a Hb increase > 1.0 g/dl on 2 consecutive occasions). A 1-year extension period investigated long term tolerability and efficacy.. A dose-dependent relationship was noted in the mean change in Hb from baseline over 6 weeks (p < 0.0001), independent of administration schedule (p = 0.9201). There was also a significant relationship between Hb change and median serum C.E.R.A. concentration (p < 0.0001). Erythropoietic responses were sustained in all groups with mean changes from baseline in Hb > 1.2 g/dl observed at doses > or = 0.30 microg/kg/wk. Hb response rate increased with increasing dose: 67, 72 and 90% with C.E.R.A. 0.15, 0.30 and 0.60 microg/kg/wk, respectively. Generally, the median Hb response time was faster with increasing dose (89, 43 and 31 days, respectively). Response was unrelated to administration frequency. Stable Hb concentrations were maintained throughout the 1-year extension period. C.E.R.A. was generally well tolerated, and the most common adverse events were hypertension, urinary tract infection and renal failure.. C.E.R.A. corrected anemia and maintained sustained and stable control of Hb over 1 year. These results suggest that 0.60 microg/kg subcutaneous C.E.R.A. given twice monthly is a suitable starting dose for further investigation in Phase III studies in patients with CKD not on dialysis.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Anemia; Area Under Curve; Biomarkers; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Female; Ferritins; Follow-Up Studies; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Regression Analysis; Renal Dialysis; Time Factors; Treatment Outcome

A continuous erythropoietin receptor activator (C.E.R.A.) is currently in development for the treatment of anemia in patients with chronic renal disease (CRD) receiving or not receiving dialysis treatment.. The objectives of this study were to determine the optimal dose and administration schedule for IV C.E.R.A. in patients with CRD previously treated with IV epoetin alfa TIW, and to assess its tolerability profile in these patients. In addition, a 12-month extension phase was used to assess the long-term efficacy and tolerability of C.E.R.A.. This randomized, open-label, dose-finding study was conducted at 14 study centers across the United States. Male and female patients aged >/=18 years with CRD and CRD-related anemia and receiving treatment with IV epoetin alfa were enrolled. After a 2-week run-in period in which all patients continued to receive their previous epoetin treatment TIW, patients were switched to C.E.R.A. at 1 of 3 doses, determined by multiplying the previous weekly epoetin dose by 1 of 3 ratios (0.25 pg/150 IU, 0.4 pg/150 IU, or 0.6 pg/150 IU). Within each dose group, patients were randomized to 1 of 2 frequency subgroups: QW or Q2W Dose adjustments were not permitted during the first 6 weeks; the total dose during this period was the same for a particular dose group across the frequency subgroups. The primary efficacy parameter was change in hemoglobin (Hb) standardized to a 6-week period between baseline and the point when the patient had a dose change or blood transfusion, thus providing an estimate of Hb change based on starting dose. Following completion of a 19-week core period, patients could enter the 12-month extension period, aiming to maintain Hb concentrations between 11 and 12 g/dL. Adverse events (AEs) were recorded in the patients' case-report forms by the investigators throughout the study.. A total of 91 patients entered the core period (mean age, 58 years; 66% male); 10 patients withdrew prematurely during this period (4 owing to AEs and 6 for other reasons). Fifty-three patients continued into the extension period; 22 patients withdrew during this period (6 because of AEs, and 16 for other reasons). There was a significant dose-response effect (P < 0.001) and a significant effect of schedule (P < 0.002) for the primary efficacy end point. Stable Hb concentrations were maintained throughout the study (11-12 g/dL, with a narrow 95% CI). No significant difference between schedules was observed during the extension period, and few dose changes were required (mean, 4 and 2 per patient per year in the QW and Q2W groups, respectively). Nineteen and 22 patients experienced serious AEs during the core and extension periods, respectively, but only 1 event was considered related to study treatment. The most frequent AEs were headache and vomiting during the core study period and dizziness, fatigue, chest pain, and pyrexia during the extension period.. In this study, N C.E.R.A. provided effective maintenance of Hb concentrations in patients receiving dialysis treatment who were switched directly from N epoetin alfa TIW to N C.E.R.A. QW or Q2W C.E.R.A. was generally well tolerated.

Topics: Analysis of Variance; Anemia; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Regression Analysis; Renal Dialysis

To study efficacy and safety of long-term administration of epoetin and iron preparations in glomerulonephritis (GN) patients with chronic kidney disease (CKD) of stage III-IV in systemic diseases.. A total of 189 patients at predialysis stage of CKD (glomerular filtration rate between 15 and 60 ml/min) were randomized into 3 groups depending on GN etiology: primary GN (group 1, 123 patients), GN in systemic diseases (group 2, 45 patients), controls (group 3, 21 patients). Anemia was characterized not only by red cells indices but also by the level of serum ferritin, C-reactive protein (CRP), saturation of transferrin with iron. Remodeling of the heart was determined in all the patients at dopplerechocardiography estimating left ventricular myocardial mass, relative thickness of its wall.. Correction of anemia was achieved in all the patients with GN and CKD of stage III-IV in systemic diseases despite the activity of systemic disease (high blood level of CRP) and persistent nephritis activity (high proteinuria). In many patients from groups 1 and 2 who were initially diagnosed to have left ventricular hypertrophy (LVH) of excentric type LVH regressed after 6 months of anemia correction. In group 3 with untreated anemia frequency of LVH increased.. Treatment of anemia in GN patients with CKD of stage III-IV in systemic diseases needed higher doses of epoetin and parenteral iron preparations compared to patients with the above stages of CKD with primary GN.

Topics: Anemia, Iron-Deficiency; C-Reactive Protein; Disease Progression; Dose-Response Relationship, Drug; Echocardiography, Doppler; Epoetin Alfa; Erythropoietin; Female; Ferritins; Follow-Up Studies; Glomerular Filtration Rate; Hematinics; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Iron; Iron Compounds; Kidney Failure, Chronic; Male; Recombinant Proteins; Severity of Illness Index; Treatment Outcome

Recombinant human erythropoietin (rhEpo) has proved to be remarkably safe and effective for the treatment of anemia. Despite the use of rhEpo, concerns about its cost, the need for frequent parenteral administration, and the development of anti-Epo antibodies have prompted the development of improved agents to rescue anemia. Patients with anemia associated with renal disease are usually treated by intravenous or subcutaneous rhEpo administration; however, some patients do not respond well to rhEpo, because of the presence of Epo antibody or other unknown reasons. A new, orally administered drug is needed as an economical and effective method to treat such patients. We administered 1.3 g/day of L-arginine to 8 elderly patients with anemia associated with renal disease. All 8 patients responded to the treatment with increases in hemoglobin levels. Six of the patients showed improved renal function. There were no significant adverse effects. Our data show that oral administration of 1.3 g/day of L-arginine significantly improves Epo production and reverses anemia without adverse effects in elderly patients who have anemia associated with renal disease and are in the predialysis state of chronic renal failure.

Topics: Aged; Aged, 80 and over; Anemia; Arginine; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Remission Induction; Reticulocyte Count

Morbidity and mortality rates in hemodialysis patients remain excessive. Alterations in the delivery of dialysis may lead to improved patient outcomes.. To compare the effects of frequent nocturnal hemodialysis vs conventional hemodialysis on change in left ventricular mass and health-related quality of life over 6 months.. A 2-group, parallel, randomized controlled trial conducted at 2 Canadian university centers between August 2004 and December 2006. A total of 52 patients undergoing hemodialysis were recruited.. Participants were randomly assigned in a 1:1 ratio to receive nocturnal hemodialysis 6 times weekly or conventional hemodialysis 3 times weekly.. The primary outcome was change in left ventricular mass, as measured by cardiovascular magnetic resonance imaging. The secondary outcomes were patient-reported quality of life, blood pressure, mineral metabolism, and use of medications.. Frequent nocturnal hemodialysis significantly improved the primary outcome (mean left ventricular mass difference between groups, 15.3 g, 95% confidence interval [CI], 1.0 to 29.6 g; P = .04). Frequent nocturnal hemodialysis did not significantly improve quality of life (difference of change in EuroQol 5-D index from baseline, 0.05; 95% CI, -0.07 to 0.17; P = .43). However, frequent nocturnal hemodialysis was associated with clinically and statistically significant improvements in selected kidney-specific domains of quality of life (P = .01 for effects of kidney disease and P = .02 for burden of kidney disease). Frequent nocturnal hemodialysis was also associated with improvements in systolic blood pressure (P = .01 after adjustment) and mineral metabolism, including a reduction in or discontinuation of antihypertensive medications (16/26 patients in the nocturnal hemodialysis group vs 3/25 patients in the conventional hemodialysis group; P < .001) and oral phosphate binders (19/26 patients in the nocturnal hemodialysis group vs 3/25 patients in the conventional dialysis group; P < .001). No benefit in anemia management was seen with nocturnal hemodialysis.. This preliminary study revealed that, compared with conventional hemodialysis (3 times weekly), frequent nocturnal hemodialysis improved left ventricular mass, reduced the need for blood pressure medications, improved some measures of mineral metabolism, and improved selected measures of quality of life.. isrctn.org Identifier: ISRCTN25858715.

Topics: Adult; Aged; Anemia; Blood Pressure; Calcium Phosphates; Circadian Rhythm; Erythropoietin; Female; Hematocrit; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Magnetic Resonance Imaging; Male; Middle Aged; Parathyroid Hormone; Quality of Life; Renal Dialysis

Although anemia is frequently found in congestive heart failure (CHF), little is known about the effect of its correction with erythropoietin (EPO) on cardiac structure and function.. The present study examines in patients with advanced CHF, chronic renal insufficiency, and anemia the effects of beta-EPO on left ventricular (LV) systolic diameter and volume (LVSD and LVSV), LV diastolic diameter and volume (LVDD and LVDV), LV mass, LV ejection fraction (LVEF), pulmonary artery pressure (PAP), and B-type natriuretic peptide (BNP) levels.. Fifty-one consecutive subjects affected with advanced CHF and anemia were studied. We performed a randomized double-blind controlled study of correction of anemia with subcutaneous EPO for 4 months (group A, 26 patients) using saline as the placebo in the control group (group B, 25 patients). We then maintained the EPO treatment in the treated group for another 8 months. Both groups received oral iron throughout the total 12-month period. Echocardiographic evaluation, BNP levels, and hematological parameters are reported at 4 and 12 months.. The patients in group A during the double-blind phase (4 months) demonstrated an increase in LVEF and mild reduction in LVSD and LVSV with respect to baseline and to group B with no differences in PAP, LVDD, and LVDV. Over the 12-month period, the hemoglobin increased from 10.40.6 to 12.4 +/- 0.8 g/dL (P < .01) in group A but did not change in group B. Compared with group B, group A had lower LVDD, LVSD, LVDV, LVSV, LV mass, PAP, and BNP and higher LVEF. The serum creatinine and creatinine clearance remained unchanged in the 2 groups.. In anemic patients with CHF, correction of anemia with EPO and oral iron over 1 year lead to an improvement in LV systolic function, LV remodeling, BNP levels, and PAP compared with a control group in which only oral iron was used.

Topics: Aged; Anemia; Creatinine; Double-Blind Method; Erythropoietin; Female; Heart Failure; Humans; Kidney Failure, Chronic; Male; Myocardial Contraction; Natriuretic Peptide, Brain; Recombinant Proteins; Stroke Volume; Syndrome; Ventricular Remodeling

Topics: Anemia; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins

This was an open-label study to asses the association of changes in hemoglobin with changes in health related quality of life (HRQOL) in patients treated with darbepoetin alfa.. Originally, 81 chronic kidney disease (CKD) patients not on dialysis and naïve to erythropoiesis stimulating agents (ESA) were randomly assigned into two open-label groups (3 : 1). As a majority of control group patients opted out of control status, this study reports on the single arm study analysis that was performed on the 48 patients who received the drug through week 16. Sixty-two patients received once-weekly darbepoetin alfa in addition to conservative management for CKD. Instruments that measured general (SF-36, FACTanemia, FACT-fatigue, ADL and IADL) and disease specific (KDQOL) HRQOL domains were administered at baseline and after 8, 16, and 24 weeks.. Compared to baseline values, mean HRQOL subscales were significantly improved in the treatment group at 16 weeks (p < 0.05 for SF-36 physical function; p < 0.001 for SF-36 vitality, FACT anemia and FACT fatigue scales). At week 16, the SF-36 mean increase for 48 treatment patients in the Vitality Subscale Score was 14.9 (SD 3.2) and the mean increase in the KDQOL Burden of Kidney Disease Subscale was 5.5 (SD 3.3). Multivariate regression analysis demonstrated a statistically significant association (p < 0.05) between hemoglobin levels and higher HRQOL scores on several physical function, energy and fatigue scales.. Improvements in hemoglobin in CKD patients not on dialysis were associated with statistically significant (p < 0.05), clinically meaningful (> 5 points) HRQOL improvements on scales measuring physical activity, vitality and fatigue. Our study did not show an association between increased hemoglobin levels and other aspects of HRQOL, such as those relating to emotional status, sexual activity or cognition. The interpretation of our results is limited by the lack of a control arm to assess whether conservative therapy for CKD, in the absence of ESA administration, would have a comparable effect on patients' HRQOL scores. Further research needs to examine whether other aspects of HRQOL improve with anemia treatment, in the same way as those aspects of HRQOL more closely related to physical activity and fatigue.

Topics: Adolescent; Adult; Anemia; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Quality of Life; Renal Dialysis; Treatment Outcome

Chronic hemodialysis (HD) patients manifest anemia and atherosclerosis with associated oxidative stress. We explored whether intravenous infusion of vitamin C (VC) and/or use of vitamin E (VE)-coated dialysis membrane could palliate HD-evoked oxidative stress. Eighty patients undergoing chronic HD were enrolled and randomly assigned into four groups: HD with intravenous VC (n=20), HD with VE-coated dialyzer (n=20), HD with both (n=20), and HD with neither (n=20). We evaluated oxidative stress in blood and plasma, erythrocyte methemoglobin/ferricyanide reductase (red blood cells (RBC)-MFR) activity, plasma methemoglobin, and pro-inflammatory cytokines in these patients. All patients showed marked increases (14-fold) in blood reactive oxygen species (ROS) after HD. The types of ROS were mostly hydrogen peroxide, and in lesser amounts, O2*- and HOCl. HD resulted in decreased plasma VC, total antioxidant status, and RBC-MFR activity and increased plasma and erythrocyte levels of phosphatidylcholine hydroperoxide (PCOOH) and methemoglobin. Intravenous VC significantly palliated HD-induced oxidative stress, plasma and RBC levels of PCOOH, and plasma methemoglobin levels and preserved RBC-MFR activity. The VE-coated dialyzer effectively prevented RBCs from oxidative stress, although it showed a partial effect on the reduction of total ROS activity in whole blood. In conclusion, intravenous VC plus a VE-coated dialyzer is effective in palliating HD-evoked oxidative stress, as indicated by hemolysis and lipid peroxidation, and by overexpression of proinflammation cytokines in HD patients. Using VE-coated dialyzer per se is, however, effective in reducing lipid peroxidation and oxidative damage to RBCs.

Topics: Antioxidants; Ascorbic Acid; Cytokines; Erythropoietin; Female; Hemolysis; Humans; Hydrogen Peroxide; Infusions, Intravenous; Kidney Failure, Chronic; Lipid Peroxidation; Male; Membranes, Artificial; Methemoglobin; NADH, NADPH Oxidoreductases; Oxalates; Oxidative Stress; Phosphatidylcholines; Reactive Oxygen Species; Renal Dialysis; Spectrophotometry, Atomic; Vitamin E

The erythropoiesis-stimulating protein darbepoetin alfa (Aranesp) can be given intravenously (i.v.) or subcutaneously (s.c.). Despite a s.c. bioavailability of only 37%, darbepoetin alfa i.v. or s.c. dose requirements were comparable in previous studies designed to evaluate other aspects of anaemia treatment. The present study was designed to compare i.v. vs s.c. dose requirements.. A single-centre open-label, prospective and randomized crossover study was undertaken in 71 stable haemodialysis patients. After a run-in period randomized to a 20 week study treatment with either s.c. or i.v. darbepoetin alfa, the patients were crossed over to the other treatment modality for another 20 week study period. The unit dose of weekly darbepoetin alfa was adjusted to maintain each patient's haemoglobin within a target range of -0.8 to +0.8 mmol/l of the individual baseline haemoglobin and between 6.8 and 8.5 mmol/l throughout the study period. The primary endpoint was the mean dose of darbepoetin alfa necessary to maintain the haemoglobin level in the defined range.. Data from 58 patients were available for analysis. Haemoglobin concentrations were maintained effectively in subjects, regardless of whether they received darbepoetin alfa i.v. or s.c.. The overall mean difference in haemoglobin levels during s.c. or i.v. was 0.052 mmol/l (95% confidence interval: -0.132 to 0.236 mmol/l). The difference had no statistical or clinical significance. The population mean darbepoetin alfa dose during i.v. treatment was 32.1 microg/week, compared with a mean value for s.c. treatment of 34.1 microg/week. A paired two-tailed ratio t-test showed that P = 0.036, indicating a 95% probability of a mean dose reduction between 1.2% and 28% by i.v. treatment instead of s.c... Renal anaemia of stable haemodialysis patients can be treated with darbepoetin alfa more effectively by the i.v. as compared with the s.c. route.

Topics: Aged; Cross-Over Studies; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Probability; Prospective Studies; Reference Values; Renal Dialysis; Risk Assessment; Treatment Outcome

Platelet activating factor acetylhydrolase (PAF-AH) is a Ca2+-independent phospholipase A2 that is secreted mainly from monocytes/macrophages. In human plasma, PAF-AH is associated primarily with low-density lipoprotein (LDL), while a small proportion of enzyme is associated with high-density lipoprotein (HDL). The ratio of HDL-PAF-AH to total plasma enzyme activity may represent a potential marker of atherogenicity. We evaluated possible alterations of lipoprotein-associated enzyme activity in Chronic Kidney Disease (CKD) patients, stages 3-4, and further investigated whether long-term therapy with recombinant human erythropoietin (epoetin) has any influence on the plasma PAF-AH activity in vivo or on the enzyme activity secreted from peripheral blood monocytes (PBMs), in vitro.. Forty-eight patients, 28 men and 20 women, with CKD (stages 3-4) participated in the study. Patients were randomized into groups I and II. Patients of group I (n = 28) were administered subcutaneously epoetin, 50 units/kg once per week. The Hb target was 13 g/dl. In group II (n = 20), epoetin was initiated only when the Hb levels decreased during follow-up to less than 9 g/dl. All patients were seen on an outpatient basis at 2, 4 and 6 months. Twenty-two normolipidemic age- and sex-matched healthy volunteers also participated in the study and were used as controls.. The PAF-AH activity in plasma of both patient groups at baseline was higher compared to controls, whereas no difference in the HDL-PAF-AH activity was observed among the studied groups. Thus, the ratio of HDL-PAF-AH to the plasma enzyme activity was significantly lower in both patient groups compared to controls. Epoetin administration in the patients of group I was associated with a significant increase in the plasma PAF-AH and in HDL-PAF-AH activities 2 months after treatment, which remained stable for up to 6 months of therapy, a phenomenon not observed in untreated patients of group II. Thus, the ratio of HDL-PAF-AH to the plasma enzyme activity was significantly increased in patients of group I compared to the baseline values, a phenomenon not observed in patients of group II. In vitro treatment with epoetin of PBMs from patients of group I (undergoing therapy with epoetin) resulted in a dose-dependent increase in total and secreted enzyme activity, a phenomenon not observed in patients of group II who did not receive therapy with epoetin. This suggests that the in vivo increase in lipoprotein-associated PAF-AH observed in patients treated with epoetin may be attributed to the drug-induced enhanced secretion of PAF-AH from PBMs of these patients.. CKD patients of stages 3-4 are characterized by an increase in plasma PAF-AH activity and a low ratio of HDL-PAF-AH to total plasma enzyme activity. Long-term therapy with epoetin may improve this atherogenic ratio thus this drug may play an important antiatherogenic role in CKD.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Adult; Aged; Aged, 80 and over; Biomarkers; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Phospholipases A2; Probability; Prognosis; Reference Values; Risk Assessment; Severity of Illness Index; Survival Rate; Treatment Outcome

Hypogonadism and anemia are common comorbid conditions in dialysis patients. Testosterone replacement may improve such clinical parameters as anemia, sarcopenia, and low libido. Additionally, by increasing hemoglobin levels, testosterone replacement may allow for a dose reduction in recombinant human erythropoietin (rHuEPO), thereby reducing cost.. This phase IV, single-center, placebo-controlled, double-blind study assessed the effect of transdermal testosterone on serum testosterone levels, rHuEPO dose required to maintain hemoglobin level, bone mineral content, lean body mass and fat content, cholesterol level, sexual function, and mood. Forty hypogonadal male hemodialysis patients who were administered rHuEPO were randomly assigned to 100 mg of topical 1% testosterone gel (Testim; Auxilium Pharmaceuticals, Norristown, PA) or placebo, applied daily for 6 months.. Forty men with a mean age of 56 years and baseline serum testosterone level less than 300 ng/dL (< 10.4 nmol/L) participated in this trial. In men assigned to administration of transdermal testosterone, there was an increase beyond that in the placebo group in mean serum testosterone (77.1 ng/dL [2.7 nmol/L]), dihydrotestosterone (DHT; 0.8 nmol/L), and estradiol levels (6.3 pg/mL [23.0 pmol/L]) and a decrease in mean serum luteinizing hormone levels (-3.1 IU/L). Compared with subjects administered placebo, participants on testosterone replacement therapy did not show an appreciable change in rHuEPO dose (mean difference adjusted for baseline values, 12.6 U/kg/wk; P = 0.73), bone mineral density, lean body mass or fat content, cholesterol level, sexual function, or mood.. Daily administration of 100 mg of topical 1% testosterone gel for 6 months failed to significantly increase serum testosterone or DHT levels in hypogonadal men with end-stage renal disease. Treatment with transdermal testosterone did not impact on rHuEPO requirement or clinical parameters in this small placebo-controlled study. Greater serum testosterone levels may be required to show clinical benefit in men with end-stage renal disease.

Topics: Administration, Cutaneous; Androgens; Anemia; Double-Blind Method; Erythropoietin; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Testosterone

Although erythropoietin (EPO)-hyporesponsive anemia in hemodialysis patients most commonly results from iron deficiency, the contributory role of chronic inflammation and oxidative stress in its pathogenesis is poorly understood. We conducted an open-label prospective study to assess the effect of vitamin C, an antioxidant, on EPO-hyporesponsive anemia in hemodialysis patients with unexplained hyperferritinemia.. Forty-six of 262 patients in an inner-city hemodialysis center met the inclusion criteria (administration of intravenous iron and EPO for > or = 6 months at a dose > or = 450 U/kg/wk, average 3-month hemoglobin [Hb] level < or = 11.0 g/dL [< or = 110 g/L], ferritin level > or = 500 ng/mL (microg/L), and transferrin saturation [TSAT] < or = 50%). Patients were excluded if they had a clear explanation for the EPO hyporesponsiveness. Four patients refused to participate. The remaining patients were randomly assigned; 20 patients to receive standard care and 300 mg of intravenous vitamin C with each dialysis session (group 1) and 22 patients to receive standard care only (group 2). Study duration was 6 months. During the study, 1 patient from group 1 was removed (upper gastrointestinal bleeding) from final analysis. Monthly assessment included Hb level, mean corpuscular volume, iron level, iron-binding capacity, ferritin level, TSAT, and Hb content in reticulocytes. In addition, biointact parathyroid hormone, aluminum, C-reactive protein (CRP), and liver enzymes were measured every 3 months.. Age, sex, race, and time on dialysis therapy were similar in both groups. At 6 months, Hb levels significantly increased from 9.3 to 10.5 g/dL (93.0 to 105.0 g/L) in group 1, but not group 2 (9.3 to 9.6 g/dL [93.0 to 96.0 g/L]; P = 0.0001). Similarly, TSAT increased from 28.9% to 37.3% in group 1, but not group 2 (28.7% to 29.3%; P = 0.0001). EPO dose (477 to 429 versus 474 to 447 U/kg/wk), iron-binding capacity (216 to 194 versus 218 to 257 microg/dL [38.7 to 34.7 versus 39 to 46 micromol/L]), and CRP level (2.8 to 0.9 versus 2.8 to 2.2 mg/dL) decreased significantly in group 1, but not in controls. Changes in Hb content in reticulocytes and ferritin level also were statistically significant in group 1. There was no change in biointact parathyroid hormone levels. Although serum iron levels and intravenous iron doses changed within each group, changes were equal between the 2 groups.. In hemodialysis patients with refractory anemia and hyperferritinemia, vitamin C improved responsiveness to EPO, either by augmenting iron mobilization from its tissue stores or through antioxidant effects.

Topics: Adult; Anemia; Antioxidants; Ascorbic Acid; Erythropoietin; Female; Ferritins; Humans; Injections, Intravenous; Iron Metabolism Disorders; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis

Darbepoetin alfa, an effective treatment for anemia of chronic kidney disease (CKD), can be administered at extended intervals. Simplify the Treatment of Anemia with Aranesp (STAAR), a multicenter, 52-week study, was conducted to assess the efficacy of darbepoetin alfa administered subcutaneously every other week (Q2W) in maintaining hemoglobin (Hb) in CKD patients not receiving dialysis.. This is a subgroup analysis of subjects converted from once-weekly (QW) recombinant human erythropoietin (rHuEPO; US Aranesp package insert) and who received up to 52 weeks of darbepoetin alfa therapy (evaluation period 20-32 weeks). Enrolled subjects had a creatinine clearance < or = 70 ml/min or an estimated glomerular filtration rate < or = 60 ml/min and transferrin saturation > or = 20%. Darbepoetin alfa doses were titrated to maintain Hb levels < or = 12 g/dl. The primary endpoint was mean Hb during evaluation.. There were 524 subjects enrolled in the study who were previously receiving rHuEPO QW. Mean Hb +/- standard deviation was 11.2 +/- 1.27 g/dl at baseline, and the least squares mean +/- SE was 11.4 +/- 0.04 during evaluation. The mean +/- SD Q2W darbepoetin alfa dose was 49.7 +/- 21.9 microg at baseline and 48.9 +/- 35.5 microg at evaluation. Darbepoetin alfa was well tolerated.. Study subjects with CKD receiving QW rHuEPO were effectively converted to Q2W darbepoetin alfa, which was well tolerated. Hb levels were maintained over 52 weeks without a significant change in darbepoetin alfa dose.

Topics: Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Injections, Subcutaneous; Iron; Kidney Failure, Chronic; Male; Middle Aged; Multicenter Studies as Topic; Recombinant Proteins; Time Factors; Treatment Outcome

Anaemia is a major and persistent manifestation of chronic kidney disease (CKD) caused by the deficient production of erythropoietin in the kidneys, the prevalence of which is proportional to the deterioration in kidney function. Darbepoetin alfa, an erythropoiesis-stimulating protein, exhibits a lower clearance and longer terminal half-life in serum than recombinant human erythropoietin, thereby allowing for a reduced dosing frequency. A recent study in patients with CKD, using a 4-week sampling period, suggested that the terminal half-life of darbepoetin alfa in serum is longer than that reported in previous studies, which were based on a 1-week sampling period. This study was conducted to characterise the pharmacokinetic profile of a single subcutaneous dose of darbepoetin alfa 1 microg/kg in patients with CKD, using a sampling duration of 4 weeks, which was hypothesised to allow better characterisation of the terminal half-life in serum.. Twenty patients with CKD not on dialysis, with a calculated glomerular filtration rate of 20-60 mL/min and who had not been treated with erythropoietic agents in the previous 12 weeks, were enrolled into this single-dose, open-label study. Patients received a single subcutaneous dose of darbepoetin alfa (Aranesp) 1 microg/kg on day 1, and blood samples were collected for pharmacokinetic analyses predose, 6 and 12 hours postdose and up to 28 days postdose. Seroreactivity sampling and further safety laboratory tests (clinical chemistry and urinalysis) were also performed. Patients were assessed for adverse events at each study visit. The primary endpoint was characterisation of the terminal half-life following a single subcutaneous dose of darbepoetin alfa 1 microg/kg.. The mean terminal half-life in serum of darbepoetin alfa was determined to be 69.6 hours. Peak serum concentrations were reached in a median time of 36 hours postdose, and a mean apparent clearance of 3.51 mL/h/kg was comparable to that observed previously in this patient population.. Based on an extended sampling schedule of 4 weeks, the terminal half-life of darbepoetin alfa was approximately 70 hours. This is longer than the 48.8 hours reported previously in patients with CKD on dialysis. These data suggest that the pharmacokinetic properties of darbepoetin alfa make this erythropoietic agent well suited to an extended dosing regimen.

Topics: Adult; Aged; Anemia; Darbepoetin alfa; Erythropoietin; Female; Half-Life; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

The urinary liver-type fatty-acid-binding protein (L-FABP) level reflects the clinical progression of chronic kidney disease. We conducted a study to determine whether administration of erythropoietin (EPO), which is produced in response to hypoxic stress, affects urinary protein excretion and L-FABP levels in patients with chronic renal failure (CRF) and anemia.. The study was an interventional trial that included 20 anemic CRF patients (median serum creatinine level 2.0 mg/dl, range 1.3-2.9 mg/dl; median hemoglobin concentration 9.2 g/dl, range 8.2-9.8 g/dl; median estimated glomerular filtration rate 20.5 ml/min, range 15.0-28.0 ml/min; group A). Recombinant EPO (12,000 U twice/month) was given to these patients for 6 months. Urinary protein, L-FABP, 8-hydroxy-2'-deoxyguanosine, and hemoglobin levels were measured before and 3 and 6 months after treatment. Twenty nonanemic CRF patients were enrolled as controls (group B).. After 6 months, the hemoglobin level was increased as compared with the baseline level in group A treated with EPO (median 11.3 g/dl, range 9.3-13.8 g/dl, vs. median 9.2 g/dl, range 8.2-9.8 g/dl; p < 0.01) but not in the untreated group B (median 11.8 g/dl, range 10.2-13.0 g/dl, vs. median 12.1 g/dl, range 10.8-13.4 g/dl; not significant). The urinary protein excretion was decreased as compared with the baseline level in group A (median 1.2 g/day, range 0.6-1.9 g/day, vs. median 1.9 g/day, range 1.1-2.6 g/day; p < 0.01) but not in group B (median 1.4 g/day, range 0.7-2.2 g/day, vs. median 1.6 g/day, range 0.7-2.3 g/day; not significant). The urinary L-FABP level was also decreased as compared with the baseline level in group A (median 50.0 microg/g creatinine, range 7.5-90.0 microg/g creatinine, vs. median 115.0 microg/g creatinine, range 20.0-225.0 microg/g creatinine; p < 0.01) but not in group B (median 82.0 microg/g creatinine, range 15.5-158.0 microg/g creatinine, vs. median 76.0 microg/g creatinine, range 25.0-138.5 microg/g creatinine; not significant). The glomerular filtration rate changed little throughout the study period in either group. The urinary 8-hydroxy-2'-deoxyguanosine level was decreased as compared with the baseline level in group A (median 22.0 ng/mg creatinine, range 8.0-30.0 ng/mg creatinine, vs. median 38.5 ng/mg creatinine, range 14.0-68.0 ng/mg creatinine; p < 0.01) but not in group B (median 33.0 ng/mg creatinine, range 9.0-56.0 ng/mg creatinine, vs. median 30.0 ng/mg creatinine, range 10.0-54.0 ng/mg creatinine; not significant).. EPO supplementation may ameliorate renal tubular damage, in part, due to a reduction of oxidative stress in CRF patients with anemia.

Topics: Adult; Aged; Anemia; Erythropoietin; Fatty Acid-Binding Proteins; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Treatment Outcome

It is becoming increasingly more common to administer intravenous (i.v.) darbepoetin alfa to haemodialysis (HD) patients at less frequent dosing intervals in routine clinical practice. This study investigated extending the dosing interval for i.v. darbepoetin alfa treatment from once a week (QW) to once every 2 weeks (Q2W) at the same dose in order to maintain target haemoglobin (Hb) concentrations (11-13 g/dl).. Stable HD patients in routine clinical practice receiving i.v. darbepoetin alfa QW for a period of 6 months (n = 105) (treatment period 1) were switched to i.v. Q2W darbepoetin alfa for a further 6 months (treatment period 2) (n = 90). The dose of i.v. darbepoetin alfa was titrated to maintain Hb concentrations between 11 and 13 g/dl throughout the full 12-month study period.. The mean change in Hb for treatment period 2 was 0.04 +/- 1.1 g/dl (+/-SD), which was not clinically relevant (11.7 +/- 0.8 g/dl vs 11.7 +/- 1.0 g/dl; P = 0.8). The mean weekly doses of darbepoetin alfa were similar throughout the treatment periods (34.0 +/- 17.1 microg/week vs 32.1 +/- 17.3 microg/week; P = 0.3, respectively for QW and Q2W dosing). Intravenous darbepoetin alfa was well tolerated.. The treatment of renal anaemia in HD patients with i.v. Q2W darbepoetin alfa effectively and safely maintains Hb concentrations at a less frequent dosing regimen than observed with QW administration. Dose requirements for i.v. darbepoetin alfa administered QW or Q2W were not different. The results of this study demonstrate that i.v. darbepoetin alfa administered Q2W is an effective regimen for HD patients requiring anaemia treatment in routine clinical practice.

Topics: Aged; Aged, 80 and over; C-Reactive Protein; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Hypertension; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis; Treatment Outcome

Darbepoetin alfa is a unique genetically engineered glycoprotein with a three-fold longer terminal half-life than recombinant human erythropoietin (rHuEPO). The objective of this study was to determine if darbepoetin alfa administered at a reduced dosing frequency relative to the prior rHuEpo regimen is an effective and safe alternative for treating renal anemia in patients undergoing dialysis. A total of 1,008 French hemodialysis and peritoneal dialysis patients receiving stable rHuEPO therapy by either the intravenous (i.v., N = 217) or subcutaneous (s.c., N = 791) route were switched to darbepoetin alfa given by the same route of administration at a reduced dosing frequency. Patients receiving rHuEPO once weekly (N = 248, 25%) were switched to darbepoetin alfa every two weeks, and those receiving rHuEPO two or three times weekly (N = 760, 75%) were switched to darbepoetin alfa once weekly. The doses of darbepoetin alfa were titrated to maintain hemoglobin concentration in the target range of 10.0 to 13.0 g/dl for up to 24 weeks. The primary endpoint was the change in hemoglobin between baseline and the evaluation period (weeks 21-24). Adjusted (for covariates that might influence hemoglobin response) mean change in hemoglobin from baseline to the evaluation period was not clinically significant: +0.11 g/dl (95% CI: -0.30; 0.52). An i.v./s.c. dose ratio of 0.96 (95% CI: 0.86; 1.06) at evaluation confirms previous findings that darbepoetin alfa dose requirements were not different for the s.c. and i.v. routes. At the end of the evaluation period, more than 98% of patients successfully maintained hemoglobin within the target range and at their darbepoetin alfa assigned dosing frequency. Darbepoetin alfa was well tolerated with a safety profile consistent with that observed in previous darbepoetin alfa studies. Darbepoetin alfa administered at a reduced dosing frequency relative to the prior rHuEpo regimen effectively maintains hemoglobin in the target range in dialysis patients with renal anemia.

Topics: Aged; Anemia; Darbepoetin alfa; Erythropoietin; Female; France; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Renal Dialysis; Treatment Outcome

To assess the efficacy and safety of every-other-week darbepoetin alfa therapy in treating anemia and maintaining hemoglobin levels for 1 year in patients with chronic kidney disease (CKD) who were not undergoing dialysis and who had not previously received erythropolesis-stimulating proteins (ESPs).. This multicenter 52-week study (evaluation period, weeks 20-32), a subanalysis of the Simplify the Treatment of Anemia with Aranesp study, enrolled patients with CKD who were not receiving dialysis (creatinine clearance < or =70 mL/min or estimated glomerular filtration rate [GFR] < or =60 mL/min). Patients evaluated in this analysis were not receiving ESPs, had hemoglobin concentrations less than 11 g/dL, and had transferrin saturation of 20% or higher during screening. Patients Initiated every-other-week darbepoetin alfa therapy at 0.75 microg/kg, with the dose subsequently titrated to maintain hemoglobin levels not to exceed 12 g/dL. The first study participant was enrolled on February 4, 2002, and the last participant completed the study on March 31, 2004.. The analysis included 911 patients (mean [SD] age, 66.4 [14.2] years; 54.3% female; 55.3% white). The least squares mean evaluation hemoglobin concentration was 11.54 g/dL (95% confidence interval, 11.47-11.61 g/dL), and the change from baseline was 1.6 g/dL (95% confidence interval, 1.5-1.7 g/dL). The mean (SD) every-other-week darbepoetin alfa dose during evaluation was 44.5 (33.7) microg. Iron supplementation was administered to 573 patients (62.9%) during the study. Darbepoetin alfa was well tolerated throughout the study period.. Darbepoetin alfa initiated every other week safely and effectively treated anemia and maintained hemoglobin for 1 year in patients with CKD who were not undergoing dialysis and who were not receiving prior ESP therapy.

Topics: Aged; Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Injections, Subcutaneous; Iron; Kidney Failure, Chronic; Male; Middle Aged

This dose-finding, open-label study examined the potential of subcutaneous Continuous Erythropoietin Receptor Activator (C.E.R.A.) to correct anaemia at extended administration intervals in 61 erythropoiesis-stimulating agent-naïve patients with chronic kidney disease (CKD) on dialysis. After a 4-week run-in, patients were randomised to C.E.R.A. 0.15, 0.30 and 0.45 microg/kg/week. Within these dose groups, patients were further randomised to once weekly, once every 2 weeks or once every 3 weeks treatment. Mean changes in haemoglobin (Hb) increased with increasing C.E.R.A. dose during a period of 6 weeks where no dose adjustments were permitted. The effect was independent of administration schedule. Erythropoietic responses were sustained until the end of the study (12 weeks) in all groups. In total, 90% of patients in the 0.30 microg/kg/week group and 79% in the 0.45 microg/kg/week group responded to treatment (Hb increase > or =1.0 g/dl), compared with 72% in the 0.15 microg/kg/week group. Faster median response time was associated with increasing dose (51, 38 and 31 days, respectively) and response was unrelated to administration frequency. C.E.R.A. was generally well tolerated. Our results suggest that 0.60 microg/kg twice monthly would be a suitable starting dose of C.E.R.A. for the initiation of anaemia correction in patients with CKD on dialysis. Phase III studies will confirm the feasibility of using C.E.R.A. at extended administration intervals in patients with CKD and anaemia.

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis; Treatment Outcome

To demonstrate the efficacy and safety of epoetin delta for the treatment of anaemia in dialysis patients with chronic kidney disease (CKD).. This was a 12-week, randomized, double-blind, active-comparator study. CKD patients who were naïve to epoetin treatment and had haemoglobin < 10 g/dL were randomized to epoetin delta 15, 50, 150, or 300 IU/kg or epoetin alfa 50 IU/kg. Patients initially entered a correction phase until they recorded haemoglobin of > or = 11.5 g/dL for two consecutive weekly measurements or one haemoglobin measurement of > or = 13 g/dL (correction success). A maintenance phase followed where the dose was adjusted to maintain haemoglobin > or = 10.5 g/dL. Maintenance success was defined as haemoglobin > 10.5 g/dL at Week 12. Total success was defined as achieving maintenance and correction success.. The primary objective was to demonstrate that the proportion of patients achieving total success was greater in the pooled 150 IU/kg and 300 IU/kg groups compared with the 15 IU/kg dose group.. Total success was achieved in 55.6% of patients in the pooled highest epoetin delta group compared with 4.5% in the lowest dose group. There was no significant difference in total success for the epoetin delta and epoetin alfa 50 IU/kg groups. Significant increases in haemoglobin and haematocrit levels were observed in the 150 and 300 IU/kg dose groups. Adverse events occurred at frequencies expected for this patient group.. Epoetin delta was effective in increasing haemoglobin levels in patients with baseline haemoglobin of < 10 g/dL.

Topics: Adult; Aged; Anemia; Dose-Response Relationship, Drug; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Treatment Outcome

Continuous Erythropoietin Receptor Activator (C.E.R.A.) is a new agent that is in development for the treatment of anemia with extended administration intervals in patients who have chronic kidney disease (CKD), both those on and those not on dialysis. This was an open-label, randomized, multicenter, two-period, crossover study in erythropoiesis-stimulating agentnaïve patients who had CKD and anemia and were receiving peritoneal dialysis. After a 1-wk run-in period, 16 patients were randomly assigned to receive a single administration of intravenous C.E.R.A. 0.4 microg/kg (n = 8) or subcutaneous C.E.R.A. 0.8 microg/kg (n = 8). Six weeks after the first administration of C.E.R.A. (4-wk assessment, 2-wk washout), the route of administration was switched so that all patients received single administrations of both intravenous C.E.R.A. 0.4 microg/kg and subcutaneous C.E.R.A. 0.8 microg/kg. C.E.R.A. had a prolonged and comparable half-life after intravenous (mean 134 h) and subcutaneous (mean 139 h) administration. Reticulocyte counts peaked at a median of 8 d after intravenous and subcutaneous administration with no difference in the time course between administration routes. This resulted in similar mean values for the area under the reticulocyte count-time curve (1191 x 10(9) and 1193 x 10(9).d per L, respectively) and the maximum absolute increase in reticulocyte counts (36 x 10(9) and 41 x 10(9)/L, respectively). C.E.R.A. has a prolonged and comparable half-life after intravenous or subcutaneous injection, suggesting that extended administration intervals may be feasible in patients with CKD.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Cross-Over Studies; Erythropoietin; Female; Hemolysis; Humans; Infusions, Intravenous; Infusions, Parenteral; Kidney Failure, Chronic; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins

Short daily hemodialysis (HD) has a protective effect against dialysis-induced hypotension (DIH). We examined whether this effect extends beyond the treatment period.. We analyzed clinical variables in 6 patients (5 with diabetes mellitus) who underwent conventional hemodialysis (CHD) for 4 h three times weekly for 12 weeks; then short daily HD for 2 h six times weekly for 12 weeks, and then 12 more weeks of CHD. All patients had been given vasopressors for severe DIH.. The severe DIH disappeared during the short daily HD. There were significant decreases in body weight (BW), cardiothoracic ratio (CTR), blood pressure (BP), normal saline solution (NSS) amount (62.8 +/- 26.4 vs. 9.8 +/- 7.4 ml/session, p < 0.05), frequency (0.60 +/- 0.26 vs. 0.10 +/- 0.07 infusions/session, p < 0.05) and postdialysis atrial natriuretic peptide (ANP) (176.8 +/- 56.4 vs. 104.8 +/- 42.3 pg/ml, p < 0.05). Weekly ultrafiltration volume (6.3 +/- 0.9 vs. 7.9 +/- 0.7 l, p < 0.05) was significantly higher during the short daily HD period than during the first CHD period. The vasopressor treatment was therefore stopped or reduced in all patients during the short daily HD period. Because DIH recurred in the second CHD period despite a significant increase in BP, the vasopressor treatment was resumed in 5 patients. BW, CTR, NSS infusion amount and frequency, or postdialysis ANP did not differ significantly between the short daily HD and second CHD periods.. The protective effect of short daily HD against DIH lasted more than 12 weeks after the treatment ended. We therefore conclude that temporary short daily HD is useful for preventing DIH.

Topics: Aged; Anemia; Antihypertensive Agents; Appointments and Schedules; Arteriovenous Shunt, Surgical; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Diabetic Nephropathies; Echocardiography; Erythropoietin; Female; Ferritins; Humans; Hypertension, Renal; Hypotension; Iron; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Quality of Life; Recombinant Proteins; Renal Dialysis; Uremia

Ascorbate supplementation for patients on regular dialysis treatment (RDT) is advised to obviate deficiency and improve epoetin response in those with functional iron deficiency. However, clear-cut safety concerns regarding hyperoxalemia are still poorly understood. This study tries to establish safety/efficacy profiles of ascorbate and oxalate during long-term intravenous ascorbate supplementation.. A prospective study was performed in 30 patients on RDT showing ascorbate deficiency (plasma ascorbate < 2.6 mg/L [<15 micromol/L]): 18 patients were administered intravenous ascorbate during 18 months (250 mg/wk, subsequently increased to 500 mg), and 12 patients were taken as reference untreated cases. Plasma ascorbate and oxalate assays and dialytic balance determinations were performed (ion chromatography and reverse-phase high-performance liquid chromatography, respectively) at baseline, during treatment, and 12 months after withdrawal.. Plasma ascorbate levels increased dose dependently with supplementation (1.6 +/- 0.8 mg/L [9.1 +/- 4.6 mumol/L] at baseline, 2.8 +/- 1.8 mg/L [15.9 +/- 10.1 micromol/L]) with 250 mg of ascorbate, and 6.6 +/- 2.8 mg/L [37.5 +/- 16.0 micromol/L] with 500 mg/wk of ascorbate), but only normalized with greater dosages for several months in 94% of patients. Baseline plasma oxalate levels increased from 3.2 +/- 0.8 mg/L (35.8 +/- 8.8 micromol/L) to 3.6 +/- 0.8 mg/L (39.5 +/- 9.1 micromol/L) and 4.5 +/- 0.9 mg/L (50.3 +/- 10.4 micromol/L) with 250 and 500 mg, respectively ( P < 0.001). The calcium oxalate saturation threshold was exceeded by 7 of 18 patients (40%) during 6 months therapy with 500 mg/wk. Ascorbate dialysis removal increased from 37.8 +/- 23.2 mg (215 +/- 132 micromol) to 99.6 +/- 51.7 mg (566 +/- 294 micromol) during supplementation (P < 0.001), with corresponding increases in oxalate removal from 82.5 +/- 33.2 mg (917 +/- 369 micromol) to 111.2 +/- 32.6 mg/L (1,236 +/- 362 micromol; P < 0.01). Withdrawal reverted plasma levels and dialysis removal to initial values. Values for untreated patients did not change during 1 year of follow-up.. Patients on RDT may resolve ascorbate deficiency with intravenous supplementation of 500 mg/wk, but this implies a significant risk for oxalate supersaturation. Oxalate measurements are strongly recommended during long-term ascorbate therapy.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Ascorbic Acid; Ascorbic Acid Deficiency; Calcium Oxalate; Drug Resistance; Erythropoietin; Female; Humans; Hyperoxaluria; Infusions, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis

In view of the recent interest in weekly erythropoietic regimens and the lack of studies directly comparing the available agents, the clinical effectiveness of darbepoetin-alpha (DA) and epoetin-beta (EB), when administered via the subcutaneous route on a weekly basis, after conversion from thrice-weekly subcutaneous EB, was studied. In this 9-mo, single-center, randomized study of an unselected hemodialysis population, anemia was managed with a computerized decision-support system. Per-protocol analysis of the 81 patients in each arm who completed the study showed similar hemoglobin outcomes between treatment arms, both at randomization and at the end of the study. After conversion from thrice-weekly EB to DA (at a ratio of 200 IU:1 microg, at which products are cost-neutral in the European Union), a significant fall in dose from a mean of 0.59 microg/kg per wk after randomization to 0.46 microg/kg per wk in the last month (P = 0.002) was observed; in the comparator arm, the reduction in frequency of administration of EB was associated with a significant dose increase from a mean of 107.5 to 133.2 IU/kg per wk (P = 0.002) during the same period. At hemoglobin stability, mean EB dose was found to be 44% higher than DA dose (when multiplied by 200). Similar significant dose differences were apparent in a modified intention-to-treat analysis. The study demonstrated that, under a decision-support system, both products were capable of adequately maintaining hemoglobin outcome when administered on a weekly basis but with significant dose differences at 9 mo.

Topics: Aged; Anemia; Darbepoetin alfa; Decision Making; Drug Therapy, Computer-Assisted; Erythropoietin; Female; Hemoglobins; Humans; Injections, Subcutaneous; Iron; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Treatment Outcome

Hemodialysis patients have uremic dyslipidemia, represented by elevated serum intermediate-density lipoprotein cholesterol (IDL-C) levels, and an increased cardiovascular mortality rate. This study was performed to determine the low-dose effects of the angiotensin II receptor blocker losartan and the angiotensin-converting enzyme inhibitor trandolapril on pulse wave velocity (PWV), which predicts cardiovascular morbidity and mortality in hemodialysis patients.. Serum lipid levels and PWV were monitored for 12 months in 64 hemodialysis patients who were administered low doses of losartan or trandolapril or a placebo.. At the start of the study, there were no differences in patient characteristics among the 3 groups. PWV tended to increase in the placebo group during the 12-month study period, but decreased significantly in the losartan and trandolapril groups, and decreases in PWV were similar in the losartan and trandolapril groups. There were no changes in blood pressure, hematocrit, erythropoietin dose, ankle-brachial index, serum lipid levels, serum 8-isoprostane levels, or serum C-reactive protein levels during the 12-month study period, but there was an increase in serum triglyceride levels in the losartan group and a decrease in serum IDL-C levels in the losartan and trandolapril groups.. In hemodialysis patients, trandolapril is as effective as losartan in decreasing PWV independent of its depressor effect and in suppressing elevated IDL-C levels. Long-term blockade of the renin-angiotensin system may have a beneficial effect on the acceleration of atherosclerosis and uremic dyslipidemia.

Topics: Aged; Anemia; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; C-Reactive Protein; Cardiovascular Diseases; Cholesterol; Comorbidity; Dinoprost; Drug Therapy, Combination; Erythropoietin; Female; Follow-Up Studies; Hematocrit; Humans; Hyperlipidemias; Indoles; Kidney Failure, Chronic; Lipids; Lipoproteins; Lipoproteins, LDL; Losartan; Male; Middle Aged; Prospective Studies; Renal Dialysis; Treatment Outcome; Vascular Resistance

Studies have consistently shown the superior dosing efficiency of subcutaneous (s.c.) compared to intravenous (i.v.) erythropoietin (r-HuEPO). Unlike r-HuEPO, data from pivotal darbepoetin trials support s.c. and i.v. dosing equivalence, however, no blinded cross-over randomized studies of s.c. and i.v. dose efficiency or intra-patient variability in response have been published.. During this 12-month study, 53 haemodialysis patients were randomized to s.c. or i.v. darbepoetin for a 6-month period and then switched to the alternative route for a second 6-month period. Darbepoetin dose was titrated during the first 4-months of each period to achieve a stable haemoglobin during the final 2-month observation period of each arm.. Twenty-four patients were included in analysis. No significant difference between s.c. and i.v. administration was observed for any measured parameter. Patients achieved a non-significantly higher haemoglobin (123.6 +/- 3.76 vs 120.9 +/- 4.42 g/L, P = 0.11) from a non-significantly lower darbepoetin dose (40.8 +/- 10.7 vs 42.5 +/- 11.0 mcg/week, P = 0.23) with i.v. administration. The population-based weight normalized s.c./i.v. dose ratio was 1.04 (0.97-1.11). Despite no significant overall difference, some patients experienced changes in individual dose efficiency response. Three of 24 patients recorded a greater than 30% change, four of 24 recorded between a 20 and 30% change, and five of 24 patients recorded between a 10 and 20% change relative to i.v. dose efficiency.. This study further supports s.c. and i.v. dosing equality and that overall the more convenient i.v. route can be used with equal dosing efficiency. However, patients switching routes of administration should be monitored due to the wide range in individual response.

Topics: Adult; Aged; Anemia; Cross-Over Studies; Darbepoetin alfa; Erythropoietin; Female; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Patient Dropouts; Renal Dialysis

It is unclear whether physiologic hemoglobin targets lead to cardiac benefit in incident hemodialysis patients without symptomatic heart disease and left ventricular dilation. In this randomized, double-blind study, lower (9.5 to 11.5 g/dl) and higher (13.5 to 14.5 g/dl) hemoglobin targets were generated with epoetin alpha over 24 wk and maintained for an additional 72 wk. Major eligibility criteria included recent hemodialysis initiation and absence of symptomatic cardiac disease and left ventricular dilation. The primary outcome measure was left ventricular volume index (LVVI). The study enrolled 596 patients. Mean age, duration of dialysis therapy, baseline predialysis hemoglobin, and LVVI were 50.8 yr, 0.8 yr, 11.0 g/dl, and 69 ml/m2, respectively; 18% had diabetic nephropathy. Mean hemoglobin levels in the higher and lower target groups were 13.3 and 10.9 g/dl, respectively, at 24 wk. Percentage changes in LVVI between baseline and last value were similar (7.6% in the higher and 8.3% in the lower target group) as were the changes in left ventricular mass index (16.8 versus 14.2%). For the secondary outcomes, the only between-group difference was an improved SF-36 Vitality score in the higher versus the lower target group (1.21 versus -2.31; P = 0.036). Overall adverse event rates were similar in both target groups; higher (P < 0.05) rates of skeletal pain, surgery, and dizziness were seen in the lower target group, and headache and cerebrovascular events were seen in the higher target group. Normalization of hemoglobin in incident hemodialysis patients does not have a beneficial effect on cardiac structure, compared with partial correction.

Topics: Adult; Aged; Anemia; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Heart Diseases; Hematinics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Darbepoetin alfa is an erythropoiesis-stimulating glycoprotein that functions by the same mechanism as recombinant human erythropoietin (rHuEPO), but has a three-fold longer serum half-life. Reduction in the frequency of darbepoetin alfa administration would be beneficial to patients with renal disease and their healthcare providers. This study evaluated the effect of extending the darbepoetin alfa dosing interval to once monthly in patients with chronic kidney disease (CKD) not receiving dialysis.. This study was a multicenter, open-label study of 97 patients with CKD not on dialysis. Patients receiving stable subcutaneous doses of darbepoetin alfa once every two weeks were converted to darbepoetin alfa once monthly for 29 weeks. The proportion of patients who successfully maintained hemoglobin concentrations between 10.0 and 12.0 g/dl and the mean darbepoetin alfa dose were evaluated. Safety measurements (e.g. adverse events, laboratory parameters, blood pressure) and seroreactivity were assessed.. Hemoglobin concentration was maintained within the target range in 79% (95% confidence interval (CI) = 71% to 87%) of all patients receiving darbepoetin alfa and in 85% (95% Cl = 78% - 93%) of patients who completed the study period. The mean +/- standard deviation monthly darbepoetin alfa dose was similar between baseline (88.7 +/- 49.9 microg) and the evaluation period (86.6 +/- 78.8 microg). The safety profile for monthly darbepoetin alfa administration was comparable with that previously observed with more-frequent administration.. Patients with CKD who are clinically stable on darbepoetin alfa administered once every two weeks can be safely and effectively converted to darbepoetin alfa administered once monthly.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Iron-Deficiency; Confidence Intervals; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Risk Assessment; Severity of Illness Index; Treatment Outcome

Recombinant human erythropoietin (EPO) is used for the treatment of last stage renal anemia. A new EPO preparation was obtained in Cuba in order to make this treatment fully nationally available. The aim of this study was to compare the pharmacokinetic, pharmacodynamic and safety properties of two recombinant EPO formulations in patients with anemia due to end-stage renal disease on hemodialysis.. A parallel, randomized, double blind study was performed. A single 100 IU/Kg EPO dose was administered subcutaneously. Heberitro (Heber Biotec, Havana, formulation A), a newly developed product and Eprex (CILAG AG, Switzerland, formulation B), as reference treatment were compared. Thirty-four patients with anemia due to end-stage renal disease on hemodialysis were included. Patients had not received EPO previously. Serum EPO level was measured by enzyme immunoassay (EIA) during 120 hours after administration. Clinical and laboratory variables were determined as pharmacodynamic and safety criteria until 216 hours.. Both groups of patients were similar regarding all demographic and baseline characteristics. EPO kinetics profiles were similar for both formulations; the pharmacokinetic parameters were very close (i.e., AUC: 4667 vs. 4918 mIU.h/mL; Cmax: 119.1 vs. 119.7 mIU/mL; Tmax: 13.9 vs. 18.1 h; half-life, 20.0 vs. 22.5 h for formulations A and B, respectively). The 90% confidence intervals for the ratio between both products regarding these metrics were close to the 0.8-1.25 range, considered necessary for bioequivalence. Differences did not reach 20% in any case and were not determined by a formulation effect, but probably by a patients' variability effect. Concerning pharmacodynamic features, a high similitude in reticulocyte counts increments until 216 hours and the percentage decrease in serum iron until 120 hours was observed. There were no differences between formulations regarding the adverse events and their intensity. The more frequent events were pain at injection site (35.3%) and hypertension (29%). Additionally, further treatment of the patients with the study product yielded satisfactory increases in hemoglobin and hematocrit values.. The formulations are comparable. The newly developed product should be acceptable for long-term application.

Topics: Adult; Aged; Anemia; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Erythrocytes represent an important component of the antioxidant capacity of blood, comprising, in particular, intracellular enzymes, including platelet-activating factor acetylhydrolase (PAF-AH) and glutathione peroxidase (Gpx). We evaluated the erythrocyte PAF-AH and Gpx activities in various stages of chronic kidney disease (CKD), and further investigated whether erythropoietin (EPO) administration in these patients has any influence on the enzyme activities.. Thirty-six patients (19 men and 17 women) with CKD (stages 1 to 5) participated in the study. Thirteen of them presented with CKD stage 1 to 2 (group I), whereas 23 patients presented with CKD stage 3 to 5 and randomized into two groups (i.e., groups II and III). Patients of group II (N= 11) were administered EPO subcutaneously, 50 units per kg once per week. In group III (N= 12), EPO was initiated only when the hemoglobin (Hb) levels decreased during follow-up to less than 9 g/dL. All patients were seen on an outpatient basis at 2 and 4 months. Fifteen normolipidemic age- and sex-matched healthy volunteers also participated in the study and were used as controls. The PAF-AH and Gpx activities were determined in isolated washed erythrocytes.. The erythrocyte-associated PAF-AH and Gpx activities were higher in all CKD patient groups at baseline compared to controls, the groups II and III exhibiting significantly higher enzyme activities compared with group I. In all studied populations, both enzyme activities were negatively correlated with the creatinine clearance values. Importantly, the PAF-AH and Gpx activities were progressively decreased during the follow-up in patients not treated with EPO (group III), a phenomenon not observed in patients receiving EPO (group II), or in patients of group I. This reduction in enzyme activities was positively correlated with the decrease in the creatinine clearance values in patients of group III.. Significant alterations in the erythrocyte-associated PAF-AH and Gpx activities related to the disease stage are observed in CKD patients. Administration of EPO prevented the reduction in enzyme activities observed during the progression of the renal insufficiency, thus preserving the erythrocyte defense mechanisms against oxidative stress.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Adult; Aged; Aged, 80 and over; Anemia; Erythrocytes; Erythropoietin; Female; Follow-Up Studies; Glutathione Peroxidase; Hemoglobins; Humans; In Vitro Techniques; Kidney Failure, Chronic; Male; Middle Aged; Oxidation-Reduction; Thiobarbituric Acid Reactive Substances

Dialysis patients with a high body mass index are less likely to experience severe anemia. Leptin, a hormone secreted by adipocytes, may have a role in protecting against renal anemia. The aim of the present study is to determine the effect of an increase in serum leptin levels by increasing energy intake on recombinant human erythropoietin (rHuEPO) response in long-term hemodialysis (HD) patients.. We enrolled 65 long-term HD patients to explore the association between leptin level and rHuEPO response by classifying them as either high- or low-leptin individuals (phase 1). Thereafter, 39 patients with malnutrition by means of Subjective Global Assessment were randomly assigned to high-energy and high-protein (an extra 475 kcal and 16.6 g of protein daily; group A; n = 12) or standard-energy, but high-protein (an extra 67.2 kcal and 16.8 g of protein daily; group B; n = 27), supplementation for 12 weeks. Serial serum leptin levels, nutritional measures, and hematologic parameters were obtained. Age- and sex-matched well-nourished patients (group C; n = 16) not administered extra nutritional supplementation served as control subjects (phase 2).. In phase 1, a significantly lower erythropoietin dose, greater hematocrit, and better nutritional measures were observed in the high-leptin group (P < 0.001). In phase 2, there was a significant increase in body fat mass (P = 0.001) and median serum leptin levels (P < 0.001) in response to 12 weeks of high-energy supplementation in group A, accompanied by markedly improved erythropoiesis (P < 0.05) compared with groups B and C.. Hyperleptinemia reflects better nutritional status and rHuEPO response in long-term HD patients. Increasing energy intake improves erythropoiesis, which may be mediated in part by an increase in serum leptin levels.

Topics: Adipose Tissue; Aged; Anemia; Body Composition; Cross-Sectional Studies; Dietary Proteins; Dietary Supplements; Drug Resistance; Energy Intake; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Prospective Studies; Protein-Energy Malnutrition; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Increased levels of soluble adhesion molecules have been reported in haemodialysis (HD) patients. Recent studies have shown that recombinant human erythropoietin (rHuEPO) elicits proliferation and migration of endothelial cells and modifies endothelial function. The present study was design to explore the effects of rHuEPO on serum levels of soluble adhesion molecules in HD patients.. Soluble serum levels of E-selectin (sE-selectin), intracellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) were measured by ELISA in 29 rHuEPO naïve HD patients (20 males, 9 females) and 10 control subjects at baseline and second month. The HD patients with a haemoglobin level lower than 10.0 mg/dL (n = 19) were administered rHuEPO therapy and other HD patients (n = 10) were followed as a placebo group.. Serum levels of soluble adhesion molecules were significantly higher in HD patients compared with the control group. A significant rise from the baseline in sE-selectin levels (77 +/- 70 vs 100 +/- 86 ng/mL, P < 0.05) was observed 2 months after rHuEPO initiation, while sICAM-1 and sVCAM-1 levels decreased (271 +/- 261 vs 197 +/- 89 and 1043 +/- 243 vs 990 +/- 236 ng/mL, respectively, P < 0.05).. The present data indicate that rHuEPO could have an important action on serum levels of soluble adhesion molecules in HD patients. rHuEPO might modify the expression of adhesion molecules from endothelial cells either. However, the exact mechanism responsible for the serum elevation of these molecules in HD patients is yet to be fully elucidated.

Topics: Adult; Aged; Anemia; Cell Adhesion Molecules; E-Selectin; Erythropoietin; Female; Humans; Intercellular Adhesion Molecule-1; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Solubility; Vascular Cell Adhesion Molecule-1

Pediatric patients with end-stage renal disease undergoing hemodialysis (HD) frequently develop anemia. Administration of recombinant human erythropoietin (rHuEPO) is effective in managing this anemia, although the additional demand for iron often results in iron deficiency. In adult patients undergoing HD, intravenous (IV) iron administration is known to replenish iron stores more effectively than oral iron administration. Nevertheless, IV iron supplementation is underutilized in pediatric patients, possibly because of unproved safety in this population. This international, multicenter study investigated the safety and efficacy of two dosing regimens (1.5 mg kg(-1) and 3.0 mg kg(-1)) of sodium ferric gluconate complex (SFGC) therapy, during eight consecutive HD sessions, in iron-deficient pediatric HD patients receiving concomitant rHuEPO therapy. Safety was evaluated in 66 patients and efficacy was evaluated in 56 patients. Significant increases from baseline were observed in both treatment groups 2 and 4 weeks after cessation of SFGC dosing for mean hemoglobin, hematocrit, transferrin saturation, serum ferritin, and reticulocyte hemoglobin content. Efficacy and safety profiles were comparable for 1.5 mg kg(-1) and 3.0 mg kg(-1) SFGC with no unexpected adverse events with either dose. Administration of SFGC was safe and efficacious in the pediatric HD population. Given the equivalent efficacy of the two doses, an initial dosing regimen of 1.5 mg kg(-1) is recommended for pediatric HD patients.

Topics: Adolescent; Anemia, Iron-Deficiency; Child; Dose-Response Relationship, Drug; Double-Blind Method; Erythropoietin; Female; Ferric Compounds; Hematinics; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Previous studies have hinted at possible associations between anemia and progression of renal disease. The study objective was to determine whether treatment with erythropoiesis-stimulating proteins (ESPs) can curb the rate of decline in renal function in predialysis patients with chronic kidney disease (CKD).. Observational, before/after analysis using electronic medical records from the Veterans Administration (VA). Included patients had at least two measurements of serum creatinine levels before and after ESP treatment initiation. The Cockcroft-Gault formula was used to derive estimates of glomerular filtration rate (GFR). Rate of renal function decline prior to and following initiation of therapy were compared.. One hundred and twenty two patients with renal impairment levels of Stage 3 (moderate) or Stage 4 (severe) at ESP treatment initiation were identified. Over 80% of patients initiated therapy with either Grade 1 or Grade 2 anemia. The rate of renal function decline was calculated as the slope of the least-squares linear regression line of the inverse serum creatinine over time during the pre-treatment initiation and post-treatment initiation time periods. Overall, patients experienced a slowing in the rate of renal function decline after treatment was initiated (mean pretreatment initiation rate of -0.094 dL/mg/yr versus mean post-treatment initiation rate of -0.057 dL/mg/yr).. Renal function declined at a slower rate following ESP initiation. Results are consistent with prior studies indicating delayed dialysis initiation in patients treated with ESPs. Analyses were limited by the observational study design and lack of information regarding some potential confounders. Longer-term, prospective trials are needed to determine whether ESPs slow progression of renal disease and the potential magnitude of such an effect.

Topics: Aged; Aged, 80 and over; Anemia; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Disease Progression; Erythropoietin; Female; Hematinics; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Retrospective Studies; Treatment Outcome

Left ventricular hypertrophy (LVH) frequently complicates chronic renal insufficiency. Anemia is also common in these patients and may contribute to LVH.. We conducted an open-label interventional trial to evaluate the effect of recombinant erythropoietin (rhEPO) on left ventricular mass index (LVMI) in anemic patients with renal insufficiency. Adults with creatinine clearance 10 to 30 mL/min (nondiabetics) or 20 to 40 mL/min (diabetics) were recruited, and rhEPO was given to those with anemia (hemoglobin level <10 g/dL). Baseline and 6-month LVMI and LVH (LVMI >130 g/m(2) in men and >100 g/m(2) in women), hemoglobin levels, creatinine clearance, blood pressure, medications, and medical history were obtained. Forty anemic and 61 nonanemic control subjects were enrolled.. Overall, the prevalence of LVH was 68.3% (95% CI 58.3-77.2), and entry hemoglobin level was the only significant predictor of baseline LVH (adjusted OR 0.69 per g/dL increase in hemoglobin, 95% CI 0.50-0.94). After 6 months, LVMI decreased in anemic patients receiving rhEPO (142 +/- 56 vs. 157 +/- 56 g/m(2)) (P= 0.007), with an increase in hemoglobin (11.3 +/- 1.9 vs. 9.1 +/- 0.7 g/dL) (P= 0.001). There were no changes in LVMI or hemoglobin level among controls. After adjusting for confounders and change in hemoglobin, receipt of rhEPO was associated with a significant reduction in LVMI (P= 0.01).. Treatment with rhEPO was not independently associated with significant changes in blood pressure or renal function. LVH is a common finding in chronic renal insufficiency and is associated with lower hemoglobin levels. Treatment with rhEPO may decrease LVH in patients with severe renal insufficiency and anemia.

Topics: Adult; Aged; Anemia; Blood Pressure; Erythropoietin; Female; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Predictive Value of Tests; Prevalence; Recombinant Proteins; Severity of Illness Index

The purpose of this study was to compare erythropoietin dosage requirements during subcutaneous versus intravenous administration in a hemodialysis population. Hemodialysis patients receiving subcutaneous epoetin alfa were switched to the intravenous route using a prospective, crossover design. Baseline anemia parameters were measured at months -2, -1, and 0 when patients were receiving subcutaneous dosing and compared to months 4, 5, and 6 after the switch to intravenous dosing. Ninety-eight patients were enrolled into the study with an average age of 54.8 years. Over the course of the study, 34 patients were excluded from analysis, leaving 64 patients with complete hemoglobin and erythropoietin dosing data throughout the subcutaneous and intravenous evaluation periods. In these patients, the dose of erythropoietin increased significantly from the subcutaneous to the intravenous period (7567.7 to 10229.2 IU/wk). The conversion of hemodialysis patients from the subcutaneous to the intravenous route of administration significantly increased epoetin alfa dosage requirements.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Cross-Over Studies; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Ferritins; Hematinics; Hemoglobins; Humans; Infusions, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis

Left ventricular hypertrophy (LVH) and inflammation independently increase risk for death in people who receive hemodialysis. A nonrandomized, controlled trial was conducted of the effect of short daily (6 sessions/wk of 3 h each) or conventional (three sessions/wk of 4 h each) hemodialysis on LVH and inflammatory factors. A total of 26 short daily hemodialysis and 51 matched conventional hemodialysis patients were enrolled, and baseline and 12-mo measures of echocardiographic left ventricular mass index (LVMI), serum C-reactive protein (CRP), serum calcium and phosphorus, and erythropoietin resistance index were collected. Baseline characteristics were similar between groups except that hemoglobin and serum calcium were lower and serum phosphorus was higher in the short daily hemodialysis group. At 12-mo follow-up, short daily hemodialysis patients experienced a 30% decrease in LVMI (154 +/- 33 to 108 +/- 25; P < 0.0001). After adjustment for potential confounders, short daily hemodialysis (beta = -41.63, P = 0.03) and percentage decrease in serum phosphorus (beta = -0.12, P = 0.04) predicted a 12-mo decrease in LVMI. Among short daily hemodialysis patients, there were significant reductions in median CRP levels [1.22 interquartile range (IQR) (0.37 to 3.70) to 0.05 IQR (0.05 to 1.17); P < 0.01] and erythropoietin resistance index [19.5 IQR (8.6 to 37.6) to 10.5 IQR (5.5 to 14.6); P < 0.001]. There were no significant changes in LVMI, CRP, or erythropoietin resistance index in the conventional hemodialysis group. Short daily hemodialysis is associated with improved fluid and phosphorus management and a reduction in LVH and inflammatory factors compared with conventional hemodialysis. Future trials are needed to determine whether short daily hemodialysis can reduce morbidity and mortality in this high-risk population.

Topics: Adult; Biomarkers; C-Reactive Protein; Calcium; Drug Resistance; Erythropoietin; Female; Humans; Hypertrophy, Left Ventricular; Inflammation Mediators; Kidney Failure, Chronic; Male; Middle Aged; Phosphorus; Prospective Studies; Recombinant Proteins; Renal Dialysis; Time Factors

Treatment with recombinant human erythropoietin (rHuEPO) has been a major advance for the management of anemia in patients on hemodialysis. Therapy, however, is often observed to be associated with recurrent cyclic fluctuations in hemoglobin levels. The purpose of this analysis was to describe the phenomenology of hemoglobin cycling during rHuEPO treatment.. Data were analyzed for 281 hemodialysis patients treated at Winthrop-University Hospital Dialysis Centers between 1998 and 2003. Eligible patients' first full 1-year period with less than 10 hospital days was studied. Hemoglobin cycling (cycles with amplitude >1.5 g/dL and duration >8 weeks) and excursions (half of one full cycle) were analyzed.. Greater than 90% of patients experienced hemoglobin cycling. The mean number of hemoglobin excursions was 3.1 +/- 1.1 per patient/year. The mean amplitude per hemoglobin excursion was 2.51 +/- 0.89 g/dL. The mean duration of hemoglobin excursions was 10.3 +/- 5.1 weeks. Factors associated with initiation of up excursions included increases in rHuEPO dose (84%), intravenous iron treatment initiation or increase in dose (27%), posthospital discharge (36%), factors associated with down excursions included rHuEPO dose hold (15%) or dose reduction (62%), infection (6%), discontinuation of intravenous iron therapy (5%), and hospitalization (14%). Patients with frequent hemoglobin cycling (>two full cycles per year) were characterized as being more responsive to rHuEPO [index of EPO responsiveness (ERI) 1036 +/- 659 compared to 1992 +/- 701 for other patients] (P = 0.02).. Hemoglobin cycling is a common occurrence in rHuEPO-treated hemodialysis patients. It is most closely associated with frequent rHuEPO dose changes, hospitalization, and iron treatment practices.

Topics: Aged; Anemia; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

To determine whether extended epoetin alfa dosing schedules of up to once every four weeks are as effective as weekly dosing in maintaining hemoglobin (Hb) levels in patients with anemia of chronic kidney disease (CKD).. This randomized, open-label trial enrolled patients with anemia of CKD not on dialysis. Patients were required to have a stable Hb level (> or = 11.0 g/dl) and to have been previously receiving epoetin alfa for two or more months. Patients were randomized to one of four subcutaneously administered epoetin alfa dosing regimens: 10,000 units (U) once weekly (QW), 20,000 U every two weeks (Q2W), 30,000 U every three weeks (Q3W) or 40,000 U every four weeks (Q4W). Dose reductions, but not escalations, were permitted. Patients received treatment for a total of 16 weeks. The primary endpoint for the trial was the mean final Hb measurements of the QW, Q2W, Q3W, and Q4W groups. The primary efficacy analyses were non-inferiority assessments of the mean final Hb measurements of the Q2W, Q3W, and Q4W groups, compared with the QW group. The primary efficacy analyses were performed using a modified intent-to-treat (MITT) population, defined as all patients meeting all inclusion/exclusion criteria (or, if not satisfying all criteria, were granted an exemption at study entry), and who were randomized and received at least one dose of study medication. A per-protocol population, based on all patients who met the MITT criteria and completed the entire study, was used to evaluate the robustness of the MITT results. Quality of life was assessed for all dosing groups throughout the study. Safety was based on all patients randomized who received at least one dose of study medication.. A total of 519 patients were enrolled; 445 were included in the MITT population. The four treatment groups were comparable with respect to baseline characteristics. The primary etiologies of CKD were diabetes (45.7%) and hypertension (29.9%). The mean baseline Hb, serum creatinine and glomerular filtration rate for all patients were 11.9 +/- 0.8 g/dl, 3.1 mg/dl, and 21.1 ml/min/1.73 m2, respectively. The mean baseline transferrin saturation was 25.2% and the mean ferritin was 201.9 ng/ml for all patients. All groups had a mean final Hb of > 11.0 g/dl. The mean final Hb levels of the Q2W and Q4W groups were statistically non-inferior to the QW group. The results of the per-protocol analysis were consistent with the MITT results. In addition, 93.5%, 89.5%, 77.2%, and 76.0% of patients maintained a mean Hb > or = 11.0 g/dl throughout the course of the study in the QW, Q2W, Q3W, and Q4W groups, respectively. Quality of life was maintained or improved from baseline to final within each dosing group. There were no significant differences in the mean final quality of life scores between the QW group and the Q2W, Q3W, and Q4W groups. Among the 513 patients evaluated for safety, epoetin alfa was well tolerated with no differences in adverse events between groups. The incidence of thrombotic adverse events was low (2.5% of patients), as was mortality (1.4% of patients).. Approximately 90% of patients dosed once every two weeks and over 75% of patients dosed once every three or four weeks maintained mean Hb levels > or = 11.0 g/dl, consistent with the Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines. This study suggests that extended epoetin alfa dosing schedules are effective and safe for maintaining Hb, and may offer the possibility of increased flexibility and convenience for the majority of patients with the anemia of CKD.

Topics: Aged; Analysis of Variance; Anemia; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Quality of Life; Recombinant Proteins; Treatment Outcome

Angiotensin-converting enzyme inhibitors (ACEIs) were accepted as a potential cause of inadequate epoetin response in chronic kidney disease (CKD) patients. We aimed to determine the effects of valsartan, an angiotensin receptor blocker (ARB), on serum ertyhropoietin levels and on certain biochemical and haematological parameters in hypertensive CKD patients. Twenty-two stage III-IV CKD patients (mean age; 56.8 +/- 8.9 years, 12 male 10 female) were included in the study. Before initiating the treatment, current anti-hypertensive treatments (if any) were discontinued, and blood samples were collected after a washout period of 3 weeks. Valsartan 80 mg/day was started, and additional anti-hypertensive agents were given according to study protocol if needed. One way Anova and paired t-tests were used for statistical comparisons. Serum blood urea nitrogen (BUN), creatinine, uric acid, potassium, haemoglobin and erythropoietin values were measured, and glomerular filtration rates were calculated before and 3, 6 and 90 days after valsartan treatment, a significant reduction in EPO level was observed at 3rd (19.6 +/- 24.0 vs. 13.8 +/- 8.5, p = 0.010), 6th (12.1 +/- 7.6, p = 0.009), and 90th days (8.3 +/- 5.4, p = 0.007). When pre-treatment values were compared with 90th day results, no significant change was observed in terms of hgb, htc, serum BUN, creatinine, uric acid, potassium, and GFR values. In conclusion, valsartan, an ARB, did not decrease haemoglobin levels in stage III-IV CKD patients despite significant reduction in serum erythropoietinlevels, so ARBs may be preferred to ACEIs in CKD patients when indicated.

Topics: Analysis of Variance; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Blood Urea Nitrogen; Creatinine; Erythropoietin; Female; Follow-Up Studies; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Potassium; Tetrazoles; Uric Acid; Valine; Valsartan

Darbepoetin alfa use has been reported in 7 children with chronic renal failure (CRF). Our objective was to evaluate the efficacy and safety of darbepoetin and determine a therapeutic dose in a larger sample of children with CRF.. Twenty-six children with chronic renal insufficiency (CRI) GFR <30 mL/min/1.73 m(2), on peritoneal dialysis (PD) or hemodialysis (HD) entered a prospective, open-label study of darbepoetin. Seven ineligible children who underwent the same evaluation were analyzed retrospectively. The starting dose was 0.45 microg/kg/week. IRB/REB approval and informed consent were obtained. The primary outcome measure was hemoglobin (Hb) response within a target range of 10.0 to 12.5 g/dL between 8 and 12 and 20 and 28 weeks.. Thirty-three children (15 CRI, 9 HD, 9 PD; aged 1-17 years) were enrolled in the study. Ten patients dropped out (3 before 12 weeks and 7 before 28 weeks), none due to darbepoetin. Mean Hbs were 11.8 and 11.4 between weeks 8 and 12 and 20 and 28, respectively; the proportion of patients with Hb values >10.0 g/dL was 97% and 91% in the same intervals. No effect of grouping patients into CRI, HD, or PD or prospective versus retrospective was observed. One of 13 serious adverse events (hypertension) was possibly related to darbepoetin; 8/14 children reported injection-site pain. At 12 and 28 weeks, respectively, 73% and 87% were receiving darbepoetin less than once weekly.. A dose approximating 0.5 microg/kg/week of darbepoetin effectively treats anemia in children with chronic renal failure; for many, this may be proportionately increased and injected less than once weekly.

Topics: Adolescent; Anemia; Antibodies; Child; Child, Preschool; Darbepoetin alfa; Erythropoietin; Hemoglobins; Humans; Infant; Kidney Failure, Chronic; Peritoneal Dialysis; Prospective Studies; Renal Dialysis; Treatment Outcome

Of the known risk factors for chronic kidney disease (CKD), race represents one that is non-modifiable, while smoking is another that is modifiable. Moreover, smoking tends to increase red blood cell mass, which is frequently diminished in CKD. No studies have examined the interplay of race with smoking on anaemia management in patients with CKD.. We examined the effects of smoking on anaemia management in CKD and its variation across race in a previously conducted study of CKD patients (n = 1312) initiated on weekly epoetin alfa and followed for 16 weeks. Smoking status was classified as current vs non-smoker. Race was classified as African-American vs non-African-American. Changes in estimated glomerular filtration rate, urinary albumin excretion, and erythropoietic response to weekly epoetin alfa were examined.. Overall, African-Americans had lower baseline Hb than non-African-Americans. African-American non-smokers did not mount an erythropoetic response comparable to other non-smokers by final Hb (mean 11.29 g/dl vs 11.64 g/dl, P<0.001) or week 16 Hb (mean 11.61 g/dl vs 11.86 g/dl, P = 0.02). However, African-American smokers had a more significant erythropoietic response than their non-smoking counterparts and were comparable to their smoking non-African-American counterparts. There was no effect of smoking on renal function or urinary protein excretion over the course of the study.. African-American non-smokers exhibit a diminished response to standard epoetin alfa dosing than non-smokers in other races. However, African-American smokers with CKD exhibit a response to epoetin alfa comparable to patients of other races. These findings may have implications for African-Americans who have CKD-related anaemia.

Topics: Aged; Anemia; Black or African American; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoiesis; Erythropoietin; Female; Ferritins; Follow-Up Studies; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Risk Factors; Smoking; Treatment Outcome; United States

Cardiovascular disease is the major cause of mortality in maintenance hemodialysis patients. Left ventricular dysfunction is present in approximately 80% of these patients and is highly predictive of future ischemic heart disease, cardiac failure, and death. Anemia has been identified as one of several risk factors responsible for cardiac complications. The treatment of renal anemia with recombinant human erythropoietin (rHuEpo) and consequent improvement of cardiac performance may reverse pathological changes in left ventricular geometry. In this study, the acute and chronic effects of rHuEpo administration on 24-hour ambulatory blood pressure recordings and echocardiographic parameters in 30 rHuEpo-naïve maintenance hemodialysis patients were examined. Twenty-four-hour ambulatory blood pressure monitoring was performed prior to and after 1 week and 6 months of rHuEpo administration. The patients underwent echocardiographic examination prior to and after 6 months of rHuEpo administration. One week treatment with rHuEpo did not cause any significant change in 24-hour ambulatory blood pressure recordings. After 6 months of therapy, serum hemoglobin levels increased from 8.8 +/- 0.66 g/dL to 10.8 +/- 0.70 g/dL (P < 0.05). Echocardiographic examination revealed elevation in ejection fraction (62.26 +/- 6.84% vs. 69.90 +/- 8.98%, P < 0.05) with reductions in fractional shortening (36.70 +/- 4.96% vs. 35.96 +/- 6.32%, P < 0.05), interventricular septum thickness (1.21 +/- 0.16 vs. 1.00 +/- 0.16 cm, P < 0.05), and left ventricular mass index (148.2 +/- 46.5 g/m2 vs. 93.6 +/- 17.2 g/m2, P < 0.05). Doppler echocardiography and tissue Doppler imaging provided additional information in comparison with conventional echocardiography. Before treatment, mitral flow E wave (E, 0.64 +/- 0.27 vs. 0.82 +/- 0.17 cm/s), mitral flow A wave (A, 0.80 +/- 0.21 vs. 0.70 +/- 0.21 cm/s), early diastolic velocity of lateral wall (Lateral E', 11.2 +/- 2.8 vs. 12.4 +/- 2.3 cm/s), late diastolic velocity of lateral wall (Lateral A', 6.7 +/- 2.5 vs. 7.8 +/- 2.1 cm/s), early diastolic velocity of septal wall (Septal E', 9.7 +/- 2.9 vs. 11.3 +/- 1.1 cm/s), and late diastolic velocity of septal wall (Septal A', 6.4 +/- 2.1 vs. 7.8 +/- 2.0 cm/s) were significantly lower in patients than in the controls. Patients and controls have similar deceleration time of mitral flow E wave (E Dec, 186 +/- 57.8 vs. 192 +/- 62.4 ms), isovolumic left ventricular relaxation time (IVRT, 111.9 +/- 30.7 vs. 91

Topics: Anemia; Blood Flow Velocity; Blood Pressure Monitoring, Ambulatory; Diastole; Echocardiography; Erythropoietin; Female; Heart Septum; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Stroke Volume; Systole

Some previous studies suggest that activation of the fibrinolytic system may induce platelet dysfunction in haemodialysis patients. Accordingly, inhibition of fibrinolysis may improve platelet dysfunction, and speculatively increase haemoglobin levels. We tested this hypothesis. The study group comprised 22 patients (14 male, 8 female, median age 62), who had been on maintenance haemodialysis for more than one year. Patients were treated for three months with low-dose tranexamic acid (TXA), a potent anti-fibrinolytic agent. The dosages of erythropoietin and the haemodialysis procedure were not changed significantly during the study. We primarily followed platelet function (by in vitro closure time test) and haemoglobin values. Patients were divided into those with substantially prolonged (N = 9) and those with slightly delayed or normal (N = 13) in vitro closure time. Treatment with TXA resulted in a significant improvement of platelet function and increased levels of haemoglobin in the first group, and no changes in either platelet function or haemoglobin values in the second group. TXA in the dosage used was biologically active, since a significant decrease in plasminogen and D-dimer were found in both groups. No significant changes in other fibrinolytic parameters or von Willebrand factor were found. No complications in terms of arterial or venous thrombosis were observed. Our pilot study suggests that long-term, low-dose TXA treatment of haemodialysis patients with substantially prolonged in vitro closure time results in a significant improvement of platelet dysfunction and a significant increase in haemoglobin values. These new, promising results merit further investigation in larger studies.

Topics: Aged; Antifibrinolytic Agents; Blood Platelets; Erythropoietin; Female; Fibrin Fibrinogen Degradation Products; Fibrinolysis; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Plasminogen; Platelet Function Tests; Prospective Studies; Renal Dialysis; Time Factors; Tranexamic Acid

Darbepoetin alfa has demonstrated its efficacy when is administered subcutaneously once-weekly and once every 2 weeks as treatment of anemia in patients with chronic kidney disease (CKD). The aim of this study is to assess the efficacy of subcutaneus darbepoetin alfa administered once monthly in patients with progressive CKD who maintained stable levels of Hb treated on once every other week dosing.. Patients included in the study maintained hemoglobin (Hb) > 11 g/dl and were receiving darbepoetin alfa once every other week during at least 4 months. We studied a frequency interval dose change: once every other week frequency was converted to once monthly at equivalent dose. The study completers were 12 patients over the third month and 7 at the end of one year evaluation period.. A statistic significant decrease in Hb and hematocrit (Hto) was observed over the third month, although all patients maintain Hb levels higher than 11 g/dl. At the same time it was appreciated a statistic significant increased on creatinine (Cr) and parathyroid hormone levels (PTH). At the end of one year evaluation period no differences were observed in any of variables.. Darbepoetin alfa administered once monthly is an efficacious option as treatment of anemia for patientes with CKD. With a dose of 1 mcg/kg/month, all patientes maintain Hb > 11 g/dl.

Topics: Aged; Anemia; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Prospective Studies

It is not known whether prevention of anemia among patients with chronic kidney disease would affect the development or progression of left ventricular (LV) hypertrophy. A randomized controlled trial was performed with 155 patients with chronic kidney disease (creatinine clearance, 15 to 50 ml/min), with entry hemoglobin concentrations ([Hb]) of 110 to 120 g/L (female patients) or 110 to 130 g/L (male patients). Patients were monitored for 2 yr or until they required dialysis; the patients were randomized to receive epoetin alpha as necessary to maintain [Hb] between 120 and 130 g/L (group A) or between 90 and 100 g/L (group B). [Hb] increased for group A (from 112 +/- 9 to 121 +/- 14 g/L, mean +/- SD) and decreased for group B (from 112 +/- 8 to 108 +/- 13 g/L) (P < 0.001, group A versus group B). On an intent-to-treat analysis, the changes in LV mass index for the groups during the 2-yr period were not significantly different (2.5 +/- 20 g/m(2) for group A versus 4.5 +/- 20 g/m(2) for group B, P = NS). There was no significant difference between the groups in 2-yr mean unadjusted systolic BP (141 +/- 14 versus 138 +/- 13 mmHg) or diastolic BP (80 +/- 6 versus 79 +/- 7 mmHg). The decline in renal function in 2 yr, as assessed with nuclear estimations of GFR, also did not differ significantly between the groups (8 +/- 9 versus 6 +/- 8 ml/min per 1.73 m(2)). In conclusion, maintenance of [Hb] above 120 g/L, compared with 90 to 100 g/L, had similar effects on the LV mass index and did not clearly affect the development or progression of LV hypertrophy. The maintenance of [Hb] above 100 g/L for many patients in group B might have been attributable to the relative preservation of renal function.

Topics: Anemia; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Time Factors

Drug doses for children are usually calculated by reducing adult doses in proportion to bodyweight. The clinically effective dose of recombinant human erythropoietin (epoetin) in children, however, seems to be higher than predicted by this calculation.. To determine the quantitative relationship between epoetin dose, bodyweight and response in children with end-stage renal disease.. The time-course of haemoglobin in 52 children during long-term treatment with epoetin beta was analysed by population pharmacodynamic modelling. Patients were 5-20 years old and weighed 16-53kg at the beginning of treatment. Epoetin beta was given intravenously three times per week after haemodialysis. Doses ranged from 110 to 7500IU (3-205 IU/kg). Haemoglobin versus time was described by assuming that the haemoglobin level rises after each dose due to the formation of new red blood cells, which then survive according to a logistic function. The initial rise after each dose was modelled in terms of absolute dose (not dose/kg). A parametric analysis was done with NONMEM, followed by a nonparametric analysis with NPAG.. Dose-response was best described by a sigmoid maximum-effect (E(max)) model with median E(max) = 0.29 g/dL, median 50% effective dose (ED(50)) = 2400IU and shape parameter gamma = 2. The estimated median survival time of the epoetin-induced red blood cells, tau, was 76 days. Neither of the dose-response parameters E(max) and ED(50) showed dependence on bodyweight. The median haemoglobin response to a standard dose, 0.042 g/dL for 1000IU, was similar to that reported for adults with intravenous administration.. Doses for children in this age range should be specified as absolute amounts rather than amounts per unit bodyweight. Initial doses can be calculated individually, based on haemoglobin level before treatment, the desired haemoglobin at steady state and the median population parameters E(max), ED(50) and tau.

Topics: Adolescent; Adult; Anemia; Body Weight; Child; Child, Preschool; Dose-Response Relationship, Drug; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Models, Biological; Recombinant Proteins; Renal Dialysis; Statistics, Nonparametric

Darbepoietin alfa (NESP) is a new long-acting erythropoietin, with a half-life 3 times longer than the old epoietins. In the present study, we evaluated the efficacy of NESP in a group of children on hemodialysis. Seven children, five male and two female, with a mean age of 11.5 +/- 3 years and a mean weight of 34.1 +/- 11 kg, were enrolled in the study. All had been treated for at least 6 months with epoietin alfa at a mean dose of 106 +/- 76 IU/kg 3 times/week i.v. They were then given NESP at a mean dose of 1.59 +/- 1.19 microg/kg once a week i.v., according to the suggested conversion index (weekly epoietin alfa dose/200=weekly NESP dose). Anemia was evaluated at the end of a dialysis session. This was especially important for children less compliant with water restriction. Serum ferritin and percentage transferrin saturation (TSAT) were also monitored, as were dialysis efficacy (Kt/V), blood pressure, and heparin requirements. Before starting the new treatment, all patients had an adequate mean hemoglobin (Hb) level (11.19 +/- 1.7 g/dl) and an adequate iron status (TSAT 24.2 +/- 11.5, serum ferritin 220 +/- 105 mg/dl). Five of the seven patients were also treated with intravenous ferric gluconate (10-20 mg/kg per week). Six children were on antihypertensive treatment. After the 1st month of treatment, we observed an excessive increase in Hb, 12.3 +/- 1.7 g/dl, (P<0.05), with severe hypertension in the youngest two patients (Hb>13 g/dl). A short discontinuation of the medication, followed by restarting at a decreased dosage, allowed us to continue with the treatment. At the 2nd month of follow-up, a mean plasma Hb level of 12.2 +/- 1.2 g/dl was observed, with a NESP mean dose of 0.79 +/- 0.4 microg/kg per week. Steady state was reached at 3 months, with a mean Hb of 11.8 +/- 1.4 g/dl and a mean NESP dose of 0.51 +/- 0.18 microg/kg per week (P<0.05). These results persisted at 6 months of follow-up; only one child had a persistent increase in platelet level (373,000 vs. 555,000). Dialysis efficiency and heparin requirements during dialysis did not change significantly. The high efficacy of NESP allowed a consistent reduction in dosage. The suggested conversion index does not appear to be correct for pediatric patients. Our experience suggests that in this population the correct dose could be 0.25-0.75 microg/kg per week. Hypertension was the only major side effect reported. The influence of NESP on platelet proliferation needs to be further investigate

Topics: Adolescent; Anemia; Blood Pressure; Body Temperature; Child; Darbepoetin alfa; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis

Anaemia correction in patients with end-stage renal disease has been enhanced following the use of epoetin alfa or beta and there are a number of studies detailing its application. Dialysis centres are dealing with greater numbers of elderly patients and anaemia correction in these individuals may differ by virtue of co-existing comorbidity and their age.. The aim of this study was to examine the response of the elderly patients to anaemia correction using a locally devised anaemia correction protocol while receiving dialysis.. An incident, non-randomised, cohort observational study in a single centre was used to compare the correction of anaemia in a population of elderly (> or =65 years of age) and young dialysis patients. All incident patients starting peritoneal dialysis and haemodialysis (HD) between January 1998 and December 2000 were selected and treated using a locally devised anaemia correction protocol and observed for at least 1 year. Anaemia correction following adjustments for factors such as age, comorbidity, dialysis type, dialysis access type and predialysis nephrological care was assessed.. 198 patients commenced dialysis with 86 elderly patients (mean age +/- SD 73.7 +/- 4.9 years). The elderly patients had similar periods of predialysis nephrological care as the younger patients. Most patients received HD and required a tunnelled dialysis catheter (TC) as vascular access. Equivalent numbers of elderly patients received peritoneal dialysis. Comorbid scores were greater in the elderly and patient survival was dependent upon these comorbid factors. Following the strict use of TCs, patient survival was similar to those patients commencing HD with arterio-venous fistulae. Anaemia correction in the elderly was similar to the younger patients, with a median haemoglobin of 11.3 g/dL. By 6 months of dialysis, most patients achieved the UK Renal Association anaemia correction standard (haemoglobin above 10 g/dL). The elderly patients maintained significantly higher serum ferritin levels throughout (median 209 microg/L) and required less epoetin alfa or beta (median 91.6 units/kg/wk), indicating that functional iron deficiency in the elderly dialysis patients is less. Intravenous iron sucrose doses were similar in both age groups and iron overload (serum ferritin above 800 microg/L) had been avoided following the use of the intravenous iron protocol.. The study has noted that elderly patients responded to anaemia corrective therapies as well as the younger patients, despite greater levels of comorbidity while requiring less epoetin alfa or beta.

Topics: Aged; Aged, 80 and over; Aging; Anemia; Comorbidity; Epoetin Alfa; Erythropoietin; Ferritins; Geriatrics; Humans; Kidney Failure, Chronic; Middle Aged; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis; Survival Analysis; Treatment Outcome

Recombinant human erythropoietin (rHuEPO) has been reported to induce hypertension. We investigated the effect of a single injection of rHuEPO on blood pressure in patients receiving hemodialysis (HD) and in patients with predialysis chronic renal failure (CRF). Forty-one patients receiving HD and 36 patients with predialysis CRF received an intravenous injection of rHuEPO, and blood pressure and plasma endothelin-1 were measured before and 30 min after the injection. Mean blood pressure was increased significantly in HD patients, but not in CRF patients (HD: 103+/-5 to 105+/-6 mmHg, p<0.05; CRF: 103+/-4 to 103+/-6, NS). The percentage of patients with increased mean blood pressure of more than 10 mmHg after rHuEPO injection was significantly larger in the HD than in the CRF group (27.0% vs. 5.5%, p<0.01). A positive correlation was found between changes in endothelin-1 level and mean blood pressure in the HD (r=0.43, p<0.01) but not in predialysis chronic renal failure. In conclusion, a single injection of rHuEPO increased blood pressure with a positive correlation with endothelin-1 release in hemodialysis patients, but not in predialysis chronic renal failure patients.

Topics: Adult; Aged; Anemia; Blood Pressure; Endothelin-1; Erythropoietin; Female; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Iron therapy maintains iron stores and optimizes the response to recombinant human erythropoietin (r-HuEPO) in patients with end-stage renal failure. Information is limited, however, regarding the preferential route of iron administration in pediatric patients receiving hemodialysis. Therefore, we prospectively randomized 35 iron-replete patients (aged >1 to <20 years) to receive up to 16 weeks of maintenance i.v. ( n=17) or daily oral ( n=18) iron. Eligible patients had received hemodialysis for >2 months, had a baseline transferrin saturation [TSAT] >20%, and were receiving maintenance r-HuEPO. Treatment arms were evenly distributed with respect to baseline demographic and clinical characteristics, with no statistically significant differences in baseline hemoglobin (Hb), hematocrit (Hct), reticulocyte Hb content (CHr), serum ferritin (SF), TSAT, or r-HuEPO dose. In the 35 patients, i.v. iron dextran and not oral iron was associated with a significant increase (138.5 to 259.1 ng/ml, P=0.003) in SF. A comparison of the change in SF between the i.v. iron group and the oral iron group was also significant ( P=0.001). Whereas only i.v. iron was associated with a significant decrease in the dose of r-HuEPO (234.0 to 157.6 U/kg per week, P=0.046) and an increase of the CHr (29.2 to 30.1 pg, P=0.049), these changes were not significantly different from those experienced by patients in the oral iron group. In both groups, the Hct remained stable and in neither group was there a significant change in the TSAT. In summary, although both oral and i.v. iron maintained patients in an iron-replete state in this short-term study, only i.v. therapy allowed for a significant improvement in iron stores.

Topics: Administration, Oral; Adolescent; Child; Erythropoietin; Female; Ferritins; Hematocrit; Hemoglobins; Humans; Infusions, Intravenous; Iron; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis; Transferrin

Darbepoetin alfa is an erythropoiesis-stimulating glycoprotein with up to 3 times longer half-life than recombinant human erythropoietin (rHuEPO) in humans. The aim of this study was to assess the efficacy and safety of darbepoetin alfa given once every other week as treatment of anemia in predialysis patients with chronic renal failure (CRF) previously treated with once-weekly epoetin alfa. A total of 42 CRF patients were included, all of whom had previously been treated with epoetin alfa and showed stable hemoglobin (Hb) levels without dose changes during the last 8 weeks prior to enrolment in this study. All patients received s.c. darbepoetin alfa once every other week at doses calculated from the protein mass equivalence between rHuEPO and darbepoetin alfa. Follow-up lasted for 24 weeks. Dose adjustments were conducted to preserve target Hb levels between 11 and 13 g/dl. Thirty-nine patients completed the 24 weeks of study. Hb levels increased during follow-up [mean values of 0.39 (p < 0.002), 0.58) (p < 0.001), and 0.83 g/dl (p < 0.001) at 8, 16 and 24 weeks, respectively] despite reducing the darbepoetin alfa dose up to 15% at 24 weeks [from 0.192 microg/kg body weight to 0.185, 0.178 and 0.163 at 8, 16, and 24 weeks, respectively (p < 0.001)]. No adverse events related to darbepoetin alfa were reported. In conclusion, these results show s.c. administration of darbepoetin alfa once every other week was superior to weekly epoetin alfa as a maintenance treatment for anemia in predialysis CRF patients, since the former provided higher Hb levels. Moreover, darbepoetin alfa administration was safe in these patients.

Topics: Aged; Anemia; Darbepoetin alfa; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hematinics; Humans; Kidney Failure, Chronic; Male; Prospective Studies; Recombinant Proteins

Partial correction of anemia by erythropoietin improves hemodialysis (HD)-associated immunosuppression. It is not known whether hemoglobin normalization improves immune status further. The authors prospectively compared the immune function of HD patients with congestive heart failure or ischemic heart disease on erythropoietin therapy randomized to normal versus anemic blood hemoglobin concentration. HD patients were randomized into a normal hemoglobin group (n = 17, target hemoglobin of 14 +/- 1 g/dl) or an anemic hemoglobin group (n = 18, target hemoglobin 10 +/- 1 g/dl). Delayed-type hypersensitivity, CD4 and CD8 counts, anti-tetanus toxoid antibody levels, erythrocyte complement receptor 1 expression, and lymphocyte proliferative responsiveness were measured. The observation period was 1 yr, and the trial was open label. Target hemoglobin was achieved and maintained in both groups. Significantly improved cutaneous reactivity was seen in the normal hemoglobin group (P = 0.003). The prevalence of anergy decreased in the normal hemoglobin group (from 60 to 20%) but increased in the anemic hemoglobin group (from 57 to 86%). The anemic hemoglobin group had higher CD8 counts compared with baseline (P = 0.0001) and compared with the normal hemoglobin group (P = 0.038). Both groups had significant increases in tetanus toxoid antibody levels after vaccination but without significant differences between groups. The anemic hemoglobin group had a progressive increase in erythrocyte complement receptor 1 levels compared with baseline (P = 0.002) and relative to the normal hemoglobin group (P = 0.023). There was no consistent pattern of altered proliferative responsiveness of lymphocytes. The data suggest that certain aspects of immune function, particularly delayed-type hypersensitivity, may be improved in HD patients by normalization of hemoglobin through the administration of increased doses of erythropoietin.

Topics: Aged; Anemia; Antibodies; CD4-CD8 Ratio; Cell Division; Erythrocytes; Erythropoietin; Female; Hemoglobins; Humans; Hypersensitivity, Delayed; Infections; Kidney Failure, Chronic; Lymphocytes; Male; Middle Aged; Prospective Studies; Receptors, Complement 3b; Recombinant Proteins; Renal Dialysis; Tetanus Toxin

Anaemia is a key component of diabetic nephropathy, but its importance has only recently been recognised. Recombinant human erythropoietin (epoetin) is an established treatment for renal anaemia, and may help to reduce complications associated with diabetic nephropathy, such as cardiovascular disease. The limited experience with the use of epoetin in this patient group prompts the urgent need for clinical data on anaemia correction in early diabetic nephropathy, particularly with regard to benefits on cardiovascular risk reduction. The Anaemia CORrection in Diabetes (ACORD) study will investigate the effects of anaemia correction on cardiac structure and function in patients with early diabetic nephropathy. This 15-month multicentre study will recruit 160 adult patients with diabetes, mild or moderate chronic kidney disease (with creatinine clearance >or=30 ml/min at screening) and moderate anaemia (haemoglobin [Hb], 10.5-13.0 g/dl). Patients will be randomised to one of two groups: the early treatment group will receive subcutaneous epoetin beta (NeoRecormon) at study entry to maintain target Hb levels of 13-15 g/dl, while the control group will reflect current practice and will not receive epoetin therapy until Hb levels decline below 10.5 g/dl. The primary efficacy variable, change in left ventricular mass index, will be evaluated at 15 months following randomisation; secondary efficacy variables will include changes in cardiac structure and function over the study period. The ACORD study should provide valuable information on the benefits of anaemia correction in patients with early diabetic nephropathy. The study will also increase awareness of the importance of treating anaemia associated with diabetes.

Topics: Anemia; Clinical Trials as Topic; Diabetic Nephropathies; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Analysis; Time Factors

Erythropoietin is known to improve outcomes in patients with anemia from chronic renal disease. However, there is uncertainty about the optimal timing of initiation of erythropoietin treatment in predialysis patients with non-severe anemia.. We conducted a randomized controlled trial of early versus deferred initiation of erythropoietin in nondiabetic predialysis patients with serum creatinine 2 to 6 mg/dL and hemoglobin 9 to 11.6 g/dL. The early treatment arm was immediately started on 50 U/kg/wk of erythropoietin alpha with appropriate titration aiming for hemoglobin of > or =13 g/dL. The deferred treatment arm would start erythropoietin only when hemoglobin decreased to <9 g/dL. The primary end point was a composite of doubling of creatinine, renal replacement, or death.. Eighty-eight patients were randomized (early treatment N= 45, deferred treatment N= 43) and followed for a median of 22.5 months. During follow-up, 13 versus 23 patients reached the primary end point in the two arms, respectively (log-rank P= 0.0078). The relative hazard for reaching an end point was 0.42 (P= 0.012). Adjusting for baseline serum creatinine, the adjusted relative hazard was 0.37 (P= 0.004), while the risk increased 2.23-fold (P < 0.001) per 1 mg/dL higher creatinine at baseline. The benefit was similar regardless of the baseline hemoglobin and proteinuria. No patients had any severe adverse events.. Early initiation of erythropoietin in predialysis patients with non-severe anemia significantly slows the progression of renal disease and delays the initiation of renal replacement therapy.

Topics: Aged; Anemia; Disease Progression; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Treatment Outcome

Catheter-related infection (CRI) is a major cause of morbidity and mortality in patients receiving hemodialysis. Antibiotic locking of these catheters has been shown to increase both the success of systemic antibiotic treatment in line sepsis, and to reduce the incidence of sepsis. We have studied the use of gentamicin locking of catheters (in combination with standard heparin rather than previously reported citrate) to reduce CRI rates. Furthermore, we have investigated the effects of this strategy on epoetin requirements and vascular access function.. Fifty patients were studied. Patients were randomized to catheter-restricted filling with either standard heparin (5000 IU/mL) alone, or gentamicin and heparin (5 mg/mL). Epoetin requirements and hemoglobin response were monitored over the study period.. The gentamicin-locked group suffered only one infective episode (0.3/1000 catheter days) compared to 10 episodes in six patients in the heparin alone group (4/1000 catheter days, P= 0.02). The isolated organisms were equally split between Staphylococcal species and coliforms. There were no statistically significant differences in delivered dialysis dose (Kt/V) or QA between the two groups. Use of antibiotic locking was associated with both a higher mean hemoglobin (10.1 +/-0.14 g/dL vs. 9.2 +/- 0.17 g/dL in the heparin group, P= 0.003) and a lower mean epoetin dose (9000 +/- 734 IU/week vs. 10790 +/-615 IU/week in the heparin group, P= 0.04).. The practice of locking newly inserted tunneled central venous catheters with gentamicin and heparin is an effective strategy to reduce line sepsis rates, and is associated with beneficial effects on epoetin requirements.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Anti-Bacterial Agents; Anticoagulants; Catheterization; Cross Infection; Epoetin Alfa; Erythropoietin; Female; Gentamicins; Hematinics; Heparin; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Sepsis

Renal anemia is an important determinant for left ventricular hypertrophy in dialysis patients and an independent prognosis parameter for the cardiovascular survival in dialysis patients. In addition, an autonomic dysfunction is associated with the uremic state and influences the cardiovascular risk in patients with end-stage renal disease (ESRD).. We investigated in this prospective longitudinal study the effect of hemoglobin normalization by a chronic treatment with recombinant human erythropoietin (rhEPO) on cardiovascular prognosis parameters in 23 patients on chronic hemodialysis with renal anemia (hemoglobin concentration < or =10.5 g/dL) and echocardiographically proven left ventricular hypertrophy. We studied muscle sympathetic nerve activity measured by microneurography; cardiopulmonary baroreflex activity by lower-body negative pressure (LBNP-) testing; left ventricular structure and mass index (LVMI) by echocardiography; blood pressure by 24-hour readings; peripheral blood flow and vascular resistance by plethysmography before (U1) and after 7 months of chronic rhEPO treatment (U2).. In the anemic state, mean (+/- SD) muscle sympathetic nerve activity in ESRD was elevated (U1 rest, 34 +/- 13 bursts per minute) and cardiopulmonary baroreflex response during LBNP markedly lacking (U1 -15 mm Hg, 34 +/- 13 bursts per minute) reflecting a severely impaired autonomic function. Normalization of the hemoglobin concentration by chronic rhEPO treatment (U1, 10.5 +/- 0.9 g/dL versus U2, 13.4 +/- 3.1 g/dL, P <0.001) did not influence sympathetic nerve activity (U2, 34 +/- 15 bursts per minute, NS) and cardiopulmonary baroreflex sensitivity did not change (U2 -15 mm Hg, 37 +/- 16 bursts per minute, NS). LVMI decreased significantly after chronic treatment with rhEPO (U1, 134 +/- 26 g/m2 versus U2, 97 +/- 25 g/m2, P < 0.001) and left ventricular geometry developed from an asymmetric to a symmetric configuration (U1, relative wall thickness 0.58 versus U2, 0.43, P < 0.001). Under treatment with rhEPO, 24-hour systolic and diastolic blood pressure did not increase (systolic U1, 132 +/- 4 mm Hg versus U2, 128 +/- 3 mm Hg, NS, and diastolic U1, 76 +/- 2 mm Hg versus U2, 73 +/- 2 mm Hg, NS). Peripheral blood flow (U1, 6.1 +/- 3.3 mL/100 mL/min versus U2, 6.2 +/- 0.6 mL/100 mL/min, NS) as well as forearm vascular resistance (U1, 15.7 +/- 3.3 mm Hg/mL/100 mL versus U2, 14.9 +/- 3.1 mm Hg/mL/100 mL, NS) did not change by chronic rhEPO treatment.. Normalization of hemoglobin by chronic rhEPO treatment in dialysis patients has beneficial cardiovascular effects with regression of left ventricular hypertrophy and improvement of left ventricular geometry. However, a reduction of sympathetic overactivity or a resetting of baroreceptor sensitivity by a rhEPO treatment in dialysis patients in the medium-term could not be demonstrated. The reason for this may be the complex and multifactorial pathomechanism of autonomic dysfunction and cardiovascular disease in ESRD.

Topics: Adult; Aged; Anemia; Baroreflex; Blood Pressure; Echocardiography; Erythropoietin; Female; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Longitudinal Studies; Male; Middle Aged; Prognosis; Prospective Studies; Recombinant Proteins; Regional Blood Flow; Renal Dialysis

Haemodialysed patients are highly exposed to different virus infections namely hepatitis B (HBV) and C (HCV). Recently it was shown, that the use of recombinant human erythropoietin (rHuEPO) in haemodialysed patients with chronic renal failure (CRF) stimulates not only erythropoesis but also increases--in an indirect or direct manner--the humoral and cell--mediated immune defense. The aim of the present study was to determine the prevalence of HBV and HCV infection in haemodialysed patients with CRF and renal anaemia treated either with rHuEPO or with allogenic blood transfusions only. 32 patients with CRF and renal anaemia (haematocrit value below 28%) were included in this study at the early stage of the dialysis therapy (0 to 6 months from the first haemodialysis session). All patients were randomly allocated into two groups. The first one consisted of 15 haemodialysed patients treated with rHuEPO, the second group composed of 17 occasionally treated with blood transfusions (No-EPO group). In patients of both groups the following parameters were examined before (0) and after 3, 6, 9, 12 months of monitoring number of units blood transfused, hemoglobin concentration, serum levels of ferritin. Before the study (0) and after 6 and 12 months presence of antigen HBs (AgHBs), antibodies anti-HBc, anti-HBs, anti-HCV, DNA HBV and RNA HCV were examined. Before the study markers of HBV infection (DNA HBV and/or AgHBs and/or anti-HBc) were found in 46.7% of patients in EPO group and in 52.9% of patients in NO-EPO group respectively (NS). After six months of the study markers of HBV infection were present in 60% of patients in EPO group and in 76.5% of patients in No-EPO group (NS). After 12 months of dialysotherapy HBV infection markers were found in 66.7% patients in EPO group and in 76.5% of patients in No-EPO group (NS). Significantly higher prevalence of HBV infections were found after 6 and 12 months respectively in No-EPO group in comparison to the prestudy period (p < 0.05). At the beginning of the study markers of HCV infection (RNA HCV and/or anti-HCV) were present in 26.7% of patients in EPO group compared to 35.3% of patients in No-EPO group (NS). After 6 months of therapy markers of HCV infection were found in 26.7% of patients in EPO group and in 64.7% of patients in No-EPO group (p < 0.05). After 12 months of treatment markers of HCV infections were present in 40% of patients in EPO group and 76.5% of patients in No-EPO group (p < 0.05).ln patients. Treatment of renal anaemia with rHuEPO contributes to the significant decrease in prevalence of HCV infection. Decrease of prevalence of HCV infection in haemodialysed patients with chronic renal failure treated with rHuEPO seems to be predominantly a result of the complete cessation of allogenic blood transfusion. Blood transfusions seem not to be the main cause of HBV transmission in haemodialysed patients.

Topics: Adult; Anemia; Erythropoietin; Female; Hepatitis B; Hepatitis C; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis; Time; Uremia

Red blood cell osmotic resistance (RBCOR) is defined as resistance to osmotic changes in cell integrity after their exposure to hypotonic saline solution. The investigation examined the effect of rHuEPO on RBCOR in hemodialysed patients. The study included 58 patients aged 49 +/- 14 years, treated by hemodialysis for 59 +/- 43 months on average. Half of the patients received rHuEPO for anemia correction. RBCOR was determined in all patients as 3 values: hemolysis start point (HSP), hemolysis end point (HEP) and middle osmotic resistance (MOR). The patients underwent laboratory checkup for parameters characteristically changed in the uremic syndrome. In the control group of healthy subjects (n = 16) RBCOR was only determined. No differences were found in the average values of HSP, HEP and MOR between the rHuEPO treated group of patinets and the untreated group. Compared to healthy individuals, the hemodialysed patients displayed significantly higher values of HSP, HEP and MOR. The only one significant correlation of RBCOR and routine laboratory features was found between MOR and predialytic serum concentrations of calcium (r = 0.28, p < 0.05) and hydrogen ions (r = 0.37, p < 0.05). Our results suggest that the administration of rHuEPO does not affect RBCOR in hemodialysed patients, that RBCOR is not always reduced in this population and that it correlates with a small number of laboratory parameters characteristic for the uremic syndrome.

Topics: Adult; Aged; Anemia; Erythrocytes; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osmotic Pressure; Recombinant Proteins; Renal Dialysis

This prospective, two-arm, clinical trial assesses the effectiveness in maintaining the levels of haemoglobin (Hb) between 11 and 13 g/d1 and the safety of changing the administration route (from subcutaneous to intravenous) of epoetin (rHuEPO) alpha at equidose versus a changeover to darbepoetin alpha, taking the exact equivalence in peptide mass between the two as referent in patients with chronic renal insufficiency (CRI) in haemodialysis. A total of 112 patients previously treated with epoetin and no dose modification during the 8 weeks prior to the study and stable levels of Hb were included. Of these, 92.1% finished the follow-up period (24 weeks). After changing the administration route of rHuEPO, a significant increase in the resistance index (REI, weekly dose per kilogram of weight/levels of hemoglobin) was observed with mean values of 2.73 (p < 0.018) and 4.37 (p < 0.001) after 16 and 24 weeks respectively, requiring an increase of the dose greater than 15% over the baseline in 6 1.1% of the patients. The changeover to, darbepoetin alpha, independently of the administration route, was accompanied by a decrease in REI starting in the 8th week (mean levels of 0.012, 0.018 and 0.023 after 8, 16 and 24 weeks respectively), significant (p < 0.001) at the 3 cutoff points of the study. The conversion factor increased significantly up to 1:260 in week 24. Both erythropoietic stimulating factors (EST) were well tolerated and no unexpected side effects were observed. In conclusion, treatment of anaemia with darbepoetin alpha in patients with CRI in haemodialysis previously treated with rHuEPO proved to be more effective than the use of epoetin intravenously, significantly improving the resistance index. In addition, the treatment with darbepoetin alpha was well tolerated in these patients.

Topics: Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Treatment Outcome

A mild anaemia is often found in patients with congestive heart failure (CHF), but its significance is uncertain. In an open uncontrolled study we investigated the effect of correcting this anaemia [haemoglobin (Hb) 9.5-11.5 g%] with subcutaneous (s.c.) erythropoietin (Epo) and intravenous (i.v.) iron (Fe) in 179 patients, 84 type II diabetics and 95 non-diabetics, with moderate to severe CHF which was resistant to maximally tolerated doses of standard CHF medications.. Epo, s.c., was given every 1-3 weeks to achieve and maintain the Hb at 12.5 g%. Fe (Fe sucrose-Venofer) was added i.v. as necessary to maintain the Fe stores. Duration of treatment was 11.8 + 8.2 months.. With the Epo-Fe treatment the Hb increased from 10.41 +/- 1.0 to 13.1 +/- 1.3 g% in diabetics and from 10.5 +/- 1.0 to 12.9 +/- 1.2 g% in non-diabetics. Comparing the diabetics and non-diabetics, the New York Heart Association functional class improved by 34.8 and 32.4%, respectively. breathlessness and/or fatigue, as measured by a self-administered Visual Analogue Scale, improved by 69.7 and 67.4%, and the left ventricular ejection fraction improved by 7.4 and 11.5%, respectively. The number of hospitalizations fell by 96.4 and 95.3%, respectively, compared with the pre-treatment period. Although the glomerular filtration rate (GFR) was falling at a rate of approximately 1 ml/min/month before the study in both groups, neither the mean serum creatinine nor the GFR changed significantly during the study period. The mean dose of Epo needed, measured in IU/week/kg body weight, was similar in the two groups.. The correction of the mild anaemia that was found in diabetics and non-diabetics with resistant CHF and mild to moderate chronic renal failure improved the cardiac function and patient functional status, stabilized the renal function and markedly reduced the need for hospitalization.

Topics: Aged; Anemia; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Iron; Kidney Failure, Chronic; Male; Recombinant Proteins; Treatment Outcome

To investigate if oral use of Sorbifer Durules (EGIS Pharmaceutical Ltd, Budapest, Hungary) (1 tablet/d) is adequate for the maintenance of serum iron and vitamin C in normal range during recombinant human erythropoietin treatment in hemodialyzed patients. One tablet of Sorbifer Durules contains 100 mg of Fe(2+) and 60 mg of vitamin C.. Short-term, open-label clinical trial.. Hemodialysis units.. Twenty-four adult patients with end-stage renal disease on hemodialysis.. Four-week treatment period of Sorbifer Durules, preceded and followed by iron and vitamin C washout periods.. Fasting predialysis serum samples were collected on days 0, 28, 56, and 84 to determine hematocrit, blood hemoglobin, serum iron, total iron-binding capacity, transferrin saturation, ferritin, vitamin C, and plasma oxalate.. Four-week treatment in hemodialyzed patients by Sorbifer Durules led to significant increase of hematocrit, blood hemoglobin, serum iron and vitamin C. This treatment did not influence the level of plasma oxalate.. Oral dose of one tablet of Sorbifer Durules per day is adequate for the maintenance of serum iron in normal range during recombinant human erythropoietin treatment in hemodialyzed patients. This treatment simultaneously prevented the development of serum vitamin C deficiency and did not lead to further increase of plasma oxalate in these patients.

Topics: Administration, Oral; Anemia, Iron-Deficiency; Ascorbic Acid; Creatinine; Erythropoietin; Female; Ferritins; Hematocrit; Hemoglobins; Humans; Iron; Iron Deficiencies; Iron, Dietary; Kidney Failure, Chronic; Male; Middle Aged; Oxalates; Recombinant Proteins; Renal Dialysis; Transferrin

Darbepoetin alfa is a new recombinant erythropoietic protein with a 3-fold longer half-life than recombinant human erythropoietin (rHuEpo). The optimal starting dose and frequency of administration of darbepoetin alfa were investigated for treating renal anaemia in dialysis patients.. Two multicentre, sequential dose-escalation studies examined the i.v. route of administration of darbepoetin alfa in haemodialysis patients (n=75) and the s.c. route in peritoneal dialysis patients (n=47). Patients were randomized to receive darbepoetin alfa at doses ranging from 0.075 to 0.75 microg/kg/week administered as either a once weekly or a three-times weekly injection. Patients achieving the primary endpoint of a > or = 1 g/dl increase in haemoglobin after 4 weeks continued darbepoetin alfa for up to 52 weeks. Safety was assessed by adverse event reports, changes in laboratory values and vital signs, and antibody screening.. Darbepoetin alfa produced dose-related increases in haemoglobin over the first 4 weeks of treatment in both studies. Two dose levels (0.45 and 0.75 microg/kg/week) increased the haemoglobin by > or = 1 g/dl in 60-80% of patients, and no difference between once weekly and three-times weekly dosing was apparent. For patients who continued treatment up to 52 weeks, haemoglobin was maintained between 10 and 13 g/dl from mean baseline values of 8.4 and 8.7 g/dl. The adverse event profile was similar to that associated with rHuEpo therapy, and no antibodies to darbepoetin alfa were detected.. Darbepoetin alfa is safe and effective for the treatment of anaemia in dialysis patients. The optimal weekly starting dose is 0.45-0.75 microg/kg and once weekly dosing is possible for both the s.c. and i.v. routes of administration.

Topics: Adult; Aged; Anemia; Cohort Studies; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Humans; Infusions, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Renal Dialysis; Time Factors

Our study is designed to establish whether supplementation with erythropoietin (EPO) exerts additional beneficial metabolic effects in patients with chronic renal failure (CRF) treated with keto acids (KAs) on a low-protein diet (LPD).. A long-term, prospective, randomized study was designed to use three therapeutic protocols: (A) EPO plus KAs plus LPD (group I), (B) EPO plus LPD (group II), and (C) LPD (group III). One hundred eighty-six randomly selected patients (90 men, 96 women; age, 22 to 78 years) with a creatinine clearance of 22 to 36 mL/min were monitored at the beginning and at every 6 months for 3 years.. During the study period, glomerular filtration rate measured as inulin clearance decreased slightly (from 26.2 +/- 3.4 to 23.4 +/- 4.1 mL/min in group I), 27.4 +/- 4.8 to 20.2 +/- 4.4 mL/min in group II, and 26.8 +/- 3.6 to 17.4 +/- 4.1 mL/min in group III; P < 0.01). Serum urea levels also declined (P < 0.01), more pronouncedly in group I (P < 0.025). In group I, there was a significant increase in levels of leucine (P < 0.01) and albumin (P < 0.01) and a decrease in proteinuria (P < 0.01). Analysis of the lipid spectrum showed a mild, yet significant, decrease in total cholesterol and low-density lipoprotein cholesterol levels (P < 0.025), more pronounced in group I. In group I, there was a decrease in plasma triglyceride levels (from 362.85 +/- 115.05 mg/dL [4.1 +/- 1.3 mmol/L] to values as low as 203.55 +/- 70.80 mg/dL [2.3 +/- 0.8 mmol/L]; P < 0.01), whereas high-density lipoprotein cholesterol levels increased (from 34.75 +/- 7.72 mg/dL [0.9 +/- 0.2 mmol/L] to 46.33 +/- 7.72 mg/dL [1.2 +/- 0.2 mmol/L]; P < 0.025). Mean arterial blood pressure was stable.. EPO supplementation in patients with CRF administered KAs potentiates the beneficial effects on metabolism of proteins, amino acids, and lipids. Long-term coadministration of EPO, KA, and LPD was associated with a delay in progression of renal failure and reduction in proteinuria.

Topics: Adult; Aged; Blood Pressure; Blood Proteins; Czech Republic; Diet, Protein-Restricted; Erythropoietin; Female; Glomerular Filtration Rate; Humans; Keto Acids; Kidney Failure, Chronic; Lipids; Male; Middle Aged; Prospective Studies; Recombinant Proteins

Iron deficiency is a frequent cause of recombinant human erythropoietin (rhEPO)-resistant anemia in hemodialysis patients. Both reticulocyte hemoglobin content (CHr) and transferrin saturation (TSAT) have been proposed as markers of iron deficiency, but it is unclear which parameter is superior.. To compare the efficacy of CHr and TSAT as an indicator for treatment of iron deficiency, we conducted a single-center, open-label, prospective, randomized, controlled trial at the Kidney Center in Shinraku-en Hospital of 197 Japanese patients on chronic hemodialysis. After 4 weeks of run-in period during which iron supplementation was suspended, 100 patients who were randomized to the CHr group received 240 mg iron colloid intravenously over 2 weeks when CHr less than 32.5 pg, and 97 patients who were randomized to the TSAT group received the same doses of iron colloid when TSAT less than 20%. We measured the rhEPO dose needed to maintain prestudy hematocrit levels, hematocrit, CHr, TSAT, serum ferritin, percentage of hypochromic red blood cells, and total iron administered.. Sixteen weeks later, 94 patients in the CHr group and 89 patients in the TSAT group finished the study. The doses of rhEPO required decreased by 35.8% (4081 to 2629 U/week, P < 0.005) in the TSAT group, but not significantly in the CHr group (4121 to 3606 U/week). Although CHr increased promptly after the iron administration in both groups, TSAT increased only in the TSAT group.. Although CHr reflects the iron status more sensitively, TSAT is a better clinical marker for iron supplementation therapy.

Topics: Adult; Aged; Anemia, Iron-Deficiency; Biomarkers; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Iron; Japan; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Reticulocytes; Transferrin

Oxidative stress has been implicated in a range of disease states, including end-stage renal failure treated with hemodialysis. Hemodialysis with vitamin E-modified membranes reduces lipid peroxidation, but the effect on erythrocyte integrity has not been determined. This study compared antioxidant defense parameters and the resistance of erythrocytes to free radical-mediated hemolysis in patients dialysed with cellulose acetate membranes at baseline and with a vitamin E-modified membrane (Excebrane Clirans; Terumo Corporation) for 13 wk. Resistance of erythrocytes to free radical attack was assessed in vitro using the peroxyl hemolysis test. The time to 50% hemolysis (T50%) increased significantly during the first 6 wk of Excebrane use (p < 0.05), but this parameter returned to baseline by 13 wk. Glutathione concentration and erythrocyte superoxide dismutase activity were unchanged during the study, but glutathione peroxidase activity increased from low levels at baseline and became significantly higher at 6 and 13 wk (p < 0.001). Total erythrocyte polyunsaturated fatty acid content and C18:2 level increased (p < 0.001) and saturated fatty acids (total, C16:0, C18:0, C22:0 and C24:0) decreased (p < 0.03). Total monounsaturated fatty acid content was unchanged. The increased resistance of erythrocytes to hemolysis, the increased glutathione peroxidase activity, and the increased degree of unsaturation of fatty acids in the erythrocyte membrane are compatible with a reduction of oxidative stress during hemodialysis with vitamin E-modified membranes.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Cellulose; Erythrocytes; Erythropoietin; Female; Glutathione; Glutathione Peroxidase; Humans; Iron; Kidney Failure, Chronic; Lipid Peroxidation; Male; Membranes, Artificial; Middle Aged; Oxidative Stress; Recombinant Proteins; Renal Dialysis; Superoxide Dismutase; Vitamin E

Vitamin E-bonded hemodialyzer is known to improve oxidative stress in patients with hemodialysis. However, there is little information available as to whether or not this membrane clinically improves atherosclerosis. Furthermore, it remains unknown whether there is any effect of the membrane on rheology of circulating red blood cells.. We conducted a randomized, open-labeled, prospective control study (N = 34) for 1 year to investigate the effect of vitamin E-bonded cellulose membrane dialyzer (EE) (N = 17) on carotid atherosclerotic changes [intima-media thickness (IMT) of carotid arteries] and the viscosity, percentage of dysmorphism (%DMR) of red blood cells (RBCs) and their distribution width-standard deviation (RDW-SD), in comparison with cellulose membrane (SU) (N = 17) identical to EE without vitamin E-bonded membrane. Erythropoietin (EPO) dose used for the treatment of uremic anemia was also calculated.. The IMT significantly decreased in the EE group, while in the SU group the IMT significantly increased. The viscosity of RBCs in hemodialysis patients (4.70 +/- 0.45 cP) was greater than that in healthy individuals (3.73 +/- 0.15 cP). EE significantly improved the viscosity (from 4.84 +/- 0.41 cP to 4.51 +/- 0.54 cP, P < 0.01), %DMR (from 2.29 +/- 2.17% to 1.90 +/- 1.49%, P < 0.01), and RDW-SD (from 54.4 +/- 7.6 fL to 49.3 +/- 5.9 fL, P < 0.01). On the contrary, these parameters all worsened in the SU group. EPO dose needed for the treatment of anemia was significantly (P < 0.05) reduced from 5383 +/- 2655 U/week to 4235 +/- 3103 U/week in the EE group. During these period, mean blood pressure, Kt/V urea, and serum beta2-microglobulin were not changed between the two groups.. These findings suggest that vitamin E-bonded hemodialyzer is very useful for improving atherosclerosis from a clinical point of view. As one of the underlying mechanisms, as well as antioxidant effects, we want to address an important role of the improvement of rheology of circulating RBCs, which may also help to reduce the requirement of EPO dose in the treatment of anemia of ESRD patients.

Topics: Aged; Anemia; Antioxidants; Arteriosclerosis; Blood Viscosity; Erythrocytes; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Membranes, Artificial; Middle Aged; Prospective Studies; Renal Dialysis; Rheology; Vitamin E

In some of the patients undergoing haemodialysis, (HD) resistance might develop against recombinant human erythropoietin (rHuEPO) used for treatment of anaemia. Recently, angiotensin-converting enzyme (ACE) inhibitors that are used to treat hypertension and congestive heart failure in HD patients have been suggested to contribute to anaemia as well by inhibiting erythropoiesis. Our purpose in this study is to investigate whether or not losartan, an angiotensin II (ATII) receptor antagonist, is causing rHuEPO resistance.. In this prospective study of 12 months, we compared the effects of high dose losartan (100 mg/day) and amlodipine (10 mg/day) on rHuEPO requirement in 40 hypertensive patients receiving rHuEPO for more than 12 months on maintenance HD. Twenty normotensive rHuEPO dependent patients served as control group. Iron deficiency, hyperparathyroidism, aluminium intoxication, infections and inflammations were excluded in all patients.. The mean haemoglobin level was found >8 g/dl in all groups. The mean weekly rHuEPO dose increased in the losartan group (p<0.0001 vs before) and remained constant in the other groups. No significant differences were found with PTH, iron status, aetiologies of renal failure in all groups.. High-dose losartan increases rHuEPO requirement and should be reserved for dialysis patients with hypertension uncontrollable with other antihypertensive medications.

Topics: Adult; Amlodipine; Anemia; Angiotensin Receptor Antagonists; Antihypertensive Agents; Dose-Response Relationship, Drug; Drug Resistance; Erythropoietin; Female; Humans; Hypertension; Kidney Failure, Chronic; Losartan; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis

To compare oral versus intravenous iron in pre-dialysis patients of chronic renal failure (CRF) receiving recombinant human erythropoietin (rHuEPO).. The study was undertaken in 40 adult patients of chronic renal failure. The patients were randomly divided into two groups A and B of 20 patients each. Group A patients were given oral iron and group B patients were given intravenous iron. All patients in both groups were given recombinant human erythropoietin 2000 IU twice weekly subcutaneously. The study was carried for up to three months. Patients were monitored every month for renal parameters and haematological parameters which included haemoglobin, reticulocyte count and packed cell volume. Ferrokinetic studies were done at baseline and at three months.. It was observed that haematological parameters showed significant statistical improvement in the intravenous iron group as compared to group A (oral iron group). The ferrokinetic studies revealed that serum iron, serum ferritin and transferrin saturation, decreased significantly in oral iron group, whereas significant increase was seen in group B (intravenous iron group). None of the patients developed any adverse effects because of erythropoietin or iron therapy.. Concomitant use of intravenous iron is better than oral iron in CRF patients treated with rHuEPO. The intravenous route of iron administration may be a preferred route along with rHuEPO therapy, more so in the Indian context where prevalence of iron deficiency anaemia is fairly high.

Topics: Administration, Oral; Adult; Aged; Dialysis; Erythropoietin; Female; Humans; Infusions, Intravenous; Iron; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins

Vitamin C has been reported to be an effective adjuvant agent in the treatment of anemia in iron-overloaded hemodialysis patients. We aim to evaluate its effect on erythropoietin (EPO) response in a prospective, randomized, double-blind, crossover study.. Sixty-three patients were randomly divided into two groups. Group 1 was treated with intravenous vitamin C, 500 mg, three times a week, and group 2, with placebo for 6 months. During the second 6-month period, group 1 was treated with placebo, and group 2, with the same dose of vitamin C. Thirty patients in group 1 and 28 patients in group 2 completed the study. Hemoglobin levels, weekly EPO dose, and ratio of EPO to hemoglobin as an index of EPO need were determined at both baseline and the end of the two periods, together with other parameters known to be associated with EPO response.. Twenty patients in group 1 (66.7%) and 18 patients in group 2 (64.3%) were responsive to vitamin C. In both groups, vitamin C resulted in a significant increase in hemoglobin levels (P < 0.0001 for both) and a significant decrease in EPO-hemoglobin ratio (P < 0.0001, P = 0.019). Transferrin saturation also increased with vitamin C treatment in both groups (P = 0.009, P = 0.005). All these parameters remained stable with placebo in both groups. Other parameters did not change throughout the study.. Vitamin C can be used as an effective adjuvant therapy to EPO in hemodialysis patients. Further studies are needed to determine possible predictors of hematologic response to vitamin C.

Topics: Adult; Anemia; Ascorbic Acid; Cross-Over Studies; Double-Blind Method; Drug Interactions; Erythropoietin; Female; Hemoglobins; Humans; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis; Transferrin; Treatment Outcome

This Spanish single-arm, multicenter, prospective clinical trial assessed the maintenance of hemoglobin concentrations (Hb) between 10-13 g/dL with unit doses of darbepoetin alfa and the safety of the treatment in dialysis patients. Eight-hundred twenty-six patients with chronic renal failure (CRF) (94% receiving haemodialysis and 6% receiving peritoneal dialysis) previously maintained on stable recombinant human erythropoietin (r-HuEPO) therapy with stable hemoglobin (Hb) concentrations (mean Hb concentration = 11.7 g/dL) were switched to darbepoetin alfa at a reduced dosing frequency for 24 weeks (a 20-week titration phase plus a 4-week treatment evaluation phase). Subjects receiving r-HuEPO two or three times weekly were switched to darbepoetin alfa once weekly, and those. who were receiving r-HuEPO once weekly were switched to darbepoetin alfa once every two weeks. The initial dose of darbepoetin alfa was determined from the r-HuEPO dose at inclusion into the study using a formula equating the peptide mass of the two molecules and rounding to the nearest available prefilled syringe dose. Overall, 86.8% of patients completed the 24-weeks of study. Changing the treatment from r-HuEPO to darbepoetin alfa and increasing the dose interval did not result in any clinically significant change in the Hb concentration. From base-line to the evaluation phase, the mean Hb fell 0.09 (95% CI, -0.2; -0.0) g/dl, with an increase of 0.19 (95% CI, 0.0;0.3) g/dL i.v. and a decrease of 0.22 (95% CI, -0.3; -0.1) g/dL s.c.). This maintenance of the mean Hb concentration was accompanied by a mean 9.8% reduction of the darbepoetin alfa dose (19.7% (95% CI, -24.9; -14.2) i.v. and 4.7% (95% CI, -8.5; -0.7) s.c. Treatment with darbepoetin alfa was well tolerated and no unexpected adverse events were reported. In conclusion, the replacement of previous r-HuEPO treatment by darbepoetin alfa in the therapy of anemia secondary to chronic renal failure in diaiyzed patients was effective, well tolerated, and decreased the frequency of dose administration compared with the previous r-HuEPO treatment. Darbepoetin alfa administered once weekly or once every two weeks maintained the baseline Hb levels whilst allowing dose reduction, which was higher in patients receiving i.v. darbepoetin alfa.

Topics: Aged; Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Hemorrhage; Humans; Hypertension; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Peritoneal Dialysis; Prospective Studies; Recombinant Proteins; Renal Dialysis; Safety; Thrombosis; Treatment Outcome

Most patients with end-stage renal disease have chronic anemia caused by inadequate erythropoietin (EPO) synthesis and require therapy with exogenous EPO to maintain recommended hematocrit and hemoglobin levels.. The London Daily/Nocturnal Hemodialysis Study compared anemia control among patients on either short daily, long nocturnal, or conventional thrice-weekly hemodialysis (HD) therapy. Patients were administered iron, either orally (900 mg/d) or intravenously (50 to 125 mg every 1 to 4 weeks), to maintain serum ferritin levels at greater than 45 ng/mL (100 microg/L) or transferrin saturations greater than 20%. EPO was administered by subcutaneous injection at frequencies ranging from twice weekly to once every second week to maintain hemoglobin levels within the target range of 11 to 12 g/dL (110 to 120 g/L).. Both the daily HD and nocturnal HD study groups showed increased hemoglobin levels at later times compared with baseline levels, although only nocturnal HD patients had a statistically significant increase in hemoglobin levels at 18 months (11.94 g/dL [119.4 g/L] versus 10.95 g/dL [109.5 g/L] at baseline; P = 0.047). Both the daily HD and control groups showed a trend for decreased EPO dose requirements at later times compared with baseline, although these decreases were not statistically significant. The nocturnal HD group showed increased EPO dose requirements, although not statistically significant.. Quotidian HD is associated with an increased quantity of blood loss that can account for some of the increased requirements in EPO dose. Additional studies with larger numbers of patients are needed to fully elucidate the effects of quotidian HD on anemia.

Topics: Adult; Aged; Anemia; Appointments and Schedules; Erythropoietin; Female; Follow-Up Studies; Hematocrit; Hemodialysis, Home; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Ontario; Prospective Studies; Transferrin; Treatment Outcome

Anemia in patients with end-stage renal disease (ESRD) is treated with recombinant human erythropoietin (rhEPO) often in combination with iron. However, iron catalyzes the formation of toxic radicals, which might promote vascular damage, is a nutrient for microorganisms, and negatively affects immune pathways, thus increasing the risk for severe infections.. We investigated 28 patients on chronic hemodialysis who were randomized to receive either rhEPO alone (N = 15) or rhEPO in combination with intravenous iron (N = 13) for a period of 12 weeks. We analyzed iron therapy associated changes in cytokine patterns and endogenous radical formation.. Tumor necrosis factor-alpha (TNF-alpha) levels were increased in ESRD patients at study entry and then decreased significantly over time in subjects receiving additional iron, while they increased with rhEPO alone. In contrast, we found serum concentrations of the anti-inflammatory cytokine interleukin (IL)-4 to increase with iron therapy. A significant negative correlation between iron availability, as determined by transferrin saturation, and TNF-alpha levels (P = 0.008) and a positive one between transferring saturation and IL-4 (P = 0.02) pointed to the potential role of iron to induce immunologic changes. Interestingly, iron therapy resulted in a slight decrease in the amounts of endogenous peroxides, which may be referred to reduced TNF-alpha concentrations since peroxide concentrations were positively correlated to TNF-alpha levels (P = 0.046) and negatively to transferrin saturation (P = 0.02).. Iron supplementation in ESRD patients down-regulates proinflammatory immune effector pathways and stimulates the expression of the anti-inflammatory cytokine IL-4. Such a condition is detrimental for host response toward invading pathogens. However, tissue damage by radicals such as endogenous peroxides may be reduced in this condition due to impaired TNF-alpha formation.

Topics: Aged; Anemia; Drug Therapy, Combination; Erythropoietin; Female; Humans; Interleukin-4; Iron; Kidney Failure, Chronic; Male; Middle Aged; Oxidative Stress; Recombinant Proteins; Renal Dialysis; Tumor Necrosis Factor-alpha

Optimizing iron and recombinant human erythropoietin (rHuEPO) therapy is necessary to achieve target hemoglobin levels and minimize costs as the end-stage renal disease (ESRD) population expands. Oral iron products in patients with ESRD have been largely abandoned, and the safety of intravenous (IV) iron preparations has improved with the introduction of new-generation compounds that have little allergenicity. Recent work suggests oral heme iron may be an effective supplement for hemodialysis (HD) patients because it is absorbed by patients with high ferritin levels, has fewer side effects, and its absorption is stimulated by erythropoietin administration.. We performed an open, 6-month, prospective evaluation of heme iron in HD patients who had been on maintenance IV iron therapy. IV iron was discontinued and replaced with oral heme iron. Serum iron level, hematocrit (Hct), and erythropoietin and IV iron dose were monitored.. During 6 months, 4 of 37 patients (11%) dropped out because of insufficient iron supplementation or intolerance and 5 patients (14%) were dropped because of unrelated complications or protocol violation. A slight reduction in average transferrin saturation (TSAT) was seen early, but reversed, and no significant changes were seen in TSAT or Hct. A significant reduction in average serum ferritin level was seen at months 4 through 6 (P < 0.01).. During the 6-month study period, heme iron polypeptide successfully replaced IV iron therapy in a majority of HD patients and maintained target Hcts with no concomitant use of IV iron. This treatment was associated with a significant increase in rHuEPO efficiency (P = 0.04).

Topics: Administration, Oral; Aged; Anemia; Erythropoietin; Female; Ferritins; Hematocrit; Humans; Infusions, Intravenous; Iron; Kidney Failure, Chronic; Male; Middle Aged; Peptides; Prospective Studies; Recombinant Proteins; Renal Dialysis; Tablets; Transferrin; Treatment Outcome

Membrane biocompatibility has long been thought to be relevant to hemodialysis outcomes and, possibly, renal anemia.. We performed a randomized, controlled, single-center study comparing the consequences on renal anemia of 2 dialyzers of equivalent performance, but different composition, during 7 months. Two hundred eleven patients of an unselected dialysis population of 235 patients gave informed consent to undergo random assignment to either group A (SF170E; modified cellulose triacetate/midflux membrane; Nipro, Osaka, Japan) or group B (HF80LS; polysulfone/high-flux membrane; Fresenius, Bad Homburg, Germany). Anemia management was identical in both treatment groups and followed strict clinical protocols managed by computer algorithms. Dialysis adequacy, hemoglobin (Hb) level, ferritin level, percentage of red blood cell hypochromicity, C-reactive protein (CRP) level, and intravenous iron and epoetin doses were monitored monthly.. One hundred seventy-seven patients completed the 7-month study. Equilibrated Kt/V increased in both groups. Hb outcome improved overall, but did not differ between the 2 study groups. Epoetin dose was not significantly different after 7 months compared with baseline in either group. Hb level, epoetin dose, iron status, CRP level, dialysis Kt/V, and residual renal function did not differ between the 2 groups. A slight but significant negative correlation was identified between dialysis Kt/V and Hb level in the population as a whole (Spearman's correlation, -0.16; P = 0.04).. No significant epoetin-sparing effect was identified through the use of the high-flux polysulfone HF80LS membrane over the modified cellulose triacetate SF170E membrane. Although not a primary outcome for this study, there was a suggestion of benefit of improved Hb level, without increased need for epoetin, through increasing delivered dialysis dose.

Topics: Adult; Aged; Anemia; C-Reactive Protein; Cellulose; Epoetin Alfa; Erythrocytes; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Male; Membranes, Artificial; Middle Aged; Parathyroid Hormone; Phosphorus; Polymers; Potassium; Recombinant Proteins; Renal Dialysis; Sulfones

Treatment of the anemia of chronic renal failure with exogenous recombinant human erythropoietin (rHuEpo) is well established. The objective of this randomized clinical trial was to evaluate an anemia management team protocol in hemodialysis patients, using subcutaneous rHuEpo and intravenous iron. A total of 215 patients were randomized to either usual care or the protocol. The primary outcome was the proportion of patient hemoglobin (Hgb) values between 11.0 and 12.5 g/dl over the final 8 wk. The study was halted after 240 d because of an institutional change to intravenous rHuEpo. The proportion of Hgb values in the target range increased from 47.4% to 62.8% overall (P = 0.001); there was no difference between treatment groups. The proportion of baseline Hgb values between 11.0 and 12.5 g/dl increased from 44.6% in patients who had enrolled within the first 3 mo of study inception to 75.0% in those who started later (P = 0.017), suggesting a Hawthorne effect. A nonsignificant decrease in rHuEpo dose was observed in the protocol group; subgroup analysis in patients who were enrolled for at least 5 mo demonstrated a reduction in the rHuEpo dose of 2788 units/wk in the protocol group (P < 0.05), independent of intravenous iron dose. Multivariate analysis demonstrated that a higher transferrin saturation and albumin and protocol group assignment were associated with a lower final rHuEpo dose. This study demonstrated that a protocolized approach to anemia management in hemodialysis patients results in comparable Hgb levels and may reduce rHuEpo requirements, independent of iron use.

Topics: Aged; Anemia; Drug Therapy, Combination; Erythropoietin; Female; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Circulating bone marrow-derived endothelial progenitor cells (EPCs) promote vascular reparative processes. In humans, their number correlate with endothelial function and cardiovascular risk. We tested the hypothesis that darbepoetin alfa [i.e., a recombinant analogue of the cytokine erythropoietin (EPO)] stimulates proliferation and differentiation of EPCs.. We assessed CD34+ circulating stem cells (cSCs) in whole blood using flow cytometry and, in addition, proliferation/differentiation of EPCs in an in-vitro assay during 6 weeks of a standard darbepoetin therapy in eight patients with renal anemia.. Darbepoetin treatment caused a significant increase in the number of CD34+ cSCs (week 2, 193%+/- 46%; and week 6, 298%+/- 90%; P < 0.05 vs. baseline). In addition, darbepoetin markedly increased the number of functionally active EPCs (week 2, 256%+/- 48%; and week 6, 299%+/- 59%; both P < 0.01 vs. baseline). The effect of darbepoetin on functional activity of EPCs assessed in a tube formation assay was dose dependent. Administration of darbepoietin caused activation of protein kinase B (Akt) in cultured EPCs.. A standard treatment with darbepoetin markedly enhances EPC proliferation and differentiation in renal patients. The use of recombinant EPO analogues may be a novel and safe therapeutic approach in patients with vascular pathology.

Topics: Aged; Anemia; Bone Marrow Cells; Cell Differentiation; Cell Division; Darbepoetin alfa; Endothelium; Erythropoietin; Female; Flow Cytometry; Hematocrit; Hematopoietic Stem Cells; Humans; Kidney Failure, Chronic; Male; Middle Aged

The aim of this study was to evaluate the relationship between uremic state and erythropoiesis in patients with predialytic chronic renal failure (CRF).. We monitored for 2 years the erythropoietin (EPO) requirement in patients with advanced CRF (creatinine clearance < or =25 mL/min), randomized to either low protein diet (LPD) group (0.6 g/kg body weight/day, N = 10) or very low protein diet (VLPD) group (0.3 g/kg body weight/day, N = 10) supplemented with a mixture of ketoanalogs and essential amino acids, both kept at target hemoglobin levels.. The achieved protein intake after 6 months was 0.79 +/- 0.02 g/kg body weight/day and 0.50 +/- 0.02 g/kg body weight/day in LPD and VLPD, respectively; such a difference was maintained up to the end of follow up. The final hemoglobin values did not differ from the basal values in either group (11.5 +/- 0.2 g/dL and 11.5 +/- 0.3 g/dL). EPO dose, that was similar at baseline (62.4 +/- 9.6 UI/kg body weight/week and 61.8 +/- 8.8 UI/kg body weight/week subcutaneously), remained unchanged in LPD but progressively decreased in VLPD down to the final value of 41.2 +/- 7.0 UI/kg body weight/week (P < 0.0001 vs. basal and LPD). VLPD was associated with a decrease of urinary excretion and serum levels of urea nitrogen and phosphate; however, EPO requirement was not correlated with the changes of these parameters. On the contrary, the variation of EPO dose directly correlated with the modification of parathyroid hormone (PTH) levels, that diminished from 229 +/- 55 pg/mL to 118 +/- 16 pg/mL (P < 0.0001) in VLPD and did not change in LPD.. In patients with advanced CRF, an effective decrease of protein intake of 0.3 g/kg body weight/day induces a reduction of about 35% of the EPO dose required to maintain the target hemoglobin levels. This effect appears dependent on the correction of a moderate secondary hyperparathyroidism.

Topics: Adult; Aged; Anemia; Diet, Protein-Restricted; Dietary Proteins; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Patient Compliance; Uremia

The external administration of recombinant human erythropoietin is the chosen treatment for those patients with secondary anemia due to chronic renal failure in periodic hemodialysis. The objective of this paper is to carry out an individualized prediction of the EPO dosage to be administered to those patients. The high cost of this medication, its side-effects and the phenomenon of potential resistance which some individuals suffer all justify the need for a model which is capable of optimizing dosage individualization. A group of 110 patients and several patient factors were used to develop the models. The support vector regressor (SVR) is benchmarked with the classical multilayer perceptron (MLP) and the Autoregressive Conditional Heteroskedasticity (ARCH) model. We introduce a priori knowledge by relaxing or tightening the epsilon-insensitive region and the penalization parameter depending on the time period of the patients' follow-up. The so-called profile-dependent SVR (PD-SVR) improves results of the standard SVR method and the MLP. We perform sensitivity analysis on the MLP and inspect the distribution of the support vectors in the input and feature spaces in order to gain knowledge about the problem.

Topics: Adult; Aged; Aged, 80 and over; Algorithms; Anemia, Hemolytic; Cohort Studies; Drug Therapy, Computer-Assisted; Erythropoietin; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Middle Aged; Neural Networks, Computer; Recombinant Proteins; Regression, Psychology; Renal Dialysis; Treatment Outcome

Vitamin E supplementation could elevate circulating vitamin E metabolites while modulating oxidative and inflammatory status in end-stage renal failure patients undergoing hemodialysis. Plasma concentrations of carboxyethyl-hydroxychromanols (alpha- and gamma-CEHC), ascorbic acid, alpha- and gamma-tocopherols, F2-isoprostanes, and inflammatory biomarkers [tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), ferritin, and C-reactive protein (CRP)] were measured in blood samples obtained from patients (n = 11) before and after dialysis on two occasions prior to, and at 1 and 2 mon of daily vitamin E supplementation (400 IU RRR-alpha-tocopherol). Supplementation nearly doubled plasma alpha-tocopherol concentrations (from 18 +/- 0.5 to 31 +/- 1.7 microM, P < 0.0001), whereas gamma-tocopherol concentrations decreased (from 2.8 +/- 0.3 to 1.7 +/- 0.2 microM, P = 0.001). Serum alpha-CEHC increased 10-fold from 68 +/- 3 to 771 +/- 175 nM (P < 0.0001), and gamma-CEHC increased from 837 +/- 164 to 1136 +/- 230 nM (P = 0.008). Vitamin E supplementation also increased postdialysis hematocrits from 38 +/- 1% to 41 +/- 1% (P < 0.001). Dietary antioxidant intakes (vitamins E and C) were low in most subjects; plasma ascorbic acid levels (88 +/- 27 microM) decreased significantly with dialysis (33 +/- 11 microM, P = 0.01). Plasma IL-6, CRP, TNF-alpha, and free F2-isoprostane concentrations were elevated throughout the study. There is a complex relationship between chronic inflammation and oxidative stress that is not mitigated by short-term vitamin E supplementation. Importantly, serum vitamin E metabolite concentrations that increased 10-fold within 30 d of supplementation did not increase further, suggesting routes other than urine for removal of metabolites.

Topics: Aged; Antioxidants; Ascorbic Acid; Biological Availability; C-Reactive Protein; Dietary Supplements; Erythropoietin; Female; Ferritins; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Solubility; Vitamin E

Human recombinant erythropoietin (rHuEPO) is administered to patients with end-stage renal disease for treatment of anemia.. To assess the impact of a structured team approach to anemia management in rHuEPO-resistant hemodialysis patients.. This was an 8-month prospective, open-label, quality-improvement initiative. Nineteen patients in a 160-bed hemodialysis unit receiving rHuEPO doses >300 units/kg/wk were defined as rHuEPO-resistant. Hemoglobin (Hb), iron indices, parathyroid hormone, folate, B12, aluminum, and reticulocyte counts were determined at baseline. The former 3 parameters were followed every 6, 12, and 26 weeks, respectively. Vascular access flow was regularly assessed via ultrasonic dilution methodology. Target Hb was 12.0-13.5 g/dL. All factors potentially contributing to rHuEPO resistance were assessed and, if possible, treated every 6 weeks by a dedicated anemia team. Downward rHuEPO dosage adjustments of 12.5-25% to the closest 1000 units were considered if underlying causes of rHuEPO resistance could not be identified or reversed, or if the Hb rose beyond the target level.. Dysfunctional vascular access and iron deficiency were the predominant treatable factors associated with rHuEPO resistance. At 8 months, mean rHuEPO dosage decreased significantly from 469 to 319 units/kg/wk (p < 0.001) and mean Hb increased significantly from 10.6 to 11.6 g/dL (p = 0.023). Eight-month cost savings approximated $45 000 (CDN$).. A structured team approach to the management of rHuEPO-resistant patients was successful in significantly lowering rHuEPO dosage with improvement in serum Hb at a substantial cost savings.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Disease Management; Drug Resistance; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Linear Models; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis

Although clinical use of recombinant human erythropoietin (rHuEPO) since 1989 has improved anemia in most end-stage renal disease patients, there are still many hemodialysis patients unable to maintain an adequate hematocrit (HCT) without large doses of rHuEPO. This suggests that anemia is not solely a consequence of rHuEPO deficiency, but may be due to other factors including functional iron deficiency. Since the optimal prescription for iron replacement is not yet known, we evaluated the effect of intravenous iron dextran (IVFe) infusion on serum ferritin (SFer) concentration and rHuEPO dose. Our objective was to raise and maintain serum ferritin concentrations to 2 different levels above the National Kidney Foundation Dialysis Outcome Quality Initiative standard of 100 ng/ml to determine whether, and by what degree rHuEPO dose could be lowered.. HD patients on i.v. rHuEPO with a SFer concentration > or = 70 ng/ml and an HCT of < or = 33% were enrolled. Subjects were divided as follows: Group 1: target SFer of 200 ng/ml, Group 2: target SFer of 400 ng/ml. Each subject below the target level received IVFe in up to 10 divided doses during consecutive dialysis sessions as needed to reach the target. HCT was maintained between 32.5% and 36% by adjusting rHuEPO dosage.. Mean SFer concentration at the study conclusion in Group 1: 261 ng/ml; Group 2: 387 ng/ml. The mean decrease in rHuEPO dose for Group 1 was 31 U/kg body weight/week (250 - 219 U/kg bw/wk) while in Group 2 it was 154 U/kg body weight/week (312 - 158 U/kg bw/wk) (p < 0.001). There was no difference in HCT between groups. Our results suggest that higher target serum ferritin concentrations can be well tolerated and lower rHuEPO requirements.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Ferritins; Follow-Up Studies; Humans; Injections, Intravenous; Iron-Dextran Complex; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis

Treatment of anemia with recombinant human erythropoietin (rHuEpo) in hemodialysis patients has been associated with improvement of several abnormalities in hypothalamic-pituitary function. The aim of the present study is to investigate the effects of long term erythropoietin therapy on the hypothalamic-pituitary-thyroid hormone axis in patients undergoing continuous ambulatory peritoneal dialysis (CAPD).. Single center, prospective study.. Ten patients who were clinically stable and had been on CAPD were evaluated. Eleven age and sex matched healthy volunteers were chosen as controls. All of the patients were clinically euthyroid. All patients were on CAPD therapy and none of them had received rHuEpo treatment previously. In all patients after basal estimations of free T3, free T4, TSH, GH and prolactin levels, a bolus of 400 microg TRH was administered intravenously. Levels of TSH, GH and prolactin were measured in blood samples collected every 30 min of the 3 h test period. After the treatment with rHuEpo, TRH test with the same protocol was repeated.. Before the improvement in serum hemoglobin levels with rHuEpo treatment, the patients on CAPD showed abnormal hypothalamic-pituitary-thyroidal functions, including delayed and prolonged TSH (NS), paradoxically elevated GH (p < 0.001) and increased and prolonged prolactin (p = 0.001) responses to TRH. After improvement of anemia with rHuEpo no significant difference was found between the patients and control groups for baseline TSH levels. In the patients peak TSH level and AUC of TSH secretion were significantly reduced after the treatment (p < 0.05 for both). Furthermore the improvement in anemia did not eliminate the paradoxic GH and prolonged prolactin responses to TRH administration.. Some hypothalamic-pituitary-thyroid function abnormalities including delayed and blunted TSH, increased and prolonged prolactin and paradoxical GH responses to TRH administration were observed in uremic patients treated with CAPD and the improvement in anemia with rHuEpo seems to cause slight changes on the hypothalamic-pituitary-thyroid axis and peripheral thyroid hormones.

Topics: Area Under Curve; Biomarkers; Creatinine; Dose-Response Relationship, Drug; Drug Evaluation; Erythropoietin; Growth Hormone; Hematocrit; Hemoglobins; Humans; Hypothalamo-Hypophyseal System; Kidney; Kidney Failure, Chronic; Male; Peritoneal Dialysis, Continuous Ambulatory; Pituitary-Adrenal System; Prolactin; Recombinant Proteins; Thyroid Function Tests; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Time; Time Factors; Treatment Outcome

Oxidant stress has a pathogenic role in uremic anemia, possibly interfering with erythropoietin (EPO) function and red blood cell (RBC) survival. Therefore, it is expected that antioxidant therapy might exert a beneficial effect on these parameters.. To test this hypothesis, we investigated some oxidant stress indices, anemia levels, and RBC survival in 47 hemodialysis (HD) patients randomly assigned to three groups. Patients in groups A (n = l8) and B (n = 20) were on dialysis therapy using conventional cellulosic and synthetic membranes and were administered high and low doses of recombinant human EPO (rHuEPO), respectively. Patients in group C (n = 9) were dialyzed with vitamin E-modified membranes (CL-Es) and investigated in a two-step prospective study. In step Cl, patients were administered rHuEPO doses similar to those of group A. In step C2, rHuEPO doses were reduced to those of group B. As oxidant stress markers, we determined in plasma the susceptibility of lipids to undergo iron-catalyzed oxidation (reactive oxygen molecules [ROMs] test) and malondialdehyde-4-hydroxynonenal (MDA-4HNE), alpha-tocopherol (alpha-T), total thiol (-SH), and total antioxidant activity. RBC survival was measured using the chromium 51 T/2 technique in 22 patients.. Results show that: (1) high rHuEPO doses (groups A and C1) were associated with decreased ROM production, low alpha-T levels, and slightly increased -SH levels compared with corresponding groups on low rHuEPO doses (groups B and C2); (2) treatment with CL-Es (group C) increased plasma alpha-T and decreased -SH levels; these data were associated with decreased indices of lipid peroxidation, particularly MDA-4HNE 1evels, only in patients administered low rHuEPO doses; (3) alpha-T concentration influenced RBC survival, which was remarkably decreased in HD patients; patients treated with CL-Es showed a better degree of anemia correction; and (4) alpha-T level correlated negatively with -SH level and seemed to be independent of the extent of peroxidation and oxidizability of plasma lipids.. Both EPO and CL-E can influence plasma antioxidants and, to an extent, lipid peroxidation processes. However, this study shows that even in patients treated with low rHuEPO doses, RBC survival close to normal and sufficient correction of anemia are achieved only when appropriate alpha-T levels are reached.

Topics: Adult; Aged; Anemia; Antioxidants; Biomarkers; Cell Survival; Drug Administration Schedule; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Lipid Peroxidation; Male; Membranes, Artificial; Middle Aged; Oxidative Stress; Prospective Studies; Recombinant Proteins; Renal Dialysis; Uremia; Vitamin E

Topics: Adult; Aged; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Inflammatory process induced by endotoxin is one of the causes of resistance to recombinant human erythropoietin (rHuEPO) in hemodialysis patients. Thus dialysate contaminated with endotoxin may diminish response to rHuEPO. We investigated whether dose of rHuEPO could be reduced with endotoxin-free ultrafiltered dialysate.. Twenty-seven chronic hemodialysis patients receiving rHuEPO were studied. The patients did not have known causes of anemia other than chronic renal failure. An endotoxin-cut polyethylene ultrafilter was installed into the dialysate fluid circuit. Hematocrit and dose of rHuEPO were monitored before and after installation. Dose of rHuEPO was adjusted to keep hematocrit at about 30%. Endotoxin concentration of dialysate was measured by commercial limulus test (Endospecy.. After installation of ultrafilter, dialysate endotoxin concentration decreased from >100 to <1.0 endotoxin units/liter (EU/l). Dose of rHuEPO decreased from 90.0 U/kg/week (median) to 57.3 U/kg/week (p < 0.05) and hematocrit increased from 30.3% (median) to 32.2% (p = 0.03) after 5 months of installation of ultrafilter. The running cost of the ultrafilter corresponded to only 4% of the cost of spared rHuEPO.. Ultrafiltered endotoxin-free dialysate caused significant reduction in dose of rHuEPO to keep target hematocrit level. Endotoxin-cut ultrafilter was beneficial to hemodialysis patients in medical and in economical aspects.

Topics: Adult; Aged; Anemia; C-Reactive Protein; Dialysis Solutions; Endotoxins; Erythropoietin; Humans; Kidney Failure, Chronic; Middle Aged; Polyethylene; Recombinant Proteins; Renal Dialysis; Treatment Outcome; Ultrafiltration

Darbepoetin alfa is a glycoprotein with a three-fold longer terminal half-life than recombinant human erythropoietin (rHuEPO). We aimed to determine whether darbepoetin alfa is as effective and well tolerated as rHuEPO for treating renal anemia in dialysis patients when administered at a reduced dose frequency.. A total of 522 European and Australian hemodialysis and peritoneal dialysis patients receiving stable rHuEPO therapy by either the intravenous (IV) or subcutaneous (SC) route were randomized, open-label in a 1:2 ratio to continue rHuEPO or to receive an equivalent dose of darbepoetin alfa at a reduced dose frequency. Patients receiving rHuEPO once weekly changed to once every other week darbepoetin alfa, and those receiving rHuEPO two or three times weekly changed to once-weekly darbepoetin alfa. The doses of rHuEPO and darbepoetin alfa were titrated to maintain hemoglobin close to the patient's baseline level for up to 52 weeks. The primary endpoint was the change in hemoglobin between baseline and the evaluation period at weeks 25 to 32 of treatment.. The mean change in hemoglobin from baseline to the evaluation period was similar in the darbepoetin alfa (-0.03 g/dL; SE 0.11) and rHuEPO (-0.06 g/dL; SE 0.13) groups, and the difference between the two treatments was 0.03 g/dL (95% CI -0.16, 0.21). This was not a statistically significant or clinically relevant difference, despite the reduced frequency of darbepoetin alfa administration. At the end of the evaluation period, >/=95% of patients had their hemoglobin successfully maintained on their assigned dose frequency for darbepoetin alfa (once weekly and once every other week) and rHuEPO (once, twice and three times weekly). The safety profiles of darbepoetin alfa and rHuEPO were similar, and no antibodies to either treatment were detected.. Darbepoetin alfa maintains hemoglobin as effectively as rHuEPO, but with a reduced dose frequency.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Darbepoetin alfa is a novel erythropoiesis-stimulating protein with a two- to threefold longer half-life than recombinant human erythropoietin (epoetin) in adult patients with chronic kidney disease (CKD). This randomized, open-label, crossover study was conducted to determine the pharmacokinetic profile of darbepoetin alfa in pediatric patients with CKD. Twelve patients 3-16 years of age with CKD were randomized and received a single 0.5 micro g/kg dose of darbepoetin alfa administered intravenously (IV) or subcutaneously (SC). After a 14- to 16-day washout period, patients received an identical dose of darbepoetin alfa by the alternate route. After IV administration, the mean clearance of darbepoetin alfa was 2.3 ml/h per kg, with a mean terminal half-life of 22.1 h. After SC administration, absorption was rate limiting, with a mean terminal half-life of 42.8 h and a mean bioavailability of 54%. Comparison of these results with those from a previous study of darbepoetin alfa in adult patients indicated that the disposition of darbepoetin alfa administered IV or SC is similar in adult and pediatric patients, although absorption may be slightly more rapid in pediatric patients after SC dosing. The mean terminal half-life of darbepoetin alfa in this study was approximately two- to fourfold longer than that previously reported for epoetin in pediatric patients.

Topics: Adolescent; Adult; Area Under Curve; Biological Availability; Child; Child, Preschool; Cross-Over Studies; Darbepoetin alfa; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Half-Life; Humans; Infant; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Renal Dialysis

Individuals with end-stage renal disease on hemodialysis therapy have reduced aerobic exercise capacity and reduced muscle strength.. This was a single-blind, randomized, placebo-controlled trial of an exercise intervention in hemodialysis patients administered erythropoietin. The intervention consisted of progressive resisted isotonic quadriceps and hamstrings exercise and training on a cycle ergometer three times weekly for 12 weeks. Individuals in the control group underwent a nonprogressive program of range-of-motion exercises. Both groups were observed for an additional 5 months without intervention. Outcomes were assessed without knowledge of treatment assignment at baseline, 12 weeks, and 5 months. A healthy age- and sex-matched sample provided comparative data.. Our sample was relatively high functioning, with a mean score on the Physical Function subscale of the Short Form 36 (SF-36) of 76 of 100. At 12 weeks, there were large and statistically significant differences in favor of the experimental group on the submaximal exercise test (14 W; 95% confidence interval, 2 to 26) and muscle strength (45 lb; 95% confidence interval, 9 to 81), but not in the 6-minute walk, symptoms questionnaire, or SF-36. Differences between the intervention and control groups at 12 weeks were not evident on retesting 5 months after the end of the intervention. Compared with the healthy sample, patients were significantly lower functioning on the submaximal exercise test, muscle strength, and 6-minute walk test at baseline.. In this high-functioning sample, the exercise program improved physical impairment measures, but had no effect on symptoms or health-related quality of life. The impact on patients with a greater degree of physical dysfunction needs to be rigorously studied.

Topics: Anemia; Drug Administration Schedule; Erythropoietin; Exercise; Exercise Test; Exercise Therapy; Health Surveys; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Single-Blind Method; Surveys and Questionnaires; Treatment Outcome; Weight Lifting

The problem of hearing loss occurrence in the course of chronic renal failure (CRF) was investigated in numerous research studies, attempting to explain both the etiological factors and treatment possibilities. According to various authors, the percentage of hearing loss occurrence in patients suffering from CRF differs between 20% and 80%. The idea of this paper is based on an observation that if peripheral blood parameters such; haemoglobin, amount of red blood cells improve when influenced by rhEPO, then tissue oxidation improvement connected with it causes also better metabolism of cilliar's cells, what helps to improve hearing. The purpose of this study has been to assess the influence of treatment with human recombinant erythropoietin obtained through genetic recombination and by haemodialysis upon the condition of the hearing organ in patients with CRF (as a result of both a single procedure and long-term treatment). 65 haemodialysed patients with chronic renal failure were enrolled in this study. 31 of them (with haematocrit value below 28%) were treated with rhEPO for 4 months (3 times a week, 4000 units). The remaining 34 patients (with haematocrit values of above 28%) were not treated with rhEPO. Impairment of hearing was found in 87.1% of the CRF patients examined, while the hearing loss in high frequency range (9-18 kHz) was significantly more pronounced than those observed in the conventional range. In 70% of the patients the hearing loss was the cochlear type. Thus, combining haemodialysis with recombinant human erythropoietin in treatment of CRF patients results in significant improvement of hearing, correlated with positive results in fighting anaemia. The improved hearing found is, most surely, related to better oxygen supply of ciliated cells of internal ear, resulting from improved oxygen supply in peripheral blood and tissues of the body, and may also be related to the centric activity of erythropoietin, as the presence of receptors for EPO was found in the central nervous system (CNS) neurocytes, and it was also proven that EPO is produced in CNS, probably in astrocytes.

Topics: Adult; Anemia; Audiometry; Combined Modality Therapy; Erythropoietin; Female; Hearing; Hearing Loss; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Time Factors; Treatment Outcome

Darbepoetin alfa is a unique erythropoetic protein whose half-life is 3 times longer than that of recombinant human erythropoetin (rHuEPO). It corrects and maintains haemoglobin (Hb) concentrations at increased dosing intervals as compared to rHuEPO. The aim of this study was to evaluate the efficacy and safety of darbepoetin alfa administered as fixed unit doses. Haemodialysis patients (n = 250) maintained on stable rHuEPO treatment 2-3 times weekly (n = 200) were switched to darbepoetin alfa once weekly (QW). Treatment for patients on rHuEPO QW (n = 50) was changed to darbepoetin alfa every other week (Q2W). The route of administration (i.v. or s.c.) was kept unchanged. The dose of darbepoetin alfa was titrated to maintain Hb levels at 10-13 g/dL between baseline and the evaluation period (weeks 21-24; primary endpoint). There was no clinically relevant change in mean Hb levels between baseline (11.69 g/dL) and evaluation (-0.28 g/dL (95% CI: -0.43; -0.13)). Mean weekly dose requirements of darbepoetin alfa decreased by 13.3% from 36.7 micrograms (95% CI: 33.9; 39.7) to 31.8 micrograms (95% CI: 28.7; 35.2). This decrease was more pronounced in patients receiving darbepoetin alfa i.v. (-18.4%) as compared to those receiving it s.c. (-6.4%). Darbepoetin alfa was well tolerated. Overall safety data were consistent with those observed in other studies. These data confirm that unit dosing with darbepoetin alfa at increased dosing intervals and reduced dose effectively and safely maintains Hb levels in haemodialysis patients.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Body Weight; Darbepoetin alfa; Data Interpretation, Statistical; Erythropoietin; Female; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Time Factors

The abnormal metabolism of macrominerals and trace metals, a frequently overlooked fact may be one of the factors influencing clinical disorders in chronic dialysis patients. The purpose of this study was to compare to what extent maintenance hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD) therapy influences the magnesium (Mg) and zinc (Zn) levels in blood of patients treated by these two methods. Additionally, we examined the influence of rhEPO therapy on Hb concentration in erythrocytes, total protein and albumin levels in plasma, and possible impact of rhEPO on Zn and Mg content in blood. Seventy-five ESRD (25 treated and 15 non treated with rhEPO on HD), and (20 treated and 15 non treated with rhEPO on CAPD) patients participated in this study. Forty-five healthy volunteers (HV) served as a reference group. The mean plasma and erythrocytes Mg concentration (mmol/l) in HD and CAPD patients without and with rhEPO treatment was found to be significantly higher than in HV. In HD and CAPD patients treated by rhEPO the mean erythrocytes Mg levels were significantly lower than in non rhEPO treated groups. The inverse relationship between Hb and Mg concentration in erythrocytes in HD and CAPD patients with rhEPO treatment was observed (r = -0.63, P < 0.05 and r = -0.59, P < 0.01 respectively). The mean plasma Zn levels (micromol/l) in HD and CAPD patients with and without rhEPO have been significantly lower than in HV. In patients treated by rhEPO significant increase of Zn erythrocytes levels was found. We was found positive correlation between plasma and erythrocyte Zn levels and Hb concentration in HD and CAPD patients treated by rhEPO (r = 0.35, P < 0.05 and r = 0.4, P < 0.05 respectively). The Hb concentrations, total protein and albumin levels in HD and CAPD with rhEPO therapy were found significantly higher than in patients without rhEPO therapy, but still lower if compared to HV. Mean levels of iron and TIBC in plasma have been found significantly lower in both studied groups treated or non treated by rhEPO, in comparison to HV. In both studied groups of patients without rhEPO or treated by rhEPO plasma GC, GSA, Cr concentrations were significantly higher from those obtained in HV. No statistical correlations were found between Mg, Zn and total protein, albumin, iron levels and TIBC. During rhEPO therapy increased Hb concentration was connected with higher plasma and erythrocytes Zn levels and lower erythrocytes Mg levels. rhEPO

Topics: Adult; Blood Proteins; Erythrocytes; Erythropoietin; Female; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Magnesium; Male; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis; Serum Albumin; Zinc

The objective of the study was to evaluate and compare the safety and effectiveness of epoetin omega (produced in baby hamster kidney cells) and epoetin alfa (produced in Chinese hamster ovary cells) in sustaining the correction of anemia in maintenance hemodialysis patients. The study, a prospective and controlled crossover, was completed in 38 stable patients treated with both epoetins for 24 weeks. Group A (17 patients) started with epoetin omega, and Group B (21 patients) started with epoetin alfa. After 24 weeks, a 4 week crossover (wash out) was made: Group A was switched to epoetin alfa and group B to epoetin omega for the next test period of 24 weeks. Both epoetins were administered subcutaneously after each dialysis. Doses were adjusted with the aim of maintaining a target hemoglobin level between 10 and 12 g/dl (hematocrit 30% to 35%). The mean weekly dose of epoetin omega/kg body weight (BW) was 67 +/- 43 U. The mean weekly dose of epoetin alfa/kg BW was 86 +/- 53 U. The average of all mean values of hemoglobin (Hb) during treatment with epoetin omega was 11.4 +/- 0.7 g/dl (hematocrit 34 +/- 2%), and during treatment with epoetin alfa was 11.3 +/- 0.7 g/dl (hematocrit 33 +/- 2%) (not significant). Thromboses of vascular access occurred in 3 patients during an epoetin omega treatment and in 3 patients during epoetin alfa treatment. At the site of injection, only 1 patient described a mild pain when treated with epoetin omega and only 6 patients when treated with epoetin alfa. In conclusion, both epoetin omega and epoetin alfa were effective in correcting the anemia of all studied patients. However, lower doses of epoetin omega were needed to maintain the same target hemoglobin level. No serious side effects with either epoetin were noted. The authors believe that additional comparisons of different epoetin preparations should be performed and will provide better insight into their biological activity and clinical responsiveness.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Cross-Over Studies; Epoetin Alfa; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Treatment Outcome

The kidney accumulates the highest level of selenium (Se) in the organism and is the major source of plasma glutathione peroxidase (GSH-Px). Se, as an integral part of the active site of GSH-Px, plays an important role in protecting cell membranes from oxidative damage. Decreased blood Se levels and GSH-Px activity are common in chronic renal failure (CRF) patients. Our study was an effort to evaluate the effect of erythropoietin (EPO) therapy and Se supplementation for CRF patients undergoing regular hemodialysis (HD) on blood Se, red cell glutathione (GSH), and blood lipid peroxidation product levels, and on blood activity levels of GSH-Px and blood superoxide dismutase (SOD).. Our subjects were divided into three groups: I - CRF patients on regular HD and EPO, II - HD patients receiving EPO and Se, and III - healthy controls. Se levels, SOD and GSH-Px activities were measured spectrofluorometrically, the GSH level by Beutler's colorimetric method, and lipid peroxidation products using TBARS.. EPO therapy with Se supplementation significantly increased whole blood and plasma Se in HD patients, and raised red cell GSH-Px activity, but plasma GSH-Px activity, plasma superoxide dismutase, and plasma and red cell TBARS did not respond to Se supplementation. EPO alone showed no effect on these parameters.. Treatment with EPO and supplementation with Se significantly increased the element concentration in whole blood and plasma, and GSH-Px activity in red cells. Plasma GSH-Px activity did not respond to Se.

Topics: Adolescent; Adult; Antioxidants; Dietary Supplements; Erythropoietin; Female; Glutathione Peroxidase; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Selenium; Spectrometry, Fluorescence; Time Factors; Uremia

Topics: Aged; Blood Platelets; Darbepoetin alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Platelet Aggregation; Recombinant Proteins; Uremia

We conducted a prospective study to determine the effect of intravenous low-dose iron administration in chronic hemodialysis patients treated with recombinant human erythropoietin (rHuEPO). Sixteen hemodialysis patients (8 males and 8 females; mean age 63.1+/-9.8 years) on maintenance rHuEPO therapy were included in the study. Patients with <100 ng/ml of ferritin received 50 mg iron during every hemodialysis session. Patients with 100-200 ng/ml of ferritin were given 50 mg iron fortnightly. Iron was not supplemented in patients with ferritin levels >200 ng/ml. Mean hematocrit, serum iron levels and transferrin saturations were significantly higher at 6 and 12 months. There was a significant reduction in weekly rHuEPO doses between the start and the 6th and 12th months. Our study shows intravenous iron administration of 100 mg/month may be sufficient to achieve a satisfactory iron status in dialysis patients on maintenance rHuEPO therapy.

Topics: Aged; Anemia; Dose-Response Relationship, Drug; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hematinics; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis

Iron sucrose has been used to provide intravenous (IV) iron therapy to patients outside the United States for more than 50 years. In a multicenter North American clinical trial, we determined the efficacy and safety of iron sucrose therapy in patients with dialysis-associated anemia, evidence of iron deficiency, and below-target hemoglobin (Hgb) levels despite epoetin therapy. Evidence of iron deficiency included a transferrin saturation (Tsat) less than 20% and ferritin level less than 300 ng/mL, and below-target Hgb levels included values less than 11.0 g/dL. We administered iron sucrose in 10 doses, each administered undiluted as 100 mg IV push over 5 minutes, without a prior test dose. We assessed efficacy by determining the subsequent change in Hgb, Tsat, and ferritin values. We assessed safety by recording blood pressure and adverse events after iron sucrose injection and comparing results with those for the same patients during an observation control period. Results showed a significant increase in Hgb level that was first evident after three doses of iron sucrose and persisted at least 5 weeks after the 10th dose. Tsat and ferritin levels also increased significantly and remained elevated. In 77 enrolled patients, including those with previous iron dextran sensitivity, other drug allergies, or concurrent angiotensin-converting enzyme inhibitor use, we saw no serious adverse drug reactions and no change in intradialytic blood pressure associated with iron sucrose administration. We conclude that iron sucrose injection administered as 1,000 mg in 10 divided doses by IV push without a prior test dose is safe and effective for the treatment of iron deficiency in patients with dialysis-associated anemia.

Topics: Aged; Anemia, Iron-Deficiency; Epoetin Alfa; Erythrocyte Indices; Erythropoietin; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hemoglobins; Humans; Injections, Intravenous; Iron; Kidney Failure, Chronic; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis

Intravenous iron (Fe) and recombinant human erythropoietin (rHuEPO) are routine treatments in the management of anemia in patients with chronic renal failure. We investigated the oxidative stress acutely induced by these therapies and whether pretreatment with oral melatonin (MEL) would have a beneficial effect. Nine patients (four women) were studied within 1 month of entering a chronic hemodialysis program in the interdialytic period. Plasma malondialdehyde (MDA), red blood cell glutathione (GSH), and catalase (CAT) activity were measured in blood samples obtained before (baseline) and 1, 3, and 24 hours after the administration of Fe (100 mg of Fe saccharate intravenously over 1 hour) or rHuEPO (4,000 U intravenously). One hour before these treatments, patients were administered a single oral dose of MEL (0.3 mg/kg) or placebo. Each patient was studied on four occasions, corresponding to studies performed using either placebo or MEL in association with intravenous Fe and rHuEPO administration. Baseline data showed increased oxidative stress in patients with end-stage renal failure. Increments in oxidative stress induced by Fe were more pronounced at the end of the administration: MDA, baseline, 0.74 +/- 0.09 nmol/mL; 1 hour, 1.50 +/- 0.28 nmol/mL (P: < 0.001); GSH, baseline, 2.51 +/- 0.34 nmol/mg of hemoglobin (Hb); 1 hour, 1.66 +/- 0.01 nmol/mg Hb (P: < 0.001); and CAT activity, baseline, 27.0 +/- 5.7 kappa/mg Hb; 1 hour, 23.3 +/- 4.2 kappa/mg Hb (P: < 0.001). rHuEPO-induced increments in oxidative stress were more pronounced (P: < 0.001) at 3 hours (MDA, 1.24 +/- 0.34 nmol/mL; GSH, 1.52 +/- 0.23 nmol/mg Hb; CAT activity, 18.0 +/- 3.1 kappa/mg Hb). MEL administration prevented the changes induced by Fe and rHuEPO and had no adverse side effects. These studies show that intravenous Fe and rHuEPO in doses commonly used to treat anemia in chronic hemodialysis patients acutely generate significant oxidative stress. Oral MEL prevents such oxidative stress and may be of clinical use.

Topics: Adult; Anemia; Catalase; Double-Blind Method; Erythrocytes; Erythropoietin; Female; Glutathione; Humans; Infusions, Intravenous; Iron; Kidney Failure, Chronic; Male; Malondialdehyde; Melatonin; Oxidative Stress; Placebos; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Pyridoxine deficiency may be the cause of failure to respond appropriately to iron and erythropoietin (EPO) administration in hemodialysis patients.. We studied 36 patients on chronic hemodialysis amply supplemented with iron and EPO, who failed to raise hematocrit levels >33%. Patients were divided into three equal groups and evaluated for 6 months as follows: Group A -- no additional therapy; group B -- supplemented with oral pyridoxine 50 mg/day, and group C received 100 mg/day pyridoxine orally.. In all our patients, erythrocyte pyridoxine levels were initially within reference range for a healthy population and did not vary significantly during the study period. Likewise, ferritin levels and iron saturation values remained normal and constant. Hemoglobin and/or hematocrit levels remained practically unchanged in all three groups.. The results indicate that in hemodialysis patients with normal pyridoxine status who, despite appropriate supplementation of iron and EPO, fail to reach optimal hematocrit levels, additional pyridoxine treatment does not produce any hematocrit elevation.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Aspartate Aminotransferases; Dietary Supplements; Erythrocytes; Erythropoietin; Female; Ferritins; Hematocrit; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Nutritional Status; Pyridoxine; Renal Dialysis

It is now more and more evident that anemia of predialysis chronic renal failure (CRF) should be actively treated, since long-standing anemia may cause irremediable damage to the heart. The most common form of treatment of this anemia is subcutaneous erythropoietin (EPO). iron (Fe) deficiency can also contribute to anemia in predialysis CRF, and intravenous iron (i.v. Fe) can frequently improve it. It is possible, therefore, that the combination of EPO and i.v. Fe may have an additive effect, and cause a rapid improvement in anemia with relatively small doses of EPO.. The purpose of this study was an initial study: to assess the ability of a combination of low-dose EPO and i.v. Fe, given weekly for 5 doses, to correct the anemia of predialysis CRF patients compared to the use of i.v. Fe alone in a randomized study. In the follow-up study: to assess the ability of the maintenance of adequate iron stores for one year to achieve and maintain the target Hct of 35% with the minimum dose of EPO. Initial study:. Ninety predialysis CRF patients (creatinine clearance 10-40 ml/min/1.73 m2 received either: Group A (45 patients): 200 mg i.v. Fe as Fe sucrose (Venofer, Vifor Int.) once per week for 5 doses in combination with 2,000 international units (IU) EPO (Eprex, Cilag-Janssen), subcutaneously given simultaneously also for 5 doses. Group B (45 patients): the same dose of i.v. Fe as in Group A but without EPO.. The mean increase in hematocrit (Hct) and hemoglobin (Hb) by one week after the last dose was greater in group A, 4.54 +/- 2.64% (p < 0.01) and 1.37 +/- 0.84 g% (p < 0.01), respectively, than in Group B, 2.74 +/- 2.72% (p < 0.05) and 0.91 +/- 0.78 g% (p < 0.05), respectively. 80% of those in Group A had an increase in Hct of 3 vol% or more compared to 48.9% in Group B (p < 0.01). 40% of those in Group A reached the target Hct of 35% compared to 28.9% in Group B (p > 0.05). Follow-up study: During a 12-month follow-up period, enough i.v. iron was given to maintain the Hct at 35%, while keeping the serum ferritin at < 400 ug/l and % Fe Sat at < 40%. If the i.v. Fe alone was not capable of maintaining the target Hct, EPO was given in increasing doses. Eighteen patients required dialysis. Of the 72 patients who did not require dialysis, 24 (33.3%) maintained the target Hct with i.v. Fe alone, without EPO. All the remaining 48 patients (66.7%) continued to receive EPO in addition to the i.v. Fe, and 47 achieved and maintained the target Hct with a mean EPO dose of 2,979 +/- 1,326 IU/week.. The combination of low-dose EPO and i.v. Fe had a rapid and additive effect on the correction of anemia in CRF predialysis patients. Maintaining adequate iron stores with i.v. Fe during a subsequent maintenance phase allowed the target Hct of 35% to be reached and maintained with low-dose EPO in two-thirds of the predialysis patients and with no EPO at all in one-third.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Drug Therapy, Combination; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Glucaric Acid; Hematocrit; Humans; Infusions, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Sucrose

Renal anaemia is an independent risk factor for the development of left ventricular hypertrophy (LVH), heart failure and mortality. Studies show that partial correction of anaemia leads to partial regression of LVH. However, early initiation of anaemia therapy may be the optimal way to reduce cardiac morbidity and mortality. The Cardiovascular risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trial will investigate the effect of early anaemia correction on cardiovascular risk reduction in patients not yet on renal replacement therapy. The primary objectives of this open, randomized, multicentre trial are to investigate the effect of early anaemia correction on the change in left ventricular mass index after 1 year, and the time to first cardiovascular event. The trial comprises two treatment arms: early intervention where patients will receive epoetin beta when their haemoglobin (Hb) level is 11-12.5 g/dl and their target Hb will be 13-15 g/dl, and late intervention, where patients will receive epoetin beta once their Hb level is <10.5 g/dl and their target Hb will be 10.5-11.5 g/dl. The study will be event-driven with a continuous evaluation and an interim analysis once every year. The inclusion of 600 patients is based on assumption of a 15-20% event rate in the control group and that 200 events are needed to detect a reduction of about one-third. In conclusion, the CREATE trial will examine whether early anaemia treatment will prevent development of LVH, reduce cardiovascular morbidity and provide other benefits.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Recombinant Proteins; Risk Factors

Cytosolic free calcium ([Ca(2+)](i)) is an important second messenger during stimulation in a wide variety of cells, including polymorphonuclear leukocytes (PMNs). Its mobilization in PMNs is altered in various diseases such as atherosclerosis and ageing. In chronic haemodialysis (HD) patients, both atherosclerosis and accelerated ageing are well known. Therefore [Ca(2+)](i) in resting PMNs of HD patients was determined along with certain parameters which might affect it, such as recombinant human erythropoietin (rHuEpo) treatment, calcium-phosphate balance, and biocompatibility of dialysis membranes.. PMNs were separated by density centrifugation and [Ca(2+)](i) was determined by spectrofluorimetry using Quin 2/AM fluorescent dye. Laboratory parameters were determined by standard methods in clinical chemistry.. It was found that [Ca(2+)](i) in resting PMNs of HD patients not undergoing rHuEpo therapy was higher than that of controls. After 12-weeks of rHuEpo therapy, [Ca(2+)](i) decreased to near normal level. The role of erythropoiesis in normalization of [Ca(2+)](i) in resting PMNs was supported by PMN [Ca(2+)](i) which was elevated in patients who had low haemoglobin (<100 g/l) or haematocrit (<0.30) values. In some patients, including those receiving rHuEpo treatment, [Ca(2+)](i) remained high, suggesting a role for other parameters in increasing [Ca(2+)](i). One possible parameter might be the disturbed calcium-phosphate metabolism of chronic renal failure, because we found a strong correlation between [Ca(2+)](i) and plasma iPTH levels in HD patients (r=0.743, P<0.001). [Ca(2+)](i) was also elevated in PMNs of those patients who had either low plasma calcium or high plasma phosphate levels. PMN [Ca(2+)](i) of HD patients correlated positively with the duration of HD (r=0.671, P<0.001). However, there was no correlation between [Ca(2+)](i) and patient age. The dialysis procedure itself also transiently increased PMN [Ca(2+)](i) HD patients, independently of the type of dialysis membrane.. PMN [Ca(2+)](i) is modulated by various parameters in HD patients, including the degree of anaemia, disturbances of calcium metabolism, and duration of dialysis treatment. The elevated [Ca(2+)](i) of resting PMNs might contribute to altered functions in these cells.

Topics: Adult; Arteriosclerosis; Blood Cell Count; Calcium; Cytosol; Erythropoiesis; Erythropoietin; Glomerulonephritis; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic; Membranes, Artificial; Neutrophils; Parathyroidectomy; Recombinant Proteins; Regression Analysis; Renal Dialysis

The European Best Practice Guidelines for the management of anemia in patients with chronic renal failure recommend the percentage of hypochromic red blood cells (%HRCs) as the best measure of iron use by erythropoietic tissues. They suggest that "sufficient iron should be administered to attain: serum ferritin 100 ng/mL, HRCs <10%. In practice, to achieve these minimum criteria will mean aiming for optimal levels of serum ferritin 200-500 ng/mL, HRCs <2.5%." We increased prospectively the delivered dose of iron supplements to a large (n = 228) unselected hemodialysis cohort with a sustained (24-month) hemoglobin (Hb) outcome meeting the UK Renal Association minimum standard of 85%, greater than or equal to 10.0 g/dL. This was managed through a computer-aided decision support system for erythropoietin (EPO) and intravenous iron sucrose therapy. Hb outcome was maintained with medians between 11.3 and 11.8 g/dL. Median red blood cell hypochromia (%HRCs) decreased from 8% (interquartile range [IQR], 3 to 15) to 4% (IQR, 2 to 8; P < 0.001, U-Mann Whitney test). Serum ferritin level increased from a median of 188 (IQR, 115 to 256) to 480 ng/mL (IQR, 397 to 595; P < 0.001, U-Mann Whitney test). Median EPO dose decreased from 136 (IQR, 83 to 216) to 72 IU/kg/wk (IQR, 33 to 134), which strongly correlated with median %HRCs through the range less than 10% (Spearman's correlation, 0.73; P < 0.01). These data suggest that EPO responsiveness continues to improve toward the normal range for %HRCs (<2.5%) and aspiring to values much less than 10% is cost-effective. The ferritin outcome required to achieve these lower values for %HRC outcome is greater than the current recommended range, although in steady state, the mean iron treatment dose is similar to that in previous studies (ie, approximately 60 mg/wk).

Topics: Anemia; Dose-Response Relationship, Drug; Erythropoietin; Ferritins; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Renal Dialysis; Time Factors; Treatment Outcome

Novel erythropoiesis stimulating protein (NESP) is a glycoprotein with a threefold longer terminal half-life than recombinant human erythropoietin (rHuEPO) in humans. The aim of this study was to determine whether NESP is effective for the treatment of anemia at a reduced dosing frequency relative to rHuEPO in patients with chronic renal failure not yet on dialysis [chronic renal insufficiency (CRI)].. This was a multicenter, randomized, open-label study. A total of 166 rHuEPO-naive patients with CRI were randomized in a 3:1 ratio to receive NESP (0.45 microg/kg once weekly) or rHuEPO (50 U/kg twice weekly) administered subcutaneously for up to 24 weeks. Dose adjustments were made as necessary to achieve a hemoglobin response, defined as an increase > or =1.0 g/dL from baseline and a concentration > or = 11.0 g/dL.. During the 24-week treatment period, 93% (95% CI, 87 to 97%) of patients receiving NESP and 92% (95% CI, 78 to 98%) of patients receiving rHuEPO achieved a hemoglobin response. The median time to response was seven weeks (range of 3 to 25 weeks) in both groups. After correction of anemia, mean hemoglobin concentrations were maintained within the target range of 11.0 to 13.0 g/dL for the remainder of the 24-week treatment period. The safety profiles of NESP and rHuEPO were similar, and no antibodies were detected to either drug.. These results demonstrate that NESP safely and effectively corrects and maintains hemoglobin concentrations at a reduced dosing frequency relative to rHuEPO in patients with CRI, providing a potential benefit to patients and health care providers.

Topics: Aged; Anemia; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Treatment Outcome

Topics: Adult; Anemia; Cytokines; Erythropoietin; Female; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Male; Middle Aged; Parathyroidectomy; Prospective Studies; Renal Dialysis

Ten normotensive hemodialysis patients with severe anemia participated in the study. Human recombinant erythropoietin (rHuEpo) was administered i.v. 3 times a week in doses of 50 U/kg of body weight. During 12 weeks of observation, the mean hematocrit value increased from 19%, before start of therapy, to 32%. Simultaneous monitoring of serum plasma noradrenaline (NA) concentration showed an elevation from 202 to 281 pg/ml. An increase of NA concentration after a cold pressure stimulating test (CP) was not statistically significant after as compared to before treatment, but became statistically significant after 12 weeks of rHuEpo therapy (281 pg/ml before to 441 pg/ml after CP test, p < 0.01). The mean arterial blood pressure increased from 92 - 109 mmHg after 12 weeks of rHuEpo therapy (p < 0.001). We have demonstrated significantly increased NA blood concentrations after 12 weeks of rHuEPO therapy in normotensive patients, which correlated with increased MAP. This may suggest that the observed increase of noradrenaline concentration as a vasoactive substance after the CP test may contribute to hypertension during rHuEPO therapy.

Topics: Adrenergic Fibers; Adult; Anemia; Blood Pressure; Cold Temperature; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Norepinephrine; Recombinant Proteins; Regression Analysis; Renal Dialysis; Stress, Physiological; Sympathetic Nervous System

To conduct a 3-month prospective study to determine the optimal way for intravenous iron supplementation in hemodialysis (HD) patients with resistance to recombinant human erythropoietin (rHuEPO) therapy due to deficient iron storage.. Thirty-five HD patients with iron deficiency were divided into three groups: (1) patients receiving an intravenous infusion of 40 mg of iron during the first ten HD sessions (n = 12); (2) patients receiving 40 mg of iron injected once a week for 10 weeks (n = 12), and (3) patients without any iron supplementation (n = 11). The rHuEPO dosage was adjusted to maintain hemoglobin levels >10.0 g/dl, and the degree of anemia was assessed 3 months later.. In group 1, the hemoglobin levels were significantly increased after 4 weeks and remained increased until the end of the study (p < 0.01). In group 2, the hemoglobin levels were gradually increased until the end of the study (p < 0.01). There was no difference in the final hemoglobin values between both groups. The rHuEPO dosage was significantly decreased from 131 +/- 18 to 90 +/- 17 U/kg/week in group 1 (p < 0.01), but could not be changed in group 2 during the observation period despite a similar elevation of the serum ferritin level. In group 3, the rHuEPO doses were rather increased at the end of the study (p < 0.05).. Aggressive iron supplementation for the short term may be effective to restore rHuEPO hyporesponsiveness in HD patients with functional iron deficiency.

Topics: Aged; Anemia, Iron-Deficiency; Drug Therapy, Combination; Erythropoietin; Female; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis

Topics: Aged; Erythropoietin; Female; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Solubility; Transferrin

The clearest benefit of recombinant human erythropoietin (rHuEPO) in end-stage renal disease is a substantial reduction in transfusion dependency and an improved quality of life. In this report, we describe the efficacy of weekly subcutaneous administration of rHuEPO in 11 elderly patients with anemia secondary to chronic renal failure.. The role of rHuEPO therapy in increasing the patient's quality of life and in decreasing the hospitalization rates secondary to cardiac morbidity was verified in 11 elderly patients (age range between 66 and 85 years) with anemia due to chronic renal failure. The mean hemoglobin level at the beginning of the study was 8.2 +/- (SD) 0.7 g/dl, and the serum creatinine concentration was 4.8 +/- 1.36 mg/dl. The patients underwent baseline and annual echocardiography, in addition to an electrocardiogram.. Most patients experienced a partial regression of left ventricular hypertrophy, and no congestive heart failure was documented. The mean hemoglobin level during rHuEPO therapy increased to 11.3 +/- 1.2 g/dl, while the mean serum creatinine concentration did not change significantly.. Our results confirm that early anemia correction in aged chronic renal failure patients permits improvement of the quality of life, of exercise performance, and of cognitive functions. Reduced transfusion need and regression of left ventricular hypertrophy favor a minor incidence of cardiac morbidity and contribute to reduce health costs.

Topics: Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Male; Myocardial Ischemia

Supplement with keto acids/amino acids (KA) and erythropoietin can independently improve the metabolic sequels of chronic renal insufficiency. Our study was designed to establish whether a supplementation with keto acids/amino acids (KA) exerts additional beneficial metabolic effects in patients with chronic renal insufficiency (CRF) treated with a low-protein diet (LPD) and recombinant human erythropoietin (EPO). In a prospective randomized controlled trial over a period of 12 months, we evaluated a total of 38 patients (20 M/18 F) aged 32-68 years with a creatinine clearance (CCr) of 20-36 ml/min. All patients were receiving EPO (40 U/kg twice a week s.c.) and a low-protein diet (0.6 g protein/kg/day and 145 kJ/kg/day). The diet of 20 patients (Group I) was supplemented with KA at a dosage of 100 mg/kg/day while 18 patients (Group II) received no supplementation. During the study period, the glomerular filtration rate slightly decreased (CCr from 28.2 +/- 3.4 to 26.4 +/- 4.1 ml/min and 29.6 +/- 4.8 to 23.4 +/- 4.4 ml/min in groups I and II, respectively and Cin); this however was more marked in Group II (Group I vs. Group II, p < 0.01). The serum levels of urea also declined (p < 0.01), more pronouncedly in Group I (p < 0.025). In Group I, there was a significant rise in the levels of leucine (p < 0.01), isoleucine (p < 0.01), valine (p < 0.02) and albumin (p < 0.01) and a decrease in protein-uria (p < 0.01). Analysis of the lipid spectrum revealed a mild yet significant decrease in total cholesterol and LDL-cholesterol (p < 0.02), more pronounced in Group I. In Group I, there was a decrease in plasma triglycerides (from 4.2 +/- 0.8 down to values a low as 2.2 +/- 0.6 mmol/L; p < 0.01) whereas HDL-cholesterol levels increased (from 0.9 +/- 0.1 to 1.2 +/- 0.1 mmol/L, p < 0.01). A further remarkable finding was a reduction in the serum concentration of free radicals (p < 0.01). We conclude that a KA supplementation in patients with CRF receiving LPD and EPO potentiates the beneficial effects on metabolism of proteins, amino acids and surprisingly, also lipids. Long-term co-administration of KA, EPO and LPD was also associated with a delay in progression of renal insufficiency and a reduction in proteinuria. Thus, concomitant administration of KA and EPO during a low-protein diet presents an effective treatment modality in the conservative management of CRF.

Topics: Adult; Aged; Amino Acids; Amino Acids, Branched-Chain; Amino Acids, Essential; Diet, Protein-Restricted; Erythropoietin; Female; Food, Formulated; Free Radicals; Humans; Keto Acids; Kidney Failure, Chronic; Lipoproteins; Male; Middle Aged; Prospective Studies; Proteins; Proteinuria; Recombinant Proteins; Treatment Outcome

Ketoacids (KA) and recombinant human erythropoietin (rHuEPO) may each, on their own, influence the metabolic status of patients with chronic renal failure (CRF). A long-term prospective randomized study was designed to monitor the metabolic and nutritional status and progression of CRF using three therapeutic protocols: (A) low-protein diet (LPD) with 0.6 g of protein and 35 kcal/kg/day, with recombinant human erythropoietin (rHuEPO) at a dose of 40 U kg/week and keto acids (KA) 100 mg/kg/day, (Group I), (B) LPD and rHuEPO (Group II), and (C) LPD only (Group III). A total of 105 patients (50M/55F), aged 26-78 years, CCr 22-36 ml/min, were monitored at the beginning, and at every 6 months for 3 years in the above three study groups. Group I comprised 35 patients, Group II 38 patients and Group III 32 patients. During follow-up, a significantly smaller decrease in GFR (CCr, Cin) and in I/SCr, and an increase in serum albumin, transferrin, leucine, body mass, index and HDL-cholesterol were found in Group I (all p < 0.01). In addition, significant decreases were also seen in proteinuria, renal fractional leucine excretion and serum triglycerides level (p < 0.01). Co-administration of LPD, rHuEPO and KA thus constitutes an effective alternative to conservative management of CRF, delaying in follow-up period progression of renal failure and correction of metabolic parameters.

Topics: Adult; Aged; Amino Acids, Essential; Diet, Protein-Restricted; Dietary Supplements; Erythropoietin; Female; Glomerular Filtration Rate; Humans; Keto Acids; Kidney Failure, Chronic; Leucine; Male; Middle Aged; Proteinuria; Recombinant Proteins; Serum Albumin; Transferrin; Triglycerides

High concentration of intraerythrocyte ATP is a common phenomenon in patients with chronic renal failure (CRF). It is likely that this is a result of increased plasma concentration of adenine--one of purine moiety donors which is necessary for ATP synthesis. In the present study we monitored changes of both adenine and intraerythrocyte ATP concentration during renal replacement therapy. We have also estimated the influence of erythropoietin treatment. 4 groups of patients were included into the study: 22 patients with CRF, 22 patients on maintenance hemodialysis treatment (11 patients with EPO therapy), 19 patients after kidney transplantation (7 patients with insufficiency of transplanted kidney) and 26 healthy volunteers served as a control group. The measurements were performed in plasma and erythrocyte extracts using HPLC. Significant decrease of high plasma adenine concentration was observed after both HD session and successful kidney transplantation, however the achieved values were still higher than in healthy volunteers. Kidney transplantation resulted in a permanent decrease of plasma adenine concentration, but along with the deterioration of transplanted kidney function, the plasma adenine concentration reincreased. Also, it started to increase right after HD session had ended. On the other hand, the intraerythrocyte concentration of adenine and ATP after successful kidney transplantation and single HD session came back to normal values. Also in this case, along with the deterioration of transplanted kidney function, both studied parameters reincreased. We have not observed any significant influence of erythropoietin treatment on studied adenine nucleotide concentration in hemodialysis patients. The present study confirms the strong interrelationship between the adenine nucleotide metabolism abnormalities and the advancement of renal failure. The abnormalities intensify along with the disease progression and the renal replacement therapy results in partial their correction.

Topics: Adenine; Adenosine Triphosphate; Adult; Aged; Erythrocytes; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Renal Dialysis

Dialysis patients run the risk of impaired antioxidative defense and increased free radicals (FR) production. The study was made in order to compare FR-related parameters in ten patients treated with erythropoietin (EPO+) and ten patients not subject to this treatment (EPO-). All patients showed stable hemoglobin levels at > 95 g/L. FR-related parameters were monitored during hemodialysis (HD) using a polysulfon (PS) or a hemophan (H) membrane for 12 of them (6 EPO+ a 6 EPO-). The EPO- group was found to have a higher activity of superoxide dismutase (SOD, 1160 + 218 vs; 882 + 125 IU/gHb, p<0.01) and a higher SOD/glutathione peroxidase (GSHPx) ratio compared with EPO+ (30.5 +/- 7.1 vs; 21.2 + 4.8, p<0.01). A total of 35 healthy volunteers were also examined. When compared with controls EPO- showed higher SOD (p<0.001), lower GSHPx (p<0.05) and a higher SOD/GSHPx ratio (p<0.001). Thiobarbituric acid reacting substances in EPO+ and EPO- were comparable with the levels found in controls. HD using H as well as PS membranes was associated with a decrease in erythrocyte glutathione levels (GSH after 30 minutes; also for H after HD). HD using H and PS membranes resulted in a decrease in the plasma antioxidant capacity (AOC). We can conclude that the intraerythrocyte antioxidant conditions of EPO+ patients are similar to those found in the general population and differ from those in EPO- exhibiting increased SOD and the SOD/GSHPx ratio. HD using the H as well as the PS membrane is accompanied by oxidative stress.

Topics: Adult; Aged; Anemia; Antioxidants; Erythropoietin; Female; Free Radicals; Humans; Kidney Failure, Chronic; Male; Membranes, Artificial; Middle Aged; Oxidative Stress; Renal Dialysis; Treatment Outcome

The optimal target hematocrit (Ht) level in recombinant human erythropoietin (rHuEPO) therapy remains controversial and has hardly been investigated in predialysis patients. We prospectively studied the regression of left ventricular hypertrophy (LVH) on echocardiography in nine predialysis patients with chronic renal failure after a partial correction (target Ht, 30%) and normalization (target Ht, 40%) of the Ht with rHuEPO treatment. Twenty-four-hour ambulatory blood pressure monitoring was also performed. The administration of rHuEPO significantly increased Ht to the target values. The rate of renal failure progression did not change during rHuEPO treatment for 12 months (Cr, from 6.2 +/- 2.0 to 5.5 +/- 2.1 mg/dL). The left ventricular mass index (LVMI) tended to decrease after a partial correction of anemia (Ht, 32.1% +/- 1.8%) at 4 months, whereas it tended to significantly decrease after normalization of Ht (Ht, 39.1% +/- 2.4%) at 12 months (baseline, 140.6 +/- 12.1 g/m2; partial correction, 126.9 +/- 10.0 g/m2; normalization, 111.2 +/- 8.3 g/m2). All patients had received antihypertensive medication before rHuEPO administration, and additional drugs were also required in four cases during the study. As a result, a good overall blood pressure control was obtained without any adverse effects on the circadian blood pressure rhythm. In conclusion, from the perspective of LVH regression, the normalization of Ht was found to be more effective than that associated with a partial correction of anemia during rHuEPO therapy.

Topics: Aged; Disease Progression; Erythropoietin; Female; Hematocrit; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis

Iron deficiency limits the efficacy of recombinant human erythropoietin (rhEPO) therapy in end-stage renal disease (ESRD) patients. Functional iron deficiency occurs with serum ferritin >500 ng/ml and/or transferrin saturation (TSAT) of 20 to 30%. This study examines the effects of a maintenance intravenous iron dextran (ivID) protocol that increased TSAT in ESRD hemodialysis patients from conventional levels of 20 to 30% (control group) to those of 30 to 50% (study group) for a period of 6 mo. Forty-two patients receiving chronic hemodialysis completed a 16- to 20-wk run-in period, during which maintenance ivID and rhEPO were administered in amounts to achieve average TSAT of 20 to 30% and baseline levels of hemoglobin of 9.5 to 12.0 g/dl. After the run-in period, 19 patients randomized to the control group received ivID doses of 25 to 150 mg/wk for 6 mo. Twenty-three patients randomized to the study group received four to six loading doses of ivID, 100 mg each, over a 2-wk period to achieve a TSAT >30% followed by 25 to 150 mg weekly to maintain TSAT between 30 and 50% for 6 mo. Both regimens were effective in maintaining targeted hemoglobin levels. Fifteen patients in the control group and 17 patients in the study group finished the study in which the primary outcome parameter by intention to treat analysis was the rhEPO dose needed to maintain prestudy hemoglobin levels. Maintenance ivID requirements in the study group increased from 176 to 501 mg/mo and were associated with a progressive increase in serum ferritin to 658 ng/ml. Epoetin dose requirements for the study group decreased by the third month and remained 40% lower than for the control group, resulting in an overall cost savings in managing the anemia. Secondary indicators of iron-deficient erythropoiesis were also assessed. Zinc protoporphyrin did not change in either group. Reticulocyte hemoglobin content increased only in the study group from 28.5 to 30.1 pg. It is concluded that maintenance of TSAT between 30 and 50% reduces rhEPO requirements significantly over a 6-mo period.

Topics: Dose-Response Relationship, Drug; Drug Therapy, Combination; Erythropoietin; Female; Hemoglobins; Humans; Injections, Intravenous; Iron; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Protoporphyrins; Recombinant Proteins; Renal Dialysis; Reticulocytes; Transferrin

It is well known that uraemia affects skeletal muscle metabolism. This has been attributed to a variety of causes, including anaemia, vitamin D, carnitine deficiency and hyperparathyroidism. The aim of this study was to ascertain whether 99Tcm-sestamibi leg scintigraphy is useful in the evaluation of skeletal muscle metabolism and the monitoring of treatment response in uraemic myopathy. Forty patients with chronic renal failure and 24 normal controls underwent examination. Fifteen patients with chronic renal failure received erythropoietin treatment. 99Tcm-sestamibi leg scintigraphy was performed in all subjects and in 15 patients after therapy. The calf-to-ankle uptake ratio was calculated by semi-quantitative analysis and normalized to lean body mass. The normalized uptake ratios were significantly different between patients and controls. After erythropoietin therapy, there was a significant increase in the normalized uptake ratios compared with pre-therapy. Our results suggest that 99Tcm-sestamibi leg scintigraphy is useful in the assessment of muscle metabolic abnormalities and the effect of treatment in uraemic myopathy.

Topics: Adult; Aged; Blood Proteins; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Kidney Failure, Chronic; Leg; Male; Middle Aged; Muscle, Skeletal; Radionuclide Imaging; Radiopharmaceuticals; Recombinant Proteins; Technetium Tc 99m Sestamibi; Ultrasonography

The authors monitored, for a period of 12 months, anemia-, nutrition-, and free radical-related parameters and the rHuEPO dose required to maintain target hemoglobin (Hb) in 20 patients with chronic renal failure. Ten patients each were randomized for treatment by either acetate-free biofiltration (AFB) or low-flux hemodialysis (HD). At baseline, Hb levels were 102+/-2 (AFB) vs. 98+/-2 g/L (HD) (not significant difference, NS), the rHuEPO dose was 4050+/-976 vs. 5100+/-1538 lU/week (NS). Compared with baseline and with HD, lower rHuEPO doses were required during AFB at months 8, 9, 10 and 11, and 12 when they were 2100+/-510 (AFB) vs. 6000+/-1153 (HD), p=0.008. Prealbumin, transferrin and cholinesterase levels rose in the AFB group. Kt/V, albumin, transferrin saturation, aluminium, bicarbonate in serum, superoxide dismutase and glutathione peroxidase in erythrocytes, and malondialdehyde and antioxidant capacity in plasma did not differ between the AFB and HD groups. In terms of anemia control, AFB using an AN69 membrane was found to be more advantageous than low-flux HD, AFB improves some nutritional parameters. The compared methods do not differ in their effect on lipid peroxidation and the antioxidant system.

Topics: Adult; Anemia; Blood Chemical Analysis; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Hemodiafiltration; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Reference Values; Renal Dialysis; Statistics, Nonparametric; Treatment Outcome

Transient ST-segment depression measured on ambulatory ECG monitors has been described as representing silent ischemia. Patients who demonstrate silent ischemia have been reported to show increased mortality compared to patients without silent ischemia. We undertook this study to determine if the correction of anemia in End Stage Renal Disease (ESRD) patients from (+/- = standard deviation) 30 +/- 3 to 42 +/- 3 with the use of Epoietin alfa would result in decreased silent ischemia in patients with clinically evident ischemic heart disease or congestive heart failure.. Thirty one ESRD patients with congestive heart failure or patients with clinically-evident ischemic heart disease were randomized into one of two arms. Patients in Group A had their hematocrit increased with the use of slowly escalating doses of Epoietin alfa to 42 +/- 3% and patients in Group B were maintained with a hematocrit of 30 +/- 3% throughout the course of the study. All patients had a 24 hour Holter monitor recording at baseline and at 28 weeks after randomization (when they had reached their target hematocrit). Significant silent ischemia was considered to be present if patients demonstrated at least 60 seconds of > or = 1 mm ST segment depression.. Fifteen patients were randomized to Group A and 16 patients were randomized to Group B. The mean hematocrit increased in group A from 29.1 +/- 2.4% to 40.8 +/- 5.2% after 30 weeks. The mean hematocrit in Group B remained stable at 30 +/- 3% throughout the course of the study. Ten patients demonstrated silent ischemia at baseline. At follow up patients in group A demonstrated a mean of 1.7 +/- 4.9 minutes of ischemia compared to 1.1 +/- 3.4 minutes in group B. These were not significantly different. A similar number of patients in group A and Group B required adjustments in their anti-anginal medication during the course of the study.. It is possible to increase hematocrit to near normal levels in hemodialysis with the administration of exogenous Epoietin alfa. The increase in hematocrit form 30 +/- 3% to 42 +/- 3% is not associated with a change in the level of silent ischemia these patients demonstrate.

Topics: Anemia; Electrocardiography; Electrocardiography, Ambulatory; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Hematinics; Hematocrit; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Ischemia; Prognosis; Recombinant Proteins; Renal Dialysis

Angiotensin-converting enzyme (ACE) inhibitors may exacerbate anemia in patients with chronic renal failure, as well as in dialysis patients. To better answer this question, a prospective, crossover study was conducted to evaluate the effect of ACE inhibitors on recombinant human erythropoietin (rHuEPO) requirements in hemodialysis patients. Patients administered an ACE inhibitor when entering the study remained on this drug for the initial 4 months and were then switched to another antihypertensive agent for 4 more months. Patients not initially administered an ACE inhibitor were switched to lisinopril at 4 months. rHuEPO doses were adjusted using a sliding scale based on weekly laboratory hematocrit values. The inclusion criteria were met by 51 patients undergoing dialysis. Demographics were as follows: 61% were women, 64% were black, 46% had diabetes, average age was 53.2 +/- 13.3 years, and time on hemodialysis was 38.0 +/- 44.5 months. Thirty-three patients completed the study. Hematocrit averaged 32.7% +/- 1.9% while on ACE inhibitor therapy and 33.1% +/- 2.1% off ACE inhibitor therapy (P = 0.217). There was no difference in rHuEPO dose per treatment during each period (3,500 +/- 1,549 U on ACE inhibitor therapy versus 3,312 +/- 1,492 U off ACE inhibitor therapy; P = 0.300). No significant differences were found in degree of blood pressure control or various clinical and laboratory parameters that might be associated with rHuEPO resistance between the two periods. Similarly, no differences were found in hospitalization days, duration of infections, or transfusion requirements. These findings suggest that ACE inhibitors do not contribute to rHuEPO resistance in hemodialysis patients.

Topics: Anemia; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Transfusion; Cross-Over Studies; Diabetes Complications; Drug Resistance; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hematocrit; Hospitalization; Humans; Infections; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Time Factors

The effect of erythropoietin administration on the absorption of dietary and therapeutic iron was examined in patients with anemia of chronic renal failure on maintenance hemodialysis. Absorption from test meals tagged extrinsically with iron 55, iron 59, or both was determined 2 weeks later by using incorporated red blood cell radioactivity and whole body counting. In an initial study of food iron absorption, the effect of initiating erythropoietin therapy was determined by measuring the absorption of heme and nonheme iron before and 2 weeks after the administration of 64 U/kg body weight erythropoietin (range, 46-85 U/kg body weight) three times weekly. Absorption of heme iron increased 1.6-fold from 18.6% to 30.1% (P < .05), and nonheme iron increased 3.7-fold from 1.3% to 4.9% (P < .01) after erythropoietin therapy. In a second study therapeutic iron absorption was evaluated at baseline and after erythropoietin administration (63 U/kg body weight (range, 48-74 U/kg body weight) three times weekly). The absorption of 50 mg of iron as ferrous sulfate increased 2.4-fold from 3.8% to 9.4% (P < .05) when given without food and 4.2-fold from 1.4% to 5.9% (P < .05) when given with food after erythropoietin administration. After adjusting for changes in iron stores with serum ferritin after erythropoietin therapy, the enhanced erythropoiesis associated with erythropoietin therapy increased absorption about 2-fold, which was similar to the response observed previously in normal subjects. In a final study we examined the absorption of therapeutic iron during the steadystate phase of erythropoietin therapy after an erythroid response to erythropoietin had occurred. The absorption of 50 mg of iron was lower than that occurring with the initiation of erythropoietin therapy at 2.2% when given alone and 1.3% when taken with food. We conclude that iron absorption with or without erythropoietin stimulation is unimpaired in patients with chronic renal failure.

Topics: Adult; Aged; Erythropoietin; Female; Ferritins; Food; Hemoglobins; Humans; Intestinal Absorption; Iron; Iron, Dietary; Kidney Failure, Chronic; Male; Middle Aged; Receptors, Transferrin; Recombinant Proteins; Renal Dialysis

Since the earliest reports of the use of Epoetin alfa in hemodialysis patients, it has been described that Epoetin alfa may exacerbate preexisting hypertension or induce hypertension in End Stage Renal Disease (ESRD) patients not previously hypertensive. We undertook this study to determine if the correction of anemia in ESRD patients with cardiac disease from a hematocrit of 30+/-3% to 42+/-3% with the use of Epoetin alfa would result in increased blood pressure. This study was a substudy of the "Normal hematocrit Study".. Thirty-one patients were randomized into one of two arms. Patients in Group A had their hematocrit increased with the use of slowly escalating doses of Epoetin alfa to 42+/-3% and patients in Group B were maintained with a hematocrit of 30+/-3% throughout the course of the study. All patients had their blood pressure recorded with a 24 hour ambulatory BP device at study entry and at 28 weeks following randomization when they had achieved their target hematocrit. Pre-dialysis systolic and diastolic BP was also recorded.. The mean hematocrit increased in Group A from 29.1+/-2.4% to 40.8+/-5.2% after 30 weeks. The hematocrit in Group B remained stable at 30+/-3% throughout the course of the study. There was no difference in mean daytime, mean nighttime or 24 hour systolic or diastolic blood pressure between Groups A and B at either baseline or follow-up. Neither was there a difference in mean pre-dialysis systolic or diastolic BP between Groups A or B at baseline or Follow-up. Four patients in Group A and 4 patients in Group B required an increase in their antihypertensive medication during the course of the study.. It is possible to increase hematocrit to normal levels in hemodialysis with the administration of Epoetin alfa. The increase in hematocrit from 30+/-3% to 42+/-3% is not associated with increased blood pressure.

Topics: Adult; Aged; Anemia; Blood Pressure Monitoring, Ambulatory; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Ischemia; Recombinant Proteins; Reference Values; Renal Dialysis; Treatment Outcome

Chronic inflammatory disorders or infections represent a major cause of hyporesponsiveness to recombinant human erythropoietin (rHuEpo). To test the hypothesis that dialysate-related cytokine induction alters the response to rHuEpo, we conducted a prospective study with matched pairs of chronic haemodialysis patients. We compared the effect of two dialysis fluids, differing in their microbiological quality, on the rHuEpo therapy.. Thirty male patients with end-stage renal disease maintained on regular haemodialysis were assigned either to a group treated with conventional (potentially microbiologically contaminated) dialysate (group I) or to a group treated with online-produced ultrapure dialysate (group II). Randomization was stratified according to the maintenance dose of rHuEpo necessary to maintain a target haemoglobin level of 10-10.5 g/dl. Patients were followed for 12 months. Kt/V was calculated by the formula of Daugirdas. Haemoglobin levels were measured weekly and serum ferritin concentrations were determined at 6-week intervals. C-reactive protein (CRP) and interleukin-6 (IL-6) was measured by an ELISA at the start of the study and after 3, 6 and 12 months.. In group I, continuous use of bicarbonate dialysate did not change the rHuEpo dosage given to achieve the target haemoglobin level and was associated with elevated surrogate markers (CRP, IL-6) of cytokine-induced inflammation. The switch from conventional to online-produced ultrapure dialysate in group II resulted in a lower bacterial contamination with a significant decrease of CRP and IL-6 blood levels. It was accompanied by a significant and sustained reduction of the rHuEpo dosage, which was required to correct the anaemia. Using multiple regression analysis, IL-6 levels are shown to have a strong predictive value for rHuEpo dosage in both groups.. Our data demonstrate that dialysate-related factors such as low bacterial contamination can induce the activation of monocytes, resulting in elevated serum levels of IL-6. Dialysate-related cytokine induction might diminish erythropoiesis. The use of pyrogen free ultrapure dialysate resulted in a better response to rHuEpo. Not only would it save money, but it would also help to maintain an optimal haemoglobin level without further increase in rHuEpo dosage.

Topics: Bacteria; Bicarbonates; Cytokines; Dialysis Solutions; Dose-Response Relationship, Drug; Drug Contamination; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis

Hemoglobin levels below 10 g/dL lead to left ventricular (LV) hypertrophy, LV dilation, a lower quality of life, higher cardiac morbidity, and a higher mortality rate in end-stage renal disease. The benefits and risks of normalizing hemoglobin levels in hemodialysis patients without symptomatic cardiac disease are unknown.. One hundred forty-six hemodialysis patients with either concentric LV hypertrophy or LV dilation were randomly assigned to receive doses of epoetin alpha designed to achieve hemoglobin levels of 10 or 13.5 g/dL. The study duration was 48 weeks. The primary outcomes were the change in LV mass index in those with concentric LV hypertrophy and the change in cavity volume index in those with LV dilation.. In patients with concentric LV hypertrophy, the changes in LV mass index were similar in the normal and low target hemoglobin groups. The changes in cavity volume index were similar in both targets in the LV dilation group. Treatment-received analysis of the concentric LV hypertrophy group showed no correlation between the change in mass index and a correlation between the change in LV volume index and mean hemoglobin level achieved (8 mL/m2 per 1 g/dL hemoglobin decrement, P = 0.009). Mean hemoglobin levels and the changes in LV mass and cavity volume index were not correlated in patients with LV dilation. Normalization of hemoglobin led to improvements in fatigue (P = 0.009), depression (P = 0.02), and relationships (P = 0.004).. Normalization of hemoglobin does not lead to regression of established concentric LV hypertrophy or LV dilation. It may, however, prevent the development of LV dilation, and it leads to improved quality of life.

Topics: Adult; Aged; Anemia; Cardiac Volume; Cardiomyopathy, Dilated; Echocardiography; Erythropoietin; Female; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Ischemia; Patient Satisfaction; Quality of Life; Renal Dialysis; Surveys and Questionnaires; Thrombosis

Recombinant human erythropoietin (rHuEPO) is an effective treatment for the anemia of chronic renal failure. However, adequate availability of iron is necessary for an optimal response. We prospectively evaluated the effect of an intravenous iron protocol in a pediatric hemodialysis unit. Patients with either a serum ferritin less than 150 ng/ml or transferrin saturation (TSAT) less than 20% received intravenous iron dextran during ten consecutive dialysis sessions. The administration of rHuEPO was adjusted using a protocol designed to maintain patient hematocrit between 33% and 36%. Thirteen courses of intravenous iron were evaluated. Patients received 4 mg/kg of iron dextran (maximum of 100 mg) during each of ten consecutive dialysis sessions. In 12 cases there was a decrease in rHuEPO use 2 months after completing the course of intravenous iron. The mean rHuEPO dose decreased from 3,784 units to 2,115 units (P<0.005). Based on the criteria of response to intravenous iron, a percentage iron saturation of less than 20% had a high specificity for detecting iron deficiency. All patients who received a course of intravenous iron had a TSAT less than 20%. The measurement of serum ferritin was less useful in our patients.

Topics: Adolescent; Anemia; Child; Dose-Response Relationship, Drug; Erythropoietin; Ferritins; Humans; Injections, Intravenous; Iron-Dextran Complex; Kidney Failure, Chronic; Pilot Projects; Prospective Studies; Recombinant Proteins; Renal Dialysis

High-flux haemodialysis (HD) has recently been vigorously promoted as a novel standard, and it can indeed efficiently reduce the occurrence of most uraemic symptoms due to middle molecular toxins and/or underdialysis. However, some symptoms remain problematical, particularly peripheral polyneuropathy (PPN). One of the possible reasons for this is that the patients may have low concentrations of some nutrients, e.g. vitamin B(6), necessary for normal peripheral neuron function.. Predialysis serum pyridoxal-5'-phosphate (P5P) level was determined in 36 chronic HD patients who were undergoing high-flux HD and receiving human recombinant erythropoietin. Among them, 26 patients suffered from PPN. Prior to supplementation, these 26 patients were examined and their neurological symptoms were ranked according to our PPN symptom score. Vitamin B(6) (60 mg/day) was randomly prescribed to 14 of them, and vitamin B(12) (500 microg/day) was prescribed to the others. After 4 weeks, all the patients were re-examined.. We found that predialysis serum P5P levels of HD patients with PPN were not significantly lower than those of matched HD patients without PPN. Nonetheless, it was demonstrated that supplementation with vitamin B(6) for 4 weeks significantly increased the predialysis level of P5P and dramatically attenuated PPN symptoms compared with initial symptoms. No improvement was observed in response to vitamin B(12) supplementation.. This result suggests that although vitamin B(6) deficiency could not be demonstrated in patients with chronic renal failure on high-flux HD, vitamin B(6) supplementation was effective in improving PPN symptoms of various aetiologies, possibly because of vitamin B(6) resistance to PPN in these patients.

Topics: Chronic Disease; Diabetic Neuropathies; Erythropoietin; Female; Glomerulonephritis; Humans; Kidney Failure, Chronic; Male; Middle Aged; Polyneuropathies; Pyridoxal Phosphate; Pyridoxine; Recombinant Proteins; Renal Dialysis; Vitamin B 12

The optimal haemoglobin concentration ([Hb]) for patients with end-stage renal failure is uncertain. In particular, it is unclear whether Hb normalization may be an advantage to such patients who are otherwise well.. A prospective, randomized, double-blind cross-over study was completed in 14 haemodialysis patients (12 male) aged between 23 and 65 years over a period of 18 months, using a variety of measures to examine the effect of epoetin at target [Hb] of 10 g/dl ([Hb](10)) and 14 g/dl ([Hb](14)). Patients were randomized to maintain one or other of the target levels for 6 weeks before being crossed over to the alternative [Hb]. Baseline data (mean [Hb]: 8.5+/-0.2 g/dl) were also included selectively. Six patients were known to be hypertensive. Comparisons were made between 24-h ambulatory blood pressure levels (ABP), echocardiographic findings and estimates of blood volume (BV), plasma volume (PV) and Hb mass. Quality of life estimates were obtained using the Sickness Impact Profile (SIP), and epoetin dosage requirements at target [Hb] were assessed.. Daytime and nocturnal ABP (systolic and diastolic) were not different at the respective target [Hb], although nocturnal diastolic levels were higher compared with baseline (73+/-4 mmHg) at both [Hb](10) (83+/-3, P:<0.01) and [Hb](14) (81+/-6, P:<0.05). Significant reductions in cardiac output (5.2+/-0.3 vs 6.6+/-0.5 l/min, P:<0.01) and left ventricular end-diastolic diameter (4.8+/-0.2 vs 5.2+/-0.2 cm, P:<0. 001) were found at [Hb](14) compared with [Hb](10). Left ventricular mass index was correlated with both PV (P:<0.001) and BV (P:<0.01), but not with Hb mass. The PV decreased as the [Hb] rose (P:<0.001) but BV remained unchanged. Quality of life was significantly improved at [Hb](14) compared with [Hb](10) for both total score (6. 5+/-1.7 vs 13.4+/-3.0, P:=0.01) and psychosocial dimension score (5. 4+/-1.9 vs 15.4+/-4.0, P:<0.01). The maintenance weekly dose of epoetin required was 80% higher at [Hb](14) compared with [Hb](10) (P:<0.001).. These data suggest there may be a significant haemodynamic and symptomatic advantage in maintaining a physiological [Hb] in haemodialysis patients. Although untoward effects were not identified in this study at [Hb](14), a substantially higher dose of epoetin is required to maintain this level.

Topics: Adult; Aged; Blood Pressure; Blood Volume; Body Weight; Cardiovascular System; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Echocardiography; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Quality of Life; Reference Values

Levels of adrenomedullin (AM) have been shown to be elevated in hypertension and chronic renal failure, suggesting that AM plays a role in the pathogenesis of these diseases. The objective of the present study was to investigate whether circulating AM is involved in erythropoietin (Epo)-induced hypertension in patients with renal anemia due to progressive renal disease. Following treatment with 6,000 IU of Epo once a week, the hematocrit (Ht) rose significantly from 25.9+/-4.0 to 33.4+/-3.3% (n=54, p<0.001) with an overall rate of increase in Ht of 0.43+/-0.04%/week. In response to treatment with Epo, a rise in mean blood pressure of >10 mmHg (Epo-induced hypertension) was found in 22% (12/54 cases) of the patients enrolled. There was no difference in the rate of Ht increase between patients with and without Epo-induced hypertension. There was a significant positive correlation between mature AM and serum creatinine (Cr) concentration before treatment with Epo. However, no correlation was found between the plasma concentration of total AM and serum Cr concentration. Long-term treatment with Epo did not influence plasma concentration of either mature AM or total AM in patients developing hypertension during the study period. These results suggest that circulating AM may play a role in the progression of renal disease. However, the present study does not support the notion that circulating AM is associated with the pathogenesis of Epo-induced hypertension. It is too early yet to claim that there is no AM-mediated mechanism in Epo-induced hypertension.

Topics: Adrenomedullin; Adult; Aged; Anemia; Creatinine; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Peptides

I.v. iron is commonly administered to haemodialysis patients suffering from anaemia to improve their response to erythropoietin therapy. It has been unclear whether routinely used doses of i.v. iron preparations could result in iron release into plasma in amounts exceeding the iron binding capacity of transferrin. Here, we have studied the effect of 100 mg of iron saccharate given as an i.v. injection on transferrin saturation and the appearance of potentially harmful catalytically active iron.. We followed serum iron, transferrin and transferrin-saturation before and 5-210 min after administration of iron saccharate in 12 patients on chronic haemodialysis due to end-stage renal disease. We measured catalytically active iron by the bleomycin-detectable iron (BDI) assay and transferrin iron forms by urea gel electrophoresis, and studied iron-dependent growth of Staphylococcus epidermidis inoculated into the serum samples in vitro.. The iron saccharate injection resulted in full transferrin saturation and appearance of BDI in the serum in seven out of the 12 patients. BDI appeared more often in patients with a low serum transferrin concentration, but it was not possible to identify patients at risk based on serum transferrin or ferritin level before i.v. iron. The average transferrin saturation and BDI level increased until the end of the follow-up time of 3.5 h. The appearance of BDI resulted in loss of the ability of patient serum to resist the growth of S. epidermidis, which was restored by adding iron-free apotransferrin to the serum. Iron saccharate, added to serum in vitro, released only little iron and promoted only slow bacterial growth, but caused falsely high transferrin saturation by one routinely used serum iron assay.. The results indicate that 100 mg of iron saccharate often leads to transferrin oversaturation and the presence of catalytically active iron within 3.5 h after i.v. injection. As catalytically active iron is potentially toxic and may promote bacterial growth, it may be recommendable to use dosage regimens for i.v. iron that would not cause transferrin oversaturation.

Topics: Adult; Aged; Bleomycin; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Humans; Injections, Intravenous; Iron; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Staphylococcus epidermidis; Transferrin

The use of recombinant human erythropoietin (rhEPO) has greatly facilitated the treatment of anemia in children with chronic renal failure, but is expensive. Several reports on adult patients have shown that supplementation with L-carnitine can decrease the requirement for rhEPO. The objective of this study was to investigate the effect of oral supplementation with L-carnitine on the rhEPO requirement in children on dialysis. We investigated 16 children on dialysis (11 hemodialysis, 5 peritoneal dialysis) with a median age of 10.2 years. All children were stable on rhEPO treatment at least 3 months before study entrance. After obtaining baseline data, all children were supplemented with L-carnitine 20 mg/kg/day. Data were collected for 26 weeks. Follow-up was completed for 12 patients (8 hemodialysis, 4 peritoneal dialysis). At baseline free carnitine (32+/-18 micromol/l) and total carnitine levels (54+/-37 micromol/l) were normal. At the end of the study free carnitine levels had increased to 97+/-56 micromol/l (P<0.05) and total carnitine levels to 163+/-90 micromol/l (P<0.05). There was no significant change in rhEPO requirement. Hemoglobin level or hematocrit did not change significantly during the study. In conclusion we could not demonstrate a beneficial effect of supplementation with L-carnitine on rhEPO requirement in children on dialysis.

Topics: Administration, Oral; Adolescent; Adult; Anemia; Carnitine; Child; Child, Preschool; Dose-Response Relationship, Drug; Erythropoietin; Female; Follow-Up Studies; Humans; Infant; Kidney Failure, Chronic; Male; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis; Time Factors

Some of the morbidity associated with chronic hemodialysis is thought to result from retention of large molecular weight solutes that are poorly removed by diffusion in conventional hemodialysis. Hemodiafiltration combines convective and diffusive solute removal in a single therapy. The hypothesis that hemodiafiltration provides better solute removal than high-flux hemodialysis was tested in a prospective, randomized clinical trial. Patients were randomized to either on-line postdilution hemodiafiltration or high-flux hemodialysis. The groups did not differ in body size, treatment time, blood flow rate, or net fluid removal. The filtration volume in hemodiafiltration was 21 +/-1 L. Therapy prescriptions were unchanged for a 12-mo study period. Removal of both small (urea and creatinine) and large (ss(2)-microglobulin and complement factor D) solutes was significantly greater for hemodiafiltration than for high-flux hemodialysis. The increased urea and creatinine removal did not result in lower pretreatment serum concentrations in the hemodiafiltration group. Pretreatment plasma beta(2)-microglobulin concentrations decreased with time (P< 0.001); however, the decrease was similar for both therapies (P = 0.317). Pretreatment plasma complement factor D concentrations also decreased with time (P<0.001), and the decrease was significantly greater with hemodiafiltration than with high-flux hemodialysis (P = 0.010). The conclusion is that on-line hemodiafiltration provides superior solute removal to high-flux hemodialysis over a wide molecular weight range. The improved removal may not result in lower pretreatment plasma concentrations, however, possibly because of limitations in mass transfer rates within the body.

Topics: Anemia; beta 2-Microglobulin; Complement Factor D; Creatinine; Electrolytes; Erythropoietin; Female; Hemodiafiltration; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Quality of Life; Renal Dialysis; Therapy, Computer-Assisted; Urea

Topics: Anemia; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Drug Interactions; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Losartan; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Intradermal administration of Hepatitis B vaccine (HBV) achieves better seroconversion in patients on dialysis compared to intramuscular administration. The aim of the study was to determine whether twice weekly intradermal injections of the vaccine can further augment the vaccine response as compared to once weekly injections. Patients with end stage renal failure on haemodialysis were randomly allocated over a period of 22 months to receive 20 mu gms of recombinant HBV by intradermal injections once a week (group 1) or twice a week (group 2) for 6 weeks. The patients recruited during the first 12 months of the study did not receive recombinant human erythropoietin (Epo) as it was not available (phase 1). During the last 10 months of study all patients received Epo (phase 2) in addition to HBV.. A total of 85 patients were enrolled of whom 77 completed the study. There were 41 patients in group 1 and 36 patients in group 2. Seroprotection (anti HBs > 10 mIU/ml in the absence of HBs Ag and anti HBc) was achieved in 56.1% patients of group I compared to 77.8% of group 2 (p < 0.05). The seroprotection rate was 78.1% among patients receiving Epo (phase 2) compared to 60% among 45 who did not receive Epo (phase 1). Anti HBs titre in responders was 308.5 +/- 148.7 mIU/ml in patients of phase 2 compared to 198 +/- 112.8 mIU/ml in patients of phase 1 (p < 0.05). The subgroup receiving both Epo and twice weekly vaccine (group 2 of phase 2) had the highest seroprotection rate of 86.7%.. Twice weekly intradermal vaccination is more effective than once weekly regime in achieving rapid seroconversion. The vaccine response may be augmented by use of Epo probably due to reduction in transfusion requirement and concomitant immunosuppression.

Topics: Adolescent; Adult; Drug Administration Schedule; Drug Therapy, Combination; Erythropoietin; Female; Hepatitis B; Hepatitis B Antibodies; Hepatitis B Antigens; Hepatitis B Vaccines; Humans; Immunity; Injections, Intradermal; Kidney Failure, Chronic; Male; Middle Aged; Probability; Reference Values; Renal Dialysis; Treatment Outcome

In the study a clinical assessment is made of the results of treatment of patients with renal anemia by epoetin-beta.. Thirty two patients (22 women, 10 men) with chronic renal failure and anemia, ranging from 18 to 77 years of age (mean age 46.29 +/- 5.84), were recruited for the study. All patients underwent treatment with epoetin-beta (Recormon, Boehringer-La Roche). The criterion for inclusion in the study was presence of severe anemia (HGB < 90 g/l). Extrarenal causes for the anemia were excluded in all patients. The main treatment objective was to increase hemoglobin to 100-120 g/l. All patients received concomitant iron supplementation at constant control of the iron status. The predialysis patients were administered iron perorally (200 mg/day) while the patients on chronic hemodialysis were given iron parenterally (intravenously) (Venofer, 100 mg/day).. Anemia was significantly corrected. Hemoglobin level rose significantly from 77.15 +/- 2.32 g/l before treatment to 110.71 +/- 6.25 g/l at the end of month three. It remained less than 100 g/l for the time of study only in one patient. Neo-Recormon had a considerable positive effect on the overall condition of patients. No significant changes were found in the rate of progression of renal failure nor were there any marked side effects and intolerability to the drug observed.. Anemia was significantly corrected in the renal anemia patients treated with epoetin beta. In predialysis patients iron supplementation can be effectively administered orally. If given in high doses (more than 4000 IU/kg), epoetin-beta can cause rapid increase of the hematologic parameters, especially in the initial phase of treatment; this affects adversely arterial pressure which necessitates changes in the antihypertensive therapy. Erythropoietin therapy reduces and even eliminates the need of transfusion in patients with chronic renal anemia.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anemia; Clinical Chemistry Tests; Dose-Response Relationship, Drug; Erythropoietin; Female; Hematologic Tests; Hemoglobins; Humans; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Topics: Child; Dietary Supplements; Erythrocytes; Erythropoietin; Humans; Kidney Failure, Chronic; Malondialdehyde; Oxidative Stress; Renal Dialysis; Reticulocyte Count; Vitamin E

Carnitine supplementation in hemodialyzed patients was studied in a double-blinded, randomized, controlled trial in order to elucidate the effect of intravenous carnitine on renal anemia in patients treated with recombinant human erythropoietin (rHuEPO). Twenty stable hemodialysis (HD) patients received intravenous L-carnitine after each dialysis session in a dosage of 5 (N = 15) and 25 (N = 5) mg/kg, respectively, together with intravenous iron saccharate (20 mg/HD session) for four months and without iron for a further four months. Twenty patients received placebo instead of carnitine with an identical iron regimen. After a run-in phase of six months with a stable rHuEPO requirement, the rHuEPO dose was adjusted monthly when necessary to maintain target hemoglobin levels. At study entry (T0), plasma and red blood cell carnitine levels did not correlate significantly with the rHuEPO requirement. However, plasma free and total carnitine levels showed a significant negative correlation with erythrocyte survival time at T0. After four months of coadministration of intravenous iron and L-carnitine (T4), the rHuEPO requirement decreased in 8 of 19 evaluable HD patients. In these responders, the weekly rHuEPO dose was decreased significantly by 36.9+/-23.3% (183.7+/-131.7 at T0 vs. 126.6+/-127.9 U/kg/week at T4, P < 0.001). The rHuEPO requirement, however, was unchanged when all carnitine-treated patients were compared between T0 and T4 (T0: 172.0+/-118.0 vs. T4: 152.3+/-118.8 U/kg/week, P = 0.07, NS), but the erythropoietin resistance index decreased significantly in this group (T0: 16.0+/-11.0 vs. T4: 13.6+/-10.5 U/kg/week/g of hemoglobin, P < 0.02). The erythrocyte survival time was measured in five HD patients treated with iron and carnitine at T0 and T4. Two out of these patients were carnitine responders and showed an increase of erythrocyte survival time of 15 and 20%, respectively. After the withdrawal of iron supplementation, the rHuEPO requirement increased comparably in both L-carnitine- and placebo-treated patients during four more months. According to our data, L-carnitine, in addition to iron supplementation, may have an effect on erythropoietin resistance and erythrocyte survival time in HD patients. More than half of our patients, however, showed no benefit. Further studies to identify those HD patients who might have a benefit of carnitine supplementation, as well as studies concerning the optimal dosage, duration, and way of administration of

Topics: Adult; Aged; Anemia; Carnitine; Double-Blind Method; Erythrocyte Aging; Erythrocyte Count; Erythropoietin; Female; Humans; Injections, Intravenous; Iron; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

A prospective randomized study of the use of recombinant human erythropoietin (rHuEPO) in children with chronic renal disease was conducted to assess dosing requirements and side effects. Forty-four children with chronic renal failure, aged 4 months to 21 years, were studied. Twenty-five patients were pre dialysis, 10 on peritoneal dialysis, and 9 on hemodialysis. Patients received either 150 U/kg per week or 450 U/kg per week divided thrice weekly of rHuEPO for 12 weeks or until target hemoglobin (Hb) was attained. Dose was then adjusted to maintain a normal Hb. Eighty-two percent of patients reached target Hb by 7.9+/-5.6 weeks (mean+/-SD); 95% of patients in the high-dose group and 66% in the low-dose group reached target Hb within 12 weeks. The overall median rHuEPO dose at target Hb was 150 U/kg per week. Hemodialysis patients tended to require more rHuEPO to maintain a normal Hb (median 250 U/kg per week). Transfusion requirements and panel-reactive antibody levels decreased during the 12 weeks. Iron deficiency and/or hypertension occurred in 30% of children. In conclusion, rHuEPO at 150 U/kg per week is safe and effective in treating anemia in children with chronic renal disease.

Topics: Adolescent; Adult; Anemia; Blood Transfusion; Child; Child, Preschool; Creatinine; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Prospective Studies; Recombinant Proteins; Reticulocyte Count

Soluble iron salts are toxic for parenteral administration because free iron catalyzes free radical generation. Pyrophosphate strongly complexes iron and enhances iron transport between transferrin, ferritin, and tissues. Hemodialysis patients need iron to replenish ongoing losses. We evaluated the short-term safety and efficacy of infusing soluble ferric pyrophosphate by dialysate.. Maintenance hemodialysis patients receiving erythropoietin were stabilized on regular doses of intravenous (i.v.) iron dextran after oral iron supplements were discontinued. During the treatment phase, 10 patients received ferric pyrophosphate via hemodialysis as monthly dialysate iron concentrations were progressively increased from 2, 4, 8, to 12 micrograms/dl and were then sustained for two additional months at 12 micrograms/dl (dialysate iron group); 11 control patients were continued on i.v. iron dextran (i.v. iron group).. Hemoglobin, serum iron parameters, and the erythropoietin dose did not change significantly from month 0 to month 6, both within and between the two groups. The weekly dose of i.v. iron (mean +/- SD) needed to maintain iron balance during month 6 was 56 +/- 37 mg in the i.v. iron group compared with 10 +/- 23 mg in the dialysate iron group (P = 0.001). Intravenous iron was required by all 11 patients in the i.v. iron group compared with only 2 of the 10 patients receiving 12 micrograms/dl dialysate iron. The incidence of adverse effects was similar in both groups.. Slow infusion of soluble iron pyrophosphate by hemodialysis may be a safe and effective alternative to the i.v. administration of colloidal iron dextran in maintenance hemodialysis patients.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Iron-Deficiency; Dialysis Solutions; Diphosphates; Drug Administration Routes; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis; Solubility; Transferrin

To determine the effects of different haemoglobin (Hb) levels on exercise performance and associated electrolyte changes, a prospective, randomized, double-blinded crossover study was completed in 14 haemodialysis patients.. Performance and changes in arterial [K+] and lactate were compared at rest and during a maximal incremental cycling exercise at a Hb concentration ([Hb]) of 10 g/dl ([Hb]10) and 14 g/dl ([Hb]14) following an initial baseline test (Hb: 8.3 +/- 0.2 g/dl, mean +/- SEM). Ages ranged from 23 to 65 years and patients were divided into younger (age 23-45 years, n = 9) and older (aged 55-65 years, n = 5) groups.. Peak work rate and VO2 peak were higher at [Hb]14 than at [Hb]10. 145 +/- 9 vs 134 +/- 9 W, mu +/- SEM, P < 0.01, and 1.90 +/- 0.11 vs 1.61 +/- 0.11 l/min, P < 0.01, respectively. Improvements were demonstrated in both younger and older groups at the higher target [Hb], with an improved aerobic performance evident particularly in younger patients. However, performance remained below that predicted for comparable sedentary controls. Resting plasma [K+] was raised at both [Hb]10 and [Hb]14 compared with baseline (P < 0.01) although the change in [K+] from rest to peak exercise (delta[K+]) was similar at each level. The delta[K+] per unit work performed (used as a marker of K+ regulation) was, however, inversely related to the [Hb] (baseline: 80 +/- 12 micromol/l/kJ vs [Hb]10, 61 +/- 8, P < 0.01, vs [Hb]14. 49 +/- 7, P < 0.05). Exercise induced a significant but similar rise in lactate concentration at both target [Hb] (P < 0.001), which remained markedly elevated for at least 10 min after exercise in both younger and older groups.. These data demonstrate that a physiological [Hb] improves, but does not normalize, exercise performance in end-stage renal failure. Both younger and older patients appear to benefit similarly from the enhanced oxygen transport. Impaired K+ regulation is apparently related to [Hb] and could well contribute to the observed limitations in performance.

Topics: Adult; Aged; Anemia; Blood Volume; Cross-Over Studies; Double-Blind Method; Epoetin Alfa; Erythropoietin; Exercise; Exercise Test; Hemoglobins; Humans; Kidney Failure, Chronic; Middle Aged; Plasma Volume; Potassium; Prospective Studies; Recombinant Proteins; Renal Dialysis

The administration of parenteral iron dextran to hemodialysis patients is typically intermittent. We sought to determine the most appropriate intervals for sampling iron parameters during intermittent need-based and continuous maintenance regimens and to quantify differences in efficacy between such regimens during long-term therapy. After a single course of 10 consecutive 100-mg iron doses administered to 14 patients on 16 occasions, transferrin saturation (TSAT) and ferritin were unreliable indices of iron status for the next 2 and 6 weeks, respectively. TSAT and ferritin levels at 1 week were virtually identical to those at 2 weeks after the administration of a single 50-mg or 100-mg iron dextran dose to 16 other patients. Twelve patients on maintenance iron therapy (25 to 100 mg/wk; TSAT, 30% to 50%) had a statistically significant decrease in the amount of recombinant human erythropoietin (rHuEPO) needed to maintain hemoglobin (Hb) levels between 10 and 11 g/dL compared with 12 patients receiving intermittent need-based dosing, an effect that persisted from week 16 to week 72 of the study. Maintenance iron was feasible even in a third group of eight patients targeted to sustain an Hb level of 14 g/dL. In both iron maintenance groups, iron indices could be measured at weekly intervals, and ferritin levels did not progressively increase over time. Continuous maintenance iron dextran used to maintain TSATs of 30% to 50% significantly reduced rHuEPO requirements and resulted in no adverse side effects in chronic hemodialysis patients. After weekly maintenance 25- to 100-mg iron dextran doses, iron indices can be measured after 1 week; a delay of 2 weeks is not necessary.

Topics: Aged; Anemia, Iron-Deficiency; Drug Administration Schedule; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Injections, Intravenous; Iron-Dextran Complex; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis; Time Factors; Transferrin

A comparative study of efficiency and safety of low-dose erythropoietin (EP) in two groups of patients with chronic renal failure (CRF): patients on chronic hemodialysis (CHD) and patients on continuous ambulatory hemodialysis (CAHD).. 51 CRF adult patients with renal anemia on hemodialysis entered the trial: 34 CHD and 17 CAHD patients. EP compounds were injected s.c. in a dose 1000-2000 U 2-3 times a week.. EP treatment provided a rapid correction of renal anemia in the majority of patients. After 3-month EP therapy a mean increment of Hct (Hct delta) was much greater (p < 0.05) in CAHD than CHD patients (12.2 +/- 6.0 and 9.0 +/- 5.1%, respectively), though EP dose were the same in both the groups.. Low doses of recombinant human EP injected subcutaneously were effective and safe for correction of anemia in both CHD and CAHD. In CAHD patients EP effectiveness was much higher than in CHD patients.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Follow-Up Studies; Hematocrit; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis; Safety; Treatment Outcome

In this study, plasma and red blood cell (RBC) antioxidant status and plasma lipid peroxidation were investigated in 46 hemodialysis patients. In addition, the effect of erythropoietin (EPO) and EPO-vitamin E combination therapy on plasma and RBC antioxidant status, and plasma lipid peroxidation were examined. There were 10 healthy subjects in the control group and 10 hemodialysis patients in the untreated group. The third group included 36 hemodialysis patients that were given EPO (100 U/kg) for 3 months, 3 times per week. The fourth group included 36 hemodialysis-patients from the EPO group that were given EPO at a 50% decreased dose + vitamin E (300 mg/day) for 3 months. MDA levels in the untreated group, the EPO group and the EPO + vitamin E groups were found to be higher than the control group (p < 0.001, in both). Furthermore, MDA levels in both of the treatment groups were lower when compared to the untreated group (p < 0.001, in both). Plasma vitamin E levels in the untreated, the EPO group and EPO + vitamin E groups were lower than the control group (p < 0. 001). In contrast, plasma vitamin E levels in the treatment groups were higher in comparison with the control group (p < 0.05). SOD activities in the untreated, the EPO group and the EPO + vitamin E groups were found to be lower than the control group (p < 0.001). SOD activities in the treatment groups were higher than the control group (p<0.001). The SOD activities in the EPO+vitamin E group increased when compared to the EPO group (p < 0.001). CAT activities in the untreated, the EPO group and the EPO + vitamin E groups were found to be lower than the control group (p < 0.001 in untreated and EPO groups, p <0.01 in EPO+ vitamin E group). CAT activities in EPO and EPO+ vitamin E groups were increased when compared to the untreated group (p < 0.01). In conclusion, our findings have shown that antioxidant status decreased and lipid peroxidation increased in hemodialysis patients. EPO has an antioxidant effect on the RBC and plasma antioxidant status, and plasma lipid peroxidation. These effects were moderately increased by the combination of vitamin E and EPO.

Topics: Adult; Anemia; Antioxidants; Catalase; Drug Therapy, Combination; Erythrocytes; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Renal Dialysis; Superoxide Dismutase; Vitamin E

Topics: Adult; Aged; Anemia; Cross-Over Studies; Dialysis Solutions; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis

Impaired erythropoiesis in continuous ambulatory peritoneal dialysis (CAPD) or continuous cyclic peritoneal dialysis (CCPD) patients receiving recombinant human erythropoietin (rHuEPO) is most often secondary to iron deficiency, either as a result of poor intestinal absorption or failure to take oral supplements as prescribed. The inconvenience of giving intravenous (i.v.) iron dextran (ID) to CAPD/CCPD patients precluded its use in this population. We therefore examined the efficacy of bolus intraperitoneal (i.p.) iron dextran (1000 mg) on erythropoiesis in a pilot study of 14 CAPD/CCPD patients. The patients ranged in age from 23-81 years, and all had iron deficiency (transferrin saturation 6%-23%; mean: 15.2% +/- 1.34%). Of the 14 patients studied, 13 were receiving rHuEPO. Pre-treatment hematocrit (Hct) ranged from 21%-38% (mean: 30.2% +/- 1.37%). After infusion of 2 L Dianeal (Baxter Healthcare Corp., Deerfield, Illinois, U.S.A.), 500 mg of undiluted ID was administered directly into the Tenckhoff catheter and subsequently flushed with 30 mm3 normal saline. The peritoneal dialysis (PD) exchange containing ID then dwelled for a period not < 6 hours before standard PD resumed. A second 500 mg dose ID was given to each patient by the same protocol 3-86 days later (mean: 14 days). No complications were seen. No patient complained of abdominal pain or other subjective symptoms during infusion or during the dwell. Repeat iron studies done 1-7 months post ID (mean: 2.8 months) showed a 1.1-fold to 4.9-fold increase (mean: 1.4-fold) in mean iron levels (40.4 +/- 3.9 mg/dL versus 57.5 +/- 5.5 mg/dL, p = 0.036); a 1.1-fold to 5.2-fold increase (mean: 1.6-fold) in mean transferrin saturation (15.2% +/- 1.3% versus 24.5% +/- 2.6%, p = 0.008); a 1.01-fold to 1.60-fold increase (mean: 1.12-fold) in mean Hct (30.2% +/- 1.37% versus 33.8% +/- 1.5%; p = 0.042). The mean dose of rHuEPO was statistically unchanged (170.0 +/- 47.4 U/kg body weight versus 178.8 +/- 49.6 U/kg body weight per week; p = 0.841). Peritoneal equilibration test (PET) score 1-4 months post ID (mean: 2 months) was 0.778 +/- 0.02 compared with a PET score at baseline of 0.767 +/- 0.03 (p = 0.734). No significant delta was observed in blood urea nitrogen (BUN) or creatinine values. We conclude that use of bolus i.p. ID is safe, effective, and convenient, and demonstrates no short-term negative effect on peritoneal membrane integrity. Long-term effects have yet to be determined.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Hypochromic; Erythropoietin; Female; Humans; Iron-Dextran Complex; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Pilot Projects; Recombinant Proteins; Treatment Outcome

There are many growth factors (GFs), which stimulate the proliferation and maturation of erythroid progenitors. The main one is erythropoietin (Epo). Epo acts in concert with other GFs. Recently it was suggested that leptin (Lep) could be involved in a very early stage of erythropoiesis (E). The aim of this study was to analyse the relations between ability of idiopathic compensation of anemia by hemodialysis patients (HD pts) and concentration of Lep in HD men and women separately. The study was performed in 25/13M, 12F/HD pts, who idiopathically compensate anemia (group 1) and 29/16M, 13F/HD pts who required rHuEpo therapy (group 2). The mean Lep level in all women together was significantly higher than in all HD men together (26.9 +/- 6.3 ng/mL vs 6.8 +/- 0.9 ng/mL) but BMI was similar in men and women. We did not find significant differences in level of Lep in both studied groups of HD pts. Perhaps the lower influence of Epo and testosterone on E in HD women is compensated by significantly higher Lep concentration.

Topics: Adult; Anemia; Erythropoiesis; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Leptin; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

The use of erythropoietin (EPO) for the amelioration of anemia has dramatically changed the quality of life of the patients with chronic renal failure (CRF). The efficacy of a low dose EPO therapy was assessed in the prospective 6 week trial.. Assessment of hematological parameters and iron stores was done in 40 patients of CRF: Group A--20 patients of CRF receiving 40 U/kg EPO biweekly for 6 weeks and Group B--20 patients of CRF not receiving EPO. The parameters were studied at the start and at 2, 4 and 6 weeks of the study.. A statistically significant rise in mean haemoglobin levels (7.27 +/- 1.26 g/dl to 8.60 +/- 1.66 g/dl); mean packed cell volume (21.4 +/- 4.04% to 25.4 +/- 6.54%) and mean reticulocyte count (1.28 +/- 0.4% to 2.14 +/- 0.86%) was observed on EPO therapy. Patients on EPO developed a significant decline in serum iron, serum ferritin levels, bone marrow iron stores; and a hypochromic-microcytic picture on the peripheral blood film suggestive of iron deficiency. Iron deficiency at the start, chronic infections like tuberculosis and inadequate haemodialysis were identified as causes of hyporesponsiveness to EPO therapy. Low dose EPO therapy was not associated with any major adverse effects.. Low dose EPO (40 U/kg, biweekly) therapy is safe and effective in the management of anaemia of CRF.

Topics: Adult; Anemia, Iron-Deficiency; Blood Transfusion; Combined Modality Therapy; Erythropoietin; Female; Hematinics; Humans; Iron; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Prognosis; Recombinant Proteins; Severity of Illness Index; Treatment Outcome

Forty-three hemodialysis patients receiving recombinant erythropoietin (rHuEPO, epoietin alpha) were randomized to receive intravenous iron dextran as a total-dose infusion, 500-mg infusion to total dose, or 100-mg bolus to total dose, in each case during the dialysis procedure. The dose of iron dextran was calculated from the patient's existing hemoglobin to achieve a desired hemoglobin. Patients were eligible to receive intravenous iron dextran if they had a serum ferritin of < or = 100 ng/mL or a serum ferritin of 100 to 200 ng/mL, along with a transferrin saturation of < or = 19%. Patients were excluded if they had prior therapy with iron dextran, aluminum intoxication, or transfusion during the study. The time to the maximum hemoglobin, acute adverse reactions, and delayed adverse reactions were analyzed statistically, and no differences were seen in any of the three groups. Total-dose intravenous iron dextran infusion is safe, convenient, less expensive, and as efficacious as divided-dose infusions.

Topics: Anemia; Erythropoietin; Female; Ferritins; Hematinics; Humans; Infusions, Intravenous; Iron-Dextran Complex; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

In cases with severe hyperparathyroidism, anaemia improves after parathyroidectomy. The objective of this study was to investigate the influence of treatment with intravenous calcitriol on anaemia in 28 haemodialysis patients. The patients showed moderate to severe hyperparathyroidism (mean parathyroid hormone level 811.6 +/- 327 pg/ml) and were treated with calcitriol (2 microg i.v.) after haemodialysis. The follow-up period was 12 months. 21 out of the 28 patients had been receiving erythropoietin (EPO) prior to calcitriol administration; the remaining 7 did not receive EPO. 24 patients received oral or intravenous iron. The doses of EPO and iron were modified throughout the study period to maintain a haematocrit equal to or higher than 30% and ferritin levels above 150 ng/ml, respectively. EPO needs were evaluated according to the relation EPO dose/haematocrit. We found a significant rise in haematocrit and haemoglobin at 3 and 12 months on calcitriol therapy, with no modification of the EPO dose nor ferritin levels. This improvement in anaemia was observed both in those patients who received EPO initially (p < 0.01) and in those who did not (p < 0.05). Upon dividing the patients according to the response of hyperparathyroidism to the intravenous calcitriol treatment, we observed in the responding patients (n = 19) significant increases in haematocrit (from 31.7 +/- 4.2 to 36.3 +/- 4.9%) and haemoglobin(from 10.6 +/- 1.5 to 12.2 +/- 1.5 g/dl; p < 0.001) at 12 months on intravenous calcitriol therapy, while this was not true of the non-responding patients. The EPO needs diminished in the group of responding patients and increased in the non-responders, although these changes were not statistically significant. We found no direct correlation between the decrease of parathyroid hormone and EPO needs in the group of responding patients. However, an inverse correlation between parathyroid hormone levels and EPO needs (r = -0.799, p < 0.05) was seen in the group of non-responding patients. Treatment with intravenous calcitriol in patients on haemodialysis controls secondary hyperparathyroidism, improves anaemia, and decreases the need for EPO. Studies including a larger number of patients are necessary to clarify the mechanisms underlying the improvement of anaemia upon control of secondary hyperparathyroidism with intravenous calcitriol treatment and to confirm our findings.

Topics: Alkaline Phosphatase; Anemia; Calcitriol; Erythropoietin; Female; Humans; Hyperparathyroidism, Secondary; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Recombinant Proteins; Renal Dialysis; Time Factors

Impaired immunological response in hemodialysis (HD) patients, which leads to inappropriate cytokine production, is partially caused by the hyperstimulation of both T lymphocytes and monocytes/macrophages. Recent data suggest that human recombinant erythropoietin (rhEPO) may have an immunological action. The goal of our study was to estimate the influence of rhEPO treatment on the production of the inflammatory cytokine tumor necrosis factor alpha (TNFalpha) and antiinflammatory cytokin interleukin-10 (IL-10) in 10 HD patients receiving rhEPO for 6 months. The levels of cytokines were measured in the in vitro cultures of whole blood. The level of IL-10 increased in all treated patients during the therapy, and it was accompanied by a transitory decrease of TNFalpha. The results of our studies suggest that rhEPO may reduce the inflammatory process by decreasing production of TNFalpha and increasing production of IL-10.

Topics: Adult; Blood Cells; Cells, Cultured; Erythropoietin; Female; Glomerulonephritis; Humans; Interleukin-10; Kidney Failure, Chronic; Male; Middle Aged; Phytohemagglutinins; Polycystic Kidney Diseases; Pyelonephritis; Recombinant Proteins; Renal Dialysis; Tumor Necrosis Factor-alpha

Despite a large body of evidence showing the beneficial effects of successful treatment of anemia with recombinant human erythropoietin (EPO) in patients with end-stage renal disease, controversy remains as to whether EPO treatment of anemia can improve the nutritional status in patients on maintenance hemodialysis. This prompted us to conduct a prospective study in 41 hemodialysis patients with basal hemoglobin less than 9 g/dl. The dose of EPO was increased for 12 weeks to achieve the target hemoglobin concentration of 10 g/dl and then titrated in the following 12 weeks to maintain the target value. Nutritional status was assessed at baseline and after 6 months of follow-up, using the global protein-calorie malnutrition (PCM) index proposed by Bilbrey and Cohen. A low global PCM score indicates better nutrition. The results showed that hemoglobin values significantly increased from 8.7 +/- 0.8 g/dl at baseline to 10.7 +/- 0.5 g/dl in the 6th month (p < 0.001). No significant changes were observed in the normalized protein catabolic rate and Kt/V during the study period. Global PCM scores improved from 30.0 +/- 7.5 to 23.6 +/- 3.1 (p < 0.001) and paralleled the correction of anemia by EPO treatment. The data were consistent with a major improvement in the nutritional markers of relative body weight, triceps skinfold, midarm circumference, midarm muscle circumference, serum albumin, serum transferrin and total lymphocyte count in the 6th month as compared to baseline. The percentages of mild and moderate-severe PCM at baseline were 32 and 58%, respectively. These percentages were significantly reduced during the 6th month to 20 and 30%, respectively (p = 0.0004). In summary, correction of renal anemia with EPO improves the nutritional status in hemodialysis patients. A postulated mechanism is that EPO may exhibit anabolic effects, with a better utilization of ingested protein.

Topics: Aged; Anemia; Body Weight; Erythropoietin; Female; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nutritional Status; Prospective Studies; Recombinant Proteins; Renal Dialysis

Chronic renal failure is characterized by a normochromic normocytic anemia, the severity of which generally increases during progression toward uremia. The purpose of the study was to evaluate the efficacy and safety of recombinant human erythropoietin (rHu-EPO) given subcutaneously (s.c.), the dose required to reach and maintain Hb levels within 10 and 11 g% and its effects, if any, on the progression of chronic renal failure. Eighty-four pre-dialysis patients (46 F, 38M, age 61.7+/-13.9 years) with Hb levels between 6 and 9 g% and serum creatinine ranging from 3 to 9 mg/dl were treated with s.c. rHu-EPO (2000 U/twice weekly). After 6 weeks, if Hb increase was below 1 g%, 1000 U of s.c. rHu-EPO were added at each administration (3000 U twice weekly). Once the Hb target was reached (10-11 g%), the rHu-EPO weekly dose was halved and administration reduced to once weekly. The patients showed a significant rise in mean Hb values (p<0.001) after 3 months. Mean Hb values were as follows: 8.00+/-0.77 g% (pretreatment), 9.35+/-1.0 (3rd month), 10.06+/-1.04 (6th month), 10.25+/-0.62 g% (12th month). The mean rHu-EPO doses were 4000 U/w (start of the study), 3592+/-1685 U/w (6th month), 2840-/+1178 U/w (12th month). Renal function was evaluated by plotting the reciprocal of serum creatinine values vs time with a two period comparison: period A (retrospective-8 mo); period B (prospective-12 mo). The residual renal function was not impaired by rHu-EPO therapy. Meanwhile, no relevant modifications were observed in mean blood pressure values. Low doses of s.c. rHu-EPO were well tolerated, safe and effective; this therapeutic approach should therefore be considered for the improvement of anemia in pre-dialysis patients. A slow and gradual correction of anemia induces an improved sense of well being and a more active of life style.

Topics: Adolescent; Adult; Aged; Anemia; Blood Pressure; Creatinine; Drug Monitoring; Drug Tolerance; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Outpatients; Quality of Life; Recombinant Proteins; Renal Dialysis

Hemodialysis patients treated with recombinant human erythropoietin (rhEPO) need adequate iron supplementation to avoid rhEPO hyporesponsiveness due to iron deficiency. Low serum ferritin reflects absolute iron deficiency, whereas normal or high ferritin values in combination with low transferrin saturation (< 20%) indicate functional iron deficiency. In this study, healthy subjects (group I) were compared with intravenous (i.v.) rhEPO-treated and i.v. iron-saccharate-treated regular hemodialysis patients that were subdivided into three groups as follows: patients with serum ferritin > 100 and < 350 micrograms/L (group II), patients with ferritin < 60 micrograms/L (group III), and patients with ferritin > 650 micrograms/L but transferrin saturation < 20% (group IV). Polymorphonuclear leukocyte (PMNL) parameters (phagocytosis, intracellular killing of bacteria, oxidative metabolism, glucose uptake, intracellular calcium) for each group were compared with those of multitransfused, iron-overloaded primary hematologic patients (group V) and those of patients suffering from hereditary hemochromatosis (group VI). Compared with PMNL obtained from healthy subjects (group I), group II hemodialysis patients showed mild inhibition of phagocytosis but significant inhibition of intracellular killing of bacteria. Oxidative burst of PMNL from group II patients was also significantly reduced after stimulation in vitro. These dysfunctions were not affected by absolute iron deficiency (comparable data in group III patients). However, impairment of PMNL was markedly aggravated in group IV patients. Intracellular calcium concentration under basal conditions and after stimulation was not different. These data suggest that iron is responsible for the PMNL dysfunctions observed in group IV patients. The PMNL defect of group IV patients was comparable to group V and group VI patients with normal renal function, suggesting again a direct inhibitory effect of iron. It is concluded that hemodialysis patients with high ferritin but low serum iron and low transferrin saturation ("functional iron deficiency") display a significant impairment of fundamental PMNL functions during i.v. iron and rhEPO therapy. This may result in increased risk of infectious complications. Therefore, overtreatment of hemodialysis patients with i.v. iron should be avoided.

Topics: Adult; Aged; Analysis of Variance; Anemia, Iron-Deficiency; Blood Cell Count; Erythropoietin; Female; Ferritins; Humans; Injections, Intravenous; Iron Compounds; Kidney Failure, Chronic; Male; Middle Aged; Neutrophils; Prognosis; Recombinant Proteins; Renal Dialysis; Transferrin

The response to recombinant human erythropoietin (rHuEPO), 50 units/kg thrice weekly, was studied prospectively in 17 children and adolescents with end-stage renal disease who were either transfusion dependent or had hematocrits < 25%. For convenience, rHuEPO was given intravenously to 12 hemodialysis (HD) patients and subcutaneously to 5 peritoneal dialysis (PD) patients. Blood pressure, hematocrit, iron indices, and serum potassium, calcium, phosphorus, alkaline phosphatase, urea nitrogen, and intact parathyroid hormone (PTH) were monitored serially. When serum ferritin was < 100 ng/ ml during therapy, 6 patients received iron supplementation. rHuEPO therapy eliminated frequent transfusions in all patients; 11 of 17 patients reached the target hematocrit of 30%-33% by week 16 of rHuEPO, 50 units/kg thrice weekly. The 5 PD patients treated subcutaneously reached target at week 6 +/- 1; 6 HD patients treated intravenously reached target at week 11 +/- 3; 6 additional HD patients never reached target at this dose; 5 of 6 had pre-rHuEPO serum PTH levels >400 pg/ml, significantly higher than those of the other patients (P < 0.005); 3 of 6 later reached a hematocrit of 30%-33% after the rHuEPO dose was increased to 120-130 units/kg thrice weekly. We conclude that most pediatric dialysis patients can be treated successfully with rHuEPO, 50 units/kg thrice weekly, unless the serum PTH concentration is markedly elevated, in which case a higher dose is likely to be needed.

Topics: Adolescent; Adult; Anemia; Child; Child, Preschool; Erythropoietin; Female; Ferritins; Hematocrit; Humans; Hyperparathyroidism; Infant; Kidney Failure, Chronic; Male; Parathyroid Hormone; Peritoneal Dialysis; Prospective Studies; Recombinant Proteins; Renal Dialysis

Previous studies comparing intravenous (i.v.) and subcutaneous (s.c.) administration of recombinant human erythropoietin (rHuEpo) often did not achieve optimal iron reserve, were restricted to a limited follow-up period (not allowing equilibration) and/or did not exclude the role of other confounding factors. In addition all papers focused on the conversion from i.v. to s.c.. In this study, 30 equilibrated patients on s.c. rHuEpo were randomized into two groups, one converting to i.v. after 6 months of follow-up and one remaining on s.c. rHuEpo. In both groups rHuEpo was administered three times weekly. Only patients completing a further 6 months follow-up were considered for statistical evaluation. Serum ferritin was targeted at 200 ng/ml and haematocrits between 28 and 36% were pursued.. The average haematocrit levels before conversion were 31.9 +/- 1.1% in the conversion group and 31.4 +/- 1.6% at the same time point in the nonconversion group (P = NS). After 6 months haematocrits were 31.5 +/- 0.5% in the conversion group and 31.1 +/- 0.9% in the non-conversion group (P = NS). Ferritin concentration in the conversion group was 219 +/- 49 ng/ml before and 230 +/- 83 ng/ml after the conversion. For the non-conversion group ferritin was 224 +/- 25 ng/ml and 236 +/- 52 ng/ml respectively (P = NS). The weight-standardized average rHuEpo dose per injection remained the same in the conversion group before and after conversion (44.0 +/- 1.8 U/kg/injection vs 45.4 +/- 4.7 U/kg/injection) (P = NS). In the non-conversion group the corresponding rHuEpo doses were 32.9 +/- 4.2 U/kg/injection and 39.6 +/- 7.0 U/kg/injection respectively (P = NS). There were no differences in serum PTH, aluminium, vitamin B12, folic-acid levels, and intake of co-trimoxazole, ACE inhibitors or theophylline.. No changes in rHuEpo dose were observed after conversion from s.c. to i.v. There were no significant differences between the conversion and non-conversion group. These results are in contrast to some earlier studies suggesting lower rHuEpo requirements in case of s.c. administration.

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Ferritins; Hematocrit; Hematopoiesis; Humans; Injections, Intravenous; Injections, Subcutaneous; Iron; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis

Pregnancy in hemodialysis (HD) patients tends to be diagnosed late because of its infrequency and the lack of validity of urine pregnancy tests, and because these patients tend to have menstrual irregularities. The outcome is influenced by pregnancy-related anemia. We investigated the characteristics of pregnancy-related anemia and whether it is a useful diagnostic clue to pregnancy in HD patients.. We retrospectively investigated six pregnancies of 5 HD patients (mean age 30 years), including 4 patients treated with recombinant human erythropoietin (rHuEpo) and a transfusion-dependent patient with two pregnancies in the pre-rHuEpo era.. The mean duration of HD was 6 years, the mean duration of the patients' marriages at the time of pregnancy was 6 years, and the mean gestational age at diagnosis was 11 weeks and 4 days. The progression of anemia (an 8% decrease in the hematocrit) was detected by 8 weeks of gestation in all patients. The prepregnancy hematocrit was stable in 5 pregnancies, facilitating the detection of changes, but during one of the pregnancies of the transfusion-dependent patient the hematocrit was low and was influenced by the transfusions. The amount of rHuEpo required to attain a target hematocrit of 30% increased gradually or rapidly until delivery.. The progression of anemia or hyporesponsiveness to rHuEpo was a useful early diagnostic clue to pregnancy in HD patients. However, the prepregnancy hematocrit should be stabilized with rHuEpo, so that decreases can be easily detected. The precise mechanisms of hyporesponsiveness to rHuEpo, which progressed during pregnancy and subsided after delivery, remain to be clarified.

Topics: Adult; Disease Progression; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Pregnancy; Recombinant Proteins; Renal Dialysis; Retrospective Studies

Topics: Aged; Dose-Response Relationship, Drug; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins

Topics: Adolescent; Adult; Anemia; Erythropoietin; Female; Flaviviridae; Hepatitis, Viral, Human; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Several studies have suggested that if recombinant human erythropoietin (epoetin) is administered subcutaneously rather than intravenously, a lower dose may be sufficient to maintain the hematocrit at a given level.. In a randomized, unblinded trial conducted at 24 hemodialysis units at Veterans Affairs medical centers, we assigned 208 patients who were receiving long-term hemodialysis and epoetin therapy to treatment with either subcutaneous or intravenous epoetin. The dose was initially reduced until the hematocrit was below 30 percent and then was gradually increased to a level that would maintain the hematocrit in the range of 30 to 33 percent for 26 weeks. We compared the average doses in the 26-week maintenance phase and the discomfort associated with the two routes of administration.. For the 107 patients treated by the subcutaneous route, the average weekly dose of epoetin during the maintenance phase was 32 percent less than that for the 101 patients treated by the intravenous route (mean [+/-SD], 95.1+/-75.0 vs. 140.3+/-88.5 U per kilogram of body weight per week; P<0.001). Only one patient in the subcutaneous-therapy group withdrew from the study because of pain at the injection site, and 86 percent rated the pain associated with subcutaneous administration as ranging from absent to mild.. In patients receiving hemodialysis, subcutaneous administration of epoetin can maintain the hematocrit in a desired target range, with an average weekly dose of epoetin that is lower than with intravenous administration.

Topics: Algorithms; Anemia; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hematocrit; Humans; Infusions, Intravenous; Injections, Subcutaneous; Iron; Kidney Failure, Chronic; Male; Middle Aged; Pain; Recombinant Proteins; Renal Dialysis

In patients with end-stage renal disease, anemia develops as a result of erythropoietin deficiency, and recombinant human erythropoietin (epoetin) is prescribed to correct the anemia partially. We examined the risks and benefits of normalizing the hematocrit in patients with cardiac disease who were undergoing hemodialysis.. We studied 1233 patients with clinical evidence of congestive heart failure or ischemic heart disease who were undergoing hemodialysis: 618 patients were assigned to receive increasing doses of epoetin to achieve and maintain a hematocrit of 42 percent, and 615 were assigned to receive doses of epoetin sufficient to maintain a hematocrit of 30 percent throughout the study. The median duration of treatment was 14 months. The primary end point was the length of time to death or a first nonfatal myocardial infarction.. After 29 months, there were 183 deaths and 19 first nonfatal myocardial infarctions among the patients in the normal-hematocrit group and 150 deaths and 14 nonfatal myocardial infarctions among those in the low-hematocrit group (risk ratio for the normal-hematocrit group as compared with the low-hematocrit group, 1.3; 95 percent confidence interval, 0.9 to 1.9). Although the difference in event-free survival between the two groups did not reach the prespecified statistical stopping boundary, the study was halted. The causes of death in the two groups were similar. The mortality rates decreased with increasing hematocrit values in both groups. The patients in the normal-hematocrit group had a decline in the adequacy of dialysis and received intravenous iron dextran more often than those in the low-hematocrit group.. In patients with clinically evident congestive heart failure or ischemic heart disease who are receiving hemodialysis, administration of epoetin to raise their hematocrit to 42 percent is not recommended.

Topics: Aged; Anemia; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Hematocrit; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Prospective Studies; Recombinant Proteins; Renal Dialysis

Iron replacement therapy reduces the demand for erythropoietin (EPO) in some dialysis patients. It has been postulated that iron supply to the bone marrow is a rate-limiting step in the process of erythropoiesis under erythropoietin stimulation.. We evaluated the economic benefit of intravenous iron therapy for this purpose in a prospective, non-blinded study of 22 haemodialysis patients, 16 male, six female, mean age 62 years (range 24-80 years). All patients had a serum ferritin (SF) of < or = 60 microg/L, despite oral iron therapy. Patients with high aluminium and/or parathyroid hormone (PTH) levels, underlying bleeding/haematological disorders or active inflammatory diseases were excluded. Patients were established on subcutaneous EPO and given intravenous iron over seven consecutive dialysis sessions (total dose 1050 mg) and supplemental monthly doses with regular monitoring for 4 months.. The median EPO dose was 4000 units/week (mean 6050 units/week) pre-treatment and 2000 units/week (mean 3700 units) at 6 weeks post intravenous iron therapy (P=0.03). No serious adverse events occurred in the 154 treatment sessions of intravenous iron. Mean haemoglobin (Hb) level remained constant at 6 and 12 weeks (P=0.087). Serum ferritin levels (P< 0.0001) rose significantly, while a reduction in transferrin saturation (TS) became significant at the end of the study (P=0.0047). The use of intravenous iron allowed a substantial monthly cost saving per patient in our unit.. Intravenous iron therapy is a safe and cost-effective method for maintaining or improving Hb levels with a more effective utilization of EPO in patients with low SF levels despite oral iron therapy.

Topics: Adult; Aged; Aged, 80 and over; Erythropoietin; Female; Ferritins; Ferrous Compounds; Hematinics; Hemoglobins; Humans; Injections, Intravenous; Iron-Dextran Complex; Iron, Dietary; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis

Recombinant human erythropoietin improves platelet function in uremia through the correction of anemia, but this effect can be seen also before the hematocrit rise. We studied 12 hemodialyzed patients (seven men, five women) who received recombinant human erythropoietin (40 IU kg(-1)i.v., three times weekly) and were evaluated before treatment and after three doses; 24 control subjects were used. Platelet aggregation induced by adenosine 5'-diphosphate (ADP), epinephrine, collagen, arachidonic acid, and ristocetin, and reticulated platelets determined by flow cytometry after staining with thiazole orange were measured. Platelet aggregation induced by all the agonists were impaired in uremic patients (P < 0.01), but ADP and ristocetin-induced aggregations improved after treatment (P < 0.01). Hemodialyzed patients had less reticulated platelets than controls (P < 0.01). Reticulated platelets increased after three doses of treatment (P < 0.01). In conclusion, improvement of platelet function at early stages of recombinant human erythropoietin treatment may be attributed to the increase in young platelets detected as reticulated platelets.

Topics: Adenosine Diphosphate; Adult; Age Factors; Aged; Blood Platelets; Erythropoietin; Female; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Platelet Aggregation; Platelet Count; Recombinant Proteins; RNA; Time Factors; Uremia

The aim of this prospective study was to test a new protocol for iron supplementation in haemodialysis patients, as well as to assess the utility of different iron metabolism markers in common use and their 'target' values for the correction of iron deficiency.. Thirty-three of 56 chronic haemodialysis patients were selected for long-term (6 months) i.v. iron therapy at 20 mg three times per week post-dialysis based on the presence of at least one of the following iron metabolism markers: percentage of transferrin saturation (%TSAT) <20%; percentage of hypochromic erythrocytes (%HypoE) > 10% and serum ferritin (SF) <400 microg/l. Reasons for patient exclusion were active inflammatory or infectious diseases, haematological diseases, psychosis, probable iron overload (SF > or =400 microg/l) and/or acute need of blood transfusion mostly due to haemorrhage and change in renal replacement treatment.. More than half (51.8%) of the patients of our dialysis centre proved to have some degree of iron deficiency in spite of their regular oral iron supplementation. At the start of the study the mean haemoglobin was 10.8 g/dl and increased after the 6 months of iron treatment to 12.8 g/dl (P<0.0001). The use of erythropoietin decreased from 118 units/kg/week to 84 units/kg/week. The criterion for iron supplementation with the best sensitivity/specificity relationship (100/87.9%) was ferritin <400 microg/l. Patients with ferritin < 100 [microg/l and those with ferritin between 100 microg/l and 400 microg/l had the same increase in haemoglobin but other parameters of iron metabolism were different between the two groups.. Routine supplementation of iron in haemodialysis patients should be performed intravenously. Target ferritin values should be considered individually and the best mean haemoglobin values were achieved at 6 months with a mean ferritin of 456 microg/l (variation from to 919 microg/l). The percentage of transferrin saturation, percentage of hypochromic erythrocytes and ferritin <100 microg/l, were not considered useful parameters to monitor routine iron supplementation in haemodialysis patients. No significant adverse reactions to iron therapy were observed.

Topics: Anemia, Iron-Deficiency; Biomarkers; Drug Administration Routes; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Follow-Up Studies; Glucaric Acid; Hemoglobins; Humans; Iron; Iron Deficiencies; Kidney Failure, Chronic; Male; Middle Aged; Nutritional Support; Practice Guidelines as Topic; Prospective Studies; Recombinant Proteins; Renal Dialysis; Sucrose; Transferrin

Patients with end-stage renal failure undergoing haemodialysis (HD) are exposed to oxidative stress. Increased levels of malondialdehyde (MDA) were demonstrated in plasma of uraemic patients, indicating accelerated lipid peroxidation (LPO) as a consequence of multiple pathogenetic factors. The aim of our investigation was to examine the role of renal anaemia in oxidative stress in HD patients.. MDA and 4-hydroxynonenal (HNE) were measured in three groups of patients undergoing HD: group I comprised eight patients with a blood haemoglobin (Hb) < 10 g/dl (mean Hb = 8.1+/-1.3 g/dl), and group II were eight patients with a Hb > 10 g/dl (mean Hb=12.4+/-1.9g/dl); none of these 16 patients had been treated with human recombinant erythropoietin (rHuEpo). Group III comprised 27 patients with a mean Hb of 10.5+/-1.6 g/dl after long-term rHuEpo treatment.. Mean plasma concentrations of both MDA and HNE were significantly higher (P<0.0001) in all 43 HD patients than in 20 healthy controls (MDA 2.85+/-0.25 vs 0.37+/-0.03 microM, HNE 0.32+/-0.03 vs 0.10+/-0.01 microM). Comparing the three groups, it was shown that HD patients with a Hb <10 g/dl had significantly higher plasma levels of LPO products (MDA 3.81+/-0.86 microM, HNE 0.45+/-0.07 microM) than HD patients with a Hb >10g/dl (MDA 2.77+/-0.58 UM, HNE 0.25+/-0.05 microM), and than HD patients treated with rHuEpo (MDA 2.50+/-0.12 microM, HNE 0.29+/-0.03 microM). Furthermore, an inverse correlation between plasma concentration of LPO products and haemoglobin levels was seen (r=0.62, P<0.0001).. Radical generation in HD patients might be caused in part by renal anemia itself. Treatment with rHuEpo may decrease radical generation effectively in HD patients due to the increase in the number of red blood cells and blood haemoglobin concentration.

Topics: Adult; Aged; Aged, 80 and over; Aldehydes; Anemia; Erythrocyte Count; Erythropoietin; Female; Follow-Up Studies; Humans; Kidney Failure, Chronic; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Recombinant Proteins; Renal Dialysis; Retrospective Studies

Insulin and lipid metabolism were studied in seven patients (19+/-1 years) with end-stage renal disease on continuous cycling peritoneal dialysis (CCPD) before and after 6 months of therapy with human recombinant erythropoietin (EPO) to correct anemia. Hematocrit increased from 22.2+/-1.8% to 34.8+/-1.8% (P<0.001) following EPO treatment. Serum ferritin (P<0.05) and serum iron (P<0.01) decreased significantly after anemia correction. There were no significant differences in the height, weight, anthropometric measures, or intakes of protein and total calories in the patients before and after the 6 months of EPO therapy. There were no differences in serum biochemical parameters, including 1,25-dihydroxyvitamin D3 and parathyroid hormone in these patients before and after 6 months of EPO therapy. Residual renal function and Kt/Vurea were also not different before and after 6 months of EPO therapy. The hyperinsulinemic euglycemic clamp technique was used to measure insulin sensitivity. Before EPO, insulin sensitivity was low in patients on CCPD (238+/-19 mg/m2 per min) compared with controls (320+/-30; P<0.01). After 6 months of EPO therapy, insulin sensitivity increased by 28% (305+/-26, P<0.01 vs. pre-EPO values), so that these values were no longer different from control values. The hyperglycemic clamp technique was used to measure insulin secretion. Before EPO, both early- and late-phase insulin secretion were elevated in patients on CCPD compared with controls (P<0.01 in both cases). These indices of insulin secretion decreased significantly (P<0.01) following 6 months of EPO. Before EPO, plasma triglycerides, total cholesterol, low-density lipoprotein, cholesterol, and apolipoprotein B were elevated in patients compared with controls. These lipid concentrations decreased significantly following 6 months of EPO. Thus, treatment of anemia by EPO is associated with improvements in insulin and lipid abnormalities in uremic patients on CCPD.

Topics: Adolescent; Adult; Anemia; Erythropoietin; Glucose Clamp Technique; Humans; Insulin; Insulin Resistance; Kidney Failure, Chronic; Lipids; Lipoproteins; Peritoneal Dialysis; Recombinant Proteins

Topics: Anemia; Cross-Over Studies; Erythropoietin; Hematocrit; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Middle Aged; Recombinant Proteins; Renal Dialysis

Topics: Anemia; Antihypertensive Agents; Erythropoietin; Humans; Hypertension; Kidney Failure, Chronic; Losartan; Prospective Studies

Short-term effects of recombinant human erythropoietin on serum levels of transforming growth factor beta-1, interleukin 1-alpha, interleukin 3, interferon gamma, and tumour necrosis factor alpha in patients with chronic renal failure on chronic haemodialysis were investigated. Recombinant human erythropoietin was applied subcutaneously in a dose of 75 IU/kg on 19 patients. Serum levels of transforming growth factor beta-1, interleukin 1-alpha, interleukin 3, interferon gamma, tumour necrosis factor alpha and erythropoietin, red blood cell parameters: red blood cell count, haemoglobin, haematocrit, and erythrocyte indices were determined before and after recombinant human erythropoietin single application. Transforming growth factor beta-1 serum levels were decreased after recombinant human erythropoietin (22.70 +/- 1.51 ng/ml versus 18.77 +/- 1.70 ng/ml (p < 0.01). None of the other investigated parameters was influenced significantly by recombinant human erythropoietin. Recombinant human erythropoietin in patients with chronic renal failure on chronic haemodialysis may influence anaemia not only through its stimulating effect on erythropoiesis, but also by direct oxygen-independent decrease of at least one of the negative regulators of erythropoiesis--the transforming growth factor beta.

Topics: Adult; Anemia; Erythropoietin; Female; Humans; Interferon-gamma; Interleukin-1; Interleukin-3; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

To assess the effect of long-term administration of human recombinant erythropoietin (EPO) on renal function, 11 anemic children aged 1.4-17.2 years were followed for 10-61 (mean 31) months on treatment. During EPO therapy the mean hemoglobin rose from 8.1 to 11.1 g/dl at the last observation. The final maintenance dose ranged between 70 and 300 U/kg per week. The rate of deterioration of renal function was calculated by comparing the slope of the regression lines of reciprocal serum creatinine values (SCr) derived from a mean of 20 values per patient obtained over 8-50 (mean 29) months before and a mean of 24 SCR values during EPO therapy. The individual slopes improved after initiation of EPO therapy in all but 3 patients, but the mean change of slope (from -0.0521 to -0.0299) was not significant. The study suggests that in most children with predialysis chronic renal failure long-term administration of EPO is not associated with accelerated deterioration but rather with delayed deterioration of renal function.

Topics: Adolescent; Blood Pressure; Child; Child, Preschool; Creatinine; Erythropoietin; Female; Hemoglobins; Humans; Infant; Kidney Failure, Chronic; Kidney Function Tests; Male; Recombinant Proteins; Renal Dialysis; Retrospective Studies

In a prospective study, 40 maintenance hemodialysis patients, randomized in two equal groups, were treated with recombinant human erythropoietin (rHuEPO) for their renal anemia, for a period of 2 years. One group was treated for 2 years, while the other was untreated control during the first year, but received rHuEPO during the second year of the study. Anemia was corrected in all treated patients and hematocrit maintained between 30 and 35 vol% by low-dose subcutaneous treatment with Recormon (Boehringer Mannheim GmbH, Germany), according to the study protocol. Bone marrow biopsy (BMB), from the posterior iliac crest, was taken by the method of Jamshidi from 32 patients. Fourteen patients from the control group were biopsied twice: once at baseline and the second time at 12 months of treatment, while 15 patients from the other group were biopsied only once, at 24 months of rHuEPO treatment. The biopsies were embedded in wax and in epoxy resin, and after staining for light and electron microscopy, they were semiquantitatively examined for several parameters: cellularity, myeloid:erythroid (M:E) ratio, megakaryocytes, fatty tissue, megaloblasts, and marrow iron. Cellularity of the bone marrow increased significantly at 12 months of treatment and it remained so at 24 months. M:E ratio was significantly reduced indicating expansion of the erythroid pool, both at 12 and 24 months of therapy. The number of megakaryocytes in the bone marrow increased significantly at 12 months and remained high at 24 months of treatment, while fatty tissue was significantly reduced at 12 and 24 months compared to the baseline values. There was no significant change in the percentage of megaloblasts in the bone marrow. Hemosiderin was reduced after treatment indicating mobilization of the bone marrow iron stores upon treatment with rHuEPO. We concluded that rHuEPO had a beneficial long-term effect on bone marrow.

Topics: Anemia; Biopsy; Bone Marrow; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Time Factors; Uremia

Functional iron deficiency occurs when recombinant human erythropoietin (rHuEPO) accelerates erythropoiesis to an extent that the iron availability cannot meet the anticipated demand. Such a phenomenon will reduce the optimal response to rHuEPO. To estimate the iron needs of functional iron deficiency in hemodialysis patients on rHuEPO therapy, we utilized a mathematical method. Forty hemodialysis patients were examined in the study, and all had a baseline serum ferritin (SF) level > 100 microg/l. They were stratified into patients with a transferrin saturation (TfS) value > or = 25% (group I) and those below this value (group II). The treatment protocol consisted of rHuEPO therapy in the two groups for 6 months and iron supplement only in group II. The target hemoglobin level was 10.5 g/dl, and iron metabolism indices were analyzed prior to and following therapy. The results showed (1) in group I (n = 20) hemoglobin rose from 7.5 +/- 0.9 to 10.7 +/- 0.7 g/dl (p < 0.01) and the mean SF level declined from 1,583 +/- 997 to 968 +/- 664 mg (p < 0.01); (2) in group II (n = 20) hemoglobin also increased from 7.8 +/- 0.9 to 10.6 +/- 0.8 g/dl (p < 0.01) following iron supplement, while the SF rose from 183 +/- 70 to 326 +/- 125 mg (p < 0.01); (3) TfS was significantly elevated in group II following iron therapy (18.9 +/- 4.8 vs. 34.5 +/- 9.1%, p < 0.01), and (4) the nomogram showed a sensitivity of 80%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 83% in estimating the iron status before rHuEPO therapy. We conclude that SF levels reflect iron stores and that TfS < 25% is an index of functional iron deficiency. Iron supplementation is not necessary in patients with SF > 100 microg/l and TfS > or = 25%. It seems rational to provide intravenous iron in EPO-resistant patients with functional iron deficiency (SF > 100 microg/l, TfS < 25%). This paper illustrates the importance that accurate assessment of iron needs by a mathematical method would enhance treatment efficacy and avoid iron overload in hemodialysis patients on rHuEPO therapy.

Topics: Anemia; Anemia, Iron-Deficiency; Erythropoietin; Female; Ferritins; Hemoglobins; Humans; Iron; Iron Overload; Kidney Failure, Chronic; Male; Mathematics; Middle Aged; Predictive Value of Tests; Recombinant Proteins; Renal Dialysis; Sensitivity and Specificity

Hearing loss is a common finding in patients with end-stage renal failure. Uremic toxins, ototoxins, and axonal uremic neuropathy appear to be likely pathogenic factors. We analyzed whether an improvement in hearing capacity can be achieved with an improvement of anemia by erythropoietin (EPO) administration. Fifty patients on long-term hemodialysis in a single center were examined audiologically by otoscopy, tympanometry, pure tone audiometry, and the short increment sensitivity index. Twenty-five patients were treated with EPO in a dose of 120 U/kg per week over a period of 5 to 8 months, and the remaining 25 patients were not treated with EPO (controls). Both groups were reexamined audiologically after the study period, and the results were compared. In the group treated with EPO, the hemoglobin level increased from 7 +/- 0.9 to 11 +/- 0.8 g/dL, as against the control group, whose hemoglobin increased from 7.1 +/- 0.9 to 8 +/- g/dL. The audiologic tests were repeated at the end of the study period, and a significant improvement of hearing was found in the patients treated with EPO as compared with the control group (p < .001). Our study suggests that improvement of anemia in patients on long-term hemodialysis by administration of EPO is associated with an improvement in hearing capacity in a significant number of patients. Thus, anemia seems to be an important factor responsible for hearing disorders in patients with end-stage renal failure. Studies with larger numbers of patients are required to confirm this observation.

Topics: Anemia; Deafness; Erythropoietin; Humans; Kidney Failure, Chronic; Uremia

Long-term effects of rHuEpo on the blood lipid profile have not been well documented. The aim of this paper is to prospectively evaluate whether rHuEpo therapy affects lipid metabolism, and whether these effects are influenced by changes in dietary habits and by route of rHuEpo administration.. The study was performed in 33 maintenance haemodialysis patients (MHP) treated for one year with rHuEpo either intravenously (n = 15) or subcutaneously (n = 18), three times per week at the end of each dialysis session. The doses were 50 IU/kg intravenously or 35 IU/kg subcutaneously during the first 6 months and 20 IU/kg during the following months. The control group consisted of 17 MHP not treated with rHuEpo. Total cholesterol, LDL-cholesterol and HDL-cholesterol, triglycerides, apolipoproteins Al and B, haemoglobin, serum albumin, blood urea nitrogen, serum creatinine, Kt/V, protein catabolic rate, and plasma erythropoietin were assessed at months 0, 2, 4, 6, 9, 12 and 2 weeks after rHuEpo discontinuation. Changes in food intake were evaluated on the basis of weekly dietary diaries before, and 3 and 9 months after treatment. Patients were divided into two groups: group A consisted of 19 patients who showed an increase in their energy intake (10% or more of basal value), and group B was formed by 14 patients without or with slight changes in their food intake. After the 6th month, dialysis schedules were adapted to new protein catabolic rate values in patients who increased their food intake.. During follow-up, there were no significant changes in any of the parameters in the control group. In group A, blood urea nitrogen, serum creatinine, protein catabolic rate, cholesterol, LDL cholesterol, triglycerides and apolipoprotein B increased significantly since the first months of rHuEpo treatment, and changes in cholesterol and apolipoprotein B correlated significantly with changes in protein catabolic rate. In group B, cholesterol, LDL cholesterol, and apolipoprotein B decreased significantly after the 6th month of treatment, without changes in blood urea nitrogen, serum creatinine and protein catabolic rate values. In both groups A and B, HDL cholesterol decreased significantly until the 6th month and returned to basal values in the following months and apolipoprotein Al decreased until the 4th month and rose to levels higher than basal values in the following months. First rHuEpo administration and rHuEpo suspension at end of follow-up did not show any acute effect on lipid profile, despite significant changes in plasma erythropoietin values. Changes in lipid profile were similar with intravenous and subcutaneous administration of rHuEpo.. We infer that long-term rHuEpo treatment positively affects the lipid profile, but in some patients who show exaggerated increase in their food intake these effects may be balanced and overcome by increment in some atherogenic blood lipid fractions. The changes in lipid and apolipoprotein patterns during rHuEpo therapy are not influenced by route of rHuEpo administration.

Topics: Adult; Aged; Anemia; Apolipoproteins; Diet; Eating; Erythropoietin; Female; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Lipids; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Time Factors

Hypertension is one of the most important complications of erythropoietin (rHuEPO) therapy in dialysis patients. In this study, the effect of two different dosage regiments of subcutaneous rHuEPO on blood pressure [BP] was evaluated in 20 anemic children on continuous ambulatory peritoneal dialysis (CAPD). Patients were randomized to receive rHuEPO 50 U/kg, either once a week (group 1, 50 U/kg per week) or three times a week (group 2, 150 U/kg per week). At the beginning of the study, 8 patients in group 1 and 8 patients in group 2 were on antihypertensive therapy. In group 1, the hematocrit increased gradually and significantly from 18.98% +/- 1.79% to 30.1% +/- 1.62% after 6 months, while in group 2 it rapidly increased from 19.53% +/- 1.86% to 32.4% +/- 1.11% after 3 months. A significant increase in the mean arterial BP was observed in group 2. Antihypertensive therapy had to be increased in all of the 8 previously hypertensive patients and had to be initiated in 1 of the 2 originally normotensive patients in the same group. None of the patients in group 1 required a change in antihypertensive medication. We conclude that during treatment with rHuEPO pre-existing hypertension and the dose of rHuEPO are the most important risk factors for the development or worsening of hypertension in children on CAPD, and gradual elevation of hematocrit by low-dose rHuEPO avoids the development of severe hypertension.

Topics: Adolescent; Anemia; Blood Pressure; Child; Child, Preschool; Erythropoietin; Female; Hematocrit; Humans; Kidney Failure, Chronic; Male; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins

Among the adverse effects possibly associated with the use of erythropoietin (EPO) in hemodialysis patients is an increased incidence of thrombosis of the vascular access. However, little is known about the effect of EPO on the stenotic lesion in the venous outflow system, which is the leading cause of fistula thrombosis. This study was designed to explore the long-term effects of EPO treatment on progressive fistula stenosis and the plasma concentrations of some potential mediators of neointimal hyperplasia. A cross-sectional and 3-yr prospective, placebo-controlled, pilot study was performed in 30 hemodialysis patients with native arteriovenous fistula. Sixteen patients received EPO and 14 received a placebo. Venous dialysis pressure, urea recirculation, color Doppler sonography, and angiography were used to monitor vascular access patency. Compared with 60 healthy subjects, the hemodialysis patients had elevated plasma levels of platelet-derived growth factor, monocyte chemoattractant protein-1, and interleukin 6, three proteins that might be involved in the neointima formation regulating the proliferation of vascular smooth muscle cells. In addition, these patients had numerous endothelial and hemostatic abnormalities that indicated a thrombophilic state. Eleven patients, six (37.5%) receiving EPO and five (35.7%) taking placebo, developed a progressive stenosis in the venous circuit of the fistula. There was no significant difference in the vascular access, event-free survival over 36 mo between patients receiving EPO therapy and placebo. EPO induced a significant decrease in the plasma values of platelet-derived growth factor and vascular cell adhesion molecule-1 and an increase of monocyte chemoattractant protein-1 concentration. After EPO withdrawal, these parameters returned to pretreatment levels. In conclusion, long-term EPO therapy does not increase the risk of progressive stenosis of native arteriovenous fistula. The use of erythropoietin does not induce any prothrombotic change in hemostatic parameters, and further studies are required to elucidate the theoretically beneficial effects on the plasma concentration of some potential mediators of neointimal formation.

Topics: Adult; Aged; Apolipoproteins; Arteriovenous Shunt, Surgical; Cell Adhesion Molecules; Chemokine CCL2; Constriction, Pathologic; Cross-Sectional Studies; Cytokines; Erythropoietin; Female; Fibrinolysis; Hemostasis; Humans; Kidney Failure, Chronic; Lipids; Male; Middle Aged; Platelet-Derived Growth Factor; Prospective Studies; Renal Dialysis; Thrombophlebitis

Altered activity of sympathetic nervous system is one of the potential factors influencing blood pressure elevation during erythropoietin (rHu-EPO) therapy in patients with end-stage renal disease (ESRD). The aim of study was to establish if rHu-EPO administration to ESRD patients affects heart rate variability (h.r.v.) indices in the time domain and activity of the autonomic nervous system (a.n.s.). 23 ESRD hemodialyzed patients were divided into those who recived rHU-EPO (+EPO), N = 12 and did not receive rHu-EPO (-EPO), N = 11. +EPO patients were given 2000-4000 IU rHu-EPO/week for 6 weeks. In both groups h.r.v. indices (mRR, SDNN, rMSSD and pNN50) were calculated during dialysis sessions and interdialytic period and then were analyzed by Cosinor method. It was shown that: 1) during dialysis session there were rhythmic changes in all h.r.v. parameters, which can be described by Cosinor formula. 2) all h.r.v. indices wee lower in +EPO group as compared with -EPO patients. 3) the differences, although not significant, may indicate sympathetic activation in +EPO ESRD patients. 4) Cosinor method applied to h.r.v. analysis may be useful tool for assessing a.n.s. activity.

Topics: Adult; Autonomic Nervous System; Creatinine; Erythropoietin; Female; Heart Rate; Hematocrit; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis

Iron balance is critical for adequate erythropoiesis in hemodialysis patients treated with recombinant human erythropoietin (EPO). The role of oral iron therapy in maintaining or replenishing iron stores has not yet been well defined in such patients. We undertook a double-blind, placebo-controlled study to evaluate the efficacy of oral iron in 49 hemodialysis patients, divided into two groups, based on adequate or deficient iron stores. These groups were treated for 3 months with 150 mg elemental iron (Polysaccharide complex, Central Pharmaceuticals) or placebo, twice daily. Laboratory parameters were followed for five months. These parameters included: hematocrit (Hct), ferritin, transferrin saturation (Tsat), and zinc protoporphyrin (ZPP). A side-effects questionnaire was recorded monthly. Our results indicate that iron replete patients show evidence of falling iron stores during the study period; this observation was identical in both oral iron and placebo subgroups. Iron deficient patients had a significantly greater drop-out rate due to side effects when compared to iron replete patients (33% vs. 8%), despite equivalent responses to the side-effect questionnaire. We conclude: 1) Oral iron fails to maintain iron stores in iron replete patients; 2) Iron deficiency observed in this study may be due to poor medication compliance rather than side-effects.

Topics: Administration, Oral; Anemia; Anemia, Iron-Deficiency; Double-Blind Method; Erythropoietin; Female; Ferritins; Follow-Up Studies; Humans; Iron; Kidney Failure, Chronic; Male; Middle Aged; Patient Compliance; Polysaccharides; Recombinant Proteins; Renal Dialysis; Time Factors

Topics: Administration, Oral; Anemia; Anemia, Iron-Deficiency; Delayed-Action Preparations; Drug Administration Schedule; Erythropoietin; Female; Ferritins; Ferrous Compounds; Humans; Injections, Intravenous; Iron; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

In order to reveal whether serum transferrin receptor (sTfR) can serve as an index in erythropoiesis during recombinant human erythropoietin (rHuEpo) therapy for anemia in pre-dialysis patients with chronic renal failure, we analyzed hematopoietic parameters and sTfR levels in 26 patients who were newly administered rHuEpo. sTfR was determined as sTfR transferrin complex (TRC) using the enzyme linked immunosolvent assay (ELISA) and the latex agglutination nephelometric immunoassay (LA). The therapeutic effect of rHuEpo was expressed as the change in the Ht from the start of treatment to 8 weeks later. (delta Ht). Ht, RBC and Hb levels were significantly increased at 4 and 8 weeks after initiating rHuEpo treatment. Furthermore, sTfR levels were significantly increased at 2 and 4 weeks after the start of rHuEpo treatment. Absolute changes in the sTfR level (sTfR before - sTfR after) and rates of change (absolute change/sTfR before x 100) at, 2, 4 weeks after the start of rHuEpo treatment showed a significant positive correlation with delta Ht. These results indicate that sTfR is a useful marker as an index of therapeutic effect of rHuEpo for anemia in pre-dialysis patients with chronic renal failure.

Topics: Adult; Aged; Aged, 80 and over; Anemia, Hypochromic; Biomarkers; Erythropoiesis; Erythropoietin; Humans; Kidney Failure, Chronic; Middle Aged; Receptors, Transferrin; Recombinant Proteins

In anaemia of chronic renal failure, the most important factor in the shortened erythrocyte survival may be lipid peroxidation of the cell membrane. Defective antioxidant activity may increase this damage. Although recombinant human erythropoietin (r-HuEPO) can effectively correct anaemia in chronic haemodialysis patients, its actions on lipid peroxidation and antioxidant activity are not clear. These actions were investigated in 13 patients undergoing chronic haemodialysis. Antioxidant activity, including red blood cell superoxide dismutase and total glutathione peroxidase levels and the lipid peroxidation product malondialdehyde, were measured before and 3 months after initiation of r-HuEPO treatment, using heparinized venous whole blood for cell and plasma determinations. Age-matched healthy volunteers were controls. Significantly higher levels of superoxide dismutase and total glutathione peroxidase were found in the patients than in the controls (p < 0.01). Plasma malondialdehyde levels were not affected by r-HuEPO. The results are explained by erythropoiesis and cellular haemoglobin synthesis due to r-HuEPO, followed by increase of circulating young red cells. The membranes of these young cells contain more antioxidant enzymes than the others. Despite r-HuEPO treatment, plasma malondialdehyde levels in haemodialysis patients may be higher than normal because of the uraemic milieu and the chronic haemodialysis.

Topics: Adult; Aged; Antioxidants; Biomarkers; Erythropoietin; Female; Glutathione Peroxidase; Hemoglobins; Humans; Kidney Failure, Chronic; Lipid Peroxidation; Male; Malondialdehyde; Middle Aged; Recombinant Proteins; Renal Dialysis; Superoxide Dismutase

The efficacy of erythropoietin (EPO) in 11 children on hemodialysis (HD) and 8 on continuous ambulatory peritoneal dialysis (CAPD) (mean age 11.8 years) was compared. The initial EPO dose was 50 U/kg s.c. once a week; the time of observation was 24 weeks. In the CAPD group, the mean hemoglobin (Hb) level increased from 7.7 +/- 0.2 to 11.2 +/- 0.6 g/dl (P < 0.001) and hematocrit (Hct) from 22.3 +/- 1.0 to 32.6 +/- 1.4% (P < 0.001), while in the HD group the mean Hb rose from 7.7 +/- 0.6 to 9.3 +/- 0.8 g/dl (P < 0.001) and mean Hct from 22.7 +/- 2.3 to 27.6 +/- 2.8% (P < 0.001) after 12 weeks of observation. An increase in Hb to over 10 g/dl was obtained in 87.5% of children on CAPD but in only 10% on HD after 8 weeks of EPO treatment. After 12 weeks of treatment, all children on CAPD had the target Hb level of more than 10 g/dl, while 7 children on HD required increased doses of EPO (100 U/kg per week). We conclude that the EPO dose of 50 u/kg given s.c. once a week is effective for children with anemia on CAPD but is insufficient for children on HD.

Topics: Adolescent; Anemia; Child; Child, Preschool; Erythropoietin; Female; Hematocrit; Humans; Infant; Kidney Failure, Chronic; Male; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis

Two previous short-term studies (12 weeks and up to 16 weeks) that used androgens to supplement recombinant human erythropoietin (rHuEPO) for the treatment of the anemia associated with end-stage renal disease showed divergent results. Both studies were limited by their brief duration, since the hematopoietic effect of androgens does not peak until 5 months. Therefore, we conducted a 6-month, prospective, randomized trial comparing low-dose rHuEPO alone and in combination with androgens for the treatment of the anemia of end-stage renal failure. Nineteen anemic chronic hemodialysis patients were randomized into two groups. Group A (n = 10) received 1,500 U rHuEPO intravenously three times a week for 26 weeks. Group B (n = 9) received the same dose of rHuEPO plus nandrolone decanoate 100 mg intramuscularly weekly. Baseline transferrin saturation, serum ferritin, intact serum parathyroid hormone, plasma aluminum, and hematocrit levels were not significantly different between the groups. At study completion, both groups showed a significant increase in mean hematocrit compared with baseline (group A: 24.8% +/- 1.4% to 28.3% +/- 2.8%, P = 0.003; group B: 25.1% +/- 1.5% to 33.2% +/- 4.5%, P = 0.001). The increase in hematocrit in the rHuEPO plus androgen-treated group was statistically greater than in the rHuEPO-alone group (8.2% +/- 4.4% v 3.5% +/- 2.8%; P = 0.012). With the exception of mild discomfort at the injection site, there were no significant side effects from nandrolone. We conclude that the combination of low-dose rHuEPO and nandrolone decanoate is effective treatment for the anemia of end-stage renal failure.

Topics: Anabolic Agents; Anemia; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Female; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nandrolone; Nandrolone Decanoate; Prospective Studies; Recombinant Proteins; Renal Dialysis; Time Factors

Therapy with human recombinant erythropoietin (EPO) has been accepted as effective for renal anemia in dialysis patients. However, studies in rats have shown that correcting anemia with EPO may affect the progression of renal dysfunction. In humans, however, the effect of EPO on residual renal function is a matter of controversy. We, therefore, investigated whether the long-term administration of EPO to predialysis patients influences residual renal function. Anemic patients at the predialysis stage with a serum creatinine (Cr) concentration ranging from 2 to 4 (average 2.9) mg/dl and a hematocrit (Ht) of less than 30% were randomly assigned to two groups which consisted of anemic patients not treated with EPO (group I, untreated anemic controls, n = 31) and anemic patients treated with EPO (group II, treated anemics, n = 42). Patients with nonsevere or moderate anemia (Ht > 30%) with a Cr ranging from 2 to 4 (average 2.6) mg/dl were also recruited as nonanemic controls (group III, untreated nonanemic controls, n = 35). Blood pressure was controlled to the same degree among the three groups by combined treatment with calcium antagonists and angiotensin-converting enzyme inhibitors. All patients were kept strictly on a low-protein (0.6 g/kg/day) and a low-salt (7 g/day) diet. The degree of control of dietary protein and blood pressure and the frequency of angiotensin-converting enzyme inhibitor administration were comparable among the three groups. The primary end point for each patient was a doubling of the baseline Cr which yielded cumulative renal survival rates which were plotted against time. Ht rose significantly from 27.0+/-2.3 to 32.1+/-3.2% in group II (n = 42, p < 0.001) with a rate of increase of 0.4+/-0.06%/week. However, it declined from 27.9+/-1.8 to 25.3+/-1.9% in group I (n = 31, p < 0.001) and from 35.9+/-3.5 to 32.2+/-3.9% in group III (n = 35, p < 0.001). Cr doubled in 26 patients (84%) in group I as compared with 22 (52%) in group II and 21 (60%) in group III. The cumulative renal survival rates in groups II and III were significantly better than that in group I: p = 0.0003 (group I vs. group II) and p = 0.0024 (group I vs. group III). However, there was no difference in the renal survival rate between groups II and III (p = 0.3111). The better survival rate obtained in group II was attributable to the better survival rate for the nondiabetic patients in this group. The present study suggests that anemia, per se, is a factor in the prog

Topics: Adult; Aged; Anemia; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetes Complications; Dietary Proteins; Disease Progression; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Time Factors

Some chronic renal failure patients respond poorly to recombinant human erythropoietin (rHuEPO). In continuous ambulatory peritoneal dialysis (CAPD) patients, such a poor response may indicate inadequate dialysis or low body iron stores. To correct iron deficiency, once-a-week intravenous iron supplementation is recommended. However, hemodialysis patients receive iron supplements three times a week. This study was designed to compare the efficacy of iron supplementation between once-weekly and twice-weekly regimens. In both groups, rHuEPO doses were similar. Seventeen CAPD patients were studied. All had hemoglobin levels less than 10 g/dL. Ten patients were given 100 mg intravenous iron once weekly, and 7 were given 50 mg intravenous iron twice weekly until a total iron dose of 600 mg was achieved (stage I). The patients were crossed over to receive another 600 mg iron (stage II). Hematocrit increased significantly in patients receiving twice-a-week iron supplementation (+3.8% and 6%) compared to those receiving once-a-week iron supplementation (+1.3% and 1.4%) during stages I and II. The ferritin levels were not different between the groups. In conclusion, rHuEPO is more effective when administered with intravenous iron.

Topics: Adult; Anemia; Drug Administration Schedule; Drug Therapy, Combination; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Glucaric Acid; Hematocrit; Humans; Injections, Intravenous; Kidney Failure, Chronic; Male; Middle Aged; Organization and Administration; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Sucrose; Transferrin

Despite the long experience in erythropoietin (EPO) treatment in end-stage renal disease (ESRD)-related anemia, controversy remains as to whether EPO treatment of anemia can improve the quality of life (QL) in elderly ESRD patients, as it does in younger ones. We conducted a prospective study of 57 stable patients on hemodialysis who started on EPO treatment. A control group of 29 hemodialysis patients not requiring EPO was simultaneously studied. Diabetic patients and patients with severe comorbidity were excluded. Quality of life was assessed at baseline before EPO treatment and after 3 and 6 months of follow-up, using the Karnofsky scale (KS) and the Sickness Impact Profile (SIP) questionnaire. A high KS score and a low SIP score indicate better QL. Erythropoietin patients were stratified into two age groups: <60 years (n = 34) and > or = 60 years (n = 23). In the EPO group mean hematocrit values improved from 21 percent at baseline to 29 percent at the sixth month; mean KS scores increased from 68 +/- 1.8 to 81 +/- 1.5 (P < 0.0001) and the mean global score of SIP decreased from 19.8 +/- 1.6 to 13.5 +/- 1.2 (P < 0.0001). No significant changes were observed in the control group. Elderly patients in the EPO group showed improved KS scores, from 61 +/- 1.5 to 75 +/- 2.5 (P < 0.0001), and the global score of SIP decreased from 27.7 +/- 2.1 to 20 +/- 1.8 (P < 0.001). Younger patients had improvement of their KS scores, from 73 +/- 2.5 to 85 +/- 1.5 (P < 0.0001), and the global score of SIP decreased from 14.5 +/- 1.9 to 9.1 +/- 1.2 (P < 0.001). No relationship was found between age groups and improvement in QL indicator scores. On regression analysis, a poor basal QL score was related to higher QL improvement under EPO treatment, and final hematocrit was positively related to global SIP improvement. Treatment of ESRD-related anemia with EPO significantly improved the QL of hemodialysis patients. Quality of life in elderly patients improved as much as in younger patients, thereby fully justifying the use of EPO for the elderly.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Analysis of Variance; Anemia; Erythropoietin; Follow-Up Studies; Hematocrit; Humans; Kidney Failure, Chronic; Linear Models; Middle Aged; Prospective Studies; Quality of Life; Renal Dialysis; Time Factors

The relationship between serum carnitine levels and erythrocyte osmotic fragility was investigated in 26 chronic hemodialysis patients (10 males and 16 females, mean age: 57.3 +/- 13.5 years). Serum total-carnitine (TC), free-carnitine (FC) and acyl-carnitine (AC) levels were determined by a spectrophotometric method. Erythrocyte osmotic fragility was measured with a coil planet centrifuge. Serum TC levels were 39.9 +/- 13.4 mumol/l (mean +/- SD), FC levels were 21.8 +/- 7.8 mumol/l and AC levels were 18.0 +/- 9.6 mumol/l. The mean hemolysis end point (HEP) was 67.4 +/- 5.4 mOsM, the hemolysis maximum point (HMP) was 86.3 +/- 5.4 mOsM and the hemolysis start point (HSP) was 101.2 +/- 4.4 mOsM. Each hemolysis point in hemodialysis patients was elevated in comparison with the normal range. There were no significant differences in hemolysis points between a recombinant human erythropoietin (rhEPO)-treated group and nontreated group. HEP correlated with serum TC (r = -0.56, p < 0.01) and AC levels (r = -0.58, p < 0.01). HMP correlated with serum TC (r = -0.42, p < 0.05) and FC levels (r = -0.41, p < 0.05). Dose requirement of rhEPO maintaining target hematocrit correlated with serum TC (r = 0.54, p < 0.05) and FC levels (r = 0.50, p < 0.05). These data support that low serum carnitine levels accelerate erythrocyte osmotic fragility. Carnitine may contribute to the metabolism of erythrocyte membrane and have an impact on the efficacy of rhEPO in correcting renal anemia.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Blood Urea Nitrogen; Carnitine; Centrifugation; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Osmotic Fragility; Recombinant Proteins; Renal Dialysis; Reticulocyte Count

Evidence for the involvement of endothelial cells in the pathogenesis or erythropoietin-induced hypertension, and for endothelial cell damage in patients with chronic renal failure, has emerged and appears to be of major concern. We, therefore, investigated the effect of recombinant human erythropoietin (rHuEPO) therapy on endothelium-derived hormones in predialysis patients with progressive renal anemia. At the entry to the trial, the serum thrombomodulin concentration (Tm) and plasma endothelin-1 concentration (ET-1) in the predialysis patients were significantly higher than those in age- and sex-matched normal subjects. Following a 16 week period of treatment with 6000IU rHuEPO given intravenously once a week, patients' hematocrit increased from 27.1 +/- 2.6% to 34.6 +/- 3.2% (n = 16, P < .001). A positive correlation was found between Tm and serum creatinine concentration (Cr) (r = 0.61, P < .05 (n = 16), but no correlation was found between ET-1 and Cr. Tm and Tm/Cr significantly decreased from 7.9 +/- 2.8 ng/mL to 6.6 +/- 2.4 ng/mL (P < .01, n = 16), and from 2.1 +/- 0.7 (x10(-10) to 1.6 +/- 0.7 (x10(-10), P < .01, n = 16), respectively. However, there was no change in ET-1 as a result of the rHuEPO therapy. Creatinine clearance (Ccr), Cr, total amount of daily Tm excretion, Tm clearance/Ccr, daily urinary protein and albumin excretion, and blood pressure also remained unchanged throughout the trail. The present study indicates that correcting anemia by rHuEPO therapy reduces an abnormally elevated Tm in predialysis patients while blood pressure and renal function remain unchanged, suggesting that rHuEPO has a beneficial effect on endothelial cell dysfunction in chronic renal failure patients. This effect may be mediated via an improved oxygen supply to the endothelial cells due to the amelioration of anemia by rHuEPO.

Topics: Adult; Aged; Anemia; Blood Pressure; Creatinine; Endothelins; Endothelium, Vascular; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Thrombomodulin; Urinalysis

The purpose of the study was to investigate the effect of route of administration of erythropoietin (EPO) on the dose requirement in dialysis patients after intravenous (IV) and subcutaneous (SC) therapy.. The study was performed as a single centre, prospective, open, combined parallel and cross-over study of 50 dialysis patients, consecutively randomised to IV or SC treatment with EPO. The initial dose was 49 U.kg-1 3-times weekly, adjusted to increase haemoglobin (Hgb) from a median 5.3 mmol.1(-1) to a target of haemoglobin 6.5-7.5 mmol.1(-1). After reaching the target level, the haemoglobin was maintained for 4 months (Period 1). Then IV and SC treatment was switched for a further 4 months (Period 2). The study included high risk patients. The adjustment period was completed by 38 patients, Period one by 32 patients (IV/SC = 15/17; male/female = 19/13; age = 54 (24- 71) y), and Period two by 22 patients.. No significant difference was found between the two groups in the reticulocyte response, the rate of Hgb increase (IV 0.7 versus SC 0.5, mmol.1(-1). month-1), time to reach target level (IV 43 versus SC 60 days), or total EPO dose per increase in haemoglobin to target level (IV 663 versus SC 946 (U.kg-1) per (mmol Hgb.1(-1)). The overall median maintenance dose during the last month of the two four month periods was 105 (range IV 51-336) U.kg-1.w-1 and SC 104 (range 21-321) U.kg-1.w-1. Through serum EPO levels were significantly higher during SC treatment. The blood pressure did not change significantly from the base level after either route of administration; start 133/80 versus 143/80 mmHg, target 127/78 versus 154/85 mmHg, and maintenance period 140/84 versus 142/85 mmHg. Thus, three-times weekly IV or SC EPO did not differ significantly in efficacy or in the effect on blood pressure in dialysis patients.

Topics: Adult; Aged; Anemia; Blood Pressure; Erythropoietin; Female; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

As a component of the open-label, multicenter National Cooperative Recombinant Human Erythropoietin (Epo) Study, the health-related quality-of-life effects of Epo therapy were assessed in 484 dialysis patients who had not previously been treated with Epo therapy (New-to-Epo) and 520 dialysis patients who were already receiving Epo therapy at the time of study enrollment (Old-to-Epo). Using scales from the Medical Outcomes Study 36-item Short Form Health Survey (SF-36), health-related quality of life was assessed on study enrollment (baseline) and at an average of 99 days follow-up. At baseline, SF-36 scores for Old- and New-to-Epo patients were well below those observed in the general population, reflecting substantial impairments in functional status and well-being among patients with chronic renal failure. Significant improvements from baseline to follow-up were observed among New-to-Epo patients in vitality, physical functioning, social functioning, mental health, looking after the home, social life, hobbies, and satisfaction with sexual activity (P < 0.05 for each). The mean improvements in hematocrit values among New-to-Epo and Old-to Epo patients were 4.6 and 0.3, respectively. At the time of follow-up, SF-36 scores for New-to-Epo patients were comparable with those observed among Old-to-Epo patients, whose scores did not change significantly from baseline to follow-up. Analysis of the relationship between Epo therapy, hematocrit values, and health-related quality of life suggest that some of the beneficial quality-of-life effects of Epo are mediated through a change in hematocrit level.

Topics: Activities of Daily Living; Adult; Aged; Anemia; Comorbidity; Depressive Disorder; Erythropoietin; Female; Heart Failure; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Patient Acceptance of Health Care; Peritoneal Dialysis; Quality of Life; Racial Groups; Recombinant Proteins; Renal Dialysis; Self-Assessment

The evolution of body iron stores was prospectively analyzed during a stable erythropoiesis period in 27 subjects (14 males and 13 females) on hemodialysis for more than 2 years in order to clarify the iron requirements of these patients and the effectiveness and safety of the administration of sodium ferric gluconate as a method to maintain adequate body iron stores. All patients had a stable hemoglobin level (variation < 1 g/dl). Sixteen subjects were on maintenance recombinant human erythropoietin therapy at regular doses. All patients received intravenous sodium ferric gluconate for 6 months (62.5 mg/month). The iron requirements were estimated as the difference between the amount of iron administered and the variation of body iron stores (calculated by the empirical formula of Cook and coworkers). The hemoglobin remained stable (basal 10.7 +/- 1.1, at 6th month 10.6 +/- 1 g/dl). Considering all cases, there were no significant variations in body iron stores (basal 457 +/- 273, at 6th month 451 +/- 316 mg). The patients were classified into three groups according to whether their body iron stores decreased (group A, n = 8), remained stable (group B, n = 11), or increased (group C, n = 8). There were no differences among groups concerning sex, age, time on hemodialysis, or erythropoietin therapy. However, there were statistically significant differences concerning their basal body iron stores (group A 457 +/- 228 mg. group B 563 +/- 146, and group C 230 +/- 297 mg; p < 0.05, analysis of variance). The iron needs, considering the total group, were 2.12 +/- 2 mg/day. There were no differences in iron requirements according to sex, but menstruating women had higher iron needs than the nonmenstruating ones (4.29 +/- 2 vs. 2.08 +/- 1.45 mg/day; p < 0.01). The iron requirements in patients on erythropoietin therapy were higher than in those without (2.63 +/- 1.59 vs. 1.88 +/- 1.68 mg/day; p < 0.05). However, excluding the menstruating women, the iron need in patients on erythropoietin were similar to those in subjects without this treatment (2.16 +/- 1.13 vs. 1.88 +/- 1.68 mg/day). All patients showed good compliance with an excellent tolerance. We have observed that in subjects on maintenance erythropoietin therapy, the iron requirements are stable. The administration of sodium ferric gluconate is safe and efficient in maintaining adequate body iron stores.

Topics: Adult; Aged; Erythropoietin; Female; Ferric Compounds; Ferritins; Hematocrit; Hemoglobins; Humans; Infusions, Intravenous; Iron; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Dialysis

Topics: Anemia; Angiotensin-Converting Enzyme Inhibitors; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

In order to assess the effect of long term erythropoietin (EPO) therapy on the nutritional status of hemodialysed (HD) patients 2 groups of HD patients were studied: I-EPO treated for 72 +/- 8 mo, 12 patients, HD for 138 +/- 66 mo, II-control group, 14 patients with Ht 30%, HD for 121 +/- 35 mo. At the onset and after 6 years of follow up patients underwent the following examination: length, body weight, body mass index, body fat stores, arm muscle circumference and total serum protein, serum albumin, lymphocyte count, creatinine, urea, cholesterol and PTH. In EPO group mean BMI, body fat, arm muscle circumference, visceral protein and total lymphocyte count were not change. In control group the decrease in height, body weight, BMI, body fat stores, arm muscle circumference and albumin were observed. Elevation of PTH estimated in half of patients in EPO group and 75% of patients in control group could influence the nutritional status of hemodialysed patients.. 1. Nutritional status of majority of hemodialysed patients was not change during six years EPO therapy. 2. Non EPO treated patients showed the decrease of anthropometric measurements and serum albumin.

Topics: Adult; Anthropometry; Drug Administration Schedule; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nutritional Status; Renal Dialysis; Serum Albumin

Topics: Anemia; Carnitine; Drug Therapy, Combination; Erythropoietin; Humans; Kidney Failure, Chronic; Recombinant Proteins; Renal Dialysis

Topics: Adolescent; Adult; Aged; Anemia; Anticonvulsants; Child; Dose-Response Relationship, Drug; Epilepsy; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis