losartan-potassium and Kidney-Diseases

The kidney is the main organ that senses changes in systemic oxygen tension, but it is also the key detoxification, transit and excretion site of transition metals (TMs). Pivotal to oxygen sensing are prolyl-hydroxylases (PHDs), which hydroxylate specific residues in hypoxia-inducible factors (HIFs), key transcription factors that orchestrate responses to hypoxia, such as induction of erythropoietin (EPO). The essential TM ion Fe is a key component and regulator of the hypoxia-PHD-HIF-EPO (HPHE) signaling axis, which governs erythropoiesis, angiogenesis, anaerobic metabolism, adaptation, survival and proliferation, and hence cell and body homeostasis. However, inadequate concentrations of essential TMs or entry of non-essential TMs in organisms cause toxicity and disrupt health. Non-essential TMs are toxic because they enter cells and displace essential TMs by ionic and molecular mimicry, e. g. in metalloproteins. Here, we review the molecular mechanisms of HPHE interactions with TMs (Fe, Co, Ni, Cd, Cr, and Pt) as well as their implications in renal physiology, pathophysiology and toxicology. Some TMs, such as Fe and Co, may activate renal HPHE signaling, which may be beneficial under some circumstances, for example, by mitigating renal injuries from other causes, but may also promote pathologies, such as renal cancer development and metastasis. Yet some other TMs appear to disrupt renal HPHE signaling, contributing to the complex picture of TM (nephro-)toxicity. Strikingly, despite a wealth of literature on the topic, current knowledge lacks a deeper molecular understanding of TM interaction with HPHE signaling, in particular in the kidney. This precludes rationale preventive and therapeutic approaches to TM nephrotoxicity, although recently activators of HPHE signaling have become available for therapy.

Topics: Erythropoietin; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Kidney Diseases; Oxygen; Transcription Factors

Anemia is a frequent complication of kidney disease. When severe, it causes symptoms that can be debilitating. The course of anemia tends to track the decline in kidney function, with prevalence increasing in more advanced disease. Although the most common cause is relative erythropoietin deficiency, other factors such as reduced iron availability contribute to the pathobiology. In this review, we use cases to explore the surprising complexity of decision-making in management of renal anemia.

Topics: Anemia; Erythropoietin; Humans; Iron; Iron Deficiencies; Kidney Diseases; Practice Patterns, Physicians'; Prevalence

Intracellular proteins continuously turn over by degradation and synthesis in all organ tissues. Owing to its irreversible nature, protein degradation is a highly selective process to avoid irreparable breakdown of cellular constituents, thereby disrupting cellular stability, integrity and signalling. The majority of intracellular proteins are degraded by the ubiquitin-proteasome system (UPS), a multi-enzyme process that involves the covalent conjugation of ubiquitin to a substrate protein and its recognition and degradation by the core multicomponent proteolytic complex of the UPS, the proteasome. In addition to labelling misfolded, damaged, aggregation-prone and intact but unneeded proteins for proteasomal degradation, ubiquitylation regulates a multitude of cellular processes, such as transcription, translation, endocytosis, and receptor activity and subcellular localization. In addition, the proteasome generates peptides for antigen presentation in the immune system and for further degradation by peptidases to provide amino acids for protein biosynthesis and gluconeogenesis. Alterations of the UPS or of protein substrates that render them more or less susceptible to degradation are responsible for disorders associated with renal cell dysfunction. In this Review, we provide insight into the elegant and complex nature of UPS-mediated proteostasis and focus on its established and potential roles in renal cell physiology and pathophysiology.

Topics: Autophagy; Biological Transport; Erythropoietin; Glucose; Homeostasis; Humans; Kidney; Kidney Diseases; Lysosomes; Muscular Atrophy; Podocytes; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Sodium; Ubiquitinated Proteins; Ubiquitination; von Hippel-Lindau Disease; Water-Electrolyte Balance

Treatment using the cell sheet technology has been applied to various organs, including the cornea, heart, esophagus, periodontium, cartilage, middle ear, and lungs. It has been shown that the therapeutic efficacy of cell sheet transplantation involves 2 aspects, supplementation of cells and provision of cytokines to the affected organ. In addition, cell sheet transplantation also promotes repair of damage through the paracrine effects of cytokines derived from the transplanted cells. It is known that in cases of cell transplantation by injection, the transplanted cells are less likely to differentiate into renal tissue to supply cells, but repair is promoted by the actions of the transplanted cell-derived renotropic factors. Renal function requires functional conjugation of various tissues, including blood vessels, glomeruli, renal tubules, and collecting ducts. It is difficult to supply the necessary cells directly to the affected site of the renal tissue composed of complex structures. On the contrary, the 2-dimensional cell sheet can produce proteins such as erythropoietin, and is thus suitable for transplantation into the living body. It would be desirable to develop cell sheet therapy for the suppression of kidney damage in the future, taking advantage of the beneficial characteristics of cell sheets.

Topics: Cell Transplantation; Cells, Cultured; Cholecalciferol; Culture Techniques; Cytokines; Erythropoietin; Humans; Kidney; Kidney Diseases; Regeneration; Renal Insufficiency; Stem Cell Transplantation; Tissue Engineering

During the exploration of factors that interfere with the erythropoietin (EPO) -EPO receptor (EPOR) interaction in anemia, a novel inhibitory factor of EPO, anti-EPOR antibody, has been detected in anemic pa- tients with immune-mediated diseases. The study also demonstrated that the antibodies were observed in some patients with chronic kidney disease (CKD). EPOR is known to be expressed not only in bone mar- row erythroblasts, but also in other organs including the kidneys. In addition, previous studies showed that EPO may contribute to protecting the kidneys from injury by binding EPOR on renal resident cells as well as through the correction of anemia. Based on this background, we recently examined the clinical significance of anti-EPOR antibodies in patients with CKD. With regard to patients with lupus nephritis, who showed the highest antibody levels among the patients examined, the antibodies were associated with overall disease activity and cell infiltration in the injured kidney, and they were inversely related to the preserved renal function. Here, we discuss the discovery of anti-EPOR antibodies in patients with anemia and CKD, and the possibil- ity of their use as an additional biomarker for the deterioration of the renal function. [Review].

Topics: Anemia; Autoantibodies; Erythropoietin; Humans; Kidney Diseases; Receptors, Erythropoietin

Innate immune system is an important modulator of the inflammatory response during infection and tissue injury/repair. The kidney as a vital organ with high energy demand plays a key role in regulating the disease related metabolic process. Increasing research interest has focused on the immune pathogenesis of many kidney diseases. However, innate immune cells such as dendritic cells, macrophages, NK cells and a few innate lymphocytes, as well as the complement system are essential for renal immune homeostasis and ensure a coordinated balance between tissue injury and regeneration. The innate immune response provides the first line of host defense initiated by several classes of pattern recognition receptors (PRRs), such as membrane-bound Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), together with inflammasomes responsible for early innate immune response. Although the innate immune system is well studied, the research on the detailed relationship between innate immunity and kidney is still very limited. In this review, we will focus on the innate immune sensing system in renal immune homeostasis, as well as the corresponding pathogenesis of many kidney diseases. The pivotal roles of innate immunity in renal injury and regeneration with special emphasis on kidney disease related immunoregulatory mechanism are also discussed.

Topics: Animals; Disease Susceptibility; Erythropoietin; Homeostasis; Humans; Immune System; Immunity, Innate; Immunomodulation; Inflammasomes; Kidney; Kidney Diseases; Receptors, Pattern Recognition; Regeneration

Long overlooked as the virtual compartment and then strictly characterized through descriptive morphologic analysis, the renal interstitium has finally been associated with function. With identification of interstitial renin- and erythropoietin-producing cells, the most prominent endocrine functions of the kidney have now been attributed to the renal interstitium. This article reviews the functional role of renal interstitium.

Topics: Adenosine; Anemia; Animals; Erythropoietin; Fibroblasts; Humans; Kidney; Kidney Diseases; Mesenchymal Stem Cells; Neural Crest; Renin; Renin-Angiotensin System

The discovery of potential anti-apoptotic and cytoprotective effects of recombinant human erythropoietin (rHuEPO) has led to clinical trials investigating the use of high-dose, short-term rHuEPO therapy for tissue protection in conditions such as stroke and myocardial infarction. Experimental studies have been favourable, but the clinical efficacy has yet to be validated.. We have reviewed clinical studies regarding the use of high-dose, short-term rHuEPO therapy for tissue protection in humans with the purpose to detail the safety and efficacy of rHuEPO for this indication. A systematic literature search was performed using the PubMed/MEDLINE database for randomized, placebo-controlled clinical trials.. Twenty-six randomized controlled trials that enrolled 3176 patients were included. The majority of trials (20 trials including 2724 patients) reported no effect of rHuEPO therapy on measures of tissue protection. Five trials including 1025 patients reported safety concerns in the form of increased mortality or adverse event rates. No studies reported reduced mortality.. Evidence is sparse to support a tissue-protective benefit of rHuEPO in humans. Moreover, a number of studies indicate that short-term administration of high-dose rHuEPO is associated with an increased risk of mortality and serious adverse events. Further work is needed to elucidate the mechanisms of toxicity of rHuEPO in humans.

Topics: Cardiotonic Agents; Cytoprotection; Erythropoietin; Hematinics; Humans; Kidney Diseases; Neuroprotective Agents; Randomized Controlled Trials as Topic; Recombinant Proteins

Erythropoietin(EPO) is an indispensable erythropoietic hormone, produced mainly from kidneys in adult, and the production declines with progression of chronic kidney disease(CKD). Renal EPO-producing cells(REPs) are peri-tubular interstitial fibroblasts. Dysfunction and myofibroblast transformation of REPs have been reported in rodent models of kidney injuries. Despite the crucial importance of EPO in health and diseases, many aspects of REPs remain to be elucidated because of technical difficulties to investi- gate the cells in vivo. This review will summarize our recent progress in characterization of REPs. We also summarize the role REPs play in kidney fibrosis and their unique character "plasticity". Future therapeutic approach targeting REPs to treat both anemia and fibrosis in CKD will also be discussed.

Topics: Animals; Erythropoietin; Fibrosis; Humans; Introns; Kidney Diseases; Oxygen

Anemia is a significant cause of morbidity and lowers the quality of life of patients suffering from chronic kidney disease (CKD). Iron deficiency is the most important cause of erythropoietin (EPO) hyporesponsiveness in CKD. EPO administration significantly increases the costs of CKD management. It follows that paramount importance must be given to enhancing responsiveness to EPO thereby ensuring that the patient derives maximum benefit. Intravenous iron (IVI) administration has been used for decades to replenish body iron stores. Multiple preparations of Iron are available in the market. However, IVI administration is fraught with dangers like adverse drug reactions, susceptibility to infection, and, as recently postulated, direct cellular toxicity. Traditional approaches to IVI administration have focused on multiple administrations of lower doses for fear of adverse reactions. However, recent studies have demonstrated that higher doses can be safely administered in a single infusion, thereby reducing hospitalization costs and patient inconvenience. Newer preparations of IVI are relatively safer, easier to administer and efficacious. Preparations like Iron sucrose, ferumoxytol, ferric carboxymaltose and iron isomaltoside do not require test doses and allow higher doses to be administered at a time with cost and effect benefits.

Topics: Anemia; Chronic Disease; Erythropoietin; Humans; Injections, Intravenous; Iron; Iron Deficiencies; Kidney Diseases

Multiple and complex abnormalities of hemostasis are revealed by laboratory tests in such common diseases as cirrhosis and end-stage renal insufficiency. Because these abnormalities are associated with a bleeding tendency, a causal relationship is plausible. Accordingly, an array of transfusional and nontransfusional medications that improve or correct these abnormalities is used to prevent or stop hemorrhage. However, recent data indicate that the use of hemostatic drugs is scarcely justified mechanistically or clinically. In patients with uremia, the bleeding tendency (mainly expressed by gastrointestinal bleeding and hematoma formation at kidney biopsy) is reduced dramatically by the improvement of anemia obtained with the regular use of erythropoietin. In cirrhosis, the most severe and frequent hemorrhagic symptom (acute bleeding from esophageal varices) is not explained by abnormalities in such coagulation screening tests as the prothrombin and partial thromboplastin times, because formation of thrombin the final coagulation enzyme is rebalanced by low naturally occurring anticoagulant factors in plasma that compensate for the concomitant decrease of procoagulants. Rebalance also occurs for hyperfibrinolysis and platelet abnormalities. These findings are consistent with clinical observations that transfusional and nontransfusional hemostatic medications are of little value as adjuvants to control bleeding in advanced liver disease. Particularly in uremia, but also in cirrhosis, thrombosis is becoming a cogent problem.

Topics: Anemia; Anticoagulants; Blood Coagulation; Blood Coagulation Disorders; Coagulants; Erythropoietin; Fibrosis; Hemorrhage; Hemostasis; Humans; Kidney Diseases; Liver Diseases; Partial Thromboplastin Time; Risk Factors; Uremia

CKD is a major public health problem in the developed and the developing world. The degree of proteinuria associated with renal failure is a generally well accepted marker of disease severity. Agents with direct antiproteinuric effects are highly desirable therapeutic strategies for slowing, or even halting, progressive loss of kidney function. We review progress on therapies acting further downstream of the renin-angiotensin-aldosterone system pathway (e.g., transforming growth factor-beta antagonism, endothelin antagonism) and on those acting independent of the renin-angiotensin-aldosterone system pathway. In all, we discuss 26 therapeutic targets or compounds and 2 lifestyle changes (dietary modification and weight loss) that have been used clinically for diabetic or nondiabetic kidney disease. These therapies include endogenous molecules (estrogens, isotretinoin), biologic antagonists (monoclonal antibodies, soluble receptors), and small molecules. Where mechanistic data are available, these therapies have been shown to exert favorable effects on glomerular cell phenotype. In some cases, recent work has indicated surprising new molecular pathways for some therapies, such as direct effects on the podocyte by glucocorticoids, rituximab, and erythropoietin. It is hoped that recent advances in the basic science of kidney injury will prompt development of more effective pharmaceutical and biologic therapies for proteinuria.

Topics: Animals; Antibodies, Monoclonal, Murine-Derived; Antihypertensive Agents; Calcineurin Inhibitors; Endothelins; Erythropoietin; Fatty Acids, Omega-3; Feeding Behavior; Glucocorticoids; Humans; Kidney Diseases; Mice; Proteinuria; Rats; Renin-Angiotensin System; Rituximab; Transforming Growth Factors; Weight Loss

Anemia is inevitable as chronic kidney disease (CKD) advances. With the advent of erythropoietin-stimulating agents (ESAs), considerable improvement has been achieved in the management of anemia. However, some patients show a reduced response to ESAs.. Many factors affect the response to ESA treatment. CKD is now considered as an inflammatory disorder and this understanding led to the recognition of the central role of inflammation in ESA resistance. Inflammation is related to untoward outcomes, including atherosclerosis and anemia, in the CKD population. Furthermore, recognition of deleterious effects of proinflammatory markers at different levels of erythropoiesis led to a change in the name of 'anemia of chronic disease' to anemia of inflammation.. The discovery of hepcidin as the major controller of iron metabolism in anemia of inflammation answered many questions regarding the interaction of erythropoietin, iron and bone marrow. Hepcidin production in the liver is driven by three major factors: inflammation, iron overload and anemia/hypoxia. Hepcidin levels are increased in patients with CKD due to the interaction of many factors; a comprehensive understanding of these pathways is thus critical in the effort to alleviate anemia of inflammation and ESA resistance.. In this review, we discussed the epidemiology, determinants and consequences of anemia of inflammation in CKD patients with special emphasis on the central role of hepcidin along with molecular pathways driving its production.

Topics: Anemia; Antimicrobial Cationic Peptides; Bone Marrow; Chronic Disease; Erythropoietin; Hepcidins; Humans; Inflammation; Iron; Iron Overload; Kidney Diseases

Erythropoietin (EPO) is used at present in clinical practice to stimulate red cell production. However, a number of reports have emerged suggesting the presence of nonerythropoietic properties for EPO. Chief among them is its ability to confer protection against acute tissue injury. In this report, we briefly review the role of EPO in tissue protection and provide examples of tissue protection using cisplatin-induced kidney injury model. Also provided is a brief description of potential pathways through which EPO may be mediating this effect.

Topics: Animals; Cisplatin; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Humans; Kidney; Kidney Diseases; Models, Biological; Rats; Receptors, Erythropoietin; Signal Transduction

Topics: Acidosis; Anemia; Bone Diseases, Metabolic; Chronic Disease; Darbepoetin alfa; Diabetic Nephropathies; Diet, Protein-Restricted; Erythropoietin; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Kidney Diseases; Male; Nephrology; Renin-Angiotensin System

The kidney is a major site of systemic oxygen sensing, regulating blood erythrocyte and hence oxygen content by hypoxia-inducible erythropoietin (Epo) expression. A constant ratio between blood perfusion and oxygen consumption, a stable corticomedullary oxygen gradient, and a relatively low tissue Po(2) are the prerequisites for the function of renal Epo-producing and oxygen-sensing (REPOS) cells, which are located in the juxtamedullary cortex. In kidney disease, renal oxygen consumption is decreased, leading to an increase in Po(2), dysfunction of REPOS cells, and anemia. The molecular principles of cellular oxygen sensing have been elucidated in the last few years, and genetically altered mouse models as well as hereditary diseases causing erythrocytosis have clarified the oxygen-signaling cascade leading to increased Epo expression in REPOS cells. However, the consequences of a number of recently discovered factors for the regulation of oxygen signaling in REPOS cells are unclear, asking for novel cell culture models which might be hampered by the putative neuron-like nature of this enigmatic cell type.

Topics: Anemia; Animals; Basic Helix-Loop-Helix Transcription Factors; Erythropoietin; Feedback, Physiological; Gene Expression Regulation; Hematinics; Humans; Hydroxylation; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Kidney; Kidney Diseases; Oxygen; Oxygen Consumption; Polycythemia; Procollagen-Proline Dioxygenase; Renal Circulation; Signal Transduction; Von Hippel-Lindau Tumor Suppressor Protein

Topics: Acute Kidney Injury; Autoantigens; Darbepoetin alfa; Diabetic Nephropathies; Erythropoietin; Glomerulonephritis, Membranous; Hematinics; Humans; Immunosuppressive Agents; Kidney Diseases; Lupus Nephritis; Randomized Controlled Trials as Topic; Renal Replacement Therapy

Sirtuins (silent information regulator 2 [Sir2] proteins) belong to an ancient family of evolutionary conserved nicotinamide adenine dinucleotide (NAD)(+)-dependent enzymes with deacetylase and/or mono-ADP-ribosyltransferase activity. They regulate DNA repair and recombination, chromosomal stability, and gene transcription, and most importantly mediate the health-promoting effects of caloric restriction (CR), which includes the retardation of aging. At least seven Sir2 homologs, sirtuins (SIRT) 1 to 7 have been identified in mammals. Mammalian SIRT1, the most extensively studied family member, couples protein deacetylation with NAD(+) hydrolysis and links cellular energy and redox state to multiple signaling and survival pathways. Cell-type and context-specific activation of sirtuins increases resistance to metabolic, oxidative, and hypoxic stress in different tissues. In particular, SIRT1 plays a central role in mediating the beneficial effects of CR, and its activation associates with longevity and the attenuation of metabolic disorders. SIRT1 in the kidney is cytoprotective and participates in the regulation of BP and sodium balance. Here, we review sirtuin biology and discuss how CR-triggered sirtuin-dependent pathways affect renal physiology and the pathogenesis of kidney diseases and related disorders.

Topics: Animals; Blood Pressure; Caloric Restriction; Erythropoietin; Humans; Hypoxia; Kidney; Kidney Diseases; Sirtuins; Sodium

Publication of the first large randomized placebo-controlled study of erythropoiesis-stimulating agent (ESA) treatment of anemia in patients with chronic kidney disease (CKD) not on dialysis, the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) along with recent changes in the regulatory environment and reimbursement policies related to ESA treatment have prompted reexamination of clinical ESA use in patients with CKD, including those on dialysis. This review addresses this and other recent studies of ESA treatment for renal anemia to higher hemoglobin (Hgb) targets above the range of 10-12 g/dl.. TREAT and other recent large randomized, controlled trials of ESA treatment in patients with CKD have not demonstrated a clinical benefit in terms of mortality, morbidity, or quality of life improvement of targeting Hgb levels greater than 12-13 g/dl. Some of these studies have demonstrated increased risk of stroke, vascular access thrombosis, hypertension, and other events. These findings are generally consistent with those of an earlier study of patients with end-stage renal disease (ESRD) on hemodialysis.. ESA treatment for renal anemia should be aimed at reducing transfusion risk, with a treatment target in most patients of 10-12 g/dl; therapy should be individualized, rapid increases in Hgb level should probably be avoided, and lowest appropriate ESA doses should be used. Temptation to increase ESA doses to very high levels in an attempt to overcome ESA hypo responsiveness should be resisted.

Topics: Anemia; Blood Transfusion; Cardiovascular Diseases; Darbepoetin alfa; Erythropoietin; Evidence-Based Medicine; Hematinics; Hematocrit; Hemoglobins; Humans; Kidney Diseases; Practice Guidelines as Topic; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome

TREAT was a recently concluded, and well-powered and designed, study of anemia treatment in chronic kidney disease (CKD). Unlike most previous studies of ESA treatment in nondialysis CKD, TREAT was a placebo-controlled trial. The placebo group in TREAT provides a unique long-term view of a conservative approach to anemia management in nondialysis CKD. The course of mean Hgb levels in the placebo group ran counter to expectations, increasing over time. We discuss possible reasons for this, including a new hypothesis that there may be an erythropoietin 'honeymoon phase' similar to that observed in diabetes mellitus. We propose investigation of this phenomenon as it could lead to less expensive and safer approaches to treatment of CKD anemia.

Topics: Anemia; Animals; Chronic Disease; Controlled Clinical Trials as Topic; Erythropoietin; Humans; Kidney Diseases

This article examines the potential mechanisms underlying adverse risk observed in four randomized controlled trials of anemia correction in chronic kidney disease (CKD) patients.. The Normal Hematocrit Study, Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin-beta, Correction of Hemoglobin and Outcomes in Renal Insufficiency, and Trial to Reduce Cardiovascular Events with Aranesp Therapy demonstrate increased risk of mortality and/or cardiovascular complications with targeting of a higher hemoglobin (Hb) in CKD patients. Although a higher Hb level was targeted in these trials, erythropoiesis-stimulating agent (ESA) exposure itself might account for the observed increased risk. This is because, in these trials, achieving a normal or near normal Hb was associated with improved survival and reduced cardiovascular risk. Indeed, it was the 'targeting' of a higher Hb with ESA that seemed to be the problem. Observational data, although conflicting, on the whole provide support for high dosage of ESA being harmful but cannot, by their very nature, prove causality.. After 20 years of ESA use, is it plausible that ESAs could be toxic? How does one reconcile conflicting observational data with a hypothesis that postulates ESA toxicity? Does the biology of erythropoietin provide a mechanistic explanation? The answers to these questions, among others, will be important in charting a future role for ESAs in treating CKD anemia.

Topics: Anemia; Chronic Disease; Erythropoiesis; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Diseases; Randomized Controlled Trials as Topic

After the patents of biopharmaceuticals have expired, based on specific regulatory approval pathways copied products ("biosimilars" or "follow-on biologics") have been launched in the EU. This article summarizes experiences with hematopoietic medicines, namely the epoetins (two biosimilars traded under five different brand names) and the filgrastims (two biosimilars, six brand names). Physicians and pharmacists should be familiar with the legal and pharmacological specialities of biosimilars: The production process can differ from that of the original, clinical indications can be extrapolated, glycoproteins contain varying isoforms, the formulation may differ from the original, and biopharmaceuticals are potentially immunogenic. Only on proof of quality, efficacy and safety, biosimilars are a viable option because of their lower costs.

Topics: Anemia; Antineoplastic Agents; Biological Products; Chronic Disease; Drug Utilization; Erythropoietin; European Union; Filgrastim; Granulocyte Colony-Stimulating Factor; Guidelines as Topic; Humans; Isoantibodies; Kidney Diseases; Legislation, Drug; Marketing; Neoplasms; Patents as Topic; Polyethylene Glycols; Quality Control; Recombinant Proteins; Red-Cell Aplasia, Pure; Therapeutic Equivalency; World Health Organization

In chronic kidney disease, anemia and oxidative stress are common features and both are involved in increasing morbidity and mortality. However, their relationship is still a matter of debate. This article is a review of published data and our experience and is intended to debate the pro and contra arguments concerning renal anemia and its 2 main therapeutic approaches, that are, erythropoietin and intravenous iron supplementation, as additional causes of oxidative stress in end-stage renal disease patients. To date, it seems more likely that renal anemia itself is the main contributor, and intravenous iron further enhances oxidative stress associated with chronic kidney disease. Future randomized prospective trials, with "hard" clinical end-points, are needed to establish the real effect of biochemical pro-oxidative changes on patient's outcome.

Topics: Anemia; Chronic Disease; Erythropoietin; Humans; Iron; Kidney Diseases; Lipid Peroxidation; Lipoproteins, LDL; Oxidants; Oxidative Stress; Renal Dialysis

Red blood cells (RBCs) often have a short circulating half-life in hemodialysis patients, which increases the difficulty of achieving a stable hemoglobin level. Fluctuations in erythropoietin (EPO) levels contribute to this increased RBC turnover because a decline in the level of EPO triggers the preferential destruction of newly-formed RBC, a process termed neocytolysis. The RBCs that are released during the treatment of renal anemia are often hypochromic, with a low content of iron; these RBCs are vulnerable to rapid turnover because iron-deficiency affects RBCs in several ways, such as, increased exposure of the phagocytic signaling molecule phosphatidylserine, loss of deformability, and increased oxidative stress. Both EPO fluctuation and the release of iron-deficient RBCs are characteristic events occurring during the management of renal anemia, and the shorter RBC lifetime is a component of the large fluctuations in hemoglobin level seen in patients on hemodialysis.

Topics: Anemia, Iron-Deficiency; Chronic Disease; Erythrocyte Aging; Erythropoietin; Hemoglobins; Humans; Kidney Diseases; Phagocytosis; Phosphatidylserines; Renal Dialysis

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

This review summarizes the evidence for a hypertensinogenic effect of Erythropoietin (Epo) in normal human subjects and predialysis, hemodialysis, and continuous ambulatory peritoneal dialysis (CAPD) patients. The possible mechanisms of Epo-induced hypertension are examined with in vivo animal and in vitro data, as well as pathophysiological human studies in both normal subjects and CKD patients. The evidence for a hypertensinogenic effect of erythropoiesis-stimulating agents (ESAs) in normal subjects, predialysis CKD, hemodialysis, and CAPD patients is compelling. Epo increases BP directly and notably independently of its erythropoietic effect and its effect on blood rheology. The potential for the development of future agents that might act as specific stimulators of erythropoiesis, devoid of direct hemodynamic side effects is underscored.

Topics: Anemia; Animals; Arteries; Blood Pressure; Chronic Disease; Erythropoietin; Evidence-Based Medicine; Hematinics; Humans; Hypertension; Kidney Diseases; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Risk Assessment

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

Anemia has been recognized as a very common and serious comorbidity in heart failure, with a prevalence ranging from 10 to 79%, depending on diagnostic definition, disease severity and patient characteristics. A clear association of anemia with worse prognosis has been confirmed in multiple heart failure trials. This finding has recently triggered intense scrutiny in order to identify the underlying pathophysiology and the best treatment options. Etiology is multifactorial, with iron deficiency and cytokine activation (anemia of chronic disease) playing the most important roles. Treatment is aimed at not only restoring hemoglobin values back to normal, but also at improving the patient's symptoms, functional capacity and hopefully the outcome. Iron supplementation and erythropoietin-stimulating agents have been used for this purpose, either alone or in combination. In this review, the recent advances in elucidating the mechanisms leading to anemia in the setting of heart failure are presented and the evidence supporting the use of different treatment approaches are discussed.

Topics: Anemia; Anemia, Iron-Deficiency; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Comorbidity; Cytokines; Erythropoietin; Heart Failure; Hemodilution; Humans; Kidney Diseases; Prevalence; Prognosis

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; Chronic Disease; Disease Progression; Erythropoietin; Hemoglobins; Humans; Iron; Kidney Diseases; Prognosis; Quality of Life; Recombinant Proteins; Treatment Outcome

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; Biomarkers; Chronic Disease; Erythropoietin; Evidence-Based Medicine; Folic Acid; Hematinics; Hemoglobins; Humans; Iron; Kidney Diseases; Recombinant Proteins; Treatment Outcome; Vitamin B 12

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Cardiovascular Diseases; Charcoal; Chronic Disease; Erythropoietin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Diseases; Life Style; Mineralocorticoid Receptor Antagonists

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

Patients with chronic kidney disease (CKD) are exposed to extremely higher risks of atherothrombotic complications of the cardio- and cerebrovascular systems. In pertinent meta-analyses, overviews, editorials and comments, it has been considered unproven, on the basis of current data from randomized controlled trials, that a higher hemoglobin (Hb) value provides overall-survival benefits for CKD. At present, there is a "gray zone" between the intervention threshold of Hb < 9 g/dl and an Hb level > 13 g/dl, at which CKD is associated with a higher risk of cardiovascular events. This paper discusses in depth the hemostaseological hypothesis of increased mortality as a result of higher Hb levels during treatment of renal anemia with erythropoiesis-stimulating agents (ESA). It seems to be clearly evident that ESA activate platelets directly and indirectly, and that pathologically extended bleeding time is normalized when an Hb level of 10 g/dl is reached; from the hemostaseological perspective, a threshold level for treatment of renal anemia with ESA is thus defined. According to the present state of knowledge, an Hb target range of 10-11 g/dl seems reasonable for renal anemia; this is also compatible with current recommendations by ESA producers and the Food and Drug Administration (FDA). This target range avoids the upper and lower risk levels for Hb, and probably ensures a positive ESA effect on quality of life; it is much more cost-efficient than the target range of 11-12 g/dl recommended by the Kidney Disease Outcomes Quality Initiative (KDOQI) in 2007.

Topics: Age Factors; Aged; Anemia; Bleeding Time; Blood Transfusion; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Follow-Up Studies; Hematinics; Hemoglobinometry; Hemoglobins; Hemolysis; Humans; Kidney Diseases; Meta-Analysis as Topic; Platelet Activation; Practice Guidelines as Topic; Quality of Life; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Survival Analysis; Time Factors

Anemia is a very common clinical problem in patients with chronic kidney disease (CKD) and is associated with increased morbidity and mortality in these patients. Erythropoietin is a hormone synthesized that is deficient in the majority of patients with advanced kidney disease, thereby predisposing these patients to anemia. The other cause of anemia is deficiency of iron. Iron deficiency anemia is common in people with CKD and its importance in supporting erythropoiesis is unquestioned, especially in those patients treated with erythropoietin. Intravenous iron is frequently used to treat anemia in CKD patients and is very efficacious in increasing hemoglobin but at the same time there are some safety issues associated with it. The objective of this review is to assess the frequency of adverse drug events associated with four different iron formulations: two iron dextran products known as high and low molecular weight iron dextran, iron sucrose, and sodium ferric gluconate complex. Several electronic databases were searched. In general, with the exception of high molecular weight iron dextran, serious or life-threatening adverse events appeared rare. Iron sucrose has the least reported adverse events and high molecular weight iron dextran has the highest number of reported adverse events. Low molecular weight iron dextran and ferric gluconate fall in between these two for number of adverse drug events.

Topics: Anemia, Iron-Deficiency; Chronic Disease; Databases, Factual; Erythropoiesis; Erythropoietin; Hematinics; Hemoglobins; Humans; Iron; Kidney Diseases; Safety

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Disease Progression; Drug Design; Erythropoietin; Fibrosis; Humans; Hypoxia-Inducible Factor 1; Kidney; Kidney Diseases; Nephrology; Renin-Angiotensin System

The biology of iron in relation to anemia is best understood by a review of the iron cycle, since the majority of iron for erythropoiesis is provided by iron recovered from senescent erythrocytes. In iron-deficiency anemia, storage iron declines until iron delivery to the bone marrow is insufficient for erythropoiesis. This can be monitored with clinical indicators, beginning with low plasma ferritin, followed by decreased plasma iron and transferrin saturation, and culminating in red blood cells with low-Hb content. When adequate dietary iron is provided, these markers show return to normal, indicating a response to the dietary supplement. Anemia of inflammation (also known as anemia of chronic disease, or ACD) follows a different course, because in this form of anemia storage iron is often abundant but not available for erythropoiesis. The diagnosis of ACD is more difficult than the diagnosis of iron-deficiency anemia, and often the first identified symptom is the failure to show a response to a dietary iron supplement. Confirmation of ACD is best obtained from elevated markers of inflammation. The treatment of ACD, which typically employs erythropoietin (EPO) supplements and intravenous iron (i.v.-iron), is empirical and often falls shorts of therapeutic goals. Dialysis patients show a complex pattern of anemia, which results from inadequate EPO production by the kidney, inflammation, changes in nutrition, and blood losses during treatment. EPO and i.v.-iron are the mainstays of treatment. Patients with heart failure can be anemic, with incidence as high as 50%. The causes are multifactorial; inflammation now appears to be the primary cause of this form of anemia, with contributions from increased plasma volume, effects of drug therapy, and other complications of heart disease. Discerning the mechanisms of anemia for the heart failure patient may aid rational therapy in each case.

Topics: Anemia; Anemia, Iron-Deficiency; Chronic Disease; Epoetin Alfa; Erythropoietin; Female; Heart Diseases; Hematinics; Humans; Inflammation; Iron; Kidney Diseases; Male; Recombinant Proteins

After almost 20 years, anemia in chronic kidney disease (CKD) and its treatment remain the focus of multiple questions for clinicians and investigators. The optimal hemoglobin (Hb) for patients with CKD is controversial and different targets are probably required for different populations. The current literature does not support an upper Hb target >12 g/dl and there is a clear demonstration of increased risk with Hb targets >13 g/dl. With this narrow target of 11-12 g/dl, fluctuations in Hb concentration are commonly observed in patients being treated with erythropoiesis-stimulating agents (ESAs). Studies to date provide a suggestion of an association between Hb cycling and mortality, but they have been primarily exploratory in nature and clinical trials comparing treatment strategies leading to different degrees of Hb variability are needed. The great majority of incidences of pure red cell aplasia (PRCA) was associated with ESA therapy and was first recognized several years ago after a change in the formulation in which human serum albumin was eliminated and replaced by polysorbate-80 in patients on epoetin alfa (Eprex). Years later, a registry (PRIMS) was established by the health authorities as part of a reapproval of the subcutaneous route to confirm that the cause of PRCA has been eliminated. The ongoing PRIMS study is a 3-year observation period prospective multicenter and international (Europe and Australia) registry that could serve as a model for assessment of the immunogenicity profiles of currently marketed and future ESAs. The association with a change in formulation makes PRCA of interest to the biotechnology industry as well as the medical community because it raises the broader question of the potential immunogenicity of biopharmaceuticals in general.

Topics: Anemia; Chronic Disease; Epoetin Alfa; Erythropoietin; Hemoglobins; Humans; Kidney Diseases; Recombinant Proteins; Red-Cell Aplasia, Pure

Methoxy polyethylene glycol-epoetin beta (Mircera) is a continuous erythropoietin receptor activator, with a long half-life (approximately 130 hours). In patients with anaemia associated with chronic kidney disease (CKD), both on and not on dialysis, who had not previously received an erythropoiesis-stimulating agent (ESA), methoxy polyethylene glycol-epoetin beta administered intravenously or subcutaneously once every 2 weeks resulted in a smooth and steady rise in haemoglobin levels. The response rates were high (up to 97.5%) in these patients at the end of the correction period; response rates with the comparator ESAs (epoetin alfa or beta, or darbepoetin alfa) were up to 96.3%. Moreover, patients with CKD on dialysis who had previously been treated with an ESA maintained stable haemoglobin levels (within +/-1 g/dL of baseline and within a range of 10-13.5 g/dL) when directly converted to methoxy polyethylene glycol-epoetin beta administered intravenously or subcutaneously once every 2 or 4 weeks. Methoxy polyethylene glycol-epoetin beta is generally well tolerated, with most adverse events being of mild to moderate severity, consistent with the co-morbidities known to occur in this patient group and those reported with other ESAs. In conclusion, in patients with anaemia associated with CKD, subcutaneous or intravenous methoxy polyethylene glycol-epoetin beta achieved a high haemoglobin response rate (ESA-naive patients) when administered once every 2 weeks and maintained stable haemoglobin levels (patients previously treated with ESAs) when administered once monthly.

Topics: Anemia; Chronic Disease; Clinical Trials, Phase III as Topic; Drug Costs; Economics, Pharmaceutical; Erythropoietin; Hematinics; Humans; Kidney Diseases; Polyethylene Glycols; Recombinant Proteins

Endocrine abnormalities are common in patients with chronic kidney disease (CKD) and lead to sexual dysfunction, anemia, hyperparathyroidism, and altered mineral metabolism. Common clinical problems include disturbances in menstruation in women, erectile dysfunction in men, and decreased libido and infertility in both sexes. Organic factors tend to be prominent and are related to uremia and other comorbid illnesses. Psychological factors and depression may exacerbate the primary problem. Alterations in the hypothalamic-pituitary axis are seen early in CKD and tend to worsen after patients start dialysis. Hypogonadism plays a dominant role in male sexual function, whereas changes in hypothalamic-pituitary function predominate in female sexual dysfunction. In patients on dialysis, treatment strategies include optimizing dose of dialysis, correction of anemia with erythropoietin, and correction of hyperparathyroidism. Successful kidney transplantation may restore normal sexual function, especially in younger patients.

Topics: Androgens; Chronic Disease; Erythropoietin; Female; Hormone Replacement Therapy; Humans; Hypogonadism; Kidney Diseases; Kidney Transplantation; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Recombinant Proteins; Sexual Dysfunction, Physiological; Sildenafil Citrate; Sulfones; Testosterone

Anemia is a well recognized complication of chronic kidney disease and is associated with significant morbidity. It is important for clinical care to identify appropriate treatments and targets for hemoglobin. This review describes current understandings of the treatment of anemia using the most recent published articles.. Numerous studies, including observational and randomized control trials, of varying sizes and using both surrogate and hard outcomes have been published. On balance, there is little to support normalization of hemoglobin in the chronic kidney disease population. While some studies have described harm, there are some issues related to overinterpretation based on study trial reporting. The treatment of anemia can be successfully achieved with the use of oral or intravenous iron and erythropoiten-stimulating agents. Caution should be exercised when treating those with significant cardiovascular morbidity, and those who require very high doses of erythropoiten-stimulating agents to achieve normal hemoglobin.. Large observational population-based studies continue to demonstrate the association of low hemoglobin with adverse outcomes, and randomized control trials fail to show a benefit of normalized hemoglobin. Anemia therapy does improve quality of life. In the current era of aggressive chronic kidney disease management, it does not appear that anemia therapy attenuates left ventricular growth or changes cardiovascular outcomes.

Topics: Anemia; Chronic Disease; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Diseases; Treatment Outcome

The recombinant human erythropoietins epoetins alfa and beta have relatively short half-lives ( approximately 24 h by subcutaneous route) and have traditionally been administered 2 or 3 times a week for the treatment of anaemia in patients with chronic kidney disease. However, multiple weekly injections are inconvenient for both the patient and the healthcare provider. With the introduction of the longer-acting erythropoiesis-stimulating agent darbepoetin alfa, there has been growing interest in longer dosing intervals for erythropoiesis-stimulating agents. Data from several randomized studies have shown that darbepoetin alfa is effective in maintaining haemoglobin levels when administered (subcutaneously, intravenously or both) every 2 weeks in dialysis patients, and every 2 weeks or monthly in patients with chronic kidney disease not yet receiving dialysis. Moreover, intravenous administration with darbepoetin alfa does not require a higher dosage compared with the subcutaneous route. Epoetins alfa and beta have also been studied in similar schedules, although few data from well-designed studies are available. Current data suggest that once-weekly administration of these forms of epoetin is feasible in dialysis patients, but dose increases are often required when switching patients from traditional twice- or thrice-weekly schedules. Also, administration of epoetins every other week is feasible in selected patients with chronic renal insufficiency. Further study is required to clarify the optimum schedule for epoetins in these settings.

Topics: Anemia; Chronic Disease; Clinical Trials as Topic; Economics, Pharmaceutical; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Diseases; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Topics: Anemia; Chronic Disease; Comorbidity; Erythropoiesis; Erythropoietin; Hemoglobins; Humans; Iron; Kidney Diseases; Nephrology

The 39th Annual Meeting of the American Society of Nephrology was held in San Diego, California, U.S.A., November 16-19, 2006. This meeting offered the latest findings in basic and clinical nephrology science and was attended by around 13,000 nephrologists from around the world. Recent data on anemia management in chronic kidney disease (CKD) patients and the results with new drugs for the treatment of renal anemia that are under development, such as the continuous erythropoietin receptor activator (CERA) or Hematide were presented. The more recent results of the Dialysis Outcomes and Practice Patterns Study (DOPPS), a large multinational, prospective observational study in hemodialysis patients were also discussed. The additional antiproteinuric effects of high doses of angiotensin AT(1) receptor antagonists in patients with diabetic nephropathy were demonstrated. Recent studies that evaluated the efficacy and safety of new immunosuppressive strategies with low doses or without calcineurin inhibitors in renal transplant recipients were also reviewed during the congress.

Topics: Anemia; Animals; Erythropoietin; Humans; Kidney Diseases; Kidney Transplantation; Renal Dialysis; Treatment Outcome

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

Anaemia is common after solid organ transplantation. Although many impressive experimental data about the organoprotective properties of erythropoietin (EPO) have been reported, there are only scant clinical and experimental data about EPO use after solid organ transplantation. Since the treatment targets of anaemia in chronic kidney disease cannot be transferred to organ recipients for several reasons (rejection, immunosuppression, infection), the recommendations for optimal targets in the treatment of anaemia remain uncertain. Moreover, further studies will be necessary to clarify whether EPO administration might have haemoglobin-independent beneficial effects.

Topics: Anemia; Chronic Disease; Endothelial Cells; Erythropoietin; Heart Transplantation; Hemoglobins; Humans; Kidney Diseases; Kidney Transplantation; Liver Transplantation; Organ Transplantation; Pilot Projects; Recombinant Proteins; Risk; Stem Cells; Treatment Outcome

C.E.R.A., a continuous erythropoietin receptor activator, has been developed for the treatment of anaemia in patients with chronic kidney disease. Compared with other erythropoiesis-stimulating agents, C.E.R.A. has a unique pharmacological profile, including a longer elimination half-life and slower clearance rate. This allows C.E.R.A. to be administered at extended intervals up to once every month. Phase III clinical trials have shown that C.E.R.A. once every 2 weeks corrects anaemia in erythropoiesis-stimulating agent-naive patients who are on or are not on dialysis, whereas once-monthly C.E.R.A. maintains stable haemoglobin levels when patients are directly converted from more frequent epoetin or darbepoetin alpha administration. C.E.R.A. is well tolerated. This review summarises clinical data on C.E.R.A. and discusses the potential effect of this novel agent on clinical practice.

Topics: Anemia; Chronic Disease; Clinical Trials as Topic; Erythropoietin; Hematinics; Humans; Kidney Diseases; Polyethylene Glycols; Recombinant Proteins; Treatment Outcome

Renal anemia is a well-recognized complication of chronic kidney disease (CKD), and the deficiency of erythropoietin (EPO) is the primary cause. Observational population-based studies continue to demonstrate the association of low hemoglobin with adverse outcomes, and renal failure, cardiac failure, and anemia all may interact to cause or worsen each other, the so-called cardio-renal anemia syndrome. Treatment of anemia can be successfully achieved with the use of erythropoiesis-stimulating agents (ESAs). From a mechanistic point of view, however, the therapeutic benefits of ESA could be far beyond the correction of anemia. ESA modulates a broad array of cellular processes that include progenitor stem cell development, cellular integrity, and angiogenesis. A pleiotropic effect of EPO has been shown in the central nervous system, the cardiovascular system, and the kidney. While recent results of randomized controlled trials have established that there is little support for normalizing hemoglobin in CKD patients, the results of these studies do not negate renoprotective effects of EPO. A large number of patients with CKD will benefit from early recognition and appropriate correction of anemia with ESA.

Topics: Anemia; Cardiotonic Agents; Chronic Disease; Erythropoiesis; Erythropoietin; Humans; Kidney; Kidney Diseases; Neuroprotective Agents

In patients with primary as well as secondary chronic kidney disease (CKD), anemia has been identified as an independent risk factor for progression. In these patients anemia is thought to be a surrogate parameter for tissue hypoxia that perpetuates preexisting renal tissue injury, and treatment of anemia with recombinant human erythropoietin (rHuEPO) was therefore expected to retard progression. However, results of recently published large trials in patients with CKD did not fulfill these expectations. The reason for the discrepant findings may be distinct molecular pathways and/or EPO tissue receptor affinities that mediate the effect of EPO on erythropoiesis and tissue protection by EPO. A pivotal intracellular pathway is the activation of Akt (i.e., serine/threonine protein kinase B), but further potential pathways have been identified that may play an important role in tissue protection. In this study, we review data on the non-hematological effects of rHuEPO in different experimental settings of acute and chronic kidney injury, and discuss clinical renoprotective strategies with rHuEPO or analogue substances that are not related to anemia correction.

Topics: Animals; Chronic Disease; Disease Progression; Erythropoietin; Humans; Kidney; Kidney Diseases; Receptors, Erythropoietin; Recombinant Proteins; Regeneration

Anemia is a frequently encountered problem of chronic kidney disease (CKD) and deteriorates as renal function declines. Anemia increases the risk of death in CKD patients with diabetes and hypertension, which are the 2 leading causes of CKD. Recent studies suggest that correction of anemia improves patient quality of life and may delay the progression to end-stage renal disease. Anemia is often only treated in the late stages of CKD or after the initiation of renal replacement therapy. Thus, anemia of CKD is often unnoticed and lacks appropriate treatment. To practically manage high-risk patients with CKD and its associated cardiovascular diseases, it is mandatory to diagnose and appropriately treat anemia of CKD earlier. The optimal level of hemoglobin for greatest clinical benefit is unclear, but at present, it is recommended to remain > or = 11 g/dL. This paper provides recommendations for the diagnosis and management of anemia associated with CKD based on international practice guidelines.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Humans; Kidney Diseases

Stage 3 chronic kidney disease (CKD), which is characterized by a glomerular filtration rate of 30 to 60 mL/min/1.73 m2 (reference range, 90-200 mL/min/1.73m2 for a 20-year-old, with a decrease of 4 mL/min per decade), affects approximately 8 million people in the United States. Anemia is common in patients with stage 3 CKD and, if not corrected, contributes to a poor quality of life. Erythropoiesis-stimulating agents (ESAs), introduced almost 2 decades ago, have replaced transfusions as first-line therapy for anemia. This review summarizes the current understanding of the role of ESAs in the primary care of patients with anemia of CKD and discusses pharmacological and pharmacoeconomic issues raised by recent data. Relevant studies in the English language were identified by searching the MEDLINE database (1987-2006). Two ESAs are currently available in the United States, epoetin alfa and darbepoetin alfa. More frequent dosing with epoetin alfa is recommended by the labeled administration guidelines because it has a shorter half-life than darbepoetin alfa. Clinical experience also supports extended dosing intervals for both these ESAs. Use of ESAs in the management of anemia of CKD is associated with improved quality of life, increased survival, and decreased progression of renal failure. Some evidence suggests that ESAs have a cardioprotective effect. However, correction of anemia to hemoglobin levels greater than 12 g/dL (to convert to g/L, multiply by 10) appears to increase the risk of adverse cardiac outcomes and progression of kidney disease in some patients. The prescription of ESAs in the primary care setting requires an understanding of the accepted use of these agents, the associated pharmacoeconomic challenges, and the potential risks. This review considers the need to balance effective ESA dosing intervals against the potential risks of treatment.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Disease Progression; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Ferric Compounds; Ferritins; Heart Failure; Hematinics; Humans; Kidney Diseases; Physician's Role; Primary Health Care; Quality of Life; Recombinant Proteins

The kidney is sensitive to changes in oxygen delivery. This sensitivity has the merit of facilitating the kidneys in their adjustment of erythropoietin (EPO) production to changes in oxygen supply. The main determinant of EPO synthesis is the transcriptional activity of its gene in kidneys, which is related to local oxygen tensions. Regulation of EPO production is mediated by hypoxia-inducible factor (HIF). When local oxygen tension decreases, accumulated HIF binds to the key sequence of the EPO gene, the hypoxia-responsive element (HRE), and activates transcription of EPO. HIF consists of a constitutive beta-subunit and one of alternative oxygen-regulated HIF alpha-subunits (HIF-1alpha, HIF-2alpha, and HIF-3alpha), and HIF-2alpha is responsible for erythropoietin production. However, the high sensitivity to changes in oxygen tension also makes the kidney prone to hypoxic injury. Severe energy depletion and subsequent activation of a number of critical alterations in metabolism occurs under hypoxic conditions. Hypoxia is also a profibrogenic stimulus. In addition to ischemic acute renal failure, hypoxia can also play a crucial role in the development of nephrotoxic acute kidney injury, radiocontrast nephropathy, and acute glomerulonephritis. Furthermore, accumulating evidence suggests that chronic hypoxia is a final common pathway to end-stage kidney failure in chronic kidney disease. Given that renal hypoxia has pivotal roles on the development and progression of both acute and chronic kidney disease, hypoxia can be a valid therapeutic target for chronic kidney disease. Activation of HIF leads to expression of a variety of adaptive genes in a coordinated manner. Studies utilizing HIF-stimulating agents proved efficacy in various kidney disease models, suggesting that HIF activation is an ideal target of future therapeutic approaches.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cobalt; Erythropoietin; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Iron Chelating Agents; Kidney; Kidney Diseases; Oxygen; Signal Transduction

Renal ischemia-reperfusion (I-R) contributes to the development of ischemic acute renal failure (ARF). Multi-factorial processes are involved in the development and progression of renal I-R injury with the generation of reactive oxygen species, nitric oxide and peroxynitrite, and the decline of antioxidant protection playing major roles, leading to dysfunction, injury, and death of the cells of the kidney. Renal inflammation, involving cytokine/adhesion molecule cascades with recruitment, activation, and diapedesis of circulating leukocytes is also implicated. Clinically, renal I-R occurs in a variety of medical and surgical settings and is responsible for the development of acute tubular necrosis (a characteristic feature of ischemic ARF), e.g., in renal transplantation where I-R of the kidney directly influences graft and patient survival. The cellular mechanisms involved in the development of renal I-R injury have been targeted by several pharmacological interventions. However, although showing promise in experimental models of renal I-R injury and ischemic ARF, they have not proved successful in the clinical setting (e.g., atrial natriuretic peptide, low-dose dopamine). This review highlights recent pharmacological developments, which have shown particular promise against experimental renal I-R injury and ischemic ARF, including novel antioxidants and antioxidant enzyme mimetics, nitric oxide and nitric oxide synthase inhibitors, erythropoietin, peroxisome-proliferator-activated receptor agonists, inhibitors of poly(ADP-ribose) polymerase, carbon monoxide-releasing molecules, statins, and adenosine. Novel approaches such as recent research involving combination therapies and the potential of non-pharmacological strategies are also considered.

Topics: Acute Kidney Injury; Animals; Antioxidants; Erythropoietin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Kidney; Kidney Diseases; Nitric Oxide; Nitric Oxide Synthase; Peroxisome Proliferator-Activated Receptors; Poly(ADP-ribose) Polymerase Inhibitors; Purinergic P1 Receptor Agonists; Reactive Nitrogen Species; Reactive Oxygen Species; Receptors, Lysosphingolipid; Recombinant Proteins; Reperfusion Injury

Anemia is prevalent in patients with chronic kidney disease (CKD) and is a risk factor for poor disease outcome. Anemia acts as a risk multiplier, significantly increasing the risk of death in anemic versus nonanemic CKD patients with similar comorbidities. Erythropoiesis-stimulating agents (ESA) are a mainstay for the treatment of anemia in renal patients on dialysis, but recent data suggests that earlier treatment of anemia in CKD may delay the onset of end-stage renal disease (ESRD) and decrease mortality. Nonetheless, anemia of CKD is under-recognized and undertreated during the period before initiation of dialysis, when anemia correction may have the greatest impact on disease outcome. This report describes anemia in CKD and its association with diabetes, cardiovascular disease, and poor disease outcome, and offers suggestions for the recognition and treatment of anemia of CKD in the primary care setting.

Topics: Algorithms; Anemia; Comorbidity; Diabetic Nephropathies; Disease Progression; Erythropoiesis; Erythropoietin; Ferritins; Humans; Hypertension; Kidney Diseases; Oxidative Stress; Primary Health Care; Quality of Life; Recombinant Proteins; Risk Factors

Pharmacologic interventions for the prevention and therapy of acute kidney injury (AKI) can be roughly divided into 2 main strategies: Optimising renal perfusion and modulation of intrarenal pathophysiological mechanisms, i.e. formation of free oxygen radicals, inflammation, tubular cast formation and renal (tubular) regeneration. Improvement of impaired renal perfusion can be achieved by optimising systemic haemodynamics by volume expansion and the appropriate use of inotropes and/or vasopressors. Up to now prospective randomised controlled trials on selective renal vasodilatation have turned out rather unsuccessful, with the exception of the adenosine antagonist theophylline, in certain indications like drug-induced renal failure or contrast nephropathy. Studies in humans on pharmacological interventions interfering with intrarenal pathophysiological mechanisms of AKI are also sparse. Investigated compounds comprise N-acetyl-cysteine, mannitol and antioxidants like selenium or vitamin C. The results are heterogeneous and a significant beneficial effect of either substance could not yet be convincingly demonstrated.

Topics: Acute Kidney Injury; Antioxidants; Contrast Media; Diuretics; Diuretics, Osmotic; Erythropoietin; Humans; Kidney Diseases; Mannitol; Multicenter Studies as Topic; Prospective Studies; Randomized Controlled Trials as Topic; Reactive Oxygen Species; Regeneration; Renal Circulation; Theophylline; Vasoconstrictor Agents; Vasodilator Agents

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

Most patients with chronic kidney disease eventually become anemic. We should view the management of anemia in these patients as part of the overall management of the many clinically relevant manifestations of chronic kidney disease. Erythropoiesis-stimulating agents (ESAs) are safe and should be used, as treating anemia may forestall some of the target-organ damage of chronic kidney disease.

Topics: Anemia; Anemia, Iron-Deficiency; Chronic Disease; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Iron; Kidney Diseases; Practice Guidelines as Topic; Recombinant Proteins; Renal Dialysis

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

A greatly expanded understanding of the biology of endogenous erythropoietin (EPO) has emerged since the early 1990s. Originally viewed as the renal hormone dedicated to erythrocyte production, it is now clear that EPO is produced locally by many other tissues in response to physical or metabolic stress. In its autocrine-paracrine roles, EPO mediates preconditioning (ischemic tolerance) and specifically limits the destructive potential of tumor necrosis factor alpha and other proinflammatory cytokines in the brain, heart, kidney, and other tissues. As local production of EPO is generally suppressed following injury, administration of exogenous EPO has been a successful therapeutic approach in preclinical and clinical studies, for example, following ischemia-reperfusion and toxin-induced renal injuries, and in human stroke. The therapeutic time window of tissue protection by EPO is typically very wide in experimental models, showing effectiveness when administered before, during, or after an insult and raising optimism for a high clinical potential. Although there is progress in understanding the signaling pathways responsible for EPO's tissue-protective actions that are similar to, but not as redundant as, those employed for erythrocyte maturation, much work remains to be carried out. Experimental observations also suggest the existence of EPO receptor (EPOR) isoforms mediating EPO's diverse biological activities and have identified a tissue-protective receptor complex consisting of the EPOR and the beta common receptor (CD131) subunit that is also employed by granulocyte-macrophage colony-stimulating factor, interleukin-3 and interleukin-5. Successfully engineered analogues of EPO that selectively activate tissue protection without stimulating hematopoiesis confirm the concept of a tissue-protective receptor and have significant potential utility in the investigational and therapeutic arenas.

Topics: Animals; Endothelium, Vascular; Erythropoietin; Humans; Kidney; Kidney Diseases; Reperfusion Injury

Many patients with congestive heart failure (CHF) fail to respond to maximal CHF therapy and progress to end stage CHF with many hospitalizations, poor quality of life (QoL), progressive chronic kidney disease (CKD) which can lead to end stage kidney disease (ESKD), or die of cardiovascular complications within a short time. One factor that has generally been ignored in many of these people is the fact that they are often anemic. The anemia in CHF is due mainly to the frequently-associated CKD but also to the inhibitory effects of cytokines on erythropoietin production and on bone marrow activity, as well as to their interference with iron absorption from the gut and their inhibiting effect on the release of iron from iron stores. Anemia itself may further worsen cardiac and renal function and make the patients resistant to standard CHF therapy. Indeed anemia in CHF has been associated with increased severity of CHF, increased hospitalization, worse cardiac function and functional class, the need for higher doses of diuretics, progressive worsening of renal function and reduced QoL. In both controlled and uncontrolled studies of CHF, the correction of the anemia with erythropoietin (EPO) and oral or intravenous (IV) iron has been associated with improvement in many cardiac and renal parameters and an increased QoL. EPO itself may also play a direct role in improving the heart unrelated to the improvement of the anemia--by reducing apoptosis of cardiac and endothelial cells, increasing the number of endothelial progenitor cells, and improving endothelial cell function and neovascularization of the heart. Anemia may also play a role in the worsening of acute myocardial infarction and chronic coronary heart disease (CHD) and in the cardiovascular complications of renal transplantation. Anemia, CHF and CKD interact as a vicious circle so as to cause or worsen each other- the so-called cardio renal anemia syndrome. Only adequate treatment of all three conditions can prevent the CHF and CKD from progressing.

Topics: Anemia; Cardiology; Chronic Disease; Erythropoietin; Heart Failure; Humans; Interdisciplinary Communication; Iron; Kidney Diseases; Nephrology; Syndrome

Rituximab, a monoclonal antibody directed against the CD20 molecule found on pre-B cells and mature B cells (but not on plasma cells), was introduced in the late 1990s for the treatment of non-Hodgkin's lymphoma. Recently, this antibody has been used to treat autoimmune diseases, especially those associated with a prominent humoral component and with potentially pathogenic autoantibodies. Small cohort studies have indicated that rituximab could have an important role in the management of these disorders. Rituximab has also been utilized in the transplant setting, to diminish levels of alloreactive antibodies in highly sensitized patients, to manage ABO-incompatible transplants, and to treat rejection associated with B cells and antibodies. The exact mechanism by which rituximab exerts its effects in autoimmunity and transplantation remains unclear, as specific autoantibody or alloantibody levels often seem not to diminish in parallel with clinical improvement. A role for rituximab in depleting B cells and compromising their antigen-presenting function seems likely; rituximab might also inhibit T-cell activation. A synergistic effect has been noted in vitro following administration of corticosteroids to B-cell lines, with accentuation of B-cell cytotoxicity; this observation might be relevant to certain studies, as some regimens have utilized both agents simultaneously. This article reviews the current use of rituximab in renal disease and transplantation, and includes discussion of the drug's potential role in novel therapeutic protocols.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Erythropoietin; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Graft Rejection; Humans; Immunologic Factors; Kidney Diseases; Kidney Transplantation; Lupus Erythematosus, Systemic; Lymphoproliferative Disorders; Recombinant Proteins; Red-Cell Aplasia, Pure; Rituximab; Vasculitis

Until recently the major physiological function of erythropoietin (EPO) was thought to be the induction of erythropoiesis. However, a growing body of evidence indicates that EPO has tissue-protective properties and prevents ischemia induced tissue damage in several organs including the kidney. A pivotal intracellular pathway mediating the beneficial effects of EPO is the activation of Akt, i.e. serine/threonine protein kinase B. As a result, Akt phosphorylates the proapoptotic factor Bad, which in turn causes inhibition of programmed cell death (apoptosis). In the present article we review data on the non-hematological effects of recombinant human EPO (rHuEPO) in different experimental settings of acute and chronic kidney injury, and discuss clinical renoprotective strategies with rHuEPO or analogues substances that are not related to anemia correction.

Topics: Anemia; Erythropoietin; Humans; Kidney; Kidney Diseases; Recombinant Proteins

The major physiological function of erythropoietin is the induction of erythropoiesis. A growing body of evidence indicates, however, that this hormone has tissue-protective effects and prevents tissue damage during ischemia and inflammation. This review article summarizes the present knowledge on the cardiovascular and renal protective effects of erythropoietin and discusses the possible underlying mechanisms.

Topics: Anemia; Cell Differentiation; Cell Proliferation; Endothelial Cells; Erythropoietin; Humans; Kidney Diseases; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Recombinant Proteins; Signal Transduction; Stem Cells

The purpose of this study was to review and analyze current research to evaluate the dose ratio of epoetin alfa and darbepoetin alfa for the treatment of anemia in chronic kidney disease (CKD) and to identify determinants of the variation in epoetin alfa:darbepoetin alfa dose ratios across studies.. A systematic review of the literature for comparative switch and non-switch studies of epoetin alfa and darbepoetin alfa treatments in CKD for the period 2000-2005 was performed. Two reviewers independently assessed the quality of the information. Data on the study design and outcomes were collected for each selected study. The dose ratio from epoetin alfa to darbepoetin alfa was calculated for each study, and the results were reported stratified by study characteristics. To control for differences in study design and characteristics that could explain the variability in the relative dosages of the two agents across studies, multivariate regression analysis was conducted. Based on these results, a dose conversion ratio for Canada was estimated.. A total of 21 studies involving 16 378 patients exposed to epoetin alfa or darbepoetin alfa in CKD were identified. Univariate analysis of the dose ratios indicated a mean dose ratio of 217:1 (IU of epoetin alfa:mug of darbepoetin alfa). Results from the multivariate analysis demonstrated that the study design (i.e., switch study versus straight comparison studies) and geographical coverage (i.e., United States) affected the results. Based on the multivariate analysis, the dose conversion ratio between epoetin alfa and darbepoetin alfa for Canada was 169:1.. Despite limitations associated with switching studies and the limited total number of studies available, this systematic review based on aggregated results provides further evidence to the clinical community that the dose conversion ratio for epoetin alfa:darbepoetin alfa in CKD patients in Canada is approximately 169:1. At that ratio, treatment with epoetin alfa is 11-18% cheaper than treatment with darbepoetin alfa in Canada.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Humans; Kidney Diseases; Multivariate Analysis; Recombinant Proteins

Topics: Anemia; Anti-Bacterial Agents; Erythropoietin; Humans; Immunoassay; Kidney Diseases; Recombinant Proteins; Red-Cell Aplasia, Pure; Sensitivity and Specificity

Recombinant human erythropoietin (epoetin) was first used for the treatment of anemia resulting from renal disease in 1986. During the first 10 years of its use, there were only three cases of epoetin-induced antibodies reported, which resulted in pure red cell aplasia (PRCA). Between 1998 and 2002, 191 chronic kidney disease patients developed PRCA during the course of epoetin treatment. Clinical characteristics of patients with PRCA include an absolute resistance to epoetin therapy, with a rapid development of severe anemia and very low reticulocyte count. In addition, patients developed high titre, high affinity neutralizing antibodies, which are detectable by immunoassays. The diagnosis of PRCA requires the onset of severe anemia, erythropoietin neutralizing antibodies in circulation, the lack of red cell precursors in the bone marrow aspirate, and normal to elevated transferrin saturation. Patients require blood transfusions to maintain an acceptable level of hemoglobin. Cessation of epoetin treatment alone does not improve PRCA. Patients have required immunosuppressive treatment. However, the most efficacious treatment has been kidney transplantation accompanied by immunosuppressive agents that prevent organ rejection. Evaluating patients receiving recombinant epeoetin therapy who experience a sudden loss of epoetin efficacy for the possibility of antibody-mediated PRCA is crucial. Timely identification and treatment of this rare syndrome can prevent the development of severe red blood cell transfusion requirements and the potential complications of iron overload, which results from these transfusions.

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

In 2002, investigators from France reported 13 patients in whom pure red cell aplasia developed during treatment with recombinant human erythropoietin (epoetin). We reviewed 208 cases of this syndrome reported worldwide. Adverse event reports describing suspected and confirmed cases of epoetin-associated PRCA in websites maintained by the manufacturers and distributors of epoetin products and other publicly available sources were reviewed. Cases were reported from countries in Europe, North America, Asia, Australia and the United States (US). For >95% of the cases, EPREX had been administered subcutaneous to persons with chronic kidney disease (CKD) and anemia for a mean of nine months prior to diagnosis of PRCA. For 80% of persons with the syndrome, reversal of antibody production and recovery of reticulocytes occurred with discontinuation of epoetin and treatment with immunosuppressive agents. Patients with anemia of CKD who developed neutralizing anti-erythropoietin antibodies and pure red cell aplasia during treatment with epoetin have been identified in a number of countries. In non-US countries, switching renal dialysis patients from subcutaneous to intravenous administration of epoetin alpha and improved handling of the drug appear to have been successful strategies for reducing the occurrence of this toxicity. The decrease in cases occurred coincident with these varied changes, although it is difficult to prove causality. PRCA is a rare, but important side effect of epoetin therapy.

Topics: Adverse Drug Reaction Reporting Systems; Antibodies; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins; Red-Cell Aplasia, Pure

Erythropoiesis-stimulating agents have dramatically changed the management of renal anaemia since their introduction almost 20 years ago. However, optimal dosing route and frequency are still a matter of debate. Intravenous application of recombinant human erythropoietin should be limited to haemodialysis patients and must be given three times weekly, as any reduction to this dosing frequency leads to a major increase in dose requirements. Administering recombinant human erythropoietin-beta once weekly via the subcutaneous route is effective. If conversion from the subcutaneous to the intravenous route is required, dose requirements for recombinant human erythropoietin therapy remain a subject of discussion.

Topics: Anemia; Chronic Disease; Drug Administration Schedule; Erythropoiesis; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Despite clinical practice guidelines for the management of anaemia of chronic kidney disease and a growing literature concerning the treatment of renal anaemia in diverse patient groups, there remain uncertainties over definitions and descriptions for optimal management of renal anaemia. The patients most likely to derive the greatest long-term benefit from correction of anaemia are those with chronic kidney disease who are pre-dialysis. Early intervention to correct anaemia has the potential to impact on the progression of chronic kidney disease and affect patient morbidity, hospitalization rates, quality of life and mortality. This review considers current guidance on anaemia management, the evidence behind the guidance and the data shortfalls in an attempt to provide a topical overview of current understanding and future directions for optimal management of renal anaemia, particularly in high-risk groups.

Topics: Anemia; Chronic Disease; Erythropoietin; Hemoglobins; Humans; Iron; Kidney Diseases; Referral and Consultation; Renal Dialysis

Resistance to erythropoiesis-stimulating agents (ESA) in patients with chronic kidney disease (CKD) can be associated with evidence of enhanced systemic inflammatory responses. This review considers the inflammatory mechanisms thought to be involved in the development and aetiology of anaemia of CKD that may help our understanding and management of patients with ESA resistance. The potential role of nutritional support and of anti-inflammatory therapies in managing resistance to ESA therapy is discussed and explored.

Topics: Anemia; Anti-Inflammatory Agents; Antioxidants; Chronic Disease; Drug Resistance; Erythropoiesis; Erythropoietin; Ferritins; Humans; Inflammation; Iron; Kidney Diseases; Nitric Oxide; Nutritional Support; Reactive Oxygen Species; Recombinant Proteins

Anemia is a common and debilitating condition in patients with chronic kidney disease and patients with cancer. Over the last 10 to 15 years, the introduction of erythropoietic therapy has transformed the management of anemia in both these conditions. The first therapeutic agent to be used for the stimulation of erythropoiesis was recombinant human erythropoietin (epoetin). At the turn of this century, darbepoetin alfa, a second-generation erythropoietic agent, became available. Darbepoetin alfa contains two additional N-linked carbohydrate chains, which confer greater metabolic stability in vivo. More recently, a third-generation molecule, Continuous Erythropoietin Receptor Activator (CERA), incorporating a large polymer chain, has been developed. CERA has an elimination half-life in humans that is considerably longer than the half-life of either epoetin or darbepoetin alfa. CERA may also have different receptor binding characteristics and pharmacology from other erythropoietic agents; these characteristics are the subject of ongoing investigation. CERA is currently in phase III clinical trials.

Topics: Adolescent; Adult; Anemia; Animals; Clinical Trials as Topic; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Half-Life; Humans; Kidney Diseases; Neoplasms; Polyethylene Glycols; Receptors, Erythropoietin; Recombinant Proteins

The glycoprotein hormone erythropoietin (EPO) is an essential growth and survival factor for erythroid progenitor cells, and the rate of red blood cell production is normally determined by the serum EPO concentration. EPO production is inversely related to oxygen availability, so that an effective feedback loop is established, which controls erythropoiesis. Since recombinant EPO became available as an effective therapeutic agent, significant progress has also been made in understanding the basis of this feedback control. The main determinant of EPO synthesis is the transcriptional activity of its gene in liver and kidneys, which is related to local oxygen tensions. This control is achieved by hypoxia-inducible transcription factors (HIF), consisting of a constitutive beta-subunit and one of two alternative oxygen-regulated HIFalpha subunits (HIF-1alpha and HIF-2alpha). In the presence of oxygen (normoxia) the HIFalpha subunits are hydroxylated, which targets them for proteasomal degradation. Under hypoxia, because of the lack of molecular oxygen, HIF cannot be hydroxylated and is thereby stabilized. Although HIF-1alpha was the first transcription factor identified through its ability to bind to an enhancer sequence of the EPO gene, more recent evidence suggests that HIF-2alpha is responsible for the regulation of EPO. Although EPO is a prime example for an oxygen- regulated gene, the role of the HIF system goes far beyond the regulation of EPO, because it operates widely in almost all cells and controls a broad transcriptional response to hypoxia, including genes involved in cell metabolism, angiogenesis and vascular tone. Further evidence suggests that apart from its effect as an erythropoietic hormone EPO acts as a paracrine, tissue-protective protein in the brain and possibly also in other organs.

Topics: Erythropoiesis; Erythropoietin; Gene Expression Regulation; Humans; Hypoxia; Kidney; Kidney Diseases; Oxygen; Transcription Factors

Somatic cell gene therapy has made considerable progress last five years and has shown clear success in some clinical trials. In the field of nephrology, both the elucidation of pathophysiology of renal diseases and the development of gene transfer technique have become driving force for new therapy of incurable renal diseases, such as Alport syndrome and polycystic kidney disease. Gene therapy of renal cancer, although its application is limited to advanced cancer, is the front-runner of clinical application. Erythropoietin gene therapy has provided encouraging results for the treatment of anemia in uremic rats and recently progressed to the inducible one in response to hypoxia. Gene therapy for glomerulonephritis and renal fibrosis showed prominent impact on experimental models, although the safety must be confirmed for prolonged treatment. Transplant kidney is an ideal material for gene modification and induction of tolerance in the transplant kidney is an attractive challenge. Emerging techniques are becoming available such as stem cell technology and messenger RNA silencing strategies. We believe that the future of gene therapy research is exciting and promising and it holds an enormous potential for clinical application.

Topics: Adenoviridae; Anemia; Erythropoietin; Fibrosis; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Glomerulonephritis; Humans; Kidney Diseases; Kidney Transplantation; Lentivirus; Polycystic Kidney Diseases; Recombinant Proteins

Topics: Anemia; Autoimmune Diseases; Cell Hypoxia; Disease-Free Survival; Double-Blind Method; Erythropoietin; Heart Failure; Humans; Kidney; Kidney Diseases; Lymphoma, Non-Hodgkin; Multiple Myeloma; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins

Topics: 2,3-Diphosphoglycerate; Bisphosphoglycerate Mutase; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Hemoglobinopathies; Homeostasis; Humans; Hypoxia; Kidney Diseases; Liver Diseases; Neoplasms; Oxygen; Polycythemia; Polycythemia Vera

Derangements of iron metabolism may be present in critically ill patients who develop anemia during a stay in the intensive care unit. Iron supplementation may be appropriate, especially if an underlying nutritional disorder is present. It may be even more critical to replace iron when erythropoietin therapy is used because of the consumption of iron stores that occurs during heme synthesis. Iron therapy is not without risks, and controversy persists regarding the potential for iron overload and infections. Clinical trials that define the optimal dose, route, and timing of iron administration in critically ill patients are lacking. However, studies of iron supplementation in chronic kidney disease, pregnancy, and anemia of prematurity may provide some guidance about approaches to treatment. Clinical evidence and limitations that can assist clinicians in managing iron therapy in the intensive care unit are presented.

Topics: Administration, Oral; Adult; Anaphylaxis; Anemia; Chronic Disease; Critical Care; Dietary Supplements; Erythroblasts; Erythropoietin; Female; Humans; Infant; Infant Care; Infant, Newborn; Infant, Premature; Iron; Iron-Dextran Complex; Kidney Diseases; Pregnancy

Topics: Animals; Erythropoiesis; Erythropoietin; Humans; Hypoxia; Kidney Diseases

Despite the high prevalence and significant morbidity and mortality rates of chronic kidney disease (CKD) related to cardiovascular disease, it remains vastly understudied. Most of the current practice recommendations come from small under-powered prospective studies, retrospective reviews, and assuming patients with CKD will similarly benefit from medications and treatments as patients with normal renal function. In addition, because of the previous lack of a consistent definition of CKD and how to measure renal function, definitions of the degree of renal dysfunction have varied widely and compounded the confusion of these data. Remarkably, despite patients with CKD representing the group at highest risk from cardiovascular complications, even greater than patients with diabetes mellitus, there has been a systematic exclusion of patients with CKD from therapeutic trials. This review outlines our current understanding of CKD as a cardiovascular risk factor, treatment options, and the future directions that are needed to treat cardiovascular disease in patients with CKD.

Topics: Cardiovascular Diseases; Chronic Disease; Erythropoietin; Glomerular Filtration Rate; Humans; Hyperhomocysteinemia; Kidney Diseases; Myocardial Revascularization; Oxidative Stress; Recombinant Proteins; Risk Factors; United States

The failure to lower systolic blood pressure at night (called non-dipping) and sleep apnea are both associated with adverse cardiovascular outcomes. Sleep apnea is a common cause of non-dipping blood pressure.. Sleep apnea increases night time blood pressure through enhanced cardiac pre-load, sleep disturbance and hypoxia. Hypoxia elicits increased levels of norepinephrine, endothelin and erythropoetin. Patients with sleep apnea tend to be elderly and obese, so they have poor endothelial nitric oxide release and blunted baroreflexes. They thus have several stimuli for high blood pressure and poor compensatory mechanisms to lower blood pressure.. Non-dipping patients without sleep apnea have evidence of volume overload and correct their blood pressure pattern in response to diuretics. Individuals with sleep apnea have evidence of increased cardiac pre-load from episodes of negative intrathoracic pressure. Their daytime blood pressure responds poorly to many drugs, but beta blockers may be effective. Their night time blood pressure responds only slightly to therapy of their sleep apnea with continuous positive airway pressure, even though continuous positive airway pressure decreases their norepinephrine, erythropoetin and endothelin levels.

Topics: Blood Pressure; Blood Volume; Cardiovascular Diseases; Circadian Rhythm; Endothelins; Erythropoietin; Humans; Hypertension; Kidney Diseases; Nitric Oxide; Racial Groups; Respiration, Artificial; Sleep Apnea Syndromes; Sleep Wake Disorders

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

Anemia is a chronic condition that affects many patients with chronic kidney disease (CKD). These patients often require recombinant human erythropoietin (rHuEPO) to stimulate bone marrow to produce red blood cells. The agent often has to be administered 2-3 times/week for maximum efficacy A new product, darbepoetin-alpha, is a hyperglycosylated erythropoiesis-stimulating protein that has a longer terminal half-life than rHuEPO (25.3 vs 8.5 hrs), which allows for less frequent dosing. At an equivalent dosage as rHuEPO, darbepoetin-alpha maintains hemoglobin values within target range and has a similar adverse effect profile. It is safe and effective for treatment of anemia of CKD. Pharmacoeconomic and quality-of-life studies are warranted to determine the compound's overall benefit.

Topics: Clinical Trials as Topic; Darbepoetin alfa; Doping in Sports; Erythropoietin; Humans; Kidney Diseases; Neoplasms

Up to 10% of patients with renal disease receiving recombinant human erythropoietin (rHuEPO) therapy show poor responsiveness to the drug. Even in patients who do respond to rHuEPO, there is a marked variability in drug sensitivity. Several factors have been recognized as causing resistance to rHuEPO, notably iron deficiency, infection/inflammation, and under dialysis. However, when these factors are excluded, the wide variation in responsiveness to rHuEPO persists. The mechanism of this effect needs to be fully elucidated. One hypothesis is that patients with uraemia showing resistance to rHuEPO may have enhanced levels of immune activation, causing increased release of pro-inflammatory cytokines in the bone marrow. Uraemia is known to be a chronic inflammatory state, with some patients showing considerably increased laboratory markers of inflammation and immune activation. Chronic inflammation can modify the process of erythropoiesis, probably mediated via pro-inflammatory cytokines such as interleukin-1 (IL-1), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). The concept that rHuEPO resistance is due to enhanced levels of immune activity has been investigated by studying T-cell phenotypes using flow cytometry, as well as cytokine release from T cells and monocytes in 'good' and 'poor' responders to rHuEPO. Poor responders had significantly reduced CD28 expression on both CD4+ and CD8+ cells, enhanced IL-10 generation from peripheral blood mononuclear cells (PBMCs), higher plasma IL-12 levels, and increased TNF-alpha and IFN-gamma release from PBMCs. Anti-cytokine antibodies may be useful for studying inflammatory cytokine secretion from T cells in patients with renal failure. Strategies utilizing anti-cytokine therapy may prove to be a useful adjuvant in optimizing the response to rHuEPO therapy.

Topics: Anemia; Cytokines; Drug Resistance; Erythropoietin; Humans; Inflammation; Kidney Diseases; Recombinant Proteins; Treatment Outcome

Anemia has multiple etiologies: it may be caused by nutritional deficiencies or congenital abnormalities, or it may be associated with a number of conditions, such as chronic kidney disease, cancer, or human immunodeficiency virus (HIV) infection. Anemia is associated with an increase in morbidity and mortality in patients with endstage renal disease, cancer, or HIV infection. Each case of anemia is different, with different causes, clinical consequences, and treatment strategies. Identifying the most appropriate treatment requires an understanding of the etiology of the anemia and investigation of the nature of the causative medical condition. In some cases, such as anemia associated with chronic kidney disease, treatment is well defined and consists of administration of erythropoiesis-stimulating agents, accompanied by iron supplementation where appropriate. In other instances, such as megaloblastic anemia, which may be caused by vitamin or folate deficiency, vitamin supplementation alone may be a clinically appropriate treatment. This article gives an overview of the etiologies and current therapies of the most commonly encountered types of anemia, highlighting both the diverse nature of the condition, and the equally diverse pharmacologic and supportive treatment approaches.

Topics: Anemia; Avitaminosis; Darbepoetin alfa; Erythrocytes; Erythropoiesis; Erythropoietin; Humans; Kidney Diseases; Models, Biological

This paper describes three recent, related surveys of anaemia management practice in patients with chronic kidney disease, with particular emphasis on initiation of epoetin therapy. It also compares current practice with the European Best Practice Guidelines (EBPG) for anaemia management. The European Survey of Anaemia Management (ESAM) was a 6 month, longitudinal prospective survey of anaemia management in dialysis patients. Although most survey data concerned patients already on dialysis, some retrospective data concerned initiation of dialysis and epoetin therapy. These findings led to the Predialysis Survey of Anaemia Management (PRESAM), a cross-sectional, retrospective survey of patients beginning dialysis, focusing on referral to renal centres and anaemia management in the year preceding dialysis. The Early Renal Insufficiency Referral Survey (ERIRS) is a further cross-sectional survey currently in progress, investigating referral practices during pre-dialysis care. Collectively, these three surveys provide a wealth of data about pre-dialysis anaemia management. ESAM included data from 14527 patients, PRESAM from 4333 patients, and data from 724 patients enrolled in ERIRS have been analysed. The evidence indicates that, at the time of referral to a renal centre, most patients have haemoglobin concentrations well below the levels recommended by the EBPG. Haemoglobin concentrations are lowest in patients referred within the month prior to the initiation of dialysis. Most patients do not start epoetin treatment until dialysis is initiated, despite having haemoglobin concentrations below the level recommended by the EBPG for the initiation of epoetin. Patients who are referred earlier (i.e. those under the care of the renal centre nephrologist for more than a month before the initiation of dialysis) tend to have higher haemoglobin concentrations and are more likely to be receiving epoetin therapy. Such patients are in the minority, however, indicating that pre-dialysis anaemia management practices continue to fall short of the recommendations of the EBPG.

Topics: Anemia; Chronic Disease; Comorbidity; Erythropoietin; Humans; Kidney Diseases; Nephrology; Referral and Consultation; Renal Dialysis

In patients with chronic kidney disease (CKD), sensitivity to recombinant human erythropoietin (r-HuEPO, epoetin) is of clinical and economic importance. Insight into factors that influence sensitivity and response to epoetin is essential for the adequate management of anaemia. Some factors influencing response to epoetin, such as gender, age, length of time on dialysis, type of dialysis and co-morbidities such as haemoglobinopathy, are not susceptible to clinical intervention. However, many other factors can be controlled. Iron deficiency is the most common factor that limits the response to epoetin. Adequate monitoring of iron status and iron supplementation in patients with CKD will result in a more efficient epoetin response. Increased dialysis dose is associated with improvements in haemoglobin outcome and reduced requirements for epoetin. Dialysis water quality (both chemical and biological) is also important in determining the response to epoetin; 'ultrapure' water reduces epoetin requirements. Some patients, despite adequate epoetin and iron therapy, still have epoetin resistance (low haemoglobin and/or high epoetin requirements). Raised C-reactive protein and/or low albumin may reflect long-standing inflammatory pathology and indicate a need for investigation.

Topics: Aging; Chronic Disease; Drug Resistance; Erythropoietin; Humans; Injections, Subcutaneous; Iron Deficiencies; Kidney Diseases; Recombinant Proteins; Renal Dialysis; Sex Characteristics

It is hypothesized that anaemia contributes to the progression of renal disease via hypoxia and oxidative stress. These effects may stimulate the production of extracellular matrix by fibroblasts, increasing interstitial fibrosis and leading to tubular destruction. Recombinant human erythropoietin (r-HuEPO, epoetin) has antioxidative and anti-apoptotic properties, though these effects have yet to be demonstrated in renal cells. In theory, epoetin treatment might slow the progression of renal failure, not only by correcting anaemia but also via direct effects on tubular and vascular cell survival. Alternative hypotheses suggest, however, that epoetin could have negative effects on the kidney because of its vasoconstrictive action, which is independent of haemoglobin levels. Retrospective and prospective clinical studies clearly show that epoetin does not accelerate progression of renal disease, provided that blood pressure is well controlled. Some studies suggest that epoetin slows the progression of renal failure, although this remains a controversial issue, as all these studies have methodological limitations. Larger randomized controlled trials and meta-analysis of the existing trials are required to establish whether treatment of anaemia with epoetin can indeed slow the progression of renal disease.

Topics: Anemia; Animals; Disease Progression; Erythropoietin; Humans; Kidney; Kidney Diseases; Recombinant Proteins

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: 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

Despite the use of recombinant human erythropoietin (rh-EPO, epoetin) for more than a decade in treating renal anaemia, there is still considerable debate over optimal target haemoglobin (Hb) levels. Current European and North American guidelines that are based on decade-old trials aim for partial anaemia correction, with a subnormal target Hb concentration. More recent randomized clinical trials examining the effect of normalizing Hb levels have produced conflicting results. A study in the USA, in patients with existing congestive heart failure or ischaemic heart disease, showed an unexpected rise in cardiac mortality and haemodialysis access failure with higher Hb levels. In contrast, three other studies (in Australia, Spain and Canada) that normalized Hb levels in healthier dialysis patients observed improvements in quality of life and exercise capacity and a slower progression of left ventricular dilatation, without an unacceptable increase in the incidence of adverse effects. These studies indicate that, while higher Hb levels may be detrimental to patients with pre-existing cardiac disease, healthier patients benefit from normalized Hb levels. Thus, there is no clear scientific rationale for setting a single Hb target for all patients, and individualized treatment targets would appear to be a more logical and patient-centred approach.

Topics: Anemia; Erythropoietin; Hemoglobins; Humans; Kidney Diseases; Recombinant Proteins

By definition, idiopathic erythrocytosis (IE) applies to a group of patients characterised by having a measured RCM above their predicted normal range (an absolute erythrocytosis) and following investigation do not have a form of primary or secondary erythrocytosis. Patients with IE are heterogenous. The possibilities include physiological variation, 'early' polycythaemia vera (10-15% develop clear features of PV over a few years), unrecognized congenital erythrocytosis, unrecognized or unrecognizable secondary acquired erythrocytosis or a currently undescribed form of primary or secondary erythrocytosis. Patients are more commonly male with a median age at presentation of 55-60 years. Approximately half of the patients present with vascular occlusive complications. Retrospective evidence indicates that vascular occlusion occurs less frequently when the PCV is controlled at normal levels. Venesection is the treatment of choice to lower the PCV. As a general approach to management, all patients with a PCV above 0.54 should be venesected to a PCV less than 0.45. This target PCV should also apply to patients with lesser degrees of raised PCV who have additional other risk factors for vascular occlusion.

Topics: Aged; Arterial Occlusive Diseases; Bone Marrow; Chlorambucil; Diagnosis, Differential; Endocrine System Diseases; Erythrocyte Volume; Erythroid Precursor Cells; Erythropoietin; Genetic Predisposition to Disease; Humans; Hypoxia; Kidney Diseases; Leukemia; Leukemia, Radiation-Induced; Middle Aged; Phosphorus Radioisotopes; Polycythemia; Polycythemia Vera; Receptors, Erythropoietin; Sequence Deletion; Smoking; Stroke

Erythropoietin is distinct among the hematopoietic growth factors because it is produced primarily in the kidneys rather than the bone marrow. The kidney functions as a critmeter in that it senses oxygen tension and extracellular volume. By regulating red cell mass through erythropoietin and plasma volume through excretion of salt and water, the kidney sets the hematocrit at a normal value of 45%. This is not a random number, but a value that maximizes oxygen delivery to peripheral tissues. The ability of the kidney to coordinate these two volumes to generate a hematocrit of 45% establishes it as the logical site for erythropoietin production. The kidney has the unique ability to translate a measure of plasma volume as tissue oxygen pressure required to regulate erythropoietin production. I hypothesize that the critmeter is a functional unit that regulates the hematocrit. The critmeter is found at the tip of the juxtamedullary region of the cortical labyrinth in the kidney, where erythropoietin is made physiologically. Renal vasculature and nephron segment heterogeneity in sodium reabsorption generate the marginal tissue oxygen pressure required to trigger the production of erythropoietin. The balance of the oxygen consumption for sodium reabsorption and the oxygen delivery to the proximal tubule is reflected by the tissue oxygen pressure that determines red blood cell mass adjusted to plasma volume. Factors that affect blood supply and sodium reabsorption in a discordant manner may modulate the critmeter (eg, angiotensin II). Examples of clinical disorders caused by dysfunction or resetting of the critmeter are described.

Topics: Anemia; Animals; Erythrocytes; Erythropoietin; Female; Hematocrit; Humans; Kidney; Kidney Diseases; Male; Oxygen Consumption; Physical Exertion; Plasma Volume; Polycythemia; Renin-Angiotensin System; Sodium

The beneficial effects of treating the anaemia of dialysis-dependent patients with erythropoietin on the improvement of cardiac status, exercise capacity, cognitive function and quality of life are well established. Equally, if not more important is the reduction in morbidity and mortality that accompanies the treatment of anaemia with epoietin. These documented improvements in outcomes of care notwithstanding, mortality and morbidity due to cardiovascular disease (CVD) remain high in dialysis patients. Recent epidemiological evidence indicates that: (i) the prevalence of CVD is very high in patients at the start of dialysis; (ii) pre-existing CVD is the major risk factor for mortality and morbidity on dialysis; (iii) CVD begins early in the course of kidney disease, shows an inverse relationship to kidney function and increases in prevalence and severity with progression of kidney disease; and (iv) corrective measures, which take 3-5 years to show a favourable effect, must be instituted well before the initiation of dialysis. Hypertension and anaemia, which develop in the course of progressive reduction in kidney function, are the principal risk factors for the prevalence of left ventricular hypertrophy (LVH) in those with chronic kidney disease, and their treatment has been shown to arrest or reverse LVH in these individuals. Whereas the treatment of hypertension early in the course of kidney disease has been incorporated into clinical practice, there has been reluctance in the treatment of anaemia because of the possibility of worsening kidney function with epoietin, as shown in rats. There is now convincing evidence that epoietin has no potential adverse effect on kidney function in humans. While the most compelling reason for the early treatment of the anaemia of kidney disease is its beneficial effect on cardiovascular function, other documented potential benefits are improvements in exercise capacity, cognitive function and quality of life.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Humans; Kidney Diseases; Prevalence; Renal Replacement Therapy; Risk Factors; Time Factors

Recombinant human erythropoietin therapy has transformed the management of renal anaemia over the last decade or so. We have learned much about the optimum regimens for using this drug, including the route of administration, dosage frequency, use of iron supplementation, and management of poor response. Thus, dosage requirements of epoetin are generally lower if the drug is administered subcutaneously, and the most commonly used dosage frequency is two or three times weekly. The vast majority of patients respond very well to treatment, but approximately 5-10% of patients show some resistance to epoetin, the most common cause of which is iron deficiency. The presence of infection or inflammation and underdialysis are other important causes of a poor response to epoetin. There is increasing interest in treating renal anaemia at an earlier stage in the course of the disease, and there is much circumstantial evidence to support this strategy. This usually involves giving epoetin to pre-dialysis patients, and a study has also recently commenced to investigate the effects of preventing renal anaemia ever developing. Other erythropoietic substances are being developed, and the first of these to be ready for clinical use is novel erythropoiesis stimulating protein (NESP), which is an analogue of erythropoietin containing two extra N-linked carbohydrate side-chains. Other potential erythropoietic substances are still at the laboratory stage of development, but may be available for therapeutic use in the next decade or so.

Topics: Anemia; Drug Administration Schedule; Erythropoietin; Hemoglobins; Humans; Iron; Iron Deficiencies; Kidney Diseases; Nephrology; Treatment Outcome

Topics: Anemia; Animals; Brain Injuries; Cardiac Output, Low; Critical Illness; Erythropoietin; Gene Expression Regulation; Genetic Therapy; Humans; Kidney Diseases

Since its introduction, recombinant human erythropoietin (rHuEPO) has become the standard of care for renal anemia. Because of its relatively short half-life, however, it generally is administered two to three times per week. Darbepoetin alfa (novel erythropoiesis stimulating protein [NESP]) is a longer acting erythropoietic agent that allows less frequent dosing to treat anemia. Decreased dosing frequency should result in enhanced patient compliance and convenience and minimize the burden of frequent administration on staff. NESP is biochemically distinct from rHuEPO, having five N-linked carbohydrate chains (two more than rHuEPO). In animal studies, NESP had a half-life approximately three times longer than rHuEPO and raised hemoglobin effectively when administered less frequently than rHuEPO. NESP has been evaluated in clinical trials of dialysis and chronic kidney disease patients. Pharmacokinetic data confirmed that patients with anemia required less frequent dosing with NESP than rHuEPO. After intravenous administration, the mean elimination half-life of NESP was 25.3 hours versus 8.5 hours for rHuEPO. In patients who are rHuEPO-naive and in patients previously managed with rHuEPO, NESP is as effective as rHuEPO for maintaining hemoglobin concentration when administered intravenously or subcutaneously at a reduced frequency of once weekly or once every other week. NESP is well tolerated and has a safety profile comparable to that of rHuEPO. There have been no reports of antibody formation associated with NESP. NESP is an important new tool for physicians to use in the treatment of anemia of chronic kidney disease.

Topics: Anemia; Animals; Chronic Disease; Clinical Trials as Topic; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Half-Life; Hemoglobins; Humans; Kidney Diseases; Recombinant Proteins

Perhaps nothing in the fields of medicine and nephrology is moving more rapidly than genetics. From this movement are opportunities for discovery, new therapy, and better counseling for patients. At a level of basic science, renal medicine has been a consistent contributor to this emerging discipline, but our current approach to training in the methods and uses of human genetics probably will not keep up with the technology, nor the needs of the modern bedside practitioner. The facile use of genetics in the next century will require the construction and exploration of new disease models, rededication to human informatics, and teaching the language of molecular and population genomics.

Topics: Erythropoietin; Forecasting; Genetic Counseling; Genetic Predisposition to Disease; Genetic Therapy; Humans; Kidney Diseases; Nephrology

Topics: Anemia; Animals; Base Sequence; Erythropoietin; Gene Expression Regulation; Genetic Therapy; Humans; Kidney Diseases; Molecular Sequence Data; Polycythemia; Regulatory Sequences, Nucleic Acid

The heart and the kidney exert a reciprocal control of their function in order to maintain a steady state of haemodynamics, both in physiological and pathological conditions. The functional relationship between the two organs becomes particularly evident during heart failure. The knowledge of such relationship may play an important role in the management of heart failure. We also report here our experience in the treatment of congestive heart failure with depletive techniques vicarious of kidney function.

Topics: Blood Pressure; Erythropoietin; Heart Failure; Humans; Hypertension; Kidney Diseases; Natriuretic Agents

Topics: Anemia; Erythropoietin; Humans; Kidney Diseases; Polycythemia

An erythrocytosis describes an increased peripheral blood packed cell volume (PCV) and is deemed to be absolute or apparent depending on whether or not the measured red cell mass (RCM) is above the reference range. This reference range must be related to the individual's height and weight to avoid erroneous interpretations using ml/kg total body weight expressions in obesity. Absolute erythrocytoses are divided into primary, where the erythropoietic compartment is intrinsically abnormal, secondary, where the erythropoietic compartment is normal but is responding to external pathological events leading to an increased erythropoietin drive, and idiopathic, where neither a primary nor a secondary erythrocytosis can be established. Both primary and secondary erythrocytoses have congenital and acquired forms. The only form of primary acquired erythrocytosis that has been defined is the clonal myeloproliferative disorder, polycythaemia vera (PV). Modified diagnostic markers for PV are proposed. Thrombocytoses can be classified into primary, where megakaryopoiesis is intrinsically abnormal, secondary, where megakaryopoiesis is normal but increased platelet production is a reaction to some other unrelated pathology, and finally idiopathic. This latter new group would be used for patients not satisfying the criteria for primary or secondary thrombocytoses, if these were more precise and rigidly used than currently is the case. While theoretically congenital and acquired forms of primary and secondary thrombocytoses might exist, only one cause of secondary congenital thrombocytosis has been established, and primary congenital thrombocytosis has not yet been precisely defined. Primary (essential) thrombocythaemia (PT) is one of the forms of primary acquired thrombocytoses. The diagnostic criteria of PT traditionally involve the exclusion of secondary thrombocytoses and other myeloproliferative disorders but marrow histology could hold a key positive diagnostic role if objective histological features of PT were agreed.

Topics: Anthropometry; Bone Marrow; Bone Marrow Diseases; Cells, Cultured; Diagnostic Imaging; Diagnostic Tests, Routine; Erythrocyte Volume; Erythroid Precursor Cells; Erythropoietin; Female; Hematocrit; Hemoglobinopathies; Humans; Hypoxia; Kidney Diseases; Liver Diseases; Male; Neoplasms; Polycythemia; Receptors, Erythropoietin; Thrombocytosis

Almost all patients with end-stage renal disease suffer from renal anaemia of multifactorial pathogenesis. The use of recombinant human erythropoietin to raise the haematocrit has been a major advance in the care of patients with end-stage renal disease. The majority of these patients develop absolute or functional iron deficiency. However, the diagnosis of iron deficiency is hindered by the inaccuracy of commonly used tests. Serum ferritin and transferrin saturations are frequently used, but limitations with both parameters in end-stage renal disease patients have resulted in the development of new tests to assess iron sufficiency. The percentage of hypochromic red blood cells and particularly reticulocyte haemoglobin content are new measures of iron status in end-stage renal disease patients. An enhanced knowledge of the interpretation of available laboratory parameters will ensure that the patients receive the full benefit from their treatment with recombinant human erythropoietin and iron.

Topics: Anemia; Clinical Laboratory Techniques; Erythropoietin; Ferritins; Humans; Iron; Kidney Diseases; Recombinant Proteins; Renal Dialysis; Transferrin

Topics: Anemia; Animals; Blood Transfusion, Autologous; Erythropoietin; Humans; Kidney Diseases; Kidney Neoplasms; Male; Rats; Recombinant Proteins

Topics: Drug Resistance; Erythropoietin; Humans; Iron; Kidney Diseases; Recombinant Proteins; Renal Dialysis; Vitamins

Topics: Algorithms; Anemia; Drug Resistance; Erythropoietin; Humans; Kidney Diseases; Treatment Outcome

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Kidney Diseases; Recombinant Proteins; Renal Dialysis

Topics: Erythropoietin; Hematuria; Humans; Kidney Diseases; Low Back Pain; Nephrectomy; Renal Dialysis; Syndrome

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Feedback; Humans; Kidney Diseases; Oxygen; Receptors, Erythropoietin; Signal Transduction

Topics: Anemia; Animals; Erythropoietin; Gene Expression Regulation; Humans; Kidney; Kidney Diseases; RNA, Messenger

Erythropoietin (EPO) is the main regulatory hormone for the control of erythropoiesis. EPO leads to enhanced mitosis and differentiation of erythroid precursors in the bone marrow. The major stimulus for EPO-formation is anaemia of various origin, resulting in an exponential relation between EPO levels and a decrease in haematocrit. Another important stimulus for increased EPO production is a fall of the arterial oxygen tension caused by either cardiopulmonary disorders or by a decrease of the oxygen tension in the inspiratory gas. Human erythropoietin was first isolated and purified from a large amount of urine of patients with aplastic anaemia. After the EPO gene had been cloned and expressed, biotechnically produced recombinant human erythropoietin (rHu-EPO) became available for clinical trials. EPO deficiency appears to be the major cause of renal anaemia, and hence the treatment of these patients is the most important indication for clinical use. Encouraging results in patients whose anaemia is not of renal origin have also been reported, using treatment with rHu-EPO. In preoperative autologous blood donation programmes prior to elective surgery, rHu-EPO therapy improved the amount of donated blood and ameliorated the decrease of haematocrit values. Side effects such as hypertension, thrombosis, hypercalcaemia, elevated liver enzymes were rare and were mostly related to the underlying disease.

Topics: Anemia; Blood Transfusion, Autologous; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins

Erythropoietin (Epo) is a glycoprotein that promotes the proliferation and differentiation of erythrocyte precursors. The major site of Epo production is the kidney and the liver is the main extra renal site of Epo production. Epo producing cells were identified by in situ hybridization, in the kidney, they are peritubular cells, most likely endothelial cells of the cortex and outer medulla; in the liver, they are mainly hepatocytes. The Epo secretion is stimulated by hypoxia, which is detected by an oxygen sensor. The Epo receptor is a multimeric protein, one chain which binds Epo has been cloned. However the structure of the Epo receptor is still puzzling, and one or more accessory chains remain to be identified. Since the clonage of the Epo gene, recombinant Epo has been available and allowed the treatment of patients with renal diseases with a constant efficacy.

Topics: Erythropoietin; Humans; Kidney; Kidney Diseases; Liver; Receptors, Cell Surface; Receptors, Erythropoietin; Recombinant Proteins

Topics: Anemia; Anemia, Sickle Cell; Animals; Erythropoiesis; Erythropoietin; Genes; Humans; Immunologic Factors; Kidney; Kidney Diseases; Mammals; Receptors, Cell Surface; Receptors, Erythropoietin; Recombinant Fusion Proteins

The last few years have seen an enormous increase in our knowledge on the haematopoietic growth factor erythropoietin (Epo), firstly with its purification and determination of its primary amino acid sequence, and more recently with the isolation of the Epo gene and its expression in mammalian cell lines. This review article summarizes the crucial biological features of Epo and critically examines the main results obtained in clinical trials on humans.

Topics: Acquired Immunodeficiency Syndrome; Anemia; Animals; Erythropoietin; Humans; Kidney Diseases; Neoplasms; Recombinant Proteins; Zidovudine

Topics: Animals; Blotting, Northern; Erythropoietin; Humans; Hypoxia; Kidney; Kidney Diseases; Mice; RNA, Messenger

Topics: Anemia; Erythropoietin; Humans; Kidney Diseases; Risk Factors

Erythropoietin (Epo) is a glycoprotein that promotes the proliferation and differentiation of erythrocyte precursors. The major site of Epo production is the kidney, while the liver is the main extrarenal site of Epo production. Within these organs, the cells synthesizing Epo were identified by using in situ hybridization in hypoxic animals with an increased Epo mRNA expression. Epo-producing cells in the kidney were peritubular cells, most likely endothelial cells of the cortex and outer medulla. Glomerular and tubular cells were not labeled. In three patients with renal adenocarcinomas associated with polycythemia, in situ hybridization showed a strong labeling of the tumor cells. Epo secretion is stimulated by hypoxia, which is detected by an oxygen sensor located in the kidney. This oxygen sensor has been recently shown to be an heme protein. At the Epo gene level, studies to identify cis-acting DNA sequences, and trans-activation factors for inducible kidney and liver Epo expression are being pursued.

Topics: Animals; Erythropoietin; Humans; Kidney; Kidney Diseases; Liver

Topics: Anemia; Animals; Cloning, Molecular; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins

Recombinant human erythropoietin (rhEPO) has now been in clinical trials for over three years. It 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. Preliminary results indicate that rhEPO is effective in increasing the ability of individuals to donate blood for self-use and early trials have shown the drug to increase the haematocrit in patients with rheumatoid arthritis. Trials in patients with anaemia associated with cancer or myelodysplastic syndromes are warranted. rhEPO will have a major impact as a therapeutic, particularly in patients with renal disease.

Topics: Anemia; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins

Topics: Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins

Topics: Animals; Blood Viscosity; Cardiovascular Diseases; Central Nervous System Diseases; Erythrocyte Deformability; Erythropoietin; Female; Fetal Hypoxia; Fetofetal Transfusion; Fetomaternal Transfusion; Fetus; Follow-Up Studies; Gastrointestinal Diseases; Genital Diseases, Male; Global Health; Growth Disorders; Hematocrit; Humans; Hyperbilirubinemia; Hypocalcemia; Hypoglycemia; Infant, Newborn; Infant, Small for Gestational Age; Kidney Diseases; Male; Mental Disorders; Polycythemia; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy in Diabetics; Prognosis; Respiration Disorders; Sheep; Thrombocytopenia

Topics: Acute Kidney Injury; Adaptation, Physiological; Adenine Nucleotides; Ammonia; Animals; Dogs; Energy Metabolism; Enzymes; Erythropoietin; Gluconeogenesis; Hormones; Kidney Diseases; Lipid Metabolism; Mitochondria; Nephrons; Oxygen Consumption; Prostaglandins; Rabbits; Rats

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Half-Life; Hematopoietic Stem Cells; Hormones; Humans; Kidney; Kidney Diseases; Kidney Failure, Chronic; Oxygen Consumption

Topics: Erythropoietin; Hormones; Humans; Kidney; Kidney Diseases; Prostaglandins; Renin-Angiotensin System; Vitamin D

Topics: Anemia; Anemia, Aplastic; Animals; Blood Transfusion; Bone Marrow; Bone Marrow Cells; Cell Differentiation; Chronic Disease; Erythropoiesis; Erythropoietin; Humans; Immune Sera; Kidney; Kidney Diseases; Lipids; Mercaptopurine; Polycythemia Vera

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; Central Nervous System Diseases; Erythropoiesis; Erythropoietin; Female; Genes, Regulator; Genital Diseases, Female; Hemodynamics; Humans; Hypertension; Hypoxia; Kidney; Kidney Diseases; Liver Diseases; Male; Polycythemia; Polycythemia Vera; Rats

Topics: Anemia; Animals; Bone Marrow; Dogs; Erythrocytes; Erythropoiesis; Erythropoietin; Hematopoiesis; Hemorrhage; Humans; Hypoxia; Iron Isotopes; Kidney; Kidney Diseases; Mice; Placenta; Polycythemia Vera; Rabbits; Rats; Stimulation, Chemical

Topics: Anemia; Blood Transfusion; Blood Urea Nitrogen; Chromium Isotopes; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Iron; Iron Isotopes; Kidney; Kidney Diseases; Polycythemia; Uremia

Topics: Anemia; Epoetin Alfa; Erythropoietin; Humans; Kidney Diseases

Topics: Anemia; Epoetin Alfa; Erythropoietin; Hematopoiesis; Humans; Kidney; Kidney Diseases; Kidney Neoplasms; Pathology; Physiology; Polycythemia

Hemodialysis treatment induces markers of inflammation and oxidative stress, which could affect hemoglobin levels and the response to erythropoietin use. This study sought to determine whether high-flux dialysis would help improve markers of renal anemia, inflammation, and oxidative stress compared with low-flux dialysis.. In a prospective, controlled study, 221 patients undergoing maintenance hemodialysis and receiving darbepoetin-alfa treatment (mean age, 66 years; 55% male) from 19 centers were screened in a 20-week run-in period of low-flux hemodialysis with a synthetic dialysis membrane. Thereafter, 166 patients were enrolled and randomly assigned to receive a synthetic high-flux membrane or to continue on low-flux dialysis for 52 weeks. Data on myeloperoxidase, oxidized LDL, high-sensitivity C-reactive protein, and the Malnutrition Inflammation Score were collected at baseline and after 52 weeks; routine laboratory data, such as hemoglobin, ferritin, and albumin, and the use of darbepoetin-alfa, were also measured in the run-in period. Results After 52 weeks, the low-flux and the high-flux groups did not differ with respect to hemoglobin (mean ± SD, 11.7±0.9 g/dl versus 11.7±1.1 g/dl; P=0.62) or use of darbepoetin-alfa (mean dosage ± SD, 29.8±24.8 μg/wk versus 26.0±31.1 μg/wk; P=0.85). Markers of inflammation, oxidative stress, or nutritional status also did not differ between groups.. Over 1 year, high-flux dialysis had no superior effects on hemoglobin levels or markers of inflammation, oxidative stress, and nutritional status. These data do not support the hypothesis that enhanced convective toxin removal would improve patient outcome.

Topics: Aged; C-Reactive Protein; Chronic Disease; Darbepoetin alfa; Endpoint Determination; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Nutritional Status; Oxidative Stress; Prospective Studies; Renal Dialysis; Serum Albumin

The continuous erythropoietin receptor activator (C.E.R.A.) has a long half-life, a relatively low binding affinity for the erythropoiesis receptor and low systemic clearance. These characteristics permit once-monthly dosing, which could reduce staffing requirements and be advantageous for patients. However, outcomes observed during controlled trials of C.E.R.A. have not been assessed under everyday clinical conditions in which physicians make all therapeutic decisions based on their own experience, rather than according to a pre-defined protocol.. This study aimed to assess whether the efficacy and safety of C.E.R.A. reported during controlled trials are reproducible under routine clinical conditions.. This was a non-interventional, single-cohort, multicentre study carried out in 92 specialist nephrology clinics and private practices in Germany. The study included patients with non-dialysis chronic kidney disease and anaemia, with or without current erythropoiesis stimulating agent (ESA) therapy. C.E.R.A. initiation and dosing was at the discretion of the physician. The primary efficacy variable was the proportion of patients for whom all measured haemoglobin (Hb) values during months 7-9 were within the range 11-12 g/dL ('responders').. 335 patients received ≥1 dose of C.E.R.A.; 150 had previously received ESA therapy. The mean number of doses was 7.6 per patient over a mean follow-up of 7.9 months. Mean ± SD Hb was 10.7 ± 1.1 g/dL at baseline and 11.3 ± 1.1 g/dL at the final visit (efficacy population, n = 205). The primary endpoint, all measured Hb values during months 7-9 within the range 11-12 g/dL, was achieved by 19.0% (39/205) of patients, increasing to 41.5% for Hb 11-13 g/dL, 42.0% for 10-12 g/dL and 76.6% for Hb ≥10 g/dL. Hb fluctuation during months 7-9 was ≤1 g/dL in 185/205 patients (90.2%). C.E.R.A. was well tolerated without novel safety concerns.. Hb levels remained stable during routine use of C.E.R.A. in an unselected population of non-dialysis chronic kidney disease patients with anaemia. C.E.R.A. was administered approximately monthly compared with 3-7 doses per month on previous ESA therapy.

Topics: Aged; Aged, 80 and over; Anemia; Chronic Disease; Erythropoietin; Female; Germany; Hematinics; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Polyethylene Glycols; Reproducibility of Results

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

The Normal Hematocrit Trial (NHT) was the largest trial of epoetin randomizing 1265 hemodialysis patients with cardiac disease to lower (9-11 g/dl) or higher (13-15 g/dl) hemoglobin (Hgb), hypothesizing that higher Hgb would reduce mortality, and improve survival and quality of life. The trial was terminated early, and a 1998 publication reported that targeting higher hematocrit levels led to an insignificant increase in the primary end points (death or myocardial infarct), or risk ratio 1.3, 95% confidence interval (CI), 0.9-1.90, but the P-value was not given, and all-cause death risk was not reported. A higher target reportedly did not increase hospitalization rates, but did significantly improve the 'physical function' domain of quality of life. Comparing the 1996 Food and Drug Administration (FDA)-filed clinical trial report to the 1998 publication, however, found several discrepancies. Among these, the 1998 article reported interim trial results with only the adjusted CI but did not state that the unadjusted CIs were 99.912th percentile, and despite being a secondary end point, reported only the association of achieved Hgb with higher quality of life score. Randomization to the higher target had actually increased the risk for the primary end point (risk ratio 1.28, 95% CI=1.06-1.56; P=0.0112; 99.92% CI=0.92-1.78), the risk of death (risk ratio 1.27, 95% CI=1.04-1.54), non-access thrombotic events (P=0.041), and hospitalization rate (P=0.04), while 'physical function' did not improve (P=0.88). Hence, disclosure of these results in the 1998 publication or access to the FDA-filed report on the NHT in the late 1990s would likely have led to earlier concerns about epoetin safety and greater doubts about its benefits.

Topics: Access to Information; Anemia; Biomarkers; Chi-Square Distribution; Early Termination of Clinical Trials; Emotions; Erythropoietin; Evidence-Based Medicine; Health Status; Heart Diseases; Hematinics; Hematocrit; Hemoglobins; Hospitalization; Humans; Kaplan-Meier Estimate; Kidney Diseases; Mental Health; Patient Safety; Practice Guidelines as Topic; Predictive Value of Tests; Proportional Hazards Models; Quality of Life; Renal Dialysis; Risk Assessment; Risk Factors; Social Behavior; Time Factors; Treatment Outcome; United States

HX575 was approved in the European Union in August 2007 as the first-ever biosimilar epoetin-α product. The present study extended the safety database on HX575 by monitoring adverse events (AEs) in clinical practice. Hemoglobin (Hb) levels and HX575 doses were recorded for the assessment of efficacy. This open, 6-month single-arm study was conducted in 10 European countries with a target enrollment of 1,500 patients with anemia due to chronic kidney disease (CKD). HX575 was intravenously (i.v.) administered aiming at an Hb target of 10 - 12 g/dl. Most patients (92.3%) had already received erythropoiesis stimulating agents (ESAs) treatment before enrolment into this study; the recorded treatments mainly comprised i.v. or subcutaneous (s.c.) administration of epoetin-α, epoetin-β or darbepoetin. The study period covered 770 patient years. The observed AE profile was in line with expectations for this patient population. Thrombotic vascular events (TVEs) were reported in 11.9% of patients (0.2612 per patient year). Tumor incidence was 1.4% (0.0299 per patient year). No subject developed anti-epoetin antibodies. Mean Hb levels were effectively maintained between 11.2 and 11.3 g/dl following the conversion from a broad spectrum of pre-study ESA treatments with stable overall mean i.v. HX575 doses. The proportion of patients within the Hb target range increased from 57.5% at baseline to 66.8% at study end.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Biomarkers; Biosimilar Pharmaceuticals; Chronic Disease; Epoetin Alfa; Erythropoietin; Europe; Female; Hematinics; Hemoglobins; Humans; Injections, Intravenous; Kidney Diseases; Male; Middle Aged; Neoplasms; Prospective Studies; Recombinant Proteins; Thrombosis; Time Factors; Treatment Outcome; Young Adult

Little is known about the effect of anemia correction with erythropoietin (EPO) on B-type natriuretic peptide (BNP) levels, NYHA class, and hospitalization rate. The aim of the study was to investigate, in patients with cardio-renal anemia syndrome, the effects of EPO on hemochrome and renal function parameters and BNP levels. We also analyzed the effect of EPO therapy on hospitalization rate and NYHA class after 12 months in comparison with a population undergoing to standard therapy. We performed a randomized double-blind controlled study of correction of the anemia with subcutaneous α (group A n = 13) or β (group B n = 14) EPO for 12 months in addition to standard therapy with oral iron in 27 subjects. Control group (n = 25 patients) received only oral iron. Significant increase in hemoglobin (Hb), hematocrit (Hct), and red blood cells (RBC) were revealed in EPO groups at 12 months; Hb, group A 12.3 ± 0.6; group B 11.7 ± 0.8; control group 10.6 ± 0.5 g/dl P < 0.0001; Hct group A 34.2 ± 2.3, group B 34 ± 2, control group 32.3 ± 1.8% P < 0.01; RBC, group A 3.9 ± 0.2, group B 3.8 ± 0.2, control group 3.3 ± 0.2, (P < 0.0001). Plasma BNP levels in EPO groups were significantly reduced after 12 months (group A: 335 ± 138 vs. group B: 449 ± 274 pg/ml control group 582 ± 209 pg/ml (P < 0.01). After 12 months of treatment, hospitalization rate and NYHA class were reduced in EPO groups with respect to control group (P < 0.05). Finally, an inverse correlation was observed between BNP and Hb levels in EPO Groups (r = -0.70 P < 0.001). EPO treatment reduces BNP levels and hospitalization rate in patients with cardio-renal anemia syndrome. The correction of anemia by EPO treatment appears able to improve clinical outcome in this subset of patients with heart failure.

Topics: Administration, Oral; Anemia; Erythropoietin; Heart Failure; Hemoglobins; Hospitalization; Humans; Injections, Subcutaneous; Iron; Kidney Diseases; Natriuretic Peptide, Brain; Severity of Illness Index; Treatment Outcome

Quality of life (QOL) is markedly impaired in patients with anemia, diabetes mellitus, and chronic kidney disease. Limited data exist regarding the effect of anemia treatment on patient perceptions. The objectives were to determine the longitudinal impact of anemia treatment on quality of life in patients with diabetes and chronic kidney disease and to determine the predictors of baseline and change in QOL.. In a large, double blind study, patients with type 2 diabetes mellitus, nondialysis chronic kidney disease (estimated GFR, 20 to 60 ml/min per 1.73 m(2)), and anemia (hemoglobin 10.4 g/dl) were randomized to darbepoetin alfa or placebo. QOL was measured with Functional Assessment of Cancer Therapy-Fatigue, Short Form-36, and EuroQol scores over 97 weeks.. Patients randomized to darbepoetin alfa reported significant improvements compared with placebo patients in Functional Assessment of Cancer Therapy-Fatigue, and EuroQol scores visual analog scores, persisting through 97 weeks. No consistent differences in Short Form-36 were noted. Consistent predictors of worse change scores include lower activity level, older age, pulmonary disease, and duration of diabetes. Interim stroke had a substantial negative impact on fatigue and physical function.. Darbepoetin alfa confers a consistent, but small, improvement in fatigue and overall quality of life but not in other domains. These modest QOL benefits must be considered in the context of neutral overall effect and increased risk of stroke in a small proportion of patients. Patient's QOL and potential treatment risk should be considered in any treatment decision.

Topics: Aged; Anemia; Darbepoetin alfa; Diabetes Complications; Double-Blind Method; Erythropoietin; Female; Health Status; Humans; Kidney Diseases; Male; Middle Aged; Quality of Life

Darbepoetin alfa (KRN321) is a recombinant protein 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. The efficacy and safety of KRN321 administered subcutaneously to patients on peritoneal dialysis (PD) were tested.. In a multicenter, open-label, single-arm study, KRN321 was administered subcutaneously to patients on PD for 26-28 weeks. Ninety-six patients initially were given a 60 μg subcutaneous dose once every 2 weeks until a target of Hb (11.0-13.0 g/dL) was achieved. Thereafter, their dose was every 2 or 4 weeks.. After the target of Hb was reached in most subjects (96.9%), it was maintained with KRN321 administered every 2 or 4 weeks. On completion of (or withdrawal from) study, 65 subjects (67.7%) maintained the target Hb. Although a number of adverse event related to hypertension occurred, their incidence did not appear to be related to Hb or its rate of increase. These events could be controlled adequately by interrupting or reducing the dose, and/or treatment with antihypertensives.. The efficacy and safety of KRN321 when administered subcutaneously for 28 weeks to PD patients were confirmed. It was suggested that the quality of life of patients can be improved by treatment with KRN321 due to the reduced frequency of administration.

Topics: Aged; Anemia; Chronic Disease; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Japan; Kaplan-Meier Estimate; Kidney Diseases; Male; Middle Aged; Peritoneal Dialysis; Quality of Life; Time Factors; Treatment Outcome

This study aims to examine predictors of cardiovascular mortality and morbidity in patients with chronic kidney disease (CKD). Individuals with the triad of diabetes, CKD, and anemia represent a significant proportion of patients with cardiovascular disease and are at particularly high risk for adverse outcomes.. Using Cox proportional hazards models, we identified independent predictors of the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for myocardial ischemia, or heart failure (HF) in 3,847 patients in the TREAT, 961 (25%) of whom experienced this outcome. The predictors (ranked by χ(2) value) were prior HF (hazard ratio [HR] 1.74, 95% CI 1.51-2.01), age (HR 1.03, 95% CI 1.02-1.04 per year), log urine protein/creatinine ratio (HR 1.19, 95% CI 1.13-1.26 per log unit ), C-reactive protein ≥6.6 mg/L (HR 1.44, 95% CI 1.23-1.69, compared with C-reactive protein ≤3.0 mg/L), and abnormal electrocardiogram (HR 1.42, 95% CI 1.21-1.66 ), all P < .0001. Addition of cardiac-derived biomarkers (subset of first 1,000 patients enrolled) significantly enhanced risk estimation, with N-terminal pro B-type natriuretic peptide becoming the highest ranked predictor of outcome (HR 1.30, 95% CI 1.15-1.46 per log unit, P < .001) and troponin T providing additional predictive information. These biomarkers improved risk classification in 17.8% (9.4%-26.2%) of patients.. In patients with diabetes, CKD, and anemia, cardiovascular risk is most strongly predicted by age, history of HF, C-reactive protein, urinary protein/creatinine ratio, abnormal electrocardiogram, and 2 specific cardiac biomarkers, serum N-terminal pro B-type natriuretic peptide and troponin T, which are elevated in many. These findings suggest ways to improve cardiovascular risk stratification of patients with predialysis CKD, support the concept of cardiorenal syndrome, and may help target therapy.

Topics: Aged; Anemia; Cardiovascular Diseases; Chronic Disease; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Female; Hematinics; Humans; Kidney Diseases; Male; Prognosis

The CHOIR trial in anemic patients with chronic kidney disease compared epoetin-alfa treatment with low (11.3 g/l) and high (13.5 g/l) hemoglobin targets on the composite end point of death, hospitalization for heart failure, stroke, and myocardial infarction. However, other anemia management trials in patients with chronic kidney disease found there was increased risk when hemoglobin is targeted above 13 g/dl. In this secondary analysis of the CHOIR trial, we compared outcomes among the subgroups of patients with diabetes and heart failure to describe the comparative relationship of treatment to these two different hemoglobin goals. By Cox regression analysis, there was no increased risk associated with the higher hemoglobin target among patients with heart failure. In patients without heart failure, however, the hazard ratio (1.86) associated with the higher target was significant. Comparing survival curves in an unadjusted model, patients with diabetes did not have a greater hazard associated with the higher target. Subjects without diabetes had a significantly greater hazard in the high as compared to the low target, but the interaction between diabetes and the target was not significant. We suggest that the increased risks associated with higher hemoglobin targets are not clinically apparent among subgroups with greater mortality risk. These differential outcomes underscore the need for dedicated trials in these subpopulations.

Topics: Aged; Aged, 80 and over; Anemia; Chronic Disease; Comorbidity; Diabetes Mellitus; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Regression Analysis; Retrospective Studies; Survival Analysis; Treatment Outcome

Topics: Aged; Anemia; Chronic Disease; Darbepoetin alfa; Double-Blind Method; Erythropoietin; Female; Follow-Up Studies; Hematinics; Humans; Kidney Diseases; Male; Renal Dialysis

We performed a double-blind placebo-controlled trial to study whether early treatment with erythropoietin could prevent the development of acute kidney injury in patients in two general intensive care units. As a guide for choosing the patients for treatment we measured urinary levels of two biomarkers, the proximal tubular brush border enzymes gamma-glutamyl transpeptidase and alkaline phosphatase. Randomization to either placebo or two doses of erythropoietin was triggered by an increase in the biomarker concentration product to levels above 46.3, with a primary outcome of relative average plasma creatinine increase from baseline over 4 to 7 days. Of 529 patients, 162 were randomized within an average of 3.5 h of a positive sample. There was no difference in the incidence of erythropoietin-specific adverse events or in the primary outcome between the placebo and treatment groups. The triggering biomarker concentration product selected patients with more severe illness and at greater risk of acute kidney injury, dialysis, or death; however, the marker elevations were transient. Early intervention with high-dose erythropoietin was safe but did not alter the outcome. Although these two urine biomarkers facilitated our early intervention, their transient increase compromised effective triaging. Further, our study showed that a composite of these two biomarkers was insufficient for risk stratification in a patient population with a heterogeneous onset of injury.

Topics: Acute Disease; Aged; Alkaline Phosphatase; Biomarkers; Creatinine; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Female; gamma-Glutamyltransferase; Hematinics; Humans; Intensive Care Units; Kidney Diseases; Male; Middle Aged; New Zealand; Patient Selection; Placebo Effect; Predictive Value of Tests; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Triage

Extended-interval dosing of epoetin alfa (EPO) is commonly used to treat anemia in patients with chronic kidney disease (CKD). This study aimed to demonstrate that EPO dosed every 2 weeks (Q2W) and every 4 weeks (Q4W) was noninferior to once-weekly (QW) dosing.. 430 anemic subjects with stage 3 to 4 CKD receiving a stable QW dose of EPO were randomized 1:1:2 to QW, Q2W, and Q4W dosing for 36 weeks. Hemoglobin (Hb) was measured weekly, and the dose of EPO was adjusted to maintain an Hb level of 11.0 to 11.9 g/dl. The primary endpoint was change in Hb from baseline to the average of the last 12 weeks of treatment.. Both the Q2W and Q4W dosing groups were noninferior to the QW group. The estimated difference of the mean change in Hb between Q2W and QW was -0.03 g/dl; and between Q4W and QW was -0.09 g/dl. From weeks 13 to 37, the mean percentage of weeks per subject with Hb 10.0 to 11.9 g/dl, inclusive, was 81% for QW, 81% for Q2W, and 75% for Q4W. Death occurred, respectively, in 4%, 3%, and 4%; thromboembolic vascular events occurred in 3%, 5%, and 3%; and serious adverse events occurred in 22%, 26%, and 26% of subjects.. Q2W and Q4W EPO dosing maintained Hb levels in subjects with stage 3 to 4 CKD. Deaths, thromboembolic vascular events, and serious adverse events were comparable across the dosing groups.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Drug Administration Schedule; Drug Monitoring; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Iron Compounds; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Risk Assessment; Severity of Illness Index; Thromboembolism; Time Factors; Treatment Outcome; United States; Young Adult

Several studies with erythropoiesis-stimulating agents claim that maintenance therapy of renal anaemia may be possible at extended dosing intervals; however, few studies were randomized, results varied, and comparisons between agents were absent. We report results of a multi-national, randomized, prospective trial comparing haemoglobin maintenance with methoxy polyethylene glycol-epoetin beta and darbepoetin alfa administered once monthly.. Haemodialysis patients (n = 490) on stable once-weekly intravenous darbepoetin alfa were randomized to methoxy polyethylene glycol-epoetin beta once monthly or darbepoetin alfa every 2 weeks for 26 weeks, with dose adjustment for individual haemoglobin target (11-13 g/dL; maximum decrease from baseline 1 g/dL). Subsequently, patients entered a second 26-week period of once-monthly methoxy polyethylene glycol-epoetin beta and darbepoetin alfa. The primary endpoint was the proportion of patients who maintained average haemoglobin ≥10.5 g/dL, with a decrease from baseline ≤1 g/dL, in Weeks 50-53; the secondary endpoint was dose change over time. The trial is registered at www.ClinicalTrials.gov, number NCT00394953.. Baseline characteristics were similar between groups. One hundred and fifty-seven of 245 patients treated with methoxy polyethylene glycol-epoetin beta and 99 of 245 patients with darbepoetin alfa met the response definition (64.1% and 40.4%; P < 0.0001). Doses increased by 6.8% with methoxy polyethylene glycol-epoetin beta and 58.8% with darbepoetin alfa during once-monthly treatment. Death rates were equal between treatments (5.7%). Most common adverse events included hypertension, procedural hypotension, nasopharyngitis and muscle spasms, with no differences between groups.. Methoxy polyethylene glycol-epoetin beta maintained target haemoglobin more successfully than darbepoetin alfa at once-monthly dosing intervals despite dose increases with darbepoetin alfa.

Topics: Aged; Anemia, Iron-Deficiency; Chronic Disease; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Carriers; Erythropoietin; Female; Hematinics; Humans; Kidney Diseases; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Anaemia is a common complication of chronic kidney disease. A number of studies have identified an adverse association between haemoglobin (Hgb) variability and mortality. To date, no study has evaluated the impact of Hgb variability on mortality in the setting of a uniform Hgb target and erythropoiesis-stimulating agents (ESA) dosing strategy.. One hundred and fifty-four haemodialysis (HD) patients from a previous randomized anaemia management study were followed up for up to 6 years. The impact of Hgb variability and ESA dosing parameters on subsequent mortality risk were evaluated.. More rapid rises in Hgb (Hgb deflect(pos)) and ESA dose increases were independently associated with mortality in multivariate analysis, whereas more rapid Hgb declines (Hgb deflect(neg)) and ESA dose decreases were not. Each gram per litre per week increase in Hgb deflect(pos) was associated with an adjusted hazard ratio (HR) of 1.23 (1.03-1.48), while for every 1000-unit increase in ESA dose, the adjusted HR was 1.12 (1.01-1.24). Factors associated with positive Hgb deflections included frequency and magnitude of ESA dose changes, baseline Hgb, patient weight and presence of an HD catheter.. Rapid Hgb rises and greater average Eprex dose increases were independently associated with a higher mortality risk in HD patients after adjustment for baseline Hgb and Eprex dose. A randomized controlled trial evaluating different ESA dosing strategies in response to individual patient ESA responsiveness is needed.

Topics: Aged; Anemia, Iron-Deficiency; Chronic Disease; Dose-Response Relationship, Drug; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Kaplan-Meier Estimate; Kidney Diseases; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Renal Dialysis; Retrospective Studies; Survival Rate; Treatment Outcome

Hepcidin is a critical inhibitor of iron export from macrophages, enterocytes, and hepatocytes. Given that it is filtered and degraded by the kidney, its elevated levels in renal failure have been suggested to play a role in the disordered iron metabolism of uremia, including erythropoietin resistance. Here, we used a novel radioimmunoassay for hepcidin-25, the active form of the hormone, to measure its levels in renal disease. There was a significant diurnal variation of hepcidin and a strong correlation to ferritin levels in normal volunteers. In 44 patients with mild to moderate kidney disease, hepcidin levels were significantly elevated, positively correlated with ferritin but inversely correlated with the estimated glomerular filtration rate. In 94 stable hemodialysis patients, hepcidin levels were also significantly elevated, but this did not correlate with interleukin-6 levels, suggesting that increased hepcidin was not due to a general inflammatory state. Elevated hepcidin was associated with anemia, but, intriguingly, the erythropoietin dose was negatively correlated with hepcidin, suggesting that erythropoietin suppresses hepcidin levels. This was confirmed in 7 patients when hepcidin levels significantly decreased after initiation of erythropoietin treatment. Our results show that hepcidin is elevated in renal disease and suggest that higher hepcidin levels do not predict increased erythropoietin requirements.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antimicrobial Cationic Peptides; Case-Control Studies; Circadian Rhythm; Erythropoietin; Female; Ferritins; Glomerular Filtration Rate; Hepcidins; Humans; Kidney Diseases; Male; Middle Aged; Radioimmunoassay; Recombinant Proteins; Young Adult

Anaemia is common in patients with chronic kidney disease (CKD) and can be managed by therapy with erythropoiesis-stimulating agents (ESAs). Epoetin delta (DYNEPO, Shire plc) is the only epoetin produced in a human cell line. The aim of this study was to demonstrate the safety and efficacy of subcutaneously administered epoetin delta for the management of anaemia in CKD patients (predialysis, peritoneal dialysis or haemodialysis). This was a 1-year, multicentre, open-label study. Patients had previously received epoetin subcutaneously and were switched to epoetin delta at an identical dose to their previous therapy. Dose was titrated to maintain haemoglobin at 10.0-12.0 g/dL. The primary endpoint was mean haemoglobin over Weeks 12-24. Secondary analyses included long-term haemoglobin, haematocrit and dosing levels. Safety was assessed by monitoring adverse events, laboratory parameters and physical examinations.. In total 478 patients received epoetin delta, forming the safety-evaluable population. Efficacy analyses were performed on data from 411 of these patients. Mean +/- SD haemoglobin over Weeks 12-24 was 11.3 +/- 1.1 g/dL. Mean +/- SD weekly dose over Weeks 12-24 was 84.4 +/- 72.7 IU/kg. Haemoglobin levels were maintained for the duration of the study. Epoetin delta was well tolerated, with adverse events occurring at rates expected for a CKD patient population; no patient developed anti-erythropoietin antibodies.. Subcutaneously administered epoetin delta is an effective and well-tolerated agent for the management of anaemia in CKD patients, irrespective of dialysis status.. http://www.controlled-trials.com ISRCTN68321818.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Chronic Disease; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Patient Dropouts; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis; Young Adult

Anemia augments the already high rates of fatal and major nonfatal cardiovascular and renal events in individuals with type 2 diabetes. In 2004, we initiated the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). This report presents the baseline characteristics and therapies of TREAT participants and subgroups defined by the presence or absence of overt proteinuria and history of cardiovascular disease. The design of TREAT and baseline characteristics also are compared with 2 recent trials of nondialysis patients with chronic kidney disease (CKD) in which treatment with another erythropoiesis-stimulating agent targeting greater hemoglobin levels had either a neutral or adverse effect on clinical outcomes.. Randomized trial.. 4,044 participants with type 2 diabetes, CKD (defined as estimated glomerular filtration rate of 20 to 60 mL/min/1.73 m(2)), and anemia (hemoglobin < or = 11 g/dL) from 24 countries.. Darbepoetin alfa to attempt to increase hemoglobin levels to 13 g/dL compared with placebo.. TREAT is an event-driven design to continue until approximately 1,203 patients experience a primary event: the composite end point of death or cardiovascular morbidity (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia). The composite end point of death or need for long-term renal replacement therapy also is a primary end point.. With several-fold more patient-years and a placebo arm, TREAT will provide a robust estimate of the safety and efficacy of darbepoetin alfa and generate prospective data regarding the risks of major cardiovascular and renal events in a contemporarily managed cohort of patients with type 2 diabetes, CKD, and anemia.

Topics: Aged; Anemia; Cardiovascular Diseases; Cohort Studies; Darbepoetin alfa; Diabetes Mellitus, Type 2; Erythropoietin; Female; Glomerular Filtration Rate; Hematinics; Humans; Kidney Diseases; Male; Middle Aged; Proteinuria; Risk Factors; Treatment Outcome

The main hypothesis of this study is that oral heme iron polypeptide (HIP; Proferrin ES) administration will more effectively augment iron stores in erythropoietic stimulatory agent (ESA)-treated peritoneal dialysis (PD) patients than conventional oral iron supplementation (Ferrogradumet).. Inclusion criteria are peritoneal dialysis patients treated with darbepoietin alpha (DPO; Aranesp(R), Amgen) for >or= 1 month. Patients will be randomized 1:1 to receive either slow-release ferrous sulphate (1 tablet twice daily; control) or HIP (1 tablet twice daily) for a period of 6 months. The study will follow an open-label design but outcome assessors will be blinded to study treatment. During the 6-month study period, haemoglobin levels will be measured monthly and iron studies (including transferring saturation [TSAT] measurements) will be performed bi-monthly. The primary outcome measure will be the difference in TSAT levels between the 2 groups at the end of the 6 month study period, adjusted for baseline values using analysis of covariance (ANCOVA). Secondary outcome measures will include serum ferritin concentration, haemoglobin level, DPO dosage, Key's index (DPO dosage divided by haemoglobin concentration), and occurrence of adverse events (especially gastrointestinal adverse events).. This investigator-initiated multicentre study has been designed to provide evidence to help nephrologists and their peritoneal dialysis patients determine whether HIP administration more effectively augments iron stores in ESP-treated PD patients than conventional oral iron supplementation.. Australia New Zealand Clinical Trials Registry number ACTRN12609000432213.

Topics: Administration, Oral; Adult; Anemia; Australia; Chronic Disease; Darbepoetin alfa; Delayed-Action Preparations; Erythropoietin; Ferritins; Ferrous Compounds; Hematinics; Hemeproteins; Hemoglobins; Humans; Iron; Kidney Diseases; Peritoneal Dialysis; Treatment Outcome

Inflammatory cytokines are important predictors of cardiovascular mortality especially in patients with chronic kidney disease. Here we explored the relationship of anemia and epoetin treatment to inflammatory cytokine levels in patients with chronic kidney disease. One hundred non-dialysis patients with chronic kidney disease over 18 years of age were evenly split into anemic and non-anemic cohorts. Of the 50 anemic patients, 23 were receiving erythropoiesis stimulating agents treatments. Levels of tumor necrosis factor (TNF)-alpha were found to be significantly higher and serum albumin was significantly lower with trends towards higher interleukin (IL)-6 and IL-8 in anemic compared to non-anemic patients. Further analysis by multiple logistic regression found that anemic patients treated with erythropoiesis stimulating agents had significantly higher odds for the upper two quartiles for IL-6, IL-8 and TNF-alpha compared to non-anemic patients. Our study found that the anemia of chronic kidney disease was associated with up regulation of TNF-alpha, and possibly IL-6 and IL-8 along with increased levels of these proinflammatory cytokines in patients treated with epoetin.

Topics: Aged; Anemia; Biomarkers; Case-Control Studies; Chronic Disease; Cytokines; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Inflammation; Interleukin-6; Interleukin-8; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Tumor Necrosis Factor-alpha; Up-Regulation

Extending the administration interval of erythropoiesis-stimulating agents (ESAs) represents an opportunity to improve the efficiency of anaemia management in patients with chronic kidney disease (CKD). However, effective haemoglobin (Hb) maintenance can be challenging with epoetin alfa and epoetin beta administered at extended intervals. C.E.R.A., a continuous erythropoietin receptor activator, has a unique pharmacologic profile and long half-life ( approximately 130 h), allowing administration at extended intervals. Phase III results have demonstrated that C.E.R.A. administered once every 4 weeks effectively maintains stable Hb levels in patients with CKD on dialysis.. STRIATA (Stabilizing haemoglobin TaRgets in dialysis following IV C.E.R.A. Treatment for Anaemia) was a multicentre, open-label randomized phase III study to evaluate the efficacy and safety of intravenous C.E.R.A. administered once every 2 weeks (Q2W) for Hb maintenance following direct conversion from darbepoetin alfa (DA). Adult patients on dialysis receiving stable intravenous DA once weekly (QW) or Q2W were randomized (1:1) to continue their current DA regimen (n = 156) or receive intravenous C.E.R.A. Q2W (n = 157) for 52 weeks. Doses were adjusted to maintain Hb levels within +/- 1.0 g/dl of baseline and between 10.0 and 13.5 g/dl. The primary endpoint was the mean Hb change between baseline and the evaluation period (weeks 29-36).. Most patients (>80%) received DA QW before randomization. The mean (95% CI) difference between C.E.R.A. and DA in the primary endpoint was 0.18 g/dl (-0.05, 0.41), within a pre-defined non-inferiority limit. C.E.R.A. was clinically non-inferior to DA (P < 0.0001) in maintaining Hb levels. Both treatments were well tolerated.. Stable Hb levels were successfully maintained in patients on haemodialysis directly converted to Q2W intravenous C.E.R.A. from DA.

Topics: Aged; Anemia; Australia; Canada; Chronic Disease; Darbepoetin alfa; Dose-Response Relationship, Drug; Endpoint Determination; Erythropoietin; Europe; Female; Hematinics; Hemoglobins; Humans; Injections, Intravenous; Kidney Diseases; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis

Trials of anemia correction in chronic kidney disease have found either no benefit or detrimental outcomes of higher targets. We did a secondary analysis of patients with chronic kidney disease enrolled in the Correction of Hemoglobin in the Outcomes in Renal Insufficiency trial to measure the potential for competing benefit and harm from achieved hemoglobin and epoetin dose trials. In the 4 month analysis, significantly more patients in the high-hemoglobin compared to the low-hemoglobin arm were unable to achieve target hemoglobin and required high-dose epoetin-alpha. In unadjusted analyses, the inability to achieve a target hemoglobin and high-dose epoetin-alpha were each significantly associated with increased risk of a primary endpoint (death, myocardial infarction, congestive heart failure or stroke). In adjusted models, high-dose epoetin-alpha was associated with a significant increased hazard of a primary endpoint but the risk associated with randomization to the high hemoglobin arm did not suggest a possible mediating effect of higher target via dose. Similar results were seen in the 9 month analysis. Our study demonstrates that patients achieving their target had better outcomes than those who did not; and among subjects who achieved their randomized target, no increased risk associated with the higher hemoglobin goal was detected. Prospective studies are needed to confirm this relationship and determine safe dosing algorithms for patients unable to achieve target hemoglobin.

Topics: Aged; Anemia; Chronic Disease; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Renal Insufficiency; Risk; Treatment Outcome

After allogeneic stem cell transplantation (allo-SCT) some patients develop persistent anemia in association with an inadequate erythropoietin (Epo) secretion. We determined the frequency and risk factors for this complication and the response to treatment with erythropoiesis stimulating proteins (ESP). Of 83 evaluable allo-SCT patients, 63 (76%) developed persistent anemia at a median of 34 (range: 30-244) days after allo-SCT. Forty-one (49%) patients had anemia considered as primary, and in all of them inadequate serum Epo levels (median 43.3, range: 2.5-134, mU/mL) were found. A high creatinine level during the first month after allo-SCT was associated with primary anemia (relative risk [RR] 2.5, P = .01). Of the 41 patients, 35 received ESP. Transfusion independence and an Hb level higher than 10 g/dL was achieved in 29 of 30 (97%) evaluable patients. Median ferritin levels at the beginning and at the end of the ESP treatment was 1628 (range: 168-5208) and 805 (range: 14-7443) ng/mL, respectively (P = .04). In conclusion, anemia associated with impaired Epo secretion after allo-SCT is more frequent than usually recognized and it is associated to early postransplantation renal damage. This complication easily reverts with ESP, which seems to contribute to reduce iron overload.

Topics: Adult; Anemia; Erythropoiesis; Erythropoietin; Female; Hematinics; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Risk Factors; Time Factors; Transplantation, Homologous; Treatment Outcome

Optimal hemoglobin targets for chronic kidney disease patients receiving erythropoiesis-stimulating agents remain controversial. The effects of different hemoglobin targets on blood transfusion requirements have not been well characterized, despite their relevance to clinical decision-making.. 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 wk using epoetin alfa as primary therapy and changes in left ventricular structure as the primary outcome (previously reported). Patients were masked to treatment assignment. Blood transfusion data were prospectively collected at 4-wk intervals.. The mean age and prior duration of dialysis therapy of the study population were 50.8 and 0.8 yr, respectively. Previously reported mortality was similar in low and high-target subjects, at 4.7 (95% confidence interval 3.0, 7.3) and 3.1 (1.8, 5.4) per hundred patient years, respectively. Transfusion rates were 0.66 (0.59, 0.74) units of blood per year in low and 0.26 (0.22, 0.32) in high-target subjects (P < 0.0001). Hemoglobin level at transfusion (7.7 [7.5, 7.9]) versus 8.1 [7.6, 8.5] g/dl) were similar with both groups. High hemoglobin target was a significant predictor of time to first transfusion independent of baseline associations (hazard ratio = 0.42; 95% confidence interval = 0.26-0.67).. In hemodialysis patients with comparatively low mortality risks, normal hemoglobin targets may reduce the need for transfusions.

Topics: Anemia; Blood Transfusion; Canada; Chronic Disease; Epoetin Alfa; Erythropoiesis; Erythropoietin; Europe; Female; Hematinics; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Time Factors; Treatment Outcome

Darbepoetin alfa is used to treat renal anemia; however, little information is available concerning its use during the posttransplant period, especially in HCV-positive patients treated with ribavirin for active hepatitis C.. This study investigated the efficacy and safety of using darbepoetin alfa in this population during a 6-month treatment period. All anemic patients were HCV/RNA-positive, treated with ribavirin, and had impaired renal function. Patients (n=7) who had not been treated previously with recombinant human erythropoietin (rHuEPO) were placed in "group no rHuEPO." Patients previously with recombinant human erythropoietin (n=16; "group rHuEPO") were switched to darbepoetin alfa according to the European summary of product characteristics.. Seventy-three percent of the patients were men. The mean creatinine clearance at baseline was 58.7 -/+ 21.5 mL/min. All patients received an immunosuppressive treatment. Although mean hemoglobin levels remained stable in group no rHuEPO and increased in group rHuEPO, the difference was not statistically significant. Also, the median darbepoetin-alfa-weighted dose in group no rHuEPO increased while it remained stable in group rHuEPO, as did the median daily dosage of ribavirin; however, these differences were not statistically significant. Creatinine levels and creatinine clearance levels remained stable throughout the study. No significant medical events related to the treatment were reported during the study.. Darbepoetin alfa was found to be efficient and well tolerated in correcting renal anemia in transplant recipients treated with ribavirin for active hepatitis C.

Topics: Anemia; Antiviral Agents; Chronic Disease; Creatinine; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Hepacivirus; Hepatitis C; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Liver Transplantation; Male; Pilot Projects; Postoperative Care; Prospective Studies; Retrospective Studies; Ribavirin; RNA, Viral; Treatment Outcome

This study examined the efficacy of C.E.R.A., a continuous erythropoietin receptor activator, for correcting anemia in patients who had chronic kidney disease (CKD) and were not on dialysis.. In this open-label, randomized, parallel-group, Phase III study, 324 adult patients with CKD not on dialysis nor receiving treatment with erythropoiesis-stimulating agents (ESAs) were randomly assigned (1:1) to receive subcutaneous C.E.R.A. once every 2 wk or darbepoetin alfa once weekly during an 18-wk correction period and a 10-wk evaluation period. Thereafter, patients receiving C.E.R.A. were randomly assigned to C.E.R.A. once every 2 wk or once monthly, and patients receiving darbepoetin alfa could receive darbepoetin alfa once weekly or once every 2 wk for a 24-wk extension period. Dosage was adjusted to achieve a hemoglobin (Hb) response and to maintain Hb +/-1 g/dl of the response level and 11 to 13 g/dl. Primary end points were Hb response rate during correction and evaluation and change in Hb concentration between baseline and evaluation.. Hb response rates were 97.5% for C.E.R.A. and 96.3% for darbepoetin alfa. Adjusted mean changes in Hb from baseline to evaluation were 2.15 g/dl (C.E.R.A.) and 2.00 g/dl (darbepoetin alfa). Analysis showed that C.E.R.A. once every 2 wk was as effective as darbepoetin alfa once weekly for correcting anemia. Hb levels remained stable in all groups during the extension period. C.E.R.A. and darbepoetin alfa were well tolerated.. Subcutaneous C.E.R.A. once every 2 wk corrects anemia in ESA-naïve patients who are not on dialysis.

Topics: Aged; Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Kidney Diseases; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins

Although epoetin alfa is commonly initiated weekly (QW) in anemic chronic kidney disease (CKD) patients, recent evidence indicates that it can be initiated every 2 wk (Q2W) and used in maintenance therapy every 4 wk (Q4W). This study examined the feasibility of initiating epoetin alfa Q4W in anemic CKD patients not receiving dialysis.. This open-label study randomized subjects (1:2:2:2) to treatment with epoetin alfa 10,000 IU QW, 20,000 IU Q2W, 20,000 IU Q4W, or 40,000 IU Q4W for 16 wk. Subjects were > or =18 yr, had hemoglobin <11 g/dl, a glomerular filtration rate of 15 to 90 ml/min per 1.73 m(2), and had not received erythropoietic therapy within 8 wk. The primary analysis was a noninferiority comparison of the 40,000 IU Q4W to the 20,000 IU Q2W group in the per-protocol population with respect to hemoglobin change from baseline to the end of study.. Of 262 subjects randomized, 229 comprised the per-protocol population. Mean hemoglobin change from baseline for the 40,000 IU Q4W group (1.24 g/dl) was not inferior to the 20,000 IU Q2W group (1.11 g/dl) with the lower limit of 95% CI, -0.21 g/dl. In the QW, 20,000 IU Q2W, 20,000 IU Q4W, and 40,000 IU Q4W groups, 90%, 87%, 75%, and 86% of subjects, respectively, achieved a hemoglobin increase > or =1 g/dl. Serious adverse events were similar across all groups.. Epoetin alfa can be initiated Q4W in anemic CKD subjects.

Topics: Aged; Aged, 80 and over; Anemia; Chronic Disease; Drug Administration Schedule; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Feasibility Studies; Female; Ferritins; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Iron Compounds; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Transferrin; Treatment Outcome; United States

Emerging evidence suggests that epoetin alfa can be administered at extended intervals of up to 4 wk. This open-label, randomized study was performed to characterize the pharmacokinetic and pharmacodynamic profiles of four dosing regimens of epoetin alfa administered subcutaneously in anemic patients who had chronic kidney disease and were not on dialysis.. Thirty-eight patients, enrolled from nine centers in the United States, were > or =18 yr of age and had hemoglobin <11.0 g/dl and GFR 12 to 60 ml/min per 1.73 m(2). Patients received one of four epoetin alfa dosing regimens: 50 IU/kg three times per week, 10,000 IU once weekly, or 20,000 IU every 2 wk for 36 d or 40,000 IU every 4 wk for 64 d. Each regimen provided a similar dosage of epoetin alfa over 4 wk. Dosage adjustments were not permitted.. Drug exposure to epoetin alfa over 4 wk, based on area under the curve, was somewhat higher with the extended interval regimens compared with the three-times-weekly regimen. Mean change in hemoglobin during the study period was similar for all regimens. No patients were transfused. Three patients experienced five serious adverse events, none of which was considered treatment related.. Extended dosing interval regimens of epoetin alfa yielded modest pharmacokinetic differences but a similar pharmacodynamic response, suggesting that less frequent, higher dosages of epoetin alfa may be as effective as the current three-times-weekly regimen in anemic patients who have chronic kidney disease and are not on dialysis.

Topics: Aged; Aged, 80 and over; Anemia; Chronic Disease; Dialysis; Drug Administration Schedule; Epoetin Alfa; Erythrocyte Count; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Reticulocyte Count; Treatment Outcome; United States

Among hemodialysis patients, achieved hemoglobin is associated with Epoetin alfa dose and erythropoietin responsiveness. A prospective erythropoietin responsiveness measure was developed and its association with mortality evaluated.. Data from 321 participants were used and randomized to the hematocrit normalization arm of the Normal Hematocrit Cardiac Trial. Subjects were to receive a 50% Epoetin alfa dose increase at randomization. The prospective erythropoietin responsiveness measure was defined as the ratio of weekly hematocrit change (over the 3 wk after randomization) per Epoetin alfa dose increase (1000 IU/wk) corresponding to the mandated 50% dose increase at randomization. The distribution of responsiveness was divided into quartiles. Over a 1-yr follow-up, Cox proportional hazard modeling evaluated associations between this responsiveness measure and mortality.. Erythropoietin responsiveness values ranged from -2.1% to 2.4% per week per 1000 IU. Although subjects were similar across response quartiles, mortality ranged between 14% and 34% among subjects in the highest and lowest response quartiles (P = 0.0004), respectively. After adjusting for baseline prognostic indicators, highest versus lowest responsiveness was associated with a hazard ratio of 0.41 (95% confidence interval, 0.20 to 0.87).. Lower erythropoietin responsiveness is a strong, independent predictor of mortality risk and should be considered when evaluating associations between clinical outcomes and potential prognostic indicators, such as Epoetin alfa dose and achieved hemoglobin values.

Topics: Adult; Aged; Anemia; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hematocrit; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Proportional Hazards Models; Recombinant Proteins; Renal Dialysis; Risk Assessment; Survival Analysis; Treatment Outcome

This analysis quantifies the population pharmacokinetics of subcutaneous and intravenous epoetin delta, an epoetin produced in a human cell line, in pediatric patients with chronic kidney disease and estimates the effects of covariate factors on epoetin delta and epoetin alfa pharmacokinetic parameters. Erythropoietin serum concentration data, taken from a phase III study conducted in 60 patients aged 1 to 17 years, were best described by a 1-compartment model with first-order absorption and elimination. The typical point estimates were clearance (0.268 L/h), central volume of distribution (1.03 L), absorption rate constant (0.0554 h(-1)), and bioavailability (0.708) for a 35-kg male < or = 10 years who was predialysis and on subcutaneous epoetin delta treatment. Erythropoietin pharmacokinetic parameters were similar in pediatric patients as compared with adults when scaled by weight. The subcutaneous administration of epoetin alfa exhibited lower systemic bioavailability than subcutaneous administration of epoetin delta.

Topics: Adolescent; Child; Child, Preschool; Chronic Disease; Erythropoietin; Female; Humans; Infant; Kidney Diseases; Male; Models, Biological; Recombinant Proteins

To demonstrate safety and efficacy of epoetin delta for the management of anaemia in predialysis patients with chronic kidney disease (CKD).. This was a multicentre, open-label, uncontrolled study with predialysis CKD patients who had previously received subcutaneous epoetin therapy. Patients were switched to epoetin delta from their previous therapy, at an identical dose. Dose was subsequently titrated to maintain haemoglobin at 10.0-12.0 g/dL. Study duration was 52 weeks.. The primary endpoint was average haemoglobin levels over Weeks 12, 16, 20 and 24. Secondary analyses were performed on the proportion of patients with haemoglobin and haematocrit levels over preset target levels, haemoglobin and haematocrit levels through to study end and dosing levels.. Haemoglobin levels were maintained at 11.3 +/- 1.2 g/dL over Weeks 12-24. Over 80% of the haemoglobin measurements and 95% of the haematocrit measurements were above the predefined target level (haemoglobin > or = 10 g/dL; haematocrit > or = 30%). Weekly dose levels did not change significantly over the course of the trial. Epoetin delta was well tolerated, with adverse events occurring at frequencies expected for this patient population; no patient developed neutralizing anti-erythropoietin antibodies.. Epoetin delta was an effective and well-tolerated agent for the management of anaemia in a subgroup of predialysis CKD patients.

Topics: Adult; Aged; Anemia; Cell Line; Chronic Disease; Erythropoietin; Female; Ferritins; Hematocrit; Hemoglobins; Humans; Injections, Subcutaneous; Iron; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Transferrin; Treatment Outcome

Darbepoetin alfa, an erythropoiesis-stimulating protein, has a longer serum half-life than recombinant human erythropoietin, allowing less-frequent administration. This study aimed to demonstrate that once-monthly (QM) darbepoetin alfa administration would maintain haemoglobin (Hb) concentrations in subjects with chronic kidney disease (CKD) not receiving dialysis who had previously been administered darbepoetin alfa every 2 weeks (Q2W).. This was a multicentre study in which subjects with CKD receiving stable Q2W darbepoetin alfa doses and with stable Hb (100-130 g/L) were started on QM darbepoetin alfa dosing. The initial QM darbepoetin alfa dose was equivalent to the cumulative darbepoetin alfa dose administered during the month preceding enrollment. Darbepoetin alfa doses were titrated to maintain Hb concentrations between 100 and 130 g/L. The primary endpoint was the proportion of subjects maintaining mean Hb >or= 100 g/L during the evaluation period (weeks 21-33).. Sixty-six subjects were enrolled in the study and all received at least one dose of darbepoetin alfa; 55 (83%) had mean Hb >or= 100 g/L during evaluation. Mean (SD) Hb concentrations at baseline and during the evaluation period were 119 (8.7) g/L and 114 (9.8) g/L, respectively. The median QM darbepoetin alfa dose at baseline and during the evaluation period was 80 microg. Darbepoetin alfa was considered to be well-tolerated.. Patients with CKD not receiving dialysis who are receiving darbepoetin alfa Q2W can be safely and effectively extended to darbepoetin alfa QM. Dosing QM may simplify anaemia management for patients and health-care providers.

Topics: Aged; Asian People; Australia; Chronic Disease; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Treatment Outcome; White People

This Phase II study aimed to determine the optimal dose and administration schedule of continuous erythropoietin receptor activator (C.E.R.A.) given subcutaneously (s.c.) in patients receiving dialysis converting directly from s.c. epoetin therapy 1-3 times/week. An extension phase examined long-term safety and efficacy.. Patients were assigned to one of three C.E.R.A. dose groups determined by multiplying the previous weekly dose of epoetin by one of three ratios (0.4/150, 0.8/150, 1.2/150 for groups A, B and C, respectively). Within each group, patients were randomized to once weekly (QW), once every 3 weeks (Q3W) and once monthly (Q4W) schedules. Dose adjustments were not permitted for the first 6 weeks. The core study period was 19 weeks (21 weeks in the Q4W cohorts). Patients could enter a 12-month extension period at the same schedule, aiming to maintain haemoglobin (Hb) at 11-12 g/dL.. 137 patients entered the core period, and 62 continued into the extension period. A dose-dependent relationship was seen in the primary efficacy variable, change in Hb standardized to a 6 week period (p < 0.0001), but effect was independent of schedule. Hb levels were maintained throughout the study, with few dose changes. C.E.R.A. was generally well tolerated and the most frequent adverse event was hypotension.. The results suggest that s.c. C.E.R.A. at up to once monthly intervals provides stable maintenance of Hb levels in dialysis patients converting directly from epoetin 1-3 times/week. Achieving tight Hb control with few dose adjustments at extended administration intervals may offer health benefits and improvements in resource management.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Algorithms; Anemia; Chronic Disease; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Epoetin delta is an epoetin that, unlike existing agents, is produced in a human cell line. The present study investigated the efficacy and tolerability of intravenous (i.v.) epoetin delta compared with i.v. epoetin alfa.. This was a 6-month, multicentre, randomized, double-blind trial in haemodialysis patients previously receiving epoetin alfa. Haematological parameters were assessed, and adverse events monitored. Equivalent efficacy was defined as a difference in mean haemoglobin between the two agents over weeks 12-24 of < or = 1 g/dl with a 90% confidence interval (CI) within the range -1 to 1 g/dl.. In total, 560 patients received epoetin delta while 192 received epoetin alfa, and 76.8% and 79.7% of patients, respectively, completed the study. Both agents showed similar efficacy in controlling anaemia: the point estimate for the difference in mean haemoglobin over weeks 12-24 was 0.01 g/dl (90% CI, -0.13, 0.15 g/dl), confirming equivalence. Adverse events were those expected in dialysis patients. Events possibly related to treatment occurred in 9.2% of patients receiving epoetin delta and 8.4% receiving epoetin alfa. Serious adverse events (SAEs) occurred in 33.0% and 26.7% of patients in the epoetin delta and epoetin alfa groups, respectively. Six patients in the epoetin delta group experienced an SAE considered possibly related to treatment (mostly access-related clotting), compared with no patient in the epoetin delta group. None of these SAEs were life threatening.. Epoetin delta was shown to have an equivalent efficacy and safety profile to epoetin alfa in this 6-month study.

Topics: Aged; Anemia; Blood Transfusion; Double-Blind Method; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Research Design; Time Factors

C.E.R.A., a continuous erythropoietin receptor activator, is in development to provide anemia correction and stable maintenance of hemoglobin (Hb) levels at extended administration intervals in patients with chronic kidney disease (CKD). This study examined its efficacy and safety when administered up to once monthly in patients who have CKD and are on dialysis and randomly convert directly from epoetin alpha or beta one to three times weekly.. In this three-arm, comparator-controlled, open-label, randomized, parallel-group, Phase III study, 572 dialysis patients (> or =18 yr) who were receiving stable subcutaneous epoetin one to three times weekly were randomly assigned (1:1:1) to continue epoetin or to receive subcutaneous C.E.R.A. once monthly or twice monthly for 52 wk. Dosage was adjusted to maintain Hb +/-1.0 g/dl of baseline level. Primary end point was mean change in Hb level between baseline and the evaluation period (weeks 29 to 36).. Mean Hb levels during the evaluation period were similar between groups (once-monthly C.E.R.A. 11.5 g/dl; twice-monthly C.E.R.A. 11.7 g/dl; epoetin 11.5 g/dl). The difference between C.E.R.A. and epoetin in mean change (97.5% confidence interval) in Hb concentration between baseline and evaluation was -0.022 g/dl (-0.262 to 0.217) for once monthly and 0.141 g/dl (-0.098 to 0.380) for twice monthly. Analysis demonstrated that C.E.R.A. was as effective as epoetin in maintaining Hb and was well tolerated.. Subcutaneous C.E.R.A. once or twice monthly successfully maintained tight and stable Hb levels in patients who were on dialysis and randomly converted directly from epoetin one to three times weekly.

Topics: Anemia; Chronic Disease; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins; Renal Dialysis

To evaluate the efficacy and safety of the first human cell line-derived erythropoietin, epoetin-delta, in the management of anemia in patients with chronic kidney disease.. This was a multicenter, randomized, double-blind, parallel-group, active-control, Phase III study. Patients aged > or = 18 years with chronic renal disease requiring hemodialysis, with hemoglobin (Hb) levels in the range 9.6-12.4 g/dl, and who had been treated with recombinant erythropoietin for > or = 90 days before study entry were eligible. In the initial double-blind comparative study phase, patients were randomized in a 3:1 ratio to 24-week treatment with either intravenous (i.v.) epoetin-delta (ED) or epoetin-alpha (EA). Patients then entered a 28-week open-label phase, receiving i.v. ED at a dose equal to that of i.v. ED or EA which they received at the end of the blinded phase.. In total, 752 patients were randomized, of whom 555 patients subsequently received ED and 191 patients EA, with 583 patients (77.5%) completing the double-blind phase and entering the open-label phase. There was no significant difference between groups for the primary endpoint: the average Hb level from Weeks 12-24 of the study. The adjusted mean average Hb level for the modified intent-to-treat (mITT) population was 11.57 g/dl in the ED group (n = 491, mean dose 63.5 IU/kg) and 11.56 g/dl in the EA group (n = 175, mean dose 62.8 IU/kg). Efficacy was maintained on long-term use. Data for Weeks 12-52 show that ED maintained patients' Hb levels in the target range (10-12 g/dl) with a mean Hb level of 11.31 g/dl at a mean ED dose of 63.7 IU/kg. ED therapy was well tolerated, with a similar overall incidence of adverse events (AEs) (94.4%) to the EA group (92.1%) in the double-blind phase (most common events: hypotension, upper respiratory tract infection, muscle cramps, headache). AEs occurring during the open-label phase were generally similar in type and frequency to those reported during the double-blind phase.. The human cell line-derived erythropoietin, epoetin-delta, provides an effective, well tolerated new option for the management of anemia in patients with chronic kidney disease.

Topics: Anemia; Cell Line; Chronic Disease; Double-Blind Method; Erythropoietin; Female; Humans; Kidney Diseases; Male; Middle Aged; Recombinant Proteins

Renal anemia is a very serious problem in hemodialysis patients. In this regard, the investigation was focused on whether ultrapure dialysate could improve renal anemia and the mechanism of renal anemia.. Ultrapure dialysate was used over a 2 years period for 61 patients on maintenance hemodialysis. During this period, the changes in renal anemia and red blood cell life span were investigated. The changes in the latter were evaluated using the creatine concentration in red blood cell.. The hemoglobin concentration, RBC count, and hematocrit concentration before the use of the ultrapure dialysate were 9.1 +/- 0.2 g/dL, 309.9 +/- L7.2 x 10(4)/microL, and 28.8 +/- 0.6%, respectively. These values significantly increased to 10.2 +/- 0.1 g/dL, 349.7 +/- 5.6 x 10(4)/microL, and 32.6 +/- 0.3%, respectively, after 2 years of ultrapure dialysate use. The increase in reticulocyte count indicated enhanced erythropoiesis by ultrapure dialysate. The red blood cell life span evaluated by creatine concentration in red blood cell was also prolonged after the use of ultrapure dialysate.. Ultrapure dialysate is considered to improve the renal anemia of dialysis patients by promoting erythropoiesis and prolonging red blood cell life span.

Topics: Aged; Anemia; C-Reactive Protein; Creatine; Dialysis Solutions; Dose-Response Relationship, Drug; Erythrocyte Count; Erythropoiesis; Erythropoietin; Female; Ferritins; Hematocrit; Hemoglobins; Humans; Kidney Diseases; Longitudinal Studies; Male; Renal Dialysis

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

C.E.R.A. (methoxy polyethylene glycol-epoetin beta), a continuous erythropoietin receptor activator, differs from traditional erythropoiesis-stimulating agents in its pharmacokinetic and receptor binding properties. This phase I, randomized, open-label, single-center, single-dose, 3-way crossover study in 42 healthy volunteers compared the pharmacokinetic and pharmacodynamic profile of C.E.R.A. 3.0 microg/kg after subcutaneous injection into the abdomen, arm, or thigh. The pharmacokinetic profile was similar at all 3 injection sites, with a prolonged apparent elimination half-life from 160 to 164 hours, area under the concentration-time curve from 4088 to 4323 ng.h/mL, and clearance/bioavailability from 0.64 to 0.68 mL/h/kg. C.E.R.A. produced a sustained erythropoietic response, and the pharmacodynamic profile (area under the reticulocyte count-time curve and maximum increase in reticulocyte count) was similar for all sites. C.E.R.A. was generally well tolerated, regardless of the administration site. This study suggests that C.E.R.A. has the potential to offer a choice of injection sites in clinical practice. The long half-life may permit effective anemia management with extended dosing intervals. Phase III clinical studies support the role of C.E.R.A. in managing anemia in patients with chronic kidney disease.

Topics: Adolescent; Adult; Aged; Anemia; Chronic Disease; Cross-Over Studies; Drug Carriers; Erythropoietin; Female; Humans; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins

This study is designed to assess the effect of early and complete correction of anemia by using recombinant human erythropoietin (epoetin) alfa on the progression of chronic kidney disease (CKD).. Patients were randomly assigned to achieve high (13 to 15 g/dL [130 to 150 g/L]) or low (11 to 12 g/dL [110 to 120 g/L]) hemoglobin-level targets during 4 months of stabilization, followed by 36 months of maintenance. Glomerular filtration rate (GFR) decrease was measured by using iohexol clearance. Quality of life, nutrition, and safety also were monitored.. Because of labeling changes for subcutaneous administration of epoetin alfa (Eprex; Johnson and Johnson, Schaffhausen, Switzerland), the study was terminated prematurely. There were 195 patients enrolled in each group; 108 high-hemoglobin and 133 low-hemoglobin patients entered the maintenance phase. Mean maintenance duration was 7.4 months for the high-hemoglobin group and 8.3 months for the low-hemoglobin group. GFR decrease was numerically, but not statistically significantly, lower with the high-hemoglobin group (0.058 versus 0.081 mL/min/1.73 m2/mo [< 0.01 mL/s/1.73 m2/mo]). Physical quality-of-life measures showed trends (Role-Physical, P = 0.055; Physical Function, P = 0.083) or statistically significant improvement (Vitality, P = 0.042) with high hemoglobin levels at the end of the stabilization phase. Adverse events were similar between groups. Cardiovascular adverse events occurred in 25% of the high-hemoglobin and 18% of the low-hemoglobin patients (P = 0.137). Neither epoetin dosage nor hemoglobin level was associated with cardiovascular adverse events or death.. These data suggest that normalization of hemoglobin levels in patients with CKD is safe. Longer duration studies are needed to clarify efficacy benefits with high hemoglobin levels.

Topics: Adolescent; Adult; Aged; Anemia; Chronic Disease; Disease Progression; Epoetin Alfa; Erythropoietin; Female; Glomerular Filtration Rate; Hematinics; Humans; Kidney Diseases; Male; Middle Aged; Quality of Life; Recombinant Proteins

Darbepoetin alfa, an erythropoiesis-stimulating glycoprotein, has proved efficacious in the treatment of anemia of chronic kidney disease (CKD) in adult subjects. However, little information is available from pediatric populations. We conducted an open-label, non-inferiority, 28-week study comparing the efficacy of darbepoetin alfa with that of recombinant human erythropoietin (rHuEpo) in pediatric subjects with CKD. Subjects, aged 1-18, who were receiving stable rHuEpo treatment (n=124) were randomized (1:2) to either continue receiving rHuEpo or convert to darbepoetin alfa, with doses titrated to achieve and maintain hemoglobin (Hb) levels between 10.0 and 12.5 g/dl. Darbepoetin alfa was considered to be non-inferior to rHuEpo if the lower limit of the two-sided 95% confidence interval (CI) for the difference in the mean change in Hb between the two treatment groups was above -1.0 g/dl. The adjusted mean change in Hb between the baseline and the evaluation period for the rHuEpo and darbepoetin alfa groups was -0.16 g/dl and 0.15 g/dl, respectively, with a difference of 0.31 g/dl (95% CI: -0.45, 1.07) between the means. These results, and the comparable safety profiles, demonstrate that darbepoetin alfa is non-inferior to rHuEpo in the treatment of anemia in pediatric patients with CKD.

Topics: Anemia; Child; Chronic Disease; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Kidney Diseases; Male

Among lipid abnormalities observed in patients with chronic kidney disease (CKD) is a significant decrease in serum high-density lipoprotein cholesterol (HDL-C) levels. In a previously published randomized control trial, we showed that early erythropoietin (EPO) administration in a predialysis population slowed the progression of CKD. In the present nested substudy, we examine whether EPO has an influence on serum HDL-C levels in comparison to other lipid parameters in this population.. Eighty-eight patients with CKD stages 3 and 4 were enrolled in the study. Forty-five patients (group 1) were treated with EPO (50 U/kg/wk), targeting to increase hemoglobin levels to 13 g/dL or greater (>or=130 g/L). The other patients (group 2) remained without treatment until hemoglobin levels decreased to less than 9 g/dL (<90 g/L). The duration of the study was 12 months.. At the end of the study, we observed a statistically significant decrease in serum levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglycerides in both groups. However, serum HDL-C levels significantly increased in only group 1 (from 42.5 +/- 10.4 to 55.9 +/- 8.1 mg/dL [1.10 +/- 0.27 to 1.45 +/- 0.21 mmol/L]; P < 0.001), whereas they were unchanged in group 2. In addition, a significant decrease in atherogenic LDL-C/HDL-C ratio was observed in only group 1. Importantly, the increase in serum HDL-C levels correlated positively with the increase in hemoglobin values in EPO-treated patients.. Our results show that EPO treatment of predialysis patients with CKD significantly increases serum HDL-C levels, which may represent an important antiatherogenic effect of this hormone.

Topics: Adult; Aged; Aged, 80 and over; Cholesterol, HDL; Chronic Disease; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Renal Dialysis

Anemia has received increasing attention as an independent cardiovascular risk factor in patients with chronic kidney disease (CKD); a number of studies have highlighted its clear relationship with CKD mortality, because its impact on cardiac function leads to the development of left ventricular hypertrophy. However, despite the association between higher hemoglobin levels and better outcomes, a number of clinical studies have failed to demonstrate that fully correcting anemia has a positive effect on morbidity and mortality in patients with CKD. The Cardiovascular Reduction Early Anemia Treatment Epoetin beta (CREATE) study was designed from the hypothesis that, as anemia develops early in the course of CKD and nearly at the same time as cardiovascular disease, its earlier correction may provide better protection against the development of cardiovascular abnormalities. This randomized, multicenter, open-label, parallel-group trial involved 603 patients who had moderate anemia (hemoglobin 11 to 12.5 g/dl) and stage 3 to 4 CKD (estimated GFR 15 to 35 ml/min) and were randomly assigned to attain complete or partial anemia correction. The final results are due to be published within a few months, but the preliminary analyses do not show that complete anemia correction leads to any cardiovascular advantage, although the cardiovascular event rate was half that expected, possibly as a result of patient selection, trial effect, and improved medical care. The baseline findings also indicated that the burden of cardiovascular disease already is very high even in relatively early stages of CKD.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins; Risk Factors; Treatment Outcome

Intravenous iron supplementation is an integral part of the management of anemia in patients with chronic kidney disease. Traditionally, this has been administered as an infusion over 1 or more hours, which requires the use of intravenous fluids and administration tubing, along with extra demands on patient and nursing time.. We prospectively investigated the safety and practicality of administering iron sucrose, 200 mg, as a bolus injection over 2 minutes in patients with chronic kidney disease. A total of 2,297 injections were administered to 657 patients. Any adverse events were recorded, including acute anaphylactoid reactions to the iron injection, along with the presence or absence of metallic taste and phlebitis, and these were classified as "serious" and "nonserious.". The most common adverse event was a mild and transient metallic taste that occurred during 412 injections (17.9%); in no case was this of significant distress to the patient. Excluding this, 2,240 injections (97.5%) proceeded uneventfully, and no case of phlebitis was recorded. Adverse events other than metallic taste were recorded in association with 57 injections (2.5%). Seven of these were caused by an acute anaphylactoid reaction to the intravenous iron. All 7 acute reactions resolved completely within 30 minutes with no sequelae, and none required hospitalization. The remaining 50 adverse events consisted of pain during the injection (n = 31), pain after the injection with or without some bruising (n = 9), nausea/gastrointestinal symptoms (n = 3), lethargy (n = 4), and lightheadedness (n = 3).. Administration of 200 mg of iron sucrose as an intravenous bolus injection over 2 minutes is a practical dosing regimen in patients with chronic kidney disease, resulting in considerable savings in time and cost.

Topics: Adult; Aged; Anaphylaxis; Anemia, Hypochromic; Chronic Disease; Cohort Studies; Dysgeusia; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Graft Rejection; Humans; Hypotension; Injections, Intravenous; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Peritoneal Dialysis; Peritoneal Dialysis, Continuous Ambulatory; Prospective Studies

This randomized clinical trial is designed to assess whether the prevention and/or correction of anemia, by immediate versus delayed treatment with erythropoietin alfa in patients with chronic kidney disease, would delay left ventricular (LV) growth. Study design and sample size calculations were based on previously published Canadian data.. One hundred seventy-two patients were randomly assigned. The treatment group received therapy with erythropoietin alfa subcutaneously to maintain or achieve hemoglobin (Hgb) level targets of 12.0 to 14.0 g/dL (120 to 140 g/L). The control/delayed treatment group had Hgb levels of 9.0 +/- 0.5 g/dL (90 +/- 5 g/L) before therapy was started: target level was 9.0 to 10.5 g/dL (90 to 105 g/L). Optimal blood pressure and parathyroid hormone, calcium, and phosphate level targets were prescribed; all patients were iron replete. The primary end point is LV growth at 24 months.. One hundred fifty-two patients were eligible for the intention-to-treat analysis: mean age was 57 years, 30% were women, 38% had diabetes, and median glomerular filtration rate was 29 mL/min (0.48 mL/s; range, 12 to 55 mL/min [0.20 to 0.92 mL/s]). Blood pressure and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were similar in the control/delayed treatment and treatment groups at baseline. Erythropoietin therapy was administered to 77 of 78 patients in the treatment group, with a median final dose of 2,000 IU/wk. Sixteen patients in the control/delayed treatment group were administered erythropoietin at a median final dose of 3,000 IU/wk. There was no statistically significant difference between groups for the primary outcome of mean change in LV mass index (LVMI) from baseline to 24 months, which was 5.21 +/- 30.3 g/m2 in the control/delayed treatment group versus 0.37 +/- 25.0 g/m2 in the treatment group. Absolute mean difference between groups was 4.85 g/m2 (95% confidence interval, -4.0 to 13.7; P = 0.28). Mean Hgb level was greater in the treatment group throughout the study and at study end was 12.75 g/dL (127.5 g/L in treatment group versus 11.46 g/dL [114.6 g/L] in control/delayed treatment group; P = 0.0001). LV growth occurred in 20.1% in the treatment group versus 31% in the control/delayed treatment group (P = 0.136). In patients with a stable Hgb level, mean LVMI did not change (-0.25 +/- 26.7 g/m2), but it increased in those with decreasing Hgb levels (19.3 +/- 28.2 g/m2; P = 0.002).. This trial describes disparity between observational and randomized controlled trial data: observed and randomly assigned Hgb level and LVMI are not linked; thus, there is strong evidence that the association between Hgb level and LVMI likely is not causal. Large randomized controlled trials with unselected patients, using morbidity and mortality as outcomes, are needed.

Topics: Adult; Aged; Anemia; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium; Canada; Chronic Disease; Epoetin Alfa; Erythropoietin; Female; Heart Failure; Heart Ventricles; Hemoglobins; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Diseases; Lipids; Male; Middle Aged; Organ Size; Parathyroid Hormone; Phosphates; Recombinant Proteins; Renal Dialysis; Single-Blind Method; Treatment Failure; Ultrasonography

Changes in blood viscosity and total peripheral resistance may contribute to increased blood pressure during partial correction of renal anemia with erythropoietin. An increase in hemoglobin level is followed by decreases in cardiac output and left ventricular mass. We examined how normalization of hemoglobin in predialysis patients affects both hemorheological and hemodynamic variables.. Twelve moderately anemic predialysis patients (hemoglobin 115.9+/-7.8 g/l) received epoetin-alpha with the aim of achieving a normal hemoglobin level (135-160 g/l). Hemorheological variables were measured using rotational viscometry. Cardiac index was determined by means of Doppler echocardiography.. After 48 weeks, the hematocrit level had increased from 37.9%+/-3.0% to 47.0%+/-3.1% (p<0.0001). Blood viscosity increased from 3.84+/-0.33 to 4.59+/-0.4 mPa x s (p<0.001). Blood viscosity standardized to a hematocrit level of 45% and a plasma viscosity of 1.31 mPa x s did not change. Plasma viscosity, erythrocyte aggregation tendency and erythrocyte fluidity remained unchanged. The cardiac index decreased from 2.64+/-0.57 to 2.19+/-0.72 l/min/m(2) (p<0.05). The total peripheral resistance index increased from 3270+/-985 to 4013+/-1046 (dyn x s/cm(5))m(2) (p<0.05). Blood pressure remained constant, but the amount of antihypertensive medication used increased by 30%.. Hemoglobin normalization in predialysis patients raised blood viscosity and total peripheral resistance due to an increase in hematocrit level, without other consistent hemorheological changes. Antihypertensive therapy had to be increased in many patients to maintain an acceptable blood pressure. The cardiac index was reduced, which may have prevented further development of left ventricular hypertrophy.

Topics: Anemia; Blood Viscosity; Cardiac Output; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Treatment Outcome; Vascular Resistance

Anemia occurs in approximately 47% of patients with chronic kidney disease (CKD) not on dialysis. Recombinant human erythropoietin (r-HuEPO, epoetin alfa) has been proven safe and effective for anemia treatment in patients with CKD using a three times-weekly regimen. The current study was conducted to evaluate the clinical safety and efficacy of a less frequent dosing regimen (once weekly) in this population.. This prospective, multicenter, open-label, non-randomized study enrolled 1,557 adult anemic (hemoglobin (Hb) < or = 10 g/dl) CKD patients not on dialysis. Epoetin alfa 10,000 U was administered subcutaneously once weekly for 16 weeks. Titration to 20,000 U once weekly at week 5 was permitted if patients had an increase in Hb < 1 g/dl. Safety and efficacy were assessed by changes in health-related quality of life (Linear Analog Scale Assessment (LASA) and Kidney Disease Questionnaire (KDQ)), changes in hematologic parameters and transfusion utilization, and incidence and severity of adverse events.. 1,338 patients were evaluable for efficacy. Mean Hb level increased from 9.1 g/dl at baseline to 11.6 g/dl at study completion (last observed value after baseline) (p < 0.0001). Overall, 89.8% of patients responded to once-weekly dosing, exhibiting an increase in Hb level of > or = 1 g/dl from baseline. The percentage of patients that required transfusion decreased from 11.1% (baseline) to 3.7% (during the study) (p < 0.0001). All quality-of-life parameters improved significantly from baseline (p < 0.0001). Mean LASA scores for energy, activity and overall quality of life increased from baseline to study completion by 27.9 mm (70.5%), 24.5 mm (57.0%) and 22.6 mm (47.4%), respectively. All 5 KDQ domains showed statistically significant improvements (p < 0.0001). Hb change was a strong predictor for all 5 KDQ domains and the overall score (p < 0.0001). Treatment with once-weekly epoetin alfa was well tolerated, similar to that reported with three times-weekly dosing.. Once-weekly epoetin alfa therapy is safe and effective for treating anemia in patients with CKD not on dialysis, and is associated with significant improvements in functional status and quality of life.

Topics: Aged; Analysis of Variance; Anemia; Blood Transfusion; Chronic Disease; Comorbidity; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Prospective Studies; Quality of Life; Recombinant Proteins; Regression Analysis; Treatment Outcome

Ketorolac, which may cause renal vasoconstriction by cyclooxygenase inhibition, is often administered to patients anesthetized with sevoflurane that is metabolized to inorganic fluoride (F(-)), another potential nephrotoxin. We assessed this possible interaction using urine N-acetyl-beta-D-glucosaminidase indexed to urinary creatinine (U-NAG/crea) as a marker of proximal tubular, beta2-microglobulin as a tubular, urine oxygen tension (P(u)O(2)) as a medullary, and erythropoietin as a marker of tubulointerstitial damage. Thirty women (ASA physical status I-II) undergoing breast surgery were included in our double-blinded study. They were allocated into two groups receiving either ketorolac 30 mg IM (Group K) or saline (Group C) at the time of premedication, at the end of, and 6 h after anesthesia maintained with sevoflurane. Urine output, U-NAG/crea, P(u)O(2,) serum creatinine, urea, and F(-) were assessed. Blood loss was larger in Group K (465 +/- 286 mL vs 240 +/- 149 mL, mean +/- SD, P < 0.05). The MAC-doses of sevoflurane were similar. U-NAG/crea increased during the first 2 h of anesthesia and serum F(-) peaked 2 h after the anesthesia without differences between the groups. There were no statistically significant changes in P(u)O(2), erythropoietin, beta2-microglobulin, serum creatinine, urea, or urine output during anesthesia or the recovery period in either group. Our results indicate that the kidneys are not affected by ketorolac administered in connection with sevoflurane anesthesia.. The different kinetics of N-acetyl-beta-D-glucosaminidase indexed to urinary creatinine and serum inorganic fluoride during and after sevoflurane anesthesia suggest that the observed mild renal tubular function deterioration is not caused by inorganic fluoride. Administration of ketorolac IM is therefore considered safe in adequately hydrated healthy adult patients given sevoflurane anesthesia.

Topics: Acetylglucosaminidase; Adult; Anesthetics, Inhalation; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Blood Loss, Surgical; Breast; Creatinine; Double-Blind Method; Drug Interactions; Erythropoietin; Female; Fluorides; Humans; Ketorolac; Kidney Diseases; Methyl Ethers; Oxygen; Sevoflurane; Sodium

We present our results on the efficacy and safety of low dose r-HuEPO given subcutaneously in the treatment of anaemia in CAPD. We have studied 10 stable patients (5 males, 5 females) on CAPD. In our study subcutaneous r-HuEPO was administered twice a week for 6 months. Mean initial dose of r-HuEPO was 67.3+/-21.7 U/kg/week, and maintenance dose was 35.8+/-12.1 U/kg/week. The target Hb concentration was 10-12 g/dl. All patients responded to r-HuEPO. During treatment significant increases of haemoglobin concentration (p<0.05), haematocrit (p<0.05), red cell count (p<0.05) and reticulocyte count (p<0.05) were observed. We found no significant changes in total white cell or platelet counts. Long-term r-HuEPO treatment did not influence significantly plasma levels of electrolytes (Na, K, Ca), urea and creatinine. We found no significant changes in ultrafiltration volumes. In the present study the mean systolic and diastolic blood pressures did not change. Liver function tests were normal at the beginning and at the end of the study. r-HuEPO treatment was associated with a decrease of ferritin (455+/-90 vs. 224+/-83 microg/l. Oral or intravenous iron substitution became necessary in 6 patients. Side effects in our study were minimal; one patient had myalgia after the first seven doses but this disappeared as treatment was continued. Two patients reported pain (mild) at the injection site. In the present study, the correction of anaemia was accompanied by a substantial improvement in the quality of life, mainly in capacity for work, household and social activities.

Topics: Adult; Aged; Anemia; Blood Chemical Analysis; Erythrocyte Count; Erythropoietin; Female; Ferritins; Hematocrit; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Reticulocyte Count; Treatment Outcome

To delineate the pathogenesis of the reduction in hemoglobin occurring in renal transplant patients treated with angiotensin converting enzyme inhibitors (ACEI) and azathioprine (AZA) a controlled, prospective trial of ACEI withdrawal was conducted. The ACEI was replaced by nifedipine or clonidine in 15 kidney transplant patients immunosuppressed with AZA and prednisone (enalapril in 14 and captopril in 1). Before and during 10 to 12 weeks after withdrawal of the ACEI, AZA metabolites, renal function parameters and hematological parameters including erythropoietin and reticulocytes were evaluated. Enalaprilat levels were measured and compared with 15 similar patients matched for transplant function and enalapril dosage immunosuppressed with cyclosporine and prednisone. AZA metabolites did not differ significantly in the presence or absence of the ACEI. Enalaprilat levels also showed no significant difference between the two patient groups treated with AZA or cyclosporine. Hematocrit and hemoglobin increased significantly from 37.5 +/- 6.4 to 39.7 +/- 3.6% (mean +/- SD, P = 0.02) and 12.8 +/- 2.2 to 13.5 +/- 1.2 g/dl, P = 0.04, respectively, 10 to 12 weeks after ACEI treatment had been discontinued. Simultaneously numbers of reticulocytes and erythropoietin concentrations rose significantly after 2, 4 and 10 weeks, with a peak at two weeks (from 14.1 +/- 3.8 to 20.6 +/- 8.0/1000, P < 0.05 and from 14.3 +/- 12.4 to 29.3 +/- 54.5 mU/ml, P < 0.05, respectively). In conclusion, ACEI-related anemia in renal transplant recipients seems to be due to the erythropoietin-lowering effect of this group of drugs. A pharmacokinetic interaction between AZA and enalapril is not likely since plasma enalaprilat levels were independent of the immunosuppressive regimen and AZA metabolite levels were unchanged in the presence and absence of the ACEI. Several mechanisms by which angiotensin converting enzyme blockade may cause a decrease in circulating erythropoietin are discussed.

Topics: Adult; Anemia; Angiotensin-Converting Enzyme Inhibitors; Azathioprine; Cyclosporine; Drug Interactions; Enalaprilat; Erythrocytes; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Thioguanine

A disease-specific questionnaire was developed for patients receiving chronic hemodialysis by interviewing patients to determine which aspects of their quality of life were adversely affected by their disease. The final questionnaire contained 26 questions in five dimensions (physical symptoms, fatigue, depression, relationships with others, frustration). The questionnaire demonstrated construct validity when compared with the Sickness Impact Profile, time trade-off technique and an exercise stress test. It was reproducible in stable, placebo-treated patients (correlation coefficient 0.85-0.98 for the 5 dimensions). It was more responsive than other measures in detecting an improvement with erythropoietin therapy in a randomized, placebo-controlled trial. This questionnaire should be useful for the assessment of the effect of various interventions upon the quality of life of hemodialysis patients.

Topics: Anemia; Depression; Double-Blind Method; Erythropoietin; Fatigue; Humans; Kidney Diseases; Quality of Life; Recombinant Proteins; Renal Dialysis; Surveys and Questionnaires

An open non-randomized clinical trial with recombinant human erythropoietin (rhEpo) was conducted in 10 chronic haemodialysis patients with considerable iron overload. Pretreatment serum erythropoietin levels were significantly decreased for the degree of anaemia (22.0 +/- 7.6 mUnits (U) ml-1). Initially all patients received 120 U kg-1 of rhEpo intravenously three times a week and after a period of 45 days the haematocrit rose from 25 +/- 3 to 36 +/- 5. A reduced dose of 30 U kg-1 was then instituted which stabilized the haematocrit at this level. The development of anti-erythropoietin antibodies to rhEpo could not be demonstrated. Endogenous serum erythropoietin levels remained unchanged during therapy with rhEpo. The serum ferritin concentration, which was initially 3118 +/- 1556 micrograms l-1, was significantly reduced to 2203 +/- 1299 micrograms l-1 after an 80-d treatment period. The side-effects in three patients included the occasional sensation of increased body heat without fever. In one previously hypertensive patient the antihypertensive therapy had to be temporarily increased, but otherwise both the mean diastolic and systolic blood pressure remained constant during the observation period. No clotting of arteriovenous fistulas occurred.

Topics: Adolescent; Adult; Aged; Blood Pressure; Clinical Trials as Topic; Erythropoietin; Female; Ferritins; Hematocrit; Humans; Kidney Diseases; Male; Middle Aged; Renal Dialysis

Topics: Adult; Aged; Anemia; Biological Availability; Clinical Trials as Topic; Erythropoietin; Female; Humans; Injections, Intraperitoneal; Injections, Intravenous; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory

The response of erythropoietin to dietary protein was examined in nine subjects with a variety of glomerular diseases. They were randomly assigned by using a crossover design to two 11-day periods, one on a high-protein diet (2 gm/kg/day) and the other on a low-protein diet (0.55 gm/kg/day). The high-protein diet was associated with increased urinary erythropoietin excretion (4.28 +/- 0.84 U/24 hr vs 1.28 +/- 0.16 U/24/hr; p less than 0.05), increased serum erythropoietin concentration (22 +/- 2 mU/ml vs 10 +/- 2 mU/ml; p less than 0.05), and increased reticulocyte count (3.0 +/- 0.8 vs 1.6 +/- 0.4; p less than 0.05), demonstrating that erythropoietin production by the diseased kidney was still responsive to dietary protein manipulation. To examine whether changes in erythrocyte survival could be responsible for the differences in erythropoietin production, red cell survival was measured in two groups of subtotally nephrectomized rats, one group ingesting a high-protein diet (30%) and the other a low-protein diet (6%). No difference in erythrocyte survival rate was found. Reticulocyte counts were, however, elevated on the high-protein diet. We conclude that in the diseased kidney, a high-protein diet, perhaps by increasing renal O2 consumption, directly stimulates erythropoietin production.

Topics: Adult; Animals; Dietary Proteins; Erythrocyte Aging; Erythrocyte Count; Erythropoietin; Female; Humans; Kidney Diseases; Male; Middle Aged; Radioimmunoassay; Random Allocation; Rats; Rats, Inbred Strains; Reticulocytes

A double blind cross-over trial of Nandrolone decanoate (Decadurabolin) was carried out in 27 patients with anaemia due to end stage renal disease, stabilised on regular haemodialysis. Sixteen patients completed the study, the other patients being excluded from the final analysis for a variety of reasons including side effects related to the androgen. There was no sustained significant rise in haemoglobin concentration or in red cell mass. Erythropoietin levels did not alter, they were within or below the normal range, but were lower than would be expected for the degree of anaemia. A majority of patients reported increased well-being including exercise tolerance, appetite and libido. Voice changes and hirsutism were noted, mainly in the females. Instability of anticoagulant therapy and abnormalities in liver function were found in some patients. The benefits, though real, were restricted essentially to the improvement in subjective findings and were unrelated to laboratory measurements. These effects might be obtained with a lower dosage of the drug.

Topics: Adult; Anemia; Clinical Trials as Topic; Double-Blind Method; Erythropoietin; Female; Humans; Kidney Diseases; Male; Middle Aged; Nandrolone; Renal Dialysis

Hypoxia-inducible factor-prolyl hydroxylase (HIF-PHD) inhibitors are therapeutic agents for renal anemia that work through HIF2-mediated upregulation of erythropoietin (EPO) and have also been reported to suppress renal fibrosis. Group 2 innate lymphoid cells (ILC2s) have been proven to be involved in the pathogenesis of fibrosis in various organs, including the kidney. However, the relationship between the HIF pathway, renal fibrosis, and kidney ILC2s remains unclear. In the present study, we found that HIF activation by HIF-PHD inhibitors suppressed type 2 cytokine production from kidney ILC2s. The enhanced HIF pathway downregulated the IL-33 receptor ST2L on ILC2s, and phosphorylation of downstream p38 MAPK was attenuated. M2 macrophages that promote renal fibrosis were polarized by ILC2 supernatants, but reduced cytokine production from ILC2s treated with HIF-PHD inhibitors suppressed this polarization. Our findings suggest that HIF-PHD inhibitors are potential therapeutic agents for renal fibrosis that are mediated by the alteration of ILC2 function.

Topics: Erythropoietin; Fibrosis; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Immunity, Innate; Kidney; Kidney Diseases; Lymphocytes; Macrophage Activation; Prolyl Hydroxylases; Prolyl-Hydroxylase Inhibitors

Topics: Administration, Oral; Anemia; Drug Approval; Erythropoietin; Hematinics; Humans; Kidney Diseases; United States; United States Food and Drug Administration

This cohort study was designed to explore whether roxadustat or erythropoietin could affect thyroid function in patients with renal anemia.. The study involved 110 patients with renal anemia. Thyroid profile and baseline investigations were carried out for each patient. The patients were divided into two groups: 60 patients taking erythropoietin served as the control group (rHuEPO group) and 50 patients using roxadustat served as the experimental group (roxadustat group).. The results indicated that there were no significant differences in serum total thyroxine (TT4), total triiodothyronine (TT3), free triiodothyronine (FT3), free thyroxine (FT4) or thyroid stimulating hormone (TSH) between the two groups at baseline. After treatment, TSH, FT3, and FT4 were significantly lower in the roxadustat group than in the rHuEPO group (. Roxadustat may lead to a higher risk of thyroid dysfunction, including low TSH, FT3 and FT4, than rHuEPO in patients with renal anemia.

Topics: Anemia; Chronic Disease; Cohort Studies; Epoetin Alfa; Erythropoietin; Humans; Kidney Diseases; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Silkworm faeces are the dry faeces of the insect Bombyx mori (Linnaeus) and have historically been used in traditional Chinese medicine to treat blood deficiency and rheumatic pain. Silkworm faeces extract (SFE) is derived from silkworm faeces.. Clinical observations of patients in the Department of Nephrology have shown that SFE effectively improves renal anaemia. However, the molecular mechanism remains unclear. This article mainly explores the regulatory effects of SFE on erythropoietin (EPO) and hepcidin to identify the molecular mechanism of SFE.. A rat model of renal anaemia was established by feeding rats food containing 0.75% adenine. SFE was orally administered to the rats, while recombinant human erythropoietin (rhEPO) was used as a positive control drug. Haematological parameters and inflammation levels were compared between rats from each group, and pathological kidney sections from each rat were observed. The serum EPO and hepcidin levels were detected using enzyme-linked immunosorbent assay (ELISA) kits, while Western blot analyses were performed to detect the levels of proteins involved in the EPO-related hypoxia-inducible factor 2α (HIF-2α)/prolyl hydroxylase 2 (PHD2) signalling pathway and hepcidin-related BMP6/SMAD4 and interleukin-6 (IL-6)/STAT3 signalling pathways.. SFE significantly ameliorated haematological parameters, renal function, and inflammation levels in the rats. A mechanistic study showed that SFE promoted EPO expression by upregulating HIF-2α expression and inhibiting the expression of NF-κB and GATA2 both in vivo and in vitro. In particular, SFE inhibited PHD2 expression, resulting in a decrease in the enzymatic reaction of HIF-2α to increase EPO expression. Furthermore, SFE inhibited hepcidin expression by blocking the BMP6/SMAD4 and IL-6/STAT3 pathways.. SFE regulated iron metabolism by inhibiting hepcidin and simultaneously promoted EPO synthesis to improve renal anaemia in rats.

Topics: Adenine; Anemia; Animals; Bombyx; Disease Models, Animal; Erythropoietin; Feces; Hepcidins; Humans; Iron; Kidney Diseases; Male; Rats; Rats, Sprague-Dawley

Erythrocyte mass contributes to maintaining systemic oxygen delivery and blood viscosity, with the latter being one of the determinants of blood pressure. However, the physiological response to blood pressure changes under anaemic conditions remain unknown.. We show that anaemia decreases blood pressure in human patients and mouse models. Analyses of pathways related to blood pressure regulation demonstrate that anaemia enhances the expression of the gene encoding the vasopressor substance renin in kidneys. Although kidney juxtaglomerular cells are known to continuously produce renin, renal interstitial fibroblasts are identified in the present study as a novel site of renin induction under anaemic hypotensive conditions in mice and rats. Notably, some renal interstitial fibroblasts are found to simultaneously express renin and the erythroid growth factor erythropoietin in the anaemic mouse kidney. Antihypertensive agents but not hypoxic stimuli induced interstitial renin expression, suggesting that blood pressure reduction triggers interstitial renin induction in anaemic mice. The interstitial renin expression was also detected in injured fibrotic kidneys of the mouse and human, and the renin-expressing interstitial cells in murine fibrotic kidneys were identified as myofibroblasts originating from renal interstitial fibroblasts. Since the elevated expression levels of renin in fibrotic kidneys along with progression of renal fibrosis were well correlated to the systemic blood pressure increase, the renal interstitial renin production seemed to affect systemic blood pressure.. Renal interstitial fibroblasts function as central controllers of systemic oxygen delivery by producing both renin and erythropoietin.. Grants-in-Aid from Japan Society for the Promotion of Science (JSPS) KAKENHI (17K19680, 15H04691, and 26111002) and the Takeda Science Foundation.

Topics: Aged; Anemia; Animals; Biomarkers; Blood Pressure; Chronic Disease; Disease Models, Animal; Erythropoietin; Female; Fibroblasts; Fibrosis; Gene Expression; Humans; Hypotension; Hypoxia; Kidney; Kidney Diseases; Male; Mice; Mice, Knockout; Mice, Transgenic; Middle Aged; Renin; Signal Transduction

Erythropoietin (EPO) is a crucial hormone for erythropoiesis and produced by adult kidneys. Insufficient EPO production in chronic kidney disease (CKD) can cause renal anemia. Although hypoxia-inducible factors (HIFs) are known as a main regulator, the mechanisms of EPO production have not been fully elucidated. In this study, we aimed to examine the roles of retinoic acid (RA) in EPO production using EPO-producing cells derived from human induced pluripotent stem cells (hiPSC-EPO cells) that we previously established. RA augmented EPO production by hiPSC-EPO cells under hypoxia or by treatment with prolyl hydroxylase domain-containing protein (PHD) inhibitors that upregulate HIF signals. Combination treatment with RA and a PHD inhibitor improved renal anemia in vitamin A-depleted CKD model mice. Our findings using hiPSC-EPO cells and CKD model mice may contribute to clarifying the EPO production mechanism and developing efficient therapies for renal anemia.

Topics: Anemia; Animals; Basic Helix-Loop-Helix Transcription Factors; Drug Evaluation, Preclinical; Drug Therapy, Combination; Erythropoietin; Glycine; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Induced Pluripotent Stem Cells; Isoquinolines; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Tretinoin

Erythropoietin (EPO) drives erythropoiesis and is secreted mainly by the kidney upon hypoxic or anemic stress. The paucity of EPO production in renal EPO-producing cells (REPs) causes renal anemia, one of the most common complications of chronic nephropathies. Although mitochondrial dysfunction is commonly observed in several renal and hematopoietic disorders, the mechanism by which mitochondrial quality control impacts renal anemia remains elusive. In this study, we showed that FUNDC1, a mitophagy receptor, plays a critical role in EPO-driven erythropoiesis induced by stresses. Mechanistically, EPO production is impaired in REPs in

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Kidney Diseases; Membrane Proteins; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Mitophagy; Reactive Oxygen Species

The number of patients with end stage kidney disease (ESKD) are increasing world-side. While interstitial fibrosis (IF) is a common step for the progression to ESKD, therapeutic options for IF is still limited in clinical settings. We have reported that bone marrow-derived fibrotic cell, fibrocyte, is involved in the pathogenesis of kidney fibrosis. Also recent studies revealed that erythropoietin has protective effect on kidney diseases. However, it is unknown whether erythropoietin (EPO) inhibits fibrosis in progressive kidney injury. Therefore, we explored the impacts of EPO on kidney fibrosis with focusing on fibrocyte.. Fibrocyte was differentiated from peripheral mononuclear cells of healthy donor. Fibrocyte was stimulated with transforming growth factor beta (TGF)-β with/without EPO treatment. Moreover, the therapeutic effect of EPO was evaluated in murine unilateral ureteral obstruction (UUO) model.. TGF-β stimulation increased the expression of COL1 mRNA in fibrocyte. EPO signal reduced the expression of COL1 mRNA in dose dependent manner. EPO reduced mitochondrial oxidative stress and ameliorated mitochondrial membrane depolarization induced by TGF-β stimulation. Moreover, EPO reduced the mRNA expression of mitochondria related molecules, TRAF6, in fibrocyte. In addition, the count of CD45+/αSMA + double-positive fibrocyte was decreased in the EPO-administered UUO kidneys.. EPO signals function to prevent kidney fibrosis, particularly in fibrocyte. Regulating the renal accumulation of fibrocyte is a part of the anti-fibrotic functions of EPO.

Topics: Animals; Bone Marrow Cells; Cells, Cultured; Collagen; Disease Models, Animal; Disease Progression; Erythropoietin; Fibrosis; Humans; Kidney; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; RNA, Messenger; Transforming Growth Factor beta

Topics: Anemia; Erythropoietin; Humans; Kidney Diseases

Preoperative treatment of anemia with intravenous iron is inconsistent despite known risks of anemia and allogeneic blood transfusions. Limited research exists on the effectiveness of preoperative intravenous iron for chronic kidney disease (CKD) patients. We discuss a patient with severe anemia from advanced CKD, endometrial cancer, and menometrorrhagia. Her hemoglobin increased more than 2 g/dL after erythropoietin and two 750-mg ferric carboxymaltose infusions 5 weeks before a total abdominal hysterectomy and avoided blood transfusions perioperatively. By raising hemoglobin, preoperative intravenous iron and erythropoietin reduce blood transfusions and consequent risk of future allograft rejection and alloimmunization in potential transplant recipients.

Topics: Administration, Intravenous; Anemia; Endometrial Neoplasms; Erythropoietin; Female; Ferric Compounds; Hemoglobins; Humans; Hysterectomy; Infusions, Intravenous; Iron; Kidney Diseases; Maltose; Middle Aged; Preoperative Care; Severity of Illness Index; Trace Elements; Treatment Outcome

to determine the efficiency of different doses of erythropoietin and carbamylated darbepoetin, to prove experimentally the possibility of increasing the efficiency of carbamylated darbepoetin when using the levorotatory stereoisomer of ethoxidol.. On the model of ischemia-reperfusion injury in male CD-1 mice that were undergone to contralateral nephrectomy, the nephroprotective effect of different doses of erythropoietin alfa, carbamylated darbepoetin, L-ethoxidol (the levorotatory enantiomer of ethylmethylhydroxypyridine malate), and the combined use of L-ethapylated carboxypyridine malate and L-etapoietin alfa was studied. The parameters of microcirculation and glomerular filtration rate were studied one day after 30-minute ischemia.. It has been established that the prophylactic use of erythropoietin alfa and carbamylated darbepoetin in the model of ischemia-reperfusion injury of a single kidney reduces the severity of microcirculatory impairment and ensures the preservation of the glomerular filtration rate in dose-dependent manner. The synergistic effect of L-ethoxidol and carbamylated darbepoetin was found when these substances were used together.. Prevention of ischemia-reperfusion kidney injury by analogs of human erythropoietin and their combination with ethylmethylhydroxypyridine derivatives is experimentally-proved.

Topics: Animals; Darbepoetin alfa; Erythropoietin; Ischemia; Kidney; Kidney Diseases; Kidney Failure, Chronic; Mice; Microcirculation

Dyslipidemia is commonly observed in various kidney diseases, renal specific secreted erythropoietin (EPO) may participate in this process. However, how this process is regulated remains elusive.. Dyslipidemia was evaluated in chronic kidney disease and ischemia kidney injury animal model. Primary cultured adipocytes were harvested to investigate the lipid metabolic effect of EPO. Lipidemia was evaluated in EPO treated animals. Blood samples from cardiac surgery-induced kidney injury patient were collected to assess correlationship between EPO and lipidemia.. We found a decrease in secreted EPO and hypertriglyceridemia in chronic kidney disease (CKD) mice. In contrast, in renal ischemia animal model, increased EPO triggered by hypoxia signaling activation, was accompanied by decreased triglyceride (TG) in serum. Mechanistically, circulating EPO modulated JAK2-STAT5 signaling, which in turn enhanced lipid catabolism in peripheral adipose tissue and contributed to dysregulated lipidemia. Delivering of recombinant EPO into both wild type and CKD mice suppressed TG in serum by accelerating lipid catabolism in adipose tissue. In a cohort of patients diagnosed with acute kidney injury after cardiopulmonary bypass surgery, the decreased TG and cholesterol negatively correlated with increased EPO in serum.. This study depicted a new mechanism by which renal secreted EPO controlled lipidemia in kidney diseases including chronic kidney disease. Circulating EPO stimulated lipid catabolism by targeting JAK2-STATA5 signaling in peripheral adipose tissue, providing new therapeutic target for dyslipidemia treatment.. This work was supported by grants from the National Natural Science Foundation of China (Nos. 81700640 and 81970608).

Topics: Adipose Tissue; Animals; Disease Models, Animal; Erythropoietin; Hyperlipidemias; Hypoxia; Janus Kinase 2; Kidney; Kidney Diseases; Lipid Metabolism; Lipids; Male; Mice; Signal Transduction; STAT5 Transcription Factor

Kidney ischemia and reperfusion injury could cause microvascular barrier dysfunction, lung inflammatory cascades activation, and programmed cell death of pulmonary endothelium, leading to acute lung injury. Our study aimed at determining whether erythropoietin (EPO) can ameliorate lung dysfunction following renal ischemia and reperfusion (IR) injury and explored the underlying mechanisms.. In vivo, C57BL/6 mice received EPO (6000 U/kg) before right renal vascular pedicles clamping for 30 minutes, followed by 24 hours of reperfusion. The lung histopathologic changes and inflammatory cytokines expression were assessed. In vitro, cultured human umbilical vein endothelial cells were treated with EPO, and apoptosis rate, proliferation capacity, and phosphorylation status of the Janus kinase-signal transducer and activator of transcription 3 (Jak-STAT3) pathway were measured respectively in the presence or absence of lipopolysaccharide stimulation.. In vivo, EPO remarkably attenuated pulmonary interstitial and alveolar epithelial edema caused by renal IR injury. In vitro, the proliferation capacity of human umbilical vein endothelial cells was significantly increased under EPO stimulation, which correlated with changes in Jak-STAT3 signaling.. Our data indicated that EPO is able to ameliorate acute lung tissue damage induced by renal IR, and at least in part, via the Jak-STAT3 pathway.

Topics: Acute Lung Injury; Animals; Cell Line; Cell Proliferation; Endothelium, Vascular; Erythropoietin; Humans; Janus Kinases; Kidney; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Reperfusion Injury; Signal Transduction; STAT3 Transcription Factor

Since the nature of ischemia/reperfusion (IR)-induced tissue damage is multifactorial and complex, in the current study, the effects of multiple treatment strategies via concomitant administration of erythropoietin (EPO) and N-acetylcysteine (NAC) with an ischemic preconditioning (IPC) regimen on renal IR injury were examined.. Thirty male Wistar rats were subjected to bilateral occlusion of the renal pedicles for 50 min followed by reperfusion. EPO (1000 IU/kg) was administered for 3 days, as well as IPC before the IR and NAC (150 mg/kg) administration for 4 days after IR. The animals were randomly allocated into 6 groups (n = 5): sham, IR, EPO+IR, IPC+IR, NAC+IR, and EPO+IPC+NAC+IR. Kidney tissues and blood samples were obtained for oxidative stress, proinflammatory cytokines, and renal functional evaluations.. IR caused significant inflammatory response, oxidative stress, and reduced renal function. Treatment with EPO, IPC, and NAC or a combination of two of them attenuated renal dysfunction and reduced the oxidative stress and inflammatory markers. Rats treated with the combination of EPO, IPC, and NAC showed a higher degree of protection compared to the other groups.. These results showed that concomitant administration of EPO and IPC along with posttreatment NAC may have additive beneficial effects on kidney IR injury during IR-induced acute renal failure.

Topics: Acetylcysteine; Animals; Blood Urea Nitrogen; Creatinine; Cytokines; Disease Models, Animal; Erythropoietin; Ischemic Preconditioning; Kidney; Kidney Diseases; Male; Oxidative Stress; Rats; Rats, Wistar; Reperfusion Injury

Etoposide (ETO) and methotrexate (MTX) are two effective chemotherapeutic drugs. However, the clinical use of these drugs is limited by its toxicity in normal tissues, especially in kidney and in liver tissues. Recombinant human erythropoietin (rhEPO), erythropoietin hormone, has also been shown to exert tissue protective effects. The purpose of this study was to explore the protective effect of rhEPO against oxidative stress and genotoxicity induced by ETO and MTX in vivo. Adult male Wistar rats were divided into 10 groups (6 animals each): control group, rhEPO alone group, ETO alone group, MTX alone group and rhEPO + ETO/MTX groups. In rhEPO + ETO/MTX groups, three doses of pretreatment with rhEPO were performed: 1000, 3000 and 6000 IU/kg. Our results showed that rhEPO pretreatment protects liver and kidney tissues against oxidative stress induced by the anticancer drugs. The glycoprotein decreased malondialdehyde (MDA) levels, reduced catalase activity and ameliorated glutathione depletion. Furthermore, we showed that rhEPO administration prevented drug-induced DNA damage accessed by comet test. Altogether, our results suggested a protective role of rhEPO, especially at 3000 IU/kg, against ETO- and MTX-induced oxidative stress and genotoxicity in vivo.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Catalase; Chemical and Drug Induced Liver Injury; DNA Damage; Erythropoietin; Etoposide; Glutathione; Kidney; Kidney Diseases; Lipid Peroxidation; Liver; Male; Malondialdehyde; Methotrexate; Protective Agents; Rats, Wistar; Recombinant Proteins

Exogenous replacement of erythropoietin (EPO) by recombinant human EPO has been considered a standard of care for the treatment of anemia in patients with chronic kidney disease for more than 20 years. Genetically engineered biologic proteins derived from human, animal, or microorganism sources are a major area of growth in modern medical care, accounting for one-third of new drug approvals in the past decade. Despite benefit to patients, the use of biologics comes at a significant cost, representing one of the fastest growing segments of strained healthcare budgets around the world.. Biosimilars, or biologic drugs that are designed to be highly similar to approved reference biologic drugs, have been available in Europe for more than 10 years with no unusual or unexpected effects compared to their reference biologics whose patents have expired. Given the success of the biosimilar approval pathway pioneered in Europe, it has served as a global reference for other regulatory authorities to establish and implement biosimilar licensure frameworks, including the United States (US), the largest pharmaceutical market in the world. Given 10 of the top 25 drugs sold in 2014 were biologics, and considering the rising costs of healthcare, biosimilars have the potential to become a significant part of the US market. Key Messages: For the nephrology community, the recent patent expiries for epoetin alfa (Epogen®, Amgen and Procrit®, Johnson & Johnson) have created the opportunity to develop biosimilar EPOs. And while no biosimilar in this therapeutic class is approved in the US, there are proposed biosimilars in development.

Topics: Anemia; Animals; Biosimilar Pharmaceuticals; Commerce; Drug Approval; Drug Industry; Epoetin Alfa; Erythropoiesis; Erythropoietin; Europe; Hematinics; History, 20th Century; History, 21st Century; Humans; Kidney; Kidney Diseases; Nephrology; Patient Safety; Recombinant Proteins; Renal Insufficiency, Chronic; United States

Renal fibrosis is an inevitable outcome of chronic kidney disease (CKD). Erythropoietin (EPO) has been recently reported to be able to mitigate renal fibrosis. The mechanism underlying the protective effect of EPO, however, remains elusive. In the present study, employing a mouse model of renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction (UUO), we demonstrated that EPO markedly reduced the disruption of the tubular basement membrane (TBM) through attenuating the activation of tissue plasminogen activator (tPA) and matrix metalloproteinase 9 (MMP9), the major matrix proteolytic network in the obstructed kidney. Instead of acting directly on tPA in the kidney, EPO strongly increased the level of circulating microRNA (miR)-144, which was delivered to the injured renal fibroblasts via extracellular vesicles (EVs) to target the tPA 3'-untranslated region and suppress tPA expression. The protective effect of EPO on mouse TBM was inhibited by miR-144 antagomir. Furthermore, in vitro results confirmed that EPO could stimulate bone marrow-derived Sca-1(+)CD44(+)CD11b(-)CD19(-) cells to secrete miR-144-containing EVs, which markedly suppressed tPA expression, as well as metalloproteinase 9 (MMP9) level and activity, in cultured renal fibroblasts. In conclusion, our study provides the first evidence that EPO protects mouse renal TBM through promoting bone marrow cells to generate and secrete miR-144, which, in turn, is efficiently delivered into the mouse kidney via EVs to inhibit the activation of the tPA/MMP9-mediated proteolytic network. This finding thus suggests that EPO, a hormone widely used to treat anemia in CKD, is a potential therapeutic strategy for renal fibrosis.

Topics: 3' Untranslated Regions; Animals; Binding Sites; Bone Marrow Cells; Cell Line; Cytoprotection; Disease Models, Animal; Enzyme Activation; Enzyme Repression; Erythropoietin; Extracellular Vesicles; Fibroblasts; Fibrosis; Glomerular Basement Membrane; Kidney Diseases; Kidney Tubules; Male; Matrix Metalloproteinase 9; Mice; MicroRNAs; Rats; Recombinant Proteins; Signal Transduction; Tissue Plasminogen Activator; Ureteral Obstruction

Renal hypoplasia due to a congenitally reduced number of nephrons progresses to chronic kidney disease and may cause renal anemia, given that the kidneys are a major source of erythropoietin in adults. Hypoplastic kidney (HPK) rats have only about 20% of the normal number of nephrons and develop CKD. This study assessed the renal function and hematologic changes in HPK rats from 70 to 210 d of age. HPK rats demonstrated deterioration of renal excretory function, slightly macrocytic erythropenia at all days examined, age-related increases in splenic hemosiderosis accompanied by a tendency toward increased hemolysis, normal plasma erythropoietin levels associated with increased hepatic and decreased renal erythropoietin production, and maintenance of the response for erythropoietin production to hypoxic conditions, with increased interstitial fibrosis at 140 d of age. These results indicate that increases in splenic hemosiderosis and the membrane fragility of RBC might be associated with erythropenia and that hepatic production of erythropoietin might contribute to maintaining the blood Hgb concentration in HPK rats.

Topics: Age Factors; Anemia; Animals; Biomarkers; Carrier Proteins; Disease Models, Animal; Disease Progression; Erythrocytes; Erythropoietin; Fibrosis; Genetic Predisposition to Disease; Hemolysis; Hemosiderosis; Iron; Kidney; Kidney Diseases; Male; Mutation; Osmotic Fragility; Phenotype; Rats; Rats, Inbred Strains; Renal Insufficiency, Chronic; Spleen

Amikacin (AK) is frequently used on the treatment of Gram-negative infections on neonates, but its usage is restricted because of nephrotoxicity. In this study, on neonatal rats, we aimed to investigate the effects of erythropoietin and vitamin E on AK induced nephrotoxicity. A total of 35 newborn Wistar Albino rats were divided into four groups: (1) injected with saline (serum physiological was administered to placebo controls), (2) injected with AK (1200 mg/kg), (3) injected with AK + vitamin E (150 mg/kg), (4) injected with AK + erythropoietin (EPO) (300 IU/kg/day). In renal tissue, AK levels were significantly high in all groups except the control. Tissue malondialdehyde (MDA) and nitric oxide (NO) levels were statistically higher in AK -treated group than the control. MDA and NO levels were significantly decreased with the administration of vitamin E and EPO. Glutathione peroxidase (GPX) levels were statistically low in AK group compared with the controls. The levels of GPX, in vitamin E group, were increased significantly. However, superoxide dismutase and catalase levels were not significantly different in none of the groups. Insulin-like growth factor-1 values in AK, EPO and vitamin E groups were significantly higher than the control group. Histomorphological changes such as tubular epithelial necrosis were seen in AK treated group. Histopathological improvements observed with EPO and vitamin E administration. AK nephrotoxicity is related to oxidative stress and is supported with biochemical and histopathological findings. Vitamin E and EPO, as antioxidants, can be useful renoprotective agents for ameliorating AK induced nephrotoxicity in neonates.

Topics: Amikacin; Animals; Animals, Newborn; Anti-Bacterial Agents; Antioxidants; Disease Models, Animal; Erythropoietin; Kidney Diseases; Kidney Function Tests; Malondialdehyde; Nitric Oxide; Oxidative Stress; Protective Agents; Rats; Rats, Wistar; Treatment Outcome; Vitamin E

Age-related macular degeneration (AMD), affecting the retinal pigment epithelium (RPE), is the leading cause of blindness in middle-aged and older people in developed countries. Genetic and environmental risk factors have been identified, but no effective cure exists. Using a mouse model we show that a transmembrane prolyl 4-hydroxylase (P4H-TM), which participates in the oxygen-dependent regulation of the hypoxia-inducible factor (HIF), is a potential novel candidate gene for AMD. We show that P4h-tm had its highest expression levels in the mouse RPE and brain, heart, lung, skeletal muscle and kidney. P4h-tm

Topics: Animals; Brain; Disease Models, Animal; Erythropoietin; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Kidney; Kidney Diseases; Lung; Macular Degeneration; Mice; Muscle, Skeletal; Myocardium; Prolyl Hydroxylases; Retinal Pigment Epithelium; Tissue Distribution

Periodontal disease (PDD) was associated with inflammation, malnutrition, and higher mortality in hemodialysis (HD) patients.. Cross-sectional observational study, aiming to assess the prevalence of PDD and the possible relationship among PDD, inflammation, and malnutrition in HD patients.. Single HD center, 263 patients (age: 57.4 ± 12.3 years; 60% males; HD vintage 6.6 ± 4.9 years; the primary renal diseases were mainly primary glomerular nephropathies in 34% cases, with 11% diabetic nephropathy).. Oral health status was assessed by the Silness and Loe plaque index, loss of clinical attachment level, periodontal pocket depth according to World Health Organization recommendations, by a single examiner. Patients were stratified by periodontal pocket depth (PPD): normal oral status/mild PDD (PPD < 4 mm), moderate PDD (PPD 4-5 mm), and severe PDD (PPD ≥ 6 mm). Demographic, smoking status, hematologic, dialysis-related data and parameters of the nutritional (Subjective Global Assessment score, anthropemetrical, and biochemical) and inflammatory status were collected.. Poor periodontal status was shown by 75% of patients, 23% of them with severe PDD. Patients with PDD were older; higher percentages of them were smokers, diabetics, had malnutrition, and inflammation. Subjects with severe PDD had higher HD vintage, lower hemoglobin, and required higher darbepoetin doses than those with healthy periodontium. Darbepoetin resistance index was higher in patients with severe PDD than in those with normal periodontium. Models of multivariable linear logistic regression for the potential promoters and for the consequences of PDD revealed smoking and HD duration as significant contributors; increased C-reactive protein was associated with severe PDD.. Cross-sectional observational design.. Impaired periodontal health is highly prevalent in HD patients. PDD is more frequent in elderly diabetic smokers and in those with longer HD vintage; smoking and HD duration seems to be the most important determinants. The prevalence is higher in malnourished and in inflamed patients; inflammation seems to accompany PDD and to influence anemia response to treatment.

Topics: Aged; C-Reactive Protein; Cross-Sectional Studies; Erythropoietin; Female; Hemoglobins; Humans; Inflammation; Kidney Diseases; Linear Models; Logistic Models; Male; Malnutrition; Middle Aged; Multivariate Analysis; Nutritional Status; Periodontal Diseases; Prevalence; Renal Dialysis

Erythropoietin (EPO) is a hematopoietic hormone that protects against renal interstitial fibrosis in animal models; however, the mechanism underlying the anti‑fibrotic activity of EPO has remained elusive. The present study aimed to elucidate this mechanism. Twenty‑four male C57BL6 mice were randomly divided into four groups, each comprising six mice: (i) control group (Sh); (ii) unilateral ureteral obstruction (UUO) plus vehicle group (U+V); (ⅲ) UUO plus 300 U/kg body weight recombinant human (rh)EPO (U+E1) and (ⅳ) UUO plus 1,000 U/kg body weight rhEPO (U+E2). Seven days post‑surgery, the mice were sacrificed for examination. UUO induced significant deposition of extracellular matrix, detected by picro‑sirius red staining, which was decreased following rhEPO treatment. UUO also induced deposition of collagen I and fibronectin, rhEPO treatment was able to attenuate this effect at protein and mRNA levels. Compared with the control groups, UUO resulted in the accumulation of α‑smooth muscle actin‑positive cells in the interstitium, an effect which was ameliorated by rhEPO. Furthermore, rhEPO abrogated the UUO‑induced increase in the number of bone marrow‑derived myofibroblasts. Mechanistically, it was discovered that rhEPO decreased CXC chemokine ligand 16 (CXCL16) expression at protein level. However, treatment with rhEPO did not alter the protein expression of CC chemokine ligand 21 or CXCL12. These results suggested that rhEPO decreased fibrocyte accumulation via the suppression of renal CXCL16, which resulted in the attenuation of renal fibrosis.

Topics: Animals; Chemokine CXCL16; Chemokines, CXC; Disease Models, Animal; Disease Progression; Erythropoietin; Fibrosis; Humans; Kidney Diseases; Male; Mice; Myofibroblasts; Receptors, Scavenger; Recombinant Proteins

Collection of hematopoietic progenitor cells by apheresis (HPC-A) requires separation of cells by density. Previous studies highlighted the challenges of HPC-A collection from patients with abnormal red blood cells (RBCs). TEMPI syndrome is a recently described condition defined by teleangiectasias, elevated erythropoietin and erythrocytosis, monoclonal gammopathy, perinephric fluid collections, and intrapulmonary shunting. Patients with TEMPI syndrome have responded to therapies used to treat plasma cell dyscrasias and may benefit from autologous HPC transplantation. We report HPC-A collection from a patient with TEMPI syndrome that was complicated by severe iron deficiency.. The patient received granulocyte-colony-stimulating factor (G-CSF) and plerixafor for HPC mobilization and underwent 3 days of HPC-A collection.. The patient presented for collection with a microcytic erythrocytosis. Over 3 days, approximately 50 L of whole blood was processed, and 2 × 10(8) CD34+ cells were collected (2.8 × 10(6) CD34+ cells/kg). The mean collection efficiency (CE), percentage of mononuclear cells, hematocrit (Hct), and RBC count were 18%, 90%, 14%, and 9 × 10(11) , respectively. Altering collection variables to avoid RBC contamination reduced CE. Ficoll preparations of the products after freeze-thaw showed RBC contamination and hemolysis. Postthaw viability exceeded 95%. The products were not RBC reduced or washed. There were no adverse reactions during or after infusion.. HPC-A collection from a patient with TEMPI syndrome was complicated by microcytic erythrocytosis, leading to RBC contamination and hemolysis in the product. Adequate HPCs were collected and the patient tolerated infusion without RBC depletion or washing. Our report highlights difficulties of HPC-A collection from iron-deficient patients.

Topics: Benzylamines; Cyclams; Cytapheresis; Erythrocytes, Abnormal; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; Heterocyclic Compounds; Humans; Kidney Diseases; Leukocyte Count; Male; Middle Aged; Paraproteinemias; Polycythemia; Syndrome

Although erythropoietin has been used for decades in the treatment of anemia, data regarding endogenous levels in the general population are scarce. Therefore, we determined erythropoietin reference ranges and its clinical, biochemical and genetic associations in the general population.. We used data from 6,777 subjects enrolled in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study. Fasting venous blood samples were obtained in the morning from all participants from 2001-2003. Serum erythropoietin concentrations were measured using a fully automated chemiluminescent enzyme-labeled immunometric assay. A genome-wide association study was performed to identify genetic determinants.. Mean age (± SD) was 53 ± 12 years and 50% were female. Median (IQR) erythropoietin concentrations were 7.6 (5.8-9.9) IU/L in men and 7.9 (6.0-10.6) IU/L in women. A strong positive correlation was found between erythropoietin and waist circumference, glucose and systolic blood pressure (all P < 0.05). In subjects with normal renal function there was a strong exponential relation between hemoglobin and erythropoietin, whereas in renal impairment (eGFR < 60 mL/min/1.73m²) this relation was linear (men) or absent (women) (P < 0.001 for interaction). Single-nucleotide polymorphisms at the HBS1L-MYB locus were shown to be related to erythropoietin levels (P < 9x10-21), more significantly than other erythrocyte parameters.. We provide age-specific reference ranges for endogenous serum erythropoietin. Erythropoietin levels are positively associated with the components of the metabolic syndrome, except cholesterol. We show that even mild renal failure blunts erythropoietin production and propose the HBS1L-MYB locus as a regulator of erythropoietin.

Topics: Adult; Age Factors; Aged; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Genome-Wide Association Study; Humans; Kidney Diseases; Male; Middle Aged; Polymorphism, Single Nucleotide; Reference Values; Sex Factors

Erythropoietin (EPO) has cytoprotective and anti-apoptotic effects in pathological conditions, including hypoxia and ischaemia-reperfusion injury. One of the targets to protect against injury is ATP-dependent potassium (KATP ) channels. These channels could be involved in EPO induced ischaemic preconditoning like a protective effect. We evaluated the cell cytoprotective effects of EPO in relation to KATP channel activation in the renal tubular cell culture model under hypoxic/normoxic conditions.. Dose and time dependent effects of EPO, KATP channel blocker glibenclamide and KATP channel opener diazoxide on cellular proliferation were evaluated by colorimetric assay MTT [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide] under normoxic and hypoxic conditions in human renal proximal tubular cell line (CRL-2830). Evaluation of the dose and time dependent effects of EPO, glibenclamide and diazoxide on apoptosis was done by caspase-3 activity levels. Hypoxia inducible factor-1 alpha (HIF-1 α) mRNA levels were measured by semi-quantative reverse transcription polymerase chain reaction (RT)-PCR. Kir 6.1 protein expresion was evalutaed by Western blot.. Glibenclamide treatment decreased the number of living cells in a time and dose dependent manner, whereas EPO and diazoxide treatments increased. Glibenclamide (100 μM) treatment significantly blocked the anti-apoptotic effects of EPO (10 IU/ml) under both normoxic and hypoxic conditions. EPO (10 IU/ml) and diazoxide (100 μM) treatments significantly increased (p <0.01) whereas glibenclamide decreased ( p<0.05) HIF-1 α mRNA expression. Glibenclamide significantly ( p<0.01) decreased EPO induced HIF-1 α mRNA expression when compared with the EPO alone group.. Our results showed that the cell proliferative, cytoprotective and anti-apoptotic effects of EPO were associated with KATP channels in the renal tubular cell culture model under hypoxic/normal conditions.

Topics: Apoptosis; Cell Line; Cell Proliferation; Diazoxide; Erythropoietin; Gene Expression Regulation; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; KATP Channels; Kidney; Kidney Diseases; Kidney Tubules; Reperfusion Injury

Topics: Anemia; Bone Density; Endocrine System Diseases; Erythropoietin; Humans; Kidney Diseases; Prognosis

Topics: Anemia; Animals; Cell Hypoxia; Erythropoietin; Fibrosis; Humans; Kidney Diseases; Oxygen

Topics: Animals; Erythropoietin; Kidney Diseases; Lung Diseases; Male; Oxidative Stress; Reperfusion Injury

Topics: Animals; Cyclosporine; Erythropoietin; Humans; Immunosuppressive Agents; Kidney Diseases; Male

Treatment of renal ischemia-reperfusion (IR) injury with recombinant human erythropoietin (rhEPO) reduces acute kidney injury and improves function. We aimed to investigate whether progression to chronic kidney disease associated with acute injury was also reduced by rhEPO treatment, using in vivo and in vitro models. Rats were subjected to bilateral 40-min renal ischemia, and kidneys were studied at 4, 7, and 28 days postreperfusion for renal function, tubular injury and repair, inflammation, and fibrosis. Acute injury was modulated using rhEPO (1,000 or 5,000 IU/kg, intraperitoneally) at the time of reperfusion. Renal tubular epithelial cells or fibroblasts in culture were subjected to hypoxia or oxidative stress, with or without rhEPO (200 IU/ml), and fibrogenesis was studied. The results of the in vivo model confirmed functional and structural improvement with rhEPO at 4 days post-IR (P < 0.05). At 7 days post-IR, fibrosis and myofibroblast stimulation were increased with IR with and without rhEPO (P < 0.01). However, at 28 days post-IR, renal fibrosis and myofibroblast numbers were significantly greater with IR plus rhEPO (P < 0.01) compared with IR only. Mechanistically, rhEPO stimulated profibrotic transforming growth factor-β, oxidative stress (marker 8-hydroxy-deoxyguanosine), and phosphorylation of the signal transduction protein extracellular signal-regulated kinase. In vitro, rhEPO protected tubular epithelium from apoptosis but stimulated epithelial-to-mesenchymal transition and also protected and activated fibroblasts, particularly with oxidative stress. In summary, although rhEPO was protective of renal function and structure in acute kidney injury, the supraphysiological dose needed for renoprotection contributed to fibrogenesis and stimulated chronic kidney disease in the long term.

Topics: Acute Kidney Injury; Animals; Apoptosis; Cells, Cultured; Disease Progression; Epoetin Alfa; Erythropoietin; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Humans; Kidney; Kidney Diseases; Male; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Reperfusion Injury; Treatment Outcome

Topics: Animals; Antineoplastic Agents; Chemical and Drug Induced Liver Injury; Cisplatin; Erythropoietin; Kidney Diseases; Protective Agents

In predialysis patients, the optimal treatment choices for controlling haemoglobin (Hb) are unknown, because targeting high Hb levels has negative effects--poorer survival--but possible positive effects as well--better health-related quality of life (HRQOL). Moreover, these effects may be different in specific subgroups (e.g. young versus elderly).. In the PREPARE-2 follow-up study, incident predialysis patients were included (2004-2011) when referred to 1 of the 25 participating Dutch outpatient clinics. HRQOL was assessed at 6-month intervals with the short form-36 (SF-36) questionnaire [physical/mental summary measure and eight subscales (range 0-100)]. A linear mixed model was used to associate Hb [<11, ≥ 11 to <12 (reference), ≥ 12 to <13 and ≥ 13 g/dL] with HRQOL, stratified by prescription of anaemia medication (erythropoietin-stimulating agent (ESA)/iron) and age (young: <65 years and elderly: ≥ 65 years).. Only elderly patients (n = 214) not prescribed ESA/iron and with a high Hb (≥ 13 versus ≥ 11 to <12 g/dL) had a statistically significant (P < 0.05) and/or clinically relevant (>3-5 points) higher physical [11.9, 95% confidence interval (CI) 1.7, 22.2] and mental (6.4, 95% CI -1.7, 14.6) summary score. High Hb was not associated with a higher HRQOL in elderly patients who were prescribed ESA/iron. However, only young patients (n = 157) prescribed ESA/iron and with a high Hb (≥ 13 versus ≥ 11 to <12 g/dL) had a higher physical (8.9, 95% CI 2.1, 15.8) and mental (6.2, 95% CI -0.4, 12.8) summary score.. The association of Hb levels with HRQOL differs by age and use of ESA/iron medication on predialysis care. Therefore, medical care should aim for shared decision-making regarding the appropriate Hb target leading to more individualized care.

Topics: Age Factors; Aged; Anemia; Biomarkers; Erythropoietin; Female; Follow-Up Studies; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Prognosis; Prospective Studies; Quality of Life; Renal Dialysis; Surveys and Questionnaires

Topics: Anemia; Erythropoietin; Humans; Kidney; Kidney Diseases

Topics: Animals; Erythropoietin; Kidney Diseases; Lung Diseases; Male; Oxidative Stress; Reperfusion Injury

Bone marrow is a key element in the diagnosis of disorders of erythropoiesis, including anemia, and a potential target in their treatment. However, because efficient delivery of diagnostic and therapeutic agents to bone marrow is difficult, such delivery is achieved by administering drugs in large quantities that often have adverse effects. Here, we achieved selective delivery of recombinant human erythropoietin (rHuEPO) to bone marrow, via its encapsulation in liposomes with l-glutamic acid, N-(3-carboxy-1-oxopropyl)-, 1,5-dihexadecyl ester (SA) (liposome-EPO). The result, in a rabbit model of renal anemia, was a beneficial effect on hematopoiesis, better than with rHuEPO alone. Also, we determined that liposome-EPO delivery to bone marrow depended on specific uptake by bone marrow macrophages because of the presence of SA. These results indicate both that liposome-EPO is a new, promising erythropoietin-stimulating agent and that liposomes with SA have potential for diagnostic and therapeutic applications in diseases originating from bone marrow.

Topics: Anemia; Animals; Bone Marrow; Cells, Cultured; Drug Carriers; Drug Delivery Systems; Epoetin Alfa; Erythropoiesis; Erythropoietin; Flow Cytometry; Humans; Kidney Diseases; Liposomes; Macrophages; Male; Rabbits; Recombinant Proteins

Resistance to erythropoietin (EPO) treatment has been associated with inflammation and malnutrition in hemodialysis (HD) patients. Depression has also been associated with both inflammation and malnutrition; however, the specific relationship between depressive symptoms and EPO resistance is not known. In the current study, the relationship between depressive symptoms and EPO resistance as evaluated by erythropoiesis stimulating agent (ESA) hyporesponsiveness index (EHRI) was analyzed. 
. Study participants had their medical history taken and underwent physical examination; dialysis adequacy calculation, biochemical analysis and evaluation of depressive symptoms by Beck Depression Inventory (BDI) were performed. EHRI was calculated as the weekly dose of EPO divided by per kilogram of body weight divided by the hemoglobin level.
. The mean BDI score of the patients was 10.99 ± 3.94. Pearson correlation analysis revealed that the logarithmically converted EHRI score was correlated with albumin (r = -0.270, p = 0.011), hs-CRP (r = 0.383, P<0.0001), hemoglobin (r = -0.617, p<0.0001), intact PTH (r = 0.215, p = 0.043) and logarithmically converted BDI (r = 0.299, p = 0.004). The stepwise linear regression analysis revealed that being female (p = 0.012), presence of diabetes mellitus (p = 0.119), hs-CRP (p = 0.009) and BDI score (p = 0.037) were independently related with logarithmically converted EHRI (as a dependent variable).
. Depressive symptoms were independently related with EHRI in HD patients. Studies are needed to highlight underlying mechanisms between depression and EHRI.

Topics: Adult; Aged; Anemia; Biomarkers; Cross-Sectional Studies; Depression; Drug Resistance; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Iron; Kidney Diseases; Linear Models; Male; Middle Aged; Psychiatric Status Rating Scales; Recombinant Proteins; Renal Dialysis; Risk Factors; Time Factors; Treatment Outcome

To investigate methoxy polyethylene glycol-epoetin beta dosing regimen in treatment naïve subjects and dose conversion in darbepoetin alpha treated subjects, in Chinese dialysis patients.. Adult Chinese patients on peritoneal dialysis (PD) or haemodialysis (HD), with no prior treatment with erythropoiesis-stimulating agents and haemoglobin below 8 g/dL (Group I) or receiving darbepoetin alpha and had stable haemoglobin at 10-12 g/dL (Group II) were included in this prospective open-label study. In Group I methoxy polyethylene glycol-epoetin beta was started at 0.6 μg/kg subcutaneously fortnightly till haemoglobin reached 10 g/dL, after which it was given monthly. A dose conversion table was devised for Group II. Follow-up was 36 weeks.. Forty-five patients were included. Haemoglobin in Group I (n=23, PD/HD:19/4) increased from 7.5 ± 0.9 g/dL at baseline to 10.7 ± 1.0 g/dL after 16 weeks, while it remained stable at 10.4 ± 1.0 g/dL after conversion in Group II (n=22, PD/HD:15/7). Actual dose required after stabilization was 1.7 μg/kg per month in Group I and 2.3 μg/kg per month in Group II. Median number of dose adjustment was three in Group I and one in Group II, while haemoglobin overshoot to 13 g/dL or above occurred in 4.4% and 9.1%, respectively. No significant side-effect was observed.. Our dosing regimen for methoxy polyethylene glycol-epoetin beta, for treatment naïve subjects or for conversion from darbepoetin alpha, is safe and effective. The dose required to achieve a haemoglobin concentration of 10-11 g/dL in Chinese dialysis patients is approximately 2 μg/kg monthly.

Topics: Adult; Aged; Analysis of Variance; Asian People; Biomarkers; Darbepoetin alfa; Drug Administration Schedule; Drug Substitution; Erythropoietin; Female; Hematinics; Hemoglobins; Hong Kong; Humans; Kidney Diseases; Male; Middle Aged; Peritoneal Dialysis; Polyethylene Glycols; Prospective Studies; Renal Dialysis; Time Factors; Treatment Outcome

Topics: Anemia; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Polyethylene Glycols

We consider a population where every individual has a unique lifespan. After expiring of its lifespan the individual has to leave the population. A realistic approach to describe these lifespans is by a continuous distribution. Such distributed lifespan models (DLSMs) were introduced earlier in the indirect response context and consist of the mathematical convolution operator to describe the rate of change. Therefore, DLSMs could not directly be implemented in standard PKPD software. In this work we present the solution representation of DLSMs with and without a precursor population and an implementation strategy for DLSMs in ADAPT , NONMEM and MATLAB . We fit hemoglobin measurements from literature and investigate computational properties.

Topics: Algorithms; Cell Survival; Erythrocytes; Erythropoietin; Hemoglobins; Humans; Kidney Diseases; Models, Biological; Models, Statistical; Numerical Analysis, Computer-Assisted; Software; Statistical Distributions

The metabolic syndrome (MS) components, such as dyslipidemia, prothrombotic status, and increased blood pressure, are risk factors for patients with renal disease. Visceral fat mass is closely related to the MS and atherosclerosis. We investigated the effects of body compositions and MS on anemia parameters and recombinant human erythropoietin (rHuEPO) requirements in maintenance hemodialysis patients.. Body composition (body mass index and bioimpedance analysis) and laboratory data were obtained from 110 dialysis patients. The MS was identified according to ATP-III criteria. Anemia parameters, hemoglobin (Hgb), albumin, C-reactive protein (CRP), calcium, phosphorus, parathormone levels, and rHuEPO requirements over the last 6 months were retrospectively analyzed.. Patients with the MS seem to reach target Hgb levels more frequently (10-12 g/dL; 66.3% vs 84.8%; P = .03) without any difference in total intravenous iron therapy dosage. MS patients also required lower rHuEPO for reaching similar Hgb levels compared with patients without MS (2679.3 ± 1936.1 vs 3702.5 ± 2213.0 U/kg/6 mo; P = .02). There were no differences in serum CRP, albumin, or Hgb levels between the 2 groups (P > .05). We observed that patients with MS had significantly higher fat mass and visceral fat ratio, but similar muscle mass values compared with no-MS counterparts (P = .0001 and .001, respectively). However, when we compared the ratios of these parameters we observed a significant reduction in muscle ratios and a significant increase in fat ratios of MS patients (P = .0001).. Our results indicate that MS might be an advantage for reaching higher Hgb levels with lower rHuEPO dosages. The possible reason for this might be the good nutritional state and increased fat mass of patients with MS.

Topics: Adiposity; Adult; Anemia; Biomarkers; Drug Dosage Calculations; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Intra-Abdominal Fat; Kidney Diseases; Male; Metabolic Syndrome; Middle Aged; Nutritional Status; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Time Factors; Treatment Outcome

To study the effect of erythropoietin (EPO) treatment on renal and lung injury following renal ischemia/reperfusion (I/R).. Thirty male Wistar rats were assigned to three groups of 10 rats each. The first group was sham-operated, the second was subjected to renal I/R (30 min of ischemia followed by 24 h of reperfusion). The third group was subjected to renal I/R and treated with EPO in two doses: the first dose 1 h prior to ischemia (1,000 U/kg) and the second dose 6 h after ischemia (1,000 U/kg).. The renal and lung tissue injury index, tissue serum blood urea nitrogen and creatinine (Cr) were higher in the renal I/R group compared to the renal I/R + EPO group; the difference was statistically significant (p < 0.05). Kidney and lung tissue glutathione peroxidase and superoxide dismutase levels were higher in the renal I/R + EPO group than the renal I/R group; the difference was also statistically significant (p < 0.05).. The data showed that EPO pretreatment could be effective in reducing renal and lung injury following renal I/R and could improve the cellular antioxidant defense system. Hence EPO pretreatment may be effective for attenuating renal and lung injury after renal I/R-induced injury during surgical procedures, hypotension, renal transplantation and other conditions inducing renal I/R.

Topics: Animals; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Erythropoietin; Glutathione Peroxidase; Kidney Diseases; Lung Diseases; Male; Oxidative Stress; Rats; Rats, Wistar; Reperfusion Injury; Superoxide Dismutase

Cisplatin (Cisp) is one of the most effective chemotherapeutic drugs. However, the dose of Cisp is greatly limited by its toxicity. Recombinant human erythropoietin (rhEPO), a hormone that regulates hematopoiesis, has also been shown to exert tissue-protective effects. The purpose of this study was to explore the protective effect of rhEPO against Cisp-induced renal and liver dysfunctions. Adult male Wistar rats were divided into six groups of six each: control, rhEPO-alone group, Cisp-alone group and rhEPO + Cisp group (pretreatment, cotreatment and posttreatment conditions). Our results showed that Cisp-induced a marked renal and liver failure characterized by a significant decrease in body weight, organ weight and organ ratio and a significant increase in creatinine, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, G-glutamyl transferase, alkaline phosphatase, bilirubin conjugated and bilirubin total levels in serum. Histological examination showed that Cisp caused kidney alterations. rhEPO treatments restored body weight, organ weight and organ ratio as well as serum biochemical parameters changed due to Cisp exposure.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Antineoplastic Agents; Aspartate Aminotransferases; Bilirubin; Blood Urea Nitrogen; Chemical and Drug Induced Liver Injury; Cisplatin; Creatinine; Erythropoietin; gamma-Glutamyltransferase; Kidney Diseases; Protective Agents; Rats; Rats, Wistar; Recombinant Proteins

Topics: Anemia; Blood Transfusion; Chronic Disease; Disease Management; Erythropoietin; Hematocrit; Hemoglobins; Humans; Kidney Diseases; Reference Standards; Renal Dialysis; Risk Adjustment

Anemia in patients with CKD is highly related to impaired erythropoietin (EPO) response, the timing and determinants of which remain unknown.. This study measured EPO levels and studied their relation to GFR measured by 51Cr-EDTA renal clearance (mGFR) in 336 all-stage CKD patients not receiving any erythropoiesis-stimulating agent.. In patients with anemia defined by World Health Organization criteria (hemoglobin [Hb] <13 g/dl in men and 12 g/dl in women), EPO response to Hb level varied by mGFR level. EPO and Hb levels were negatively correlated (r=-0.22, P=0.04) when mGFR was >30 ml/min per 1.73 m(2), whereas they were not correlated when mGFR was <30 (r=0.09, P=0.3; P for interaction=0.01). In patients with anemia, the ratio of observed EPO to the level predicted by the equation for their Hb level decreased from 0.72 (interquartile range, 0.57-0.95) for mGFR ≥60 ml/min per 1.73 m(2) to 0.36 (interquartile range, 0.16-0.69) for mGFR <15. Obesity, diabetes with nephropathy other than diabetic glomerulopathy, absolute iron deficiency, and high C-reactive protein concentrations were associated with increased EPO levels, independent of Hb and mGFR.. Anemia in CKD is marked by an early relative EPO deficiency, but several factors besides Hb may persistently stimulate EPO synthesis. Although EPO deficiency is likely the main determinant of anemia in patients with advanced CKD, the presence of anemia in those with mGFR >30 ml/min per 1.73 m(2) calls for other explanatory factors.

Topics: Adult; Aged; Chronic Disease; Erythropoietin; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Multivariate Analysis; Time Factors

Erythropoiesis-stimulating agents (ESAs) stimulate formation of red blood cells by binding to and activating Epo receptors (EpoR) on erythroid progenitor cells. Beyond successful treatment of anemia, ESAs have been reported to reduce damage following insult to organs, including the kidney, possibly via direct activation of EpoR. However, data on ESA effects outside hematopoietic functions are conflicting. Furthermore, limited use of appropriate EpoR-positive and EpoR-negative controls and lack of specific anti-EpoR antibodies make interpretation of data difficult. Recently positive and negative control cell types were validated and a sensitive and specific anti-EpoR antibody (A82) that detects low levels of EpoR protein was described.. A82 was used to measure EpoR protein levels in tissues, human renal cells and human cell lines by western blot analysis. Surface EpoR was examined on renal cells by measuring binding of [125I]-rHuEpo or antibodies. Renal cells and cell lines were treated with rHuEpo to see if phosphorylation of signaling proteins or proliferation/survival could be induced. Small inhibitory RNA (siRNA) were used to determine if EpoR knockdown affected cell viability.. Total EpoR protein was low to undetectable in tissues and renal cells with no detectable EpoR on cell surfaces. EpoR knockdown had no effect on viability of renal cell lines. RHuEpo had no detectable effect on intracellular signaling on renal cell lines with no growth-promoting or survival effect on primary human renal cells.. These results suggest that functional EpoR protein is absent on renal cells and that non-EpoR mechanisms should be explored to explain non-hematopoietic effects of ESAs.

Topics: Blotting, Western; Cell Proliferation; Cell Survival; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Flow Cytometry; Humans; Kidney; Kidney Diseases; Megakaryocytes; Phosphorylation; Real-Time Polymerase Chain Reaction; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Signal Transduction

Topics: Anemia; Erythropoietin; Female; Humans; Kidney Diseases; Kidney Transplantation; Male; Recombinant Proteins

Anemia can contribute to chronic allograft injury by limiting oxygen delivery to tissues, particularly in the tubulointerstitium. To determine mechanisms by which erythropoietin (EPO) prevents chronic allograft injury we utilized a rat model of full MHC-mismatched kidney transplantation (Wistar Furth donor and Lewis recipients) with removal of the native kidneys. EPO treatment entirely corrected post-transplant anemia. Control rats developed progressive proteinuria and graft dysfunction, tubulointerstitial damage, inflammatory cell infiltration, and glomerulosclerosis, all prevented by EPO. Normalization of post-transplant hemoglobin levels by blood transfusions, however, had no impact on chronic allograft injury, indicating that EPO-mediated graft protection went beyond the correction of anemia. Compared to syngeneic grafts, control allografts had loss of peritubular capillaries, higher tubular apoptosis, tubular and glomerular oxidative injury, and reduced expression of podocyte nephrin; all prevented by EPO treatment. The effects of EPO were associated with preservation of intragraft expression of angiogenic factors, upregulation of the anti-apoptotic factor p-Akt in tubuli, and increased expression of Bcl-2. Inhibition of p-Akt by Wortmannin partially antagonized the effect of EPO on allograft injury and tubular apoptosis, and prevented EPO-induced Bcl-2 upregulation. Thus non-erythropoietic derivatives of EPO may be useful to prevent chronic renal allograft injury.

Topics: Anemia; Animals; Apoptosis; Biomarkers; Blood Transfusion; Chronic Disease; Erythropoietin; Glomerulonephritis; Hematinics; Hemoglobins; Histocompatibility; Kidney; Kidney Diseases; Kidney Transplantation; Mice; Primary Graft Dysfunction; Proteinuria; Rats; Rats, Inbred Lew; Rats, Inbred WF; Time Factors

Topics: Chronic Disease; Epoetin Alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Kidney Diseases; Patient Education as Topic; Physician-Patient Relations; Recombinant Proteins; Renal Dialysis; Risk Assessment; Risk Factors; Risk Management; Stroke; United States; United States Food and Drug Administration

Oxidative stress (OS) is involved in left ventricular hypertrophy (LVH). Short-term treatment with erythropoietin (EPO) in chronic kidney disease (CKD) complicated by anemia and LVH is associated with a reduction in left ventricular mass (LVM). We proposed to assess whether the pro-oxidant status of CKD influences these outcomes.. Predialysis patients (n = 76) with CKD and hemoglobin (Hb) levels < 11 g/dl received EPO for 6 months. The effects of this anemia correction on LVH regression were evaluated using echocardiography. Patients with LVM decrease > 10% were considered "responders" (n = 25) to treatment and those with LVM change < 10% were considered "non-responders" (n = 24). Measurement of OS included plasma and erythrocyte oxidized (GSSG) and reduced (GSH) glutathione, GSH redox ratio (GSSG/GSH), erythrocyte glutathione peroxidase (GPx) and oxidized LDL (Ox- LDL).. 49 patients completed the study. With EPO therapy, mean Hb levels increased from 9.9 ± 0.6 to 12.8 ± 1.5 g/ dl (p < 0.0001) and LVM index decreased from 69.2 ± 17.7 to 64.1 ± 19.6 g/m2.7 (p = 0.01). At 6 months, "non-responders" had higher systolic blood pressure, pulse pressure, GSSG and GSH redox ratio and lower GSH than "responders". In multivariate analysis, and following adjustment for confounding variables, systolic blood pressure and GSH redox ratio independently predicted LVH regression.. Blood pressure and plasma GSH redox ratio (a marker of OS) are important predictors of LVH regression in anemic predialysis patients treated with EPO.

Topics: Aged; Anemia; Biomarkers; Blood Pressure; Chi-Square Distribution; Chronic Disease; Erythropoietin; Female; Glutathione; Glutathione Disulfide; Glutathione Peroxidase; Hematinics; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Lipoproteins, LDL; Logistic Models; Male; Middle Aged; Multivariate Analysis; Oxidative Stress; Recombinant Proteins; Time Factors; Treatment Outcome; Ultrasonography

The introduction of cyclosporine (CsA) has improved graft survival, but it causes nephropathy, which limits its clinical utility. Recently, we reported that carbamylated erythropoietin (CEPO) protected kidneys from ischemia reperfusion injury as well as EPO. To investigate the clinical applications of CEPO, we next evaluated the long-term therapeutic effect of CEPO using a CsA-induced nephropathy model. CsA caused renal dysfunction, while EPO/CEPO administration significantly improved renal function. EPO treatment significantly increased Hb concentration, while CEPO treatment neither enhanced nor reduced Hb concentration. CsA treatment induced tubular apoptosis, while EPO/CEPO administration inhibited it and increased PI3 kinase activation and Akt phosphorylation. In parallel, morphological assessment revealed that EPO/CEPO significantly reduced CsA-induced interstitial fibrosis and inhibited interstitial macrophage infiltration. In addition, real-time RT-PCR demonstrated that cortical mRNA levels of TGF-β1 and type I collagen were suppressed in the EPO/CEPO group. These results suggest a new therapeutic approach using CEPO to protect kidneys from CsA-induced nephropathy.

Topics: Animals; Apoptosis; Collagen Type I; Cyclosporine; Disease Models, Animal; Dogs; Erythropoiesis; Erythropoietin; Fibrosis; Hemoglobins; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Macrophages; Male; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction; Transforming Growth Factor beta1

Topics: Erythropoietin; Humans; Kidney; Kidney Diseases; Megakaryocytes; Receptors, Erythropoietin; Signal Transduction

Patients with chronic kidney disease (CKD) frequently suffer from heart disease as well. The combination of the two processes can exacerbate inflammation, resulting in increases in both resistance to erythropoietin (EPO) and mortality.. The aim of this study was to determine the prevalence of heart disease in a representative group of non-dialysis patients with stage 4-5 CKD, and the influence of that entity on EPO requirements and on mortality during a period of 36 months.. 134 patients (68% on EPO at the beginning, increasing to 72.3% during follow-up) were monitored for 36 months. To evaluate the dose-response effect of EPO therapy, we used the erythropoietin resistance index (ERI) calculated as the weekly weight-adjusted dose of EPO divided by the haemoglobin level. The ERI was determined both initially and during the last six months before the end of the study.. 39 patients (29.1%) had history of heart disease; 22 (16.4%) had suffered from heart failure (HF). The ERI was higher in patients with a history of heart disease or HF and those treated with drugs acting on the renin-angiotensin system (ACE inhibitors or ARBs). Using ERI as the dependent variable in the multivariate analysis, the variables that composed the final model were ferritin, haemoglobin, glomerular filtration rate and history of HF. The 36 month mortality rate (n=39 patients) was higher in the group having ERI above the median (2.6IU/week/kg/gram of haemoglobin in 100ml) (P=.002), and in the groups with heart disease (P=.001) or HF (P=.001) according to the Kaplan-Meier survival analysis.. Patients with history of heart disease or HF have a higher ERI, and all of these characteristics are associated with lower survival. ERI can be considered a marker for risk of death in the short to-medium term.

Topics: Aged; Aged, 80 and over; Anemia; Autoimmune Diseases; Cardio-Renal Syndrome; Cardiovascular Agents; Comorbidity; Cross-Sectional Studies; Dose-Response Relationship, Drug; Drug Resistance; Erythropoietin; Female; Ferritins; Glomerular Filtration Rate; Heart Diseases; Heart Failure; Hemoglobins; Humans; Kaplan-Meier Estimate; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Severity of Illness Index

Iron metabolism is an important factor of anemia in chronic kidney disease (CKD). Hepcidin is a regulator of iron homeostasis and has a major role in the anemia of chronic disease (ACD). Oxidative stress (OS) is also associated with iron metabolism. However, the clinical utility of hepcidin, especially its association with OS, in CKD patients not receiving dialysis is still unclear.. We recruited 117 patients (62 ± 15 years, 85 males, and median estimated glomerular filtration rate (eGFR) 22 ml/min/1.73 m2) with CKD not receiving dialysis. Serum 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of DNA oxidative injury, and serum hepcidin-25 were measured by ELISA and by liquid chromatography tandem mass spectrometry, respectively.. Hepcidin-25 was associated positively with ferritin, high-sensitive C-reactive protein (hsCRP) and 8-OHdG, and negatively with eGFR and hemoglobin. Sex, oral iron, hemoglobin, transferrin saturation (TSAT), ferritin, and hsCRP were independently associated with hepcidin-25 in a multiple regression model. In contrast, neither eGFR nor 8-OHdG independently affected hepcidin- 25.. The close association between hepcidin and serum ferritin, oral iron and hsCRP indicates that it plays a key role in the pathogenesis of anemia in patients with CKD not receiving dialysis. In contrast, effects of eGFR and OS were not apparent.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Aged; Antimicrobial Cationic Peptides; C-Reactive Protein; Chronic Disease; Deoxyguanosine; Erythropoietin; Female; Hepcidins; Humans; Kidney Diseases; Male; Middle Aged; Oxidative Stress; Renal Dialysis

Topics: Anemia; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Diseases; Product Surveillance, Postmarketing; Recombinant Proteins; Renal Dialysis

The tissue-protective effects of erythropoietin (EPO) have been extensively investigated, and EPO administration can raise the hemoglobin (Hb) concentration. Recently, we reported that carbamylated erythropoietin (CEPO) protected kidneys from ischemia-reperfusion injury as well as EPO.. To investigate the clinical applications of CEPO, we next evaluated the long-term therapeutic effect of CEPO using a tubulointerstitial model rat. We randomized remnant kidney model rats to receive saline, EPO, or CEPO for 8 weeks.. CEPO- and EPO-treated rats had improved serum creatinine levels compared with saline-treated remnant kidney model rats, although the Hb level was significantly increased in EPO-treated rats. Two-photon microscopy revealed that EPO/CEPO significantly ameliorated tubular epithelial cell damage assessed by endocytosis. In addition, CEPO or EPO protected endothelial cells with a sustained blood flow rate. EPO or CEPO suppressed the number of TUNEL-positive apoptotic cells with weak αSMA staining. Furthermore, PCR analysis demonstrated that TGF-β and type I collagen expression was attenuated in EPO- or CEPO-treated rats, accompanied by a significant decrease in interstitial fibrosis.. We established a long-term therapeutic approach to protect tubulointerstitial injury with CEPO, and thus, the therapeutic value of this approach warrants further attention and preclinical studies.

Topics: Animals; Collagen Type I; Creatinine; Disease Models, Animal; Erythropoietin; Fibrosis; Hemoglobins; Kidney; Kidney Diseases; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Transforming Growth Factor beta

The Normal Hematocrit Cardiac Trial, published in 1998, was a foundational study testing erythropoietin analog treatment to normal hematocrit targets. It served as a warning that erythropoietin replacement was not a panacea. Its large size gave it disproportionate weighting in evidence reviews and guideline development and thereby impacted treatment decisions. Coyne shows that the published results did not completely and clearly represent the study's actual results. We discuss the implications and make recommendations to prevent such occurrences.

Topics: Anemia; Erythropoietin; Heart Diseases; Hematinics; Hematocrit; Hemoglobins; Humans; Kidney Diseases; Quality of Life; Renal Dialysis

Topics: Anemia; Erythropoietin; Heart Diseases; Hematinics; Hematocrit; Hemoglobins; Humans; Kidney Diseases; Quality of Life; Renal Dialysis

Topics: Anemia; Chronic Disease; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Diseases; Practice Guidelines as Topic; Quality of Life; Recombinant Proteins; Renal Dialysis; United States

Oxidative stress-related renal pathologies apparently include rhabdomyolysis and ischemia/reperfusion phenomenon. These two pathologies were chosen for study in order to develop a proper strategy for protection of the kidney. Mitochondria were found to be a key player in these pathologies, being both the source and the target for excessive production of reactive oxygen species (ROS). A mitochondria-targeted compound which is a conjugate of a positively charged rhodamine molecule with plastoquinone (SkQR1) was found to rescue the kidney from the deleterious effect of both pathologies. Intraperitoneal injection of SkQR1 before the onset of pathology not only normalized the level of ROS and lipid peroxidized products in kidney mitochondria but also decreased the level of cytochrome c in the blood, restored normal renal excretory function and significantly lowered mortality among animals having a single kidney exposed to ischemia/reperfusion. The SkQR1-derivative missing plastoquinone (C12R1) possessed some, although limited nephroprotective properties and enhanced animal survival after ischemia/reperfusion. SkQR1 was found to induce some elements of nephroprotective pathways providing ischemic tolerance such as an increase in erythropoietin levels and phosphorylation of glycogen synthase kinase 3β in the kidney. SkQR1 also normalized renal erythropoietin level lowered after kidney ischemia/reperfusion and injection of a well-known nephrotoxic agent gentamicin.

Topics: Animals; Antioxidants; Blotting, Western; Cells, Cultured; Erythropoietin; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Kidney; Kidney Diseases; Male; Microscopy, Confocal; Mitochondria; Molecular Structure; Oxidative Stress; Phosphorylation; Plastoquinone; Protective Agents; Rats; Reperfusion Injury; Rhabdomyolysis; Rhodamines; Survival Rate

Topics: Algorithms; Anemia; Chronic Disease; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Diseases; Risk Factors; Stroke; United States; United States Food and Drug Administration

Insulin resistance is an independent predictor of cardiovascular mortality in hemodialysis (HD) patients. Inflammation plays an important role in insulin resistance, and adipocytokines, including tumor necrosis factor-alpha and leptin, can induce insulin resistance. However, data on insulin resistance and erythropoietin responsiveness in HD patients are lacking.. We conducted a prospective, observational cohort study to clarify the relationship between insulin resistance and erythropoietin responsiveness in HD patients. Insulin resistance as assessed by the homeostasis model assessment for insulin resistance (HOMA-IR), levels of adiponectin and inflammatory cytokines, required erythropoietin (EPO) dose, and other metabolic parameters were measured in patients with (n = 52) and without diabetes (n = 55) over the course of 12 months.. The diabetes group had significantly higher serum leptin, high-sensitivity C-reactive protein, and interleukin-6 concentrations but lower serum adiponectin concentration. Average hemoglobin (Hb) levels during the 12-month study period were significantly lower in the diabetes group than in the non-diabetes group, and a higher dose of EPO was required in the diabetes group. There was a significant negative correlation between adiponectin and HOMA-IR, a significant positive correlation between EPO dose and HOMA-IR, and a significant negative correlation between EPO dose and adiponectin in the two groups. Insulin resistance as established by HOMA-IR and adiponectin was associated with EPO responsiveness in HD patients. HOMA-IR, Hb, and adiponectin levels were found to be independent predictors of EPO dose in HD patients with diabetes.. Insulin resistance is associated with EPO responsiveness in HD patients. Patients in the diabetes group had a lower response to EPO than those in the non-diabetes group. For improvement in EPO response, insulin resistance may be a new target for treating HD patients.

Topics: Adiponectin; Aged; Anemia; Biomarkers; Cytokines; Diabetes Mellitus, Type 2; Erythropoiesis; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Inflammation Mediators; Insulin Resistance; Japan; Kidney Diseases; Linear Models; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Time Factors; Treatment Outcome

Patients with renal graft dysfunction constitute an increasingly prevalent group of end-stage kidney disease (ESKD) patients that require dialysis therapy. These patients have special characteristics that set them apart from the ESKD general population. The aim of this study was to analyse the clinical condition and evolution of patients entering dialysis with a failed kidney graft at the time of restarting dialysis and over a year of therapy according to the K/DOQI guidelines, and to compare them with incidental patients with end-stage kidney disease. We also investigated whether the modality of kidney replacement therapy may determine the clinical improvement of transplant patients.. This is a retrospective observational study of 106 patients with ESKD followed up in the Ramon y Cajal Hospital. They were classified in two groups. Group one was made up of 50 failed native kidney patients who started dialysis between 2000 and 2009. Group two was comprised of 56 transplant patients with graft dysfunction who returned to dialysis between 1997 and 2009. We studied parameters of kidney function, anaemia, calcium-phosphorus metabolism, cardiovascular risk factors and nutritional status at the time both groups started on dialysis and one year later.. Both groups had a similar clinical status at the time they started on dialysis in most of the parameters analysed with the exception of anaemia. This was more severe in transplant patients, despite the fact that transplant patients received a higher dose of erythropoietin than non-transplant patients. One year later the main difference between both groups was the residual kidney function rate, higher in non-transplant patients. There were no significant differences in the parameters analysed in patients with a failed graft according to the modality of kidney replacement therapy.. Failed transplant patients start dialysis with more severe anaemia than patients entering dialysis for the first time. Twelve months later both groups present a similar clinical condition with the exception of residual kidney function, higher in failed native kidney patients. The method of dialysis treatment after kidney transplant failure did not have a bearing on the clinical improvement of our patients.

Topics: Adult; Aged; Anemia; Calcium; Cardiovascular Diseases; Chronic Disease; Darbepoetin alfa; Erythropoietin; Female; Follow-Up Studies; Graft Rejection; Humans; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Peritoneal Dialysis; Phosphorus; Postoperative Complications; Recurrence; Renal Dialysis; Retrospective Studies; Risk Factors; Treatment Outcome

Erythropoietin (EPO) is a multifunctional cytokine with anti-apoptotic, anti-inflammatory, and organ protective effects. EPO protects against ischemia-reperfusion injuries, and recent reports suggest that EPO also prevents organ dysfunction in experimental sepsis. The aims of this study were to determine whether EPO prevents endotoxemia-induced organ dysfunction in a porcine model and to characterize the immunomodulatory and anti-apoptotic effects of EPO.. Twenty-eight pigs were randomly assigned to three groups: (1) endotoxemia treated with EPO 5000 IU/kg, (2) endotoxemia treated with placebo, and (3) a sham group anesthetized and submitted to sham operation without treatment. A laparotomy was performed, and a flow probe was placed around the left renal artery, which allowed renal blood flow (RBF) measurements. Endotoxemia was induced by an infusion of lipopolysaccharide. After 2 h, the infusion was reduced to a maintenance dose and the animals were fluid resuscitated. The glomerular filtration rate (GFR), RBF, renal oxygen consumption, and plasma cytokines [interleukin (IL)-1β, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha] were analyzed. Renal biopsies were analyzed for cytokine content and apoptosis.. Endotoxemia elicited impaired renal function, estimated as GFR, and increased the levels of renal apoptotic cells, with no modifying effect of EPO. Furthermore, EPO had no effect on RBF, renal oxygen consumption, or the systemic hemodynamic response to endotoxemia. EPO did not modify the inflammatory response, measured as changes in cytokine levels in plasma and organs.. EPO did not confer renal protection in this fluid-resuscitated porcine model of endotoxemia, and EPO did not modify the inflammatory response.

Topics: Animals; Apoptosis; Caspase 3; Cytokines; Endotoxemia; Erythropoietin; Female; Glomerular Filtration Rate; Hemodynamics; Immunohistochemistry; Inflammation; Kidney; Kidney Diseases; Kidney Function Tests; Lipopolysaccharides; Oxygen Consumption; Recombinant Proteins; Renal Circulation; Resuscitation; Swine; Tumor Necrosis Factor-alpha

Chronic inflammation plays a pivotal role in the development of renal disease. Circadian sleep-wake rhythm is disturbed in renal disease. Awareness of other disturbed rhythms, such as inflammation processes, can affect the treatment of patients with renal disease. Knowledge of possibly related circadian misalignment of the cytokines erythropoietin (EPO), Insulin Growth Factor-1 (IGF-1) and interleukins (IL) however is limited. We therefore performed an observational study. The objective of this study was to characterize levels of EPO, IGF-1 and inflammation markers IL-6 and TNF-α, related to renal function.. The study population consisted of patients with various degrees of renal function, admitted to our hospital. During 24 hours, blood of 28 subjects with various degrees of renal function was collected every 2 hours. The patients were stable, not acutely ill and they were waiting for a procedure, such as elective surgery. Circadian parameters of EPO, IGF-1, IL-6 and TNF-α were measured in serum and were correlated with glomerular filtration rate (GFR) and Hb, using Pearson correlations.. Although diurnal variations in EPO level were found in 15 out of 28 patients, the curves did not show a consistent phase. The presence of an EPO rhythm was not related to GFR. No diurnal rhythm could be detected for IGF-1, IL-6 and TNF-α. Mean levels of IGF-1 were correlated inversely to mean levels of EPO (p=0.03). When divided based on GFR and Hb subjects with GFR 10-30 ml/min and lower Hb had the highest IGF-1 levels (p=0.02). A relationship between Il-6, TNF-α and EPO or GFR was not found.. The existence of a circadian (mis)alignment of EPO, IGF-1, IL-6 and TNF-α was not found. The association between high IGF-1 and low Hb suggests that EPO and IGF-1 have an alternating role, dependent on GFR, in stimulating erythropoiesis. These results could have consequences for the treatment of anemia.

Topics: Aged; Biomarkers; Chronic Disease; Circadian Rhythm; Erythropoietin; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Insulin-Like Growth Factor I; Interleukin-6; Kidney; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Retrospective Studies; Tumor Necrosis Factor-alpha

Endothelial progenitor cells (EPCs) are thought to be important for maintaining normal vascular function. We conducted a prospective study evaluating the effect of the erythropoiesis-stimulating agent darbepoetin alfa on EPCs and vascular function in patients with chronic kidney disease (CKD), with or without diabetes. Thirty subjects with CKD (20 subjects with type II diabetes mellitus and 10 without diabetes mellitus) received weekly subcutaneous administration of darbepoetin alfa for 4 weeks. EPCs were measured at baseline and 2 and 4 weeks after drug administration. Vascular function was measured with brachial ultrasound and cell activity was measured with a cell proliferation assay. Cells expressing CD133, CD34, CD146 and CD146/31 were significantly elevated (all p < 0.05), flow-mediated vasodilatation increased 2.1%, 95% CI: (0.4%, 3.8%) and colony-forming units increased twofold, 95% CI: (1.7, 2.3) after 4 weeks of treatment with darbepoetin alfa. Subjects with diabetes exhibited an increase in a subset of EPCs (CD133( +) and 34(+), p < 0.01 and p = 0.06, respectively), vasodilatation and proliferation. In conclusion, the administration of darbepoetin alfa for 4 weeks increased a subset of EPCs, improved endothelial function and increased cell proliferation, including those with diabetes, which is consistent with a favorable improvement in vascular health.

Topics: AC133 Antigen; Aged; Antigens, CD; Antigens, CD34; Biomarkers; Cell Proliferation; Chronic Disease; Darbepoetin alfa; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelial Cells; Erythropoietin; Female; Glycoproteins; Hematinics; Humans; Kidney Diseases; Linear Models; Male; Middle Aged; Peptides; Philadelphia; Prospective Studies; Stem Cells; Time Factors; Treatment Outcome; Vasodilation

Anemia of chronic kidney disease (CKD) has been traditionally treated by erythropoiesis-stimulating agents (ESAs) and/or iron following manual determination of dose. We hypothesized that once-monthly (QM) algorithmically dosed darbepoetin α (DA) and iron administration would successfully treat anemia of CKD in ESA-naïve CKD subjects.. QM DA and iron doses were determined via a computerized program targeting a hemoglobin (Hb) of 10.5 - 12.5 g/dl in anemic, ESA-naïve, CKD Stages 3 - 5 subjects. Six consecutive QM doses were administered. Hb, ferritin, and transferrin saturation were recorded. Data are presented as means ± standard deviation.. Anemia was identified in 133 subjects, with a mean follow-up of 188 days. DA doses and Hb were significantly greater at Months 3 and 6 compared to baseline (p < 0.05); DA doses were 109 ± 68 μg and 118 ± 91, respectively, at Months 3 and 6. Hemoglobin levels were correspondingly 11.3 ± 1.1 g/dl and 11.3 ± 1.0. 78% of patients achieved the target Hb by 6 months of therapy. The elevation of Hb was greater in non-proteinuric than proteinuric subjects at 6 months of treatment (11.6 ± 0.8 g/dl vs. 11.0 ± 1.1; p < 0.05), despite lower DA dose (96 ± 76 μg vs. 139 ± 98; p < 0.05).. Successful treatment of the anemia of CKD by QM DA based upon a computerized dosing program was achieved by 6 months in 78% of ESA-naïve, CKD subjects.

Topics: Algorithms; Anemia; Chronic Disease; Darbepoetin alfa; Drug Administration Schedule; Drug Therapy, Computer-Assisted; Erythropoietin; Female; Ferritins; Ferrous Compounds; Hematinics; Hemoglobins; Humans; Kidney Diseases; Male; Transferrin

Frequent dosing and requirements for dose adjustments of erythropoiesis-stimulating agents (ESAs) create significant burdens for healthcare providers and have been associated with hemoglobin (Hb) cycling, hampering maintenance of target Hb levels. We compared the frequency of dose changes in dialysis patients who received methoxy polyethylene glycolepoetin beta; (a continuous erythropoietin receptor activator (C.E.R.A.)) or a shorter-acting ESA.. Data were analyzed from three Phase III maintenance trials, using almost identical protocols, in dialysis patients treated with C.E.R.A. every 2 weeks (q2w) or every 4 weeks (q4w) or a comparator ESA (epoetin or darbepoetin alpha; at their previous dose/administration interval). Dosage was adjusted to maintain Hb ± 1 g/dl of baseline and 10 - 13.5 g/dl during titration (28 weeks) and evaluation (8 weeks), and 11 - 13 g/dl during follow-up (16 weeks).. Data were analyzed from 564 patients treated with C.E.R.A. q2w, 410 with C.E.R.A. q4w and 572 with comparator ESA at their usual dosing interval. Significantly fewer dose changes were needed in patients receiving C.E.R.A. q2w (p < 0.05) or C.E.R.A. q4w (p < 0.001) than in patients treated with comparator ESAs.. This retrospective analysis suggests that C.E.R.A. q4w maintains Hb levels in dialysis patients and requires fewer dose changes compared with other ESAs.

Topics: Anemia; Chronic Disease; Clinical Trials, Phase III as Topic; Darbepoetin alfa; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Polyethylene Glycols; Recombinant Proteins

The four currently available erythropoiesis-stimulating agents (ESAs), the main drugs for correcting anemia in patients with chronic kidney disease (CKD), are epoetin alfa, epoetin beta, darbepoetin alfa, and continuous erythropoietin receptor activator. The last two have much longer half-lives, which means they can be administered less frequently. The expiry of the patents for epoetin alfa and epoetin beta some years ago opened up the way for the production of a number of biosimilars that are now marketed in the European Union. Because biosimilars cannot be identical to their originator, a complex and still-evolving regulatory policy has been generated, but there are still a number of issues concerning international naming, automatic substitution, and safety. All ESAs are effective in correcting renal anemia and increasing hemoglobin levels, but the choice of which to use should also take into account their pharmacokinetics and pharmacodynamics, their administration route, and economic issues. Following the publication of a number of trials indicating no benefit (and even possible harm) when ESAs are used to aim at near-normal hemoglobin levels in CKD patients, the hemoglobin target has become a major subject of discussion. According to the position statement of the Anemia Group of the European Renal Best Practice, it should generally be about 11-12 g/dL; however, a risk-benefit evaluation is warranted in individual patients, and high ESA doses driven by hyporesponsiveness should be avoided.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; European Union; Hematinics; Hemoglobins; Humans; Kidney Diseases; Polyethylene Glycols; Recombinant Proteins

Observational studies relating epoetin alfa (EPO) dose and mortality frequently use analytic methods that do not control time-dependent confounding by indication (CBI). The relationship between EPO dose and 1-year mortality, adjusting for the effects of time-dependent CBI, was examined using a marginal structural model.. This retrospective cohort study included 27,791 hemodialysis patients between July 2000 and June 2002. Patients were grouped at successive 2-wk intervals into a zero-dose category or four nonzero-dose categories. Ordinal regression was used to calculate inverse probability of treatment weights of patients receiving their own dose level given their covariate and treatment history. Three treatment models with an increasing number of treatment predictors were evaluated to assess the effect of model specification. A small number of excessively large patient weights were truncated. Relative hazards for higher-dose groups compared with the lowest nonzero-dose group varied by treatment model specification and by level of weight truncation.. Results differed appreciably between the simplest treatment model, which incorporated only hemoglobin and EPO dosing history with 2% weight truncation (hazard ratio: 1.51; 95% confidence interval: 1.09, 1.89 for highest-dose patients), and the most comprehensive treatment model with 1% weight truncation (hazard ratio: 0.98; 95% confidence interval: 0.76, 1.74).. There is appreciable CBI at higher EPO doses, and EPO dose was not associated with increased mortality in marginal structural model analyses that more completely addressed this confounding.

Topics: Adult; Aged; Biomarkers; Confounding Factors, Epidemiologic; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Diseases; Logistic Models; Male; Middle Aged; Models, Statistical; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; United States

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Epoetin Alfa; Erythrocytes; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Diseases; Randomized Controlled Trials as Topic; Recombinant Proteins

Anemia is common in chronic kidney disease (CKD). The CHOIR study found increased risk of a composite cardiovascular outcome when anemia was treated with epoetin-alfa to a target hemoglobin level of 13.5 as compared with 11.3 g/dl. Whether this increase applies to all patient subgroups equally is unclear. We discuss an analysis by Szczech and colleagues of the effects of the higher hemoglobin target in CKD patients with diabetes mellitus or congestive heart failure.

Topics: Anemia; Chronic Disease; Diabetes Mellitus; Epoetin Alfa; Erythropoietin; Heart Failure; Hemoglobins; Humans; Kidney Diseases; Recombinant Proteins

The erythropoietic response in hemodialysis patients depends on several physiologic factors. Most epidemiologic studies include the effect of these factors by representing them as confounders. This study tested the hypothesis that iron stores, inflammation, dialysis adequacy, nutritional status, and hyperparathyroidism act as nonlinear effect modifiers of the erythropoietic response and quantified the magnitude of those effects over clinically relevant ranges.. The following retrospective data from 209 hemodialysis patients receiving Epoetin alfa (Epo) were collected: monthly: predialysis hemoglobin (Hgb), transferrin saturation, serum albumin, dialysis adequacy (Kt/V); quarterly: predialysis serum ferritin and intact parathyroid hormone over a period of 13 to 69 months. The study analyzed the dynamic relationship between hemoglobin and Epo, considering nonlinear effect modification by ferritin, transferrin saturation, Kt/V, albumin, and parathyroid hormone individually.. Maximum Hgb response to Epo was achieved for serum ferritin between 350 and 500 ng/ml, transferrin saturation greater than 30%, Kt/V greater than 1.4, and albumin greater than 3.8 g/dl. Hgb sensitivity to Epo decreases by about 30% as parathyroid hormone increases from 0 through 1000 pg/ml.. Serum ferritin, transferrin saturation, Kt/V, serum albumin, and intact parathyroid hormone are markers of nonlinear effect modification of the erythropoietic response in hemodialysis patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Biomarkers; Confounding Factors, Epidemiologic; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoiesis; Erythropoietin; Female; Ferritins; Hematinics; Hemoglobins; Humans; Hyperparathyroidism; Inflammation; Iron; Kidney Diseases; Likelihood Functions; Logistic Models; Male; Middle Aged; Nonlinear Dynamics; Nutritional Status; Parathyroid Hormone; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Serum Albumin; Time Factors; Transferrin; Treatment Outcome; Young Adult

Topics: Anemia; Animals; Chronic Disease; Erythropoietin; Humans; Hypertension; Kidney Diseases; Oxidative Stress; Rats; Recombinant Proteins

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Hematinics; Humans; Kidney Diseases; Kidney Transplantation

Vitamin D deficiency is highly prevalent in chronic kidney disease. The aim of this study was to evaluate the effects of oral cholecalciferol supplementation on mineral metabolism, inflammation, and cardiac dimension parameters in long-term hemodialysis (HD) patients.. This 1-year prospective study included 158 HD patients. Serum levels of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], intact parathyroid hormone, and plasma brain natriuretic peptide as well as circulating bone metabolism and inflammation parameters were measured before and after supplementation. Baseline 25(OH)D and 1,25(OH)(2)D levels were measured twice (end of winter and of summer, respectively). Therapy with paricalcitol, sevelamer, and darbepoietin was evaluated.. There was an increase in serum 25(OH)D and 1,25(OH)(2)D levels after supplementation. Conversely, serum calcium, phosphorus, and intact parathyroid hormone were decreased. There was a reduction in the dosage and in the number of patients who were treated with paricalcitol and sevelamer. Darbepoietin use was also reduced, with no modification of hemoglobin values. Serum albumin increased and C-reactive protein decreased during the study. Brain natriuretic peptide levels and left ventricular mass index were significantly reduced at the end of the supplementation.. Oral cholecalciferol supplementation in HD patients seems to be an easy and cost-effective therapeutic measure. It allows reduction of vitamin D deficiency, better control of mineral metabolism with less use of active vitamin D, attenuation of inflammation, reduced dosing of erythropoiesis-stimulating agents, and possibly improvement of cardiac dysfunction.

Topics: Administration, Oral; Aged; Biomarkers; Bone Density Conservation Agents; Bone Remodeling; C-Reactive Protein; Calcitriol; Calcium; Chelating Agents; Cholecalciferol; Chronic Disease; Darbepoetin alfa; Dietary Supplements; Ergocalciferols; Erythropoietin; Female; Hematinics; Humans; Hypertrophy, Left Ventricular; Inflammation Mediators; Kidney Diseases; Male; Middle Aged; Natriuretic Peptide, Brain; Parathyroid Hormone; Phosphorus; Polyamines; Prospective Studies; Renal Dialysis; Serum Albumin; Sevelamer; Time Factors; Treatment Outcome; Vitamin D; Vitamin D Deficiency; Vitamins

C.E.R.A., a continuous erythropoietin receptor activator, offers once-monthly dosing without compromising haemoglobin control. This study was undertaken to examine whether monthly C.E.R.A. using pre-filled syringes maintains stable haemoglobin levels when administered according to local clinical judgement.. MIRACEL was a prospective, open-label, single-arm, multicentre study performed at 90 nephrology centres in Germany. After a 2-month screening phase, haemodialysis patients receiving epoetin or darbepoetin were converted to monthly intravenous C.E.R.A., with a 5-month titration phase followed by a 2-month evaluation phase.. Clinicaltrials.gov: NCT00413894 RESULTS: Of 661 patients screened, 424 (64.1%) started C.E.R.A. therapy (previous treatment: 72.2% epoetin, 27.8% darbepoetin); 416 were eligible for inclusion in the intent-to-treat population. A mean of two C.E.R.A. dose changes were required during the 7-month treatment period. The primary efficacy variable, haemoglobin within 11-12.5 g/dL or 10-13 g/dL during the evaluation phase, was achieved in 109 (30.8%) and 265 (74.9%) of the 354 evaluable patients, respectively, with no differences observed between patients formerly receiving epoetin or darbepoetin or different dosing frequencies. During the screening, titration and evaluation phases, mean haemoglobin was 11.7 +/- 0.7 g/dL, 11.6 +/- 0.9 g/dL and 11.4 +/- 1.0 g/dL, respectively, and 90.6% (377/416), 70.4% (293/416) and 82.9% (345/416) of patients exhibited < or = 1 g/dL change from phase-specific individual means. C.E.R.A. was well-tolerated with a safety profile similar to that reported in phase III studies.. In this single-arm, open-label, multicentre study, conversion of a large population of haemodialysis patients from epoetin or darbepoetin to monthly C.E.R.A. administration using pre-filled syringes was shown to be practical, convenient and offer good control of haemoglobin levels, regardless of the previous type of therapy or dosing frequency.

Topics: Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hemoglobins; Humans; Kidney Diseases; Recombinant Proteins; Renal Dialysis

The aim of study was to analyze the results of anemia treatment with darbepoetin alfa and erythropoietin beta in patients with chronic kidney disease (3-5 stage of CKD) in predialysis period.. In the study the results of anemia treatment with darbepoetin alfa and erythropoietin beta were analyzed in respectively 35 and 20 patients during 11 months, and its influence on blood pressure and the rate of progression of chronic kidney disease. After 2 months of darbepoetin alfa treatment 10 mg/month and after 4 months of darbepoetin alfa treatment 20 mg/month the hemoglobin target serum levels in male and female patients were reached. In 3 patients the hemoglobin serum level was increased over 13 g/dl and was stable up to the end of treatment. During 11 months observation the value of blood pressure was not changed. Similarly, a creatinine serum level was stable in females but increased in males. Therapy with darbepoetin alfa was well tolerated, however some patients were complained for subcutaneous injection pain.. After erythropoietin beta treatment 2000 IU/week the hemoglobin target level in serum was achieved in 3 females after 9 months and 7 males after 6 months. In 3 patients, in one male after 6 months and two females after 8 months the hemoglobin serum levels were increased over 13 g/dl and was stable up to the end of treatment.. During 11 months of observation blood pressure was not changed but a creatinine serum level was increased in females and in males. Erythropoietin beta was well tolerated and injection pain was smaller compared to darbepoetin alfa.

Topics: Anemia; Blood Pressure; Chronic Disease; Creatinine; Darbepoetin alfa; Disease Progression; Erythropoietin; Female; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Pain; Treatment Outcome

To evaluate the effects of L-carnitine oral supplementation on anemia and cardiac function in patients on maintenance hemodialysis (HD), we studied 55 adult chronic HD patients at our center during the period from January 2006 to June 2006 and divided them into two groups; a group of 20 patients who received 1500 mg/day oral L-carnitine and a control group of 35 patients. Both groups were on erythropoietin therapy. Echogardiographic studies were performed before and at the end of the study. The mean hemoglobin levels were comparable in the L-carnitine group and the control group at the start and after 6 months of therapy (8.63 +/- 1.77 and 9.39 +/- 2.02 gm/dL, P = 0.18; 10.49 +/- 1.65 and 10.92 +/- 2.48 gm/dL, P = 0.76, respectively). The mean weekly maintenance dose of erythropoietin was not statistically significantly different in L-carnitine group (80.16 +/- 35.61 units/kg) and the control group (91.9 +/- 38.21 units/kg, P = 0.20). In addition no significant improvement could be observed in the echogardiographic findings in the L-carnitine group after therapy. We conclude that our study revealed no significant improvement in hemoglobin, erythropoietin dose and echocardiographic findings after six months of therapy. Long-term studies including larger number of patients are required to clarify the questionable role of L-carnitine in the HD patients.

Topics: Administration, Oral; Adult; Anemia; Carnitine; Chronic Disease; Dietary Supplements; Echocardiography; Egypt; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Renal Dialysis; Time Factors; Treatment Outcome; Ventricular Function; Young Adult

Topics: Chronic Disease; Diuretics; Drinking Behavior; Drug Therapy, Combination; Erythropoietin; Hemodilution; Hemoglobins; Humans; Hydrochlorothiazide; Kidney Diseases; Losartan; Proteinuria; Renin-Angiotensin System; Urination

Whether and when to intervene and with which therapeutic agent are key questions physicians face daily in managing patients. Biomarkers are emerging to define the course of acute kidney injury and offer an opportunity to provide targeted interventions. The EARLYARF study by Endre et al. provides a glimpse of the challenges and opportunities that lie ahead.

Topics: Acute Disease; Alkaline Phosphatase; Biomarkers; Creatinine; Drug Administration Schedule; Erythropoietin; gamma-Glutamyltransferase; Hematinics; Humans; Intensive Care Units; Kidney Diseases; Patient Selection; Predictive Value of Tests; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Triage

Topics: Anemia; Chronic Disease; Drug Hypersensitivity; Erythropoietin; Female; Humans; Hypersensitivity, Delayed; Injections, Subcutaneous; Kidney Diseases; Polyethylene Glycols; Recombinant Proteins

Topics: Anemia; Animals; Diabetes Mellitus; Erythropoietin; Humans; Kidney Diseases; Nephrons; Potassium Channels; Sodium-Glucose Transport Proteins

The objective was to determine the cost-effectiveness of treating anemic patients with chronic kidney disease (CKD) with erythropoiesis-stimulating agents (ESAs) to a low (9-10.9 g/dL), intermediate (11-12 g/dL), or high (> 12 g/dL) hemoglobin level target compared with a strategy of managing anemia without ESAs.. Cost-utility analysis.. Publicly funded health care system. Anemic patients with CKD, overall and stratified into dialysis-/non-dialysis-dependent subgroups.. Decision analysis, health care payer, patient's lifetime.. Cost per quality-adjusted life-year (QALY) gained.. For dialysis patients, compared with anemia management without ESAs, using ESAs to target a low hemoglobin level is associated with a cost per QALY of $96,270. Given a lack of direct trials comparing low and intermediate targets, significant uncertainty exists between these strategies. Treatment to a high hemoglobin target was always associated with worse clinical outcomes and higher costs compared with a low hemoglobin target. Results were similar in non-dialysis-dependent patients with CKD, with a cost per QALY for a low target compared with no ESA of $147,980.. Given limitations in the available randomized controlled trials, we were able to model only 4 treatment strategies, balancing the need to consider relevant targets with the requirement for accurate estimates of clinical effect. We assumed that the efficacy of the different strategies would continue over a patient's lifetime.. Using ESAs to target a hemoglobin level > 12 g/dL is associated with worse clinical outcomes and significant additional cost compared with using ESAs to target lower hemoglobin levels (9-12 g/dL). Given a lack of studies comparing low (9-10.9 g/dL) and intermediate (11-12 g/dL) hemoglobin targets for clinical outcomes, including quality of life, the most cost-effective hemoglobin level target within the range of 9-12 g/dL is uncertain, although aiming for higher targets within this range will lead to higher costs.

Topics: Aged; Aged, 80 and over; Anemia; Chronic Disease; Cohort Studies; Cost-Benefit Analysis; Decision Support Techniques; Dose-Response Relationship, Drug; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Quality-Adjusted Life Years; Renal Dialysis

Epoetin alfa (EPO) and darbepoetin alfa are erythropoiesis-stimulating agents (ESAs) used to treat anemia in patients with chronic kidney disease. EPO and darbepoetin alfa have a non-proportional dose conversion relationship across the dosing spectrum. However, reports comparing the dose relationship between the two ESAs do not adjust for the non-proportional dose relationship or for population differences. Because drug cost is directly related to dosage, appropriate methods to assess the dose relationship between the two ESAs are important to understand the economic implications of converting patient populations from one ESA treatment to another.. To describe dose conversion methods that take into account the non-proportional dose relationship between EPO and darbepoetin alfa, and calculate the dose conversion ratio (DCR) between the two ESAs in a hospital-based dialysis patient population.. This was a retrospective observational study where longitudinal data from medical charts were collected for chronic hemodialysis patients being treated at hospital-based dialysis centers. Mean maintenance DCRs were calculated at the population level for hemodialysis patients converted from EPO to darbepoetin alfa treatment and subsequently maintained on darbepoetin alfa. Two methods were used to determine the DCRs: a regression-based method using ordinary least squares regression, and ratio-based method using an arithmetic mean.. The estimated population mean maintenance DCR for the population in this analysis was 320:1 (Units EPO:µg darbepoetin alfa) using the regression-based method, and 350:1 using the ratio-based method. Sensitivity analysis yielded DCRs ranging from 311 to 333:1.. The two methods in estimating the DCR presented here provide payers with an empirical way of comparing ESA utilization for pharmacoeconomic evaluation. DCR results may vary according to patient characteristics; however, mean DCRs of greater than 300:1 were obtained in this analysis. Exclusion of other patient-related factors that may influence ESA dose is a possible limitation of the study.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Economics, Pharmaceutical; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemodialysis Units, Hospital; Humans; Kidney Diseases; Male; Medical Audit; Middle Aged; Recombinant Proteins; Regression Analysis; Retrospective Studies; Young Adult

Topics: Anemia; Erythropoietin; Female; Humans; Kidney Diseases; Polycythemia; Pregnancy

the kidney is the major site of erythropoietin production. Many efforts have been made to identify renal erythropoietin-producing cells. Previous studies showed conflicting results, but the predominant localization reported was the peritubular interstitial and tubular epithelial cells. This study was conducted to identify the erythropoietin-producing cells in renal biopsies from 10 cadaveric donors and 45 patients with familial amyloidosis ATTR V30M, thirteen of them with anemia. Familial amyloidosis Type I (FAP-I) is a genetic disorder caused by a transthyretin (TTR) protein variant presenting a single amino acid substitution of methionine for valine at position 30 of the polypeptide chain (TTR V30M). Anemia in FAP-I is associated with inappropriately low serum erythropoietin levels.. erythropoietin expression was detected by in situ hybridization (ISH) and confirmed by laser capture microdissection followed by PCR. Renal segments were identified by immunohistochemistry.. erythropoietin was mainly expressed by epithelial distal tubular cells and collecting tubules and additionally, in a few biopsies, by glomerular cells. A similar expression pattern was observed in donors and FAP-I patients. No increased mRNA erythropoietin expression was found in anemic patients, all of them presenting only a slight expression in medulla and cortex.. these results suggest the distal nephron as the major site of erythropoietin production, and support the notion that an inappropriate erythropoietin production is the cause of anemia in familial amyloidosis ATTR V30M.

Topics: Adult; Amyloidosis, Familial; Anemia; Biopsy; Cadaver; Case-Control Studies; Erythropoietin; Female; Humans; Immunohistochemistry; In Situ Hybridization; Kidney Diseases; Male; Middle Aged; Mutation; Nephrons; Polymerase Chain Reaction; Portugal; Prealbumin; RNA, Messenger

Erythropoietin has transformed the treatment of the anemia of chronic kidney disease (CKD) by preventing the need for blood transfusions and improving the quality of life in all patients, including children. Anemia in children, in the age group 1-19 years, may be defined as hemoglobin (Hgb) levels < 12.1-13.5 g/dl for boys and < 11.4-11.5 g/dl for girls, based on the National Health and Nutrition Examination Survey (NHANES) norms. The prevalence of anemia in children ranges from 31.2% in stage 1 CKD to 93.3% in stages 4 and 5 CKD. The recent publication of trials evaluating the optimal hemoglobin level in adult CKD patients has generated considerable uncertainty about the target Hgb level in children with CKD. It is unclear whether generalizing of results from these trials in adults to children is appropriate. Adequately powered, randomized, controlled studies have not been conducted on children, and none to our knowledge are currently planned. The Food and Drug Administration (FDA) offers scant guidance on the Hgb target level for children, other than implying that it should be no different from that for adults. The purpose of this editorial is to critically scrutinize whether there is a benefit to the normalization of anemia in children with CKD and whether adoption of the results from adult studies is appropriate.

Topics: Adult; Anemia; Child; Chronic Disease; Erythropoietin; Hemoglobins; Humans; Kidney Diseases; Quality of Life; Recombinant Proteins

Anti-r-HuEpo associated PRCA developed in patients received subcutaneous injection of r-HuEpo for treatment of renal anemia in chronic kidney disease. This adverse immunological effect of r-HuEpo causes sudden loss of r-HuEpo efficacy, low circulating reticulocyte count and bone marrow biopsy shows an absence of erythroid precursor cells with normal cell population of non-erythroid lineage. There are postulation cause of anti-r-HuEpo associated PRCA including genetic factor, immunogenicity factor, storage and handlings factor and formulation of r-HuEpo product. Previous observation of our report showed an aggregation of HLA-DRB1*09 in four anti-r-HuEpo associated PRCA cases. This allele is rare in Caucasian (<1%) but more common in Thai population (8.4-12.5%). This study was aimed to investigate the possible association between HLA-DRB1*09 or other specific HLA and anti-r-HuEpo associated PRCA.. Twenty two cases of proven anti-r-HuEpo associated PRCA were recruited and studied retrospectively based on the incidence report of serious adverse drug reaction. The EDTA bloods were drawn for HLA typing using sequence specific primer polymerase chain reaction (SSP-PCR). The HLA data of 1,800 potential cadaveric kidney transplantation recipients in the waiting list as chronic kidney disease control and 1,500 potential bone marrow stem cell donors in national stem cell registry as healthy population control were retrieved from the database of Thai Red Cross for comparison.. The distribution of gene frequency of HLA-A, -B, -DR and -DQ alleles in anti-r-HuEpo associated PRCA cases showed high gene frequency of HLA-A*02, HLA-A*11 and HLA-A*24 for HLA-A loci, HLA-B*18, HLA-B*46, HLA-B*60 and HLA-B*62 for HLA-B loci, and HLA-DRB1*09, HLA-DRB1*12 and HLA-DRB1*15 for HLA-DR loci. There was a significant difference of HLA-DRB1*09 gene frequency (P < 0.001) which associated with HLA-DQB1*0309 between anti-r-HuEpo associated PRCA cases, and potential cadaveric kidney transplantation in the waiting list or potential national stem cell registry donor. The odd ratio of HLA-DRB1*09 allele for anti-r-HuEpo associated PRCA was 2.89 (95% CI: 1.88-4.46; p-value: <0.001).. Our data demonstrated the association of HLA-DRB1*09-DQB1*0309 and anti-r-HuEpo associated PRCA cases. This association may be used in identifying the risk of the patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Anemia; Antibodies, Anti-Idiotypic; Case-Control Studies; Chronic Disease; Erythropoietin; Female; Gene Frequency; Genetic Predisposition to Disease; HLA-DQ Antigens; HLA-DQ beta-Chains; HLA-DR Antigens; HLA-DRB1 Chains; Humans; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Retrospective Studies; Risk Factors; Young Adult

There are no investigations demonstrating that body size-adapted doses of erythropoietin (EPO) are as equally effective in children as in adults. A treatment starting with 150 IU/kg body weight per week leads to an insufficient rise in hemoglobin levels in anemic children with chronic kidney disease (CKD). Nevertheless, this strategy is widely used and seems to be the reason for a high percentage of young anemic children in spite of EPO treatment. In children and in adults, 1,000 IU EPO intravenously increases the hemoglobin level equally by 0.04 g/l. This strongly argues for specifying the EPO dose in the treatment of children with CKD in absolute amounts. A prediction model exists which allows the determination of the EPO dose which is expected to raise hemoglobin from a given pretreatment level to a desired steady state level.

Topics: Adult; Anemia; Body Size; Child; Chronic Disease; Erythropoietin; Hemoglobins; Humans; Kidney Diseases

Anaemia is frequently found in patients with diabetes, in whom it is associated with increased morbidity and mortality. Low testosterone levels are also common in men with type 2 diabetes. We hypothesized that low testosterone levels are also associated with anaemia in men with type 2 diabetes, over the effects of chronic kidney disease.. Cross-sectional cohort study, performed in 2005 in a tertiary diabetes clinic. Patients 464 men with type 2 diabetes.. Anaemia (haemoglobin (Hb) < 13.7 g/dl in men aged < 60, or < 13.2 g/dl in men aged 60 and older).. About 24% of study participants had anaemia, which was associated with the presence and severity of chronic kidney disease, systemic inflammation, increased age, and reduced iron availability. In addition, testosterone levels were independently associated with reduced Hb levels, determining between 6 and 8% of the total variability in raw Hb levels in this population after adjusting for these other factors. Individuals with total testosterone level < 10 nmol/l (43% of the cohort) were more likely to have anaemia (adjusted odds ratio 1.7; 95% CI 1.1-2.8). Similarly, anaemia was twice as common in individuals with a calculated free testosterone of < 0.23 nmol/l (adjusted odds ratio 2.0, 95% CI 1.2-3.1).. These findings suggest that testosterone deficiency may contribute to the increased frequency of anaemia in men with type 2 diabetes. However, the appropriate clinical response to testosterone deficiency in anaemic patients remains to be established by prospective clinical trials.

Topics: Aged; Anemia; C-Reactive Protein; Chronic Disease; Cohort Studies; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Erythropoietin; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Regression Analysis; Severity of Illness Index; Testosterone

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Hematinics; Humans; Kidney Diseases

Anemia is a well known complication of chronic kidney disease (CKD); however, the prevalence of anemia within CKD stages in the pediatric population has not been established. Additionally, the associated morbidity of anemia in the pediatric CKD population has not been elucidated.. 2,779 patients ages 2 yr and older in the North American Pediatric Renal Trials and Collaborative Studies database with CKD stage II to V (excluding dialysis or previous transplant patients) were identified. Descriptive statistics and multivariate modeling using logistic regression was performed to determine the prevalence of anemia and to evaluate the correlation between baseline anemia and hospitalization.. The prevalence of anemia (hematocrit < 33%) increased from 18.5% in CKD stage II to 68% in CKD stage V (predialysis). Anemic children were 55% more likely to be hospitalized when compared with nonanemic children (odds ratio 1.55; 95% confidence interval 1.23 to 1.94). Similar results were obtained using hematocrit cutoffs of 36 and 39%.. In this pediatric predialysis CKD population, anemia increases with increasing CKD stage and is significantly associated with hospitalization risk. Hematocrit levels above 36 and 39% were not associated with increased risk of hospitalization. Further examination into the effect of correcting anemia on hospitalization rates may provide additional useful information.

Topics: Adolescent; Anemia; Canada; Child; Child, Preschool; Chronic Disease; Erythropoietin; Female; Hematinics; Hematocrit; Hospitalization; Humans; Kidney Diseases; Logistic Models; Male; Odds Ratio; Prevalence; Registries; Retrospective Studies; Risk Assessment; Risk Factors; United States

Erythropoietin was recently shown to exert important cytoprotective and anti-apoptotic effects in injury models of the brain, heart and kidney. We examined whether erythropoietin also attenuates renal injury in a rat model of unilateral ureteral obstruction via anti-apoptotic and anti-inflammatory actions.. We divided Sprague-Dawley rats (Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea) into 4 groups, including 1-vehicle treated with sham operation, 2-vehicle treated with unilateral ureteral obstruction for 3 days, 3-erythropoietin treatment with sham operation and 4-erythropoietin treatment for unilateral ureteral obstruction for 3 days. The erythropoietin treatment dose was 3,000 IU/kg per day intraperitoneally, administered daily. We compared competitive reverse transcriptase-polymerase chain reaction data on transforming growth factor-beta, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, osteopontin, Fas and Bcl-2. Furthermore, we examined Western blots for caspase-3 and light microscopy findings with hematoxylin and eosin staining. We applied immunohistochemistry for transforming growth factor-beta, ED-1 and caspase-3, and TUNEL in each group.. Transforming growth factor-beta, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, osteopontin and Fas mRNA levels in the erythropoietin treated, unilateral ureteral obstruction group were significantly lower than in the obstruction only group. The Bcl-2 mRNA level in the erythropoietin treated obstruction group was significantly higher than in the obstruction only group. Caspase-3 activity in the erythropoietin treated obstruction group was significantly lower than in the obstruction only group. On light microscopy interstitially infiltrated inflammatory cells were significantly decreased in the erythropoietin treated obstruction group compared to the obstruction only group. On immunohistochemistry the erythropoietin treated obstruction group showed significantly fewer reactions for transforming growth factor-beta, ED-1 and caspase-3 compared to the obstruction only group. Erythropoietin treatment in rats with unilateral ureteral obstruction significantly decreased the number of TUNEL positive cells.. Erythropoietin exerts renoprotective effects in an experimental unilateral ureteral obstruction rat model via anti-apoptotic and anti-inflammatory actions.

Topics: Animals; Apoptosis; Disease Models, Animal; Erythropoietin; Inflammation; Kidney Diseases; Male; Rats; Rats, Sprague-Dawley; Ureteral Obstruction

Renal disease is commonly encountered by primary care physicians during their day-to-day visits with patients. Common renal disorders include hypertension, proteinuria, kidney stones, and chronic kidney disease. Despite their prevalence, many physicians may be unfamiliar with the diagnosis and initial treatment of these common renal disorders. Early recognition and intervention are important in slowing the progression of chronic kidney disease and preventing its complications. The evidence-based pearls in this article will help primary care physicians avoid common pitfalls in the recognition and treatment of such disorders and guide their decision to refer their patients to a specialist.

Topics: Aluminum; Anemia; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antacids; Blood Pressure; Blood Urea Nitrogen; Cardiovascular Diseases; Cathartics; Chronic Disease; Contraindications; Creatinine; Cyclosporine; Disease Progression; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Evidence-Based Medicine; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppressive Agents; Kidney Diseases; Magnesium; Nephrolithiasis; Nephrology; Phosphates; Primary Health Care; Proteinuria; Recombinant Proteins; Referral and Consultation; Tacrolimus; Urinalysis

Topics: Aged; Drug Tolerance; Erythropoietin; Europe; Female; Humans; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Therapeutic Equivalency

Intrapatient variability of hemoglobin (Hb) is a newly proposed determinant of adverse outcome in chronic kidney disease (CKD). We evaluated whether intensity of epoetin therapy affects Hb variability and renal survival in nondialysis CKD.. We calculated the individual therapeutic index (TI) for epoetin (EPO; difference between rates of visits that required EPO dosage change and those with effective EPO change) from 1198 visits during the first year of EPO in 137 patients. Renal death was registered in the subsequent 18.1 mo. Analysis was made by TI tertile (lower, middle, and higher; i.e., from more to less intensive therapy).. Main features and visit number were similar in tertiles. Lower Hb response to first EPO dosage was an independent predictor of higher TI (P = 0.002). The area under the curve for Hb (11.56 +/- 0.87, 11.46 +/- 1.20, and 10.95 +/- 1.48 g/dl per yr; P = 0.040) decreased from lower to higher tertile. Hb variability increased in parallel, as shown by the reduction of time with Hb at target (time in target, from 9.2 +/- 2.0 to 3.0 +/- 2.2 mo; P < 0.0001) and the wider values of within-patient Hb standard deviation (from 0.70 to 0.96; P = 0.005) and Hb fluctuations across target (P < 0.0001). In Cox analyses (hazard ratio [95% confidence interval]), risk for renal death was increased in the middle and higher tertiles (2.79 [1.36 to 5.73] and 2.94 [1.40 to 6.20]) and reduced by longer time in target (0.90 [0.83 to 0.98]).. Lack of adjustment of EPO worsens Hb variability in CKD. Hb variability may be associated with renal survival, but further studies are needed to explore the association versus causal relationship.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Italy; Kidney Diseases; Male; Middle Aged; Proportional Hazards Models; Recombinant Proteins; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

The mortality risk associated with attempting to raise hemoglobin (Hb) levels by increasing Epoetin alfa (EPO) doses in hemodialysis patients with persistently low Hb remains poorly understood. Design, setting, participants, & measurements. We included hemodialysis patients from a large dialysis provider between July 2000 and June 2001 who had EPO dose and Hb data for 6 consecutive months, and a mean Hb <11 g/dl in months 4 to 6 (sub-11 period). We identify predictors of EPO dose changes during the sub-11 period; evaluate the proportion of patients achieving a Hb >or=11 g/dl after the sub-11 period by dose-change categories; and evaluate the association between EPO dose changes and mortality risk.. Patients were more likely to receive greater EPO dose increases if they had lower EPO doses, higher Hb levels, or were recently hospitalized. Greater EPO dose increases elevated the likelihood of achieving an Hb >or=11 g/dl in the subsequent 3 mo. Larger EPO dose changes over the sub-11 period were not associated with an elevated mortality risk, but having an Hb <9 g/dl at the end of that period independent of dose change was associated with mortality risk. We found that patients receiving larger dose changes and whose resulting Hb level remained <9.5 g/dl at the end of the 3 mo were at elevated mortality risk.. In patients with persistently low Hb levels, mortality risk was strongly associated with the patient's ability to achieve a hematopoietic response rather than the magnitude of EPO dose titrations.

Topics: Adult; Aged; Anemia, Iron-Deficiency; Biomarkers; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kaplan-Meier Estimate; Kidney Diseases; Male; Middle Aged; Proportional Hazards Models; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Topics: Anemia; Chronic Disease; Cohort Studies; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins

We aimed in this study to assess the opinion of medical directors of dialysis centers in the Kingdom of Saudi Arabia (KSA) about updates of strategies for treatment of anemia in patients with chronic kidney disease (CKD). A questionnaire was sent to the medical directors of the 174 active dialysis centers in the KSA including centers under the Ministry of Health (MOH) (67 %), the governmental non-MOH sector (12%) and private hospitals (21 %) that together care for a population of more than 11,300 chronic dialysis patients. The study was performed between November 2008 and March 2009. A total of 143 of the 174 (82.1%) medical directors answered the questionnaire. This covered 9563 (84%) dialysis patients in the KSA. There were 95 (68.8%) respondents who believed that the mechanism of action of ESAs is due to both blood concentration and direct action on the stem cells that form red cells. Only 81 (57%) respondents believed that the half-life of the short-acting ESAs is less than one day, 67 (46.9%) believed the half-life of darbepoetin is 2-4 days, and 52 (36.6%) believed the half-life of CERA is 5-10 days; 79 (55.6%) respondents believed that the interval of dosing of darbepoetin is once biweekly, and 92 (71.9%) believed that the interval of dosing of CERA is once a month. There were 110 (76.9%) respondents who believed the CKD should receive a long-acting than short-acting ESAs for the more stable hemoglobin levels, 64 (44.8%) believed that pharmacodynamics of the CERA are better than other ESAs and warrant its use over all of them, and 115 (80.6%) believed that the target hemoglobin is 11-13 g/dL in CKD patients is well established. Finally, 65 (51.5%) respondents would request more than 30% of the stock of ESAs in the future as short-acting ESAs vs 71 (55%) for darbepoetin and 40 (37.4%) for CERA. There were no statistically significant differences among the respondents according to their affiliations (MOH, non MOH and private sector) on any of the issues in the questionnaire. We conclude that our results showed inadequate awareness of the medical directors of the dialysis centers in the KSA of the mechanisms of action of ESAs and the new agents such as the CERA. However, they were well informed about the limits of the targeted hemoglobin levels and showed a trend toward using the long-acting ESAs.

Topics: Anemia; Attitude of Health Personnel; Awareness; Biomarkers; Chronic Disease; Darbepoetin alfa; Erythropoietin; Guideline Adherence; Health Care Surveys; Health Knowledge, Attitudes, Practice; Hematinics; Hemoglobins; Humans; Kidney Diseases; Perception; Physician Executives; Polyethylene Glycols; Practice Guidelines as Topic; Practice Patterns, Physicians'; Recombinant Proteins; Renal Dialysis; Saudi Arabia; Surveys and Questionnaires; Treatment Outcome

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Dose-Response Relationship, Drug; Erythropoietin; Hematocrit; Hemoglobins; Humans; Kidney Diseases; Risk Factors

Some time has passed since the torrent of discussion surrounding the cardiovascular risk of pushing up hemoglobin concentrations in dialysis patients with erythropoietin. The debate here reflects a look back on the tension produced by confusing data and outcomes. Is it the target hemoglobin per se or the high doses of erythropoietin in subsets of resistant patients that is the problem? You decide.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Dose-Response Relationship, Drug; Erythropoietin; Hematocrit; Hemoglobins; Humans; Kidney Diseases; Risk Factors

Anaemia is a common complication of chronic kidney disease (CKD) and is associated with increased rates of mortality and diminished quality of life in patients with CKD. Although extended dosing with darbepoetin alfa, an erythropoiesis-stimulating agent (ESA), has been shown to be effective in maintaining haemoglobin (Hb) levels in CKD patients, little information is published on the use of darbepoetin alfa in the correction and maintenance of Hb levels in elderly CKD patients naive to ESA therapy.. This post hoc subanalysis of data from two clinical trials was conducted to investigate the efficacy and safety profile of de novo every-other-week (q2w) darbepoetin alfa in elderly patients with CKD-associated anaemia (not on dialysis), as compared with that of a younger (aged <65 years) patient cohort.. This analysis was based on data obtained from two open-label, single-arm, multicentre studies of similar design. Patients were aged >or=18 years and naive to previous ESA therapy. Darbepoetin alfa administration was initiated at 0.75 microg/kg and titrated according to individual patient requirements to achieve and maintain Hb levels between 11.0 and 13.0 g/dL. The proportion of patients who achieved the primary endpoint, Hb >or=11.0 g/dL (study 1), and an Hb level between 11.0 and 13.0 g/dL (study 2) at weeks 4, 8 and 12 weeks and at the end of the study were determined. The results of this subanalysis were stratified by age (<65, 65-74 and >or=75 years).. A total of 203 patients were enrolled in the two studies; 60% were female, 84 (41%) were aged <65 years, 57 (28%) were aged 65-74 years and 62 (31%) were aged >or=75 years. The proportion of patients who achieved Hb levels of >or=11.0 g/dL in study 1 and 11.0-13.0 g/dL in study 2 at week 20 were 93%, 96% and 92%, respectively, for the three age groups. Weight-adjusted q2w darbepoetin alfa doses were similar between the age groups and stable throughout the study period. The mean (standard deviation) Hb levels at week 21 were 12.0 (1.2), 12.7 (1.1) and 12.6 (1.0) g/dL in subjects aged <65, 65-74 and >or=75 years, respectively. The median (standard error) time to reach the primary endpoint was 5.0 (4.7), 5.0 (5.7) and 5.0 (5.7) weeks for subjects aged <65 years, 65-74 years and >or=75 years, respectively. The safety profiles of q2w darbepoetin alfa in both the older and younger age-groups were consistent with those expected for patients with CKD not receiving dialysis.. The results of this study suggest that ESA-naive subjects aged <65, 65-74 and >or=75 years of age with CKD (not receiving dialysis) who received q2w darbepoetin alfa were able to achieve and maintain Hb levels at 11.0-13.0 g/dL. The de novo q2w treatment regimen with darbepoetin alfa described in the present report may help optimize anaemia management in CKD-associated anaemia patients, including those in the older adult population.

Topics: Adolescent; Adult; Aged; Chronic Disease; Clinical Trials as Topic; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Treatment Outcome; Young Adult

Renal ischemia and reperfusion injury leads to acute renal failure when proinflammatory and apoptotic processes in the kidney are activated. The increase in hypoxia-inducible transcription factor-alpha (HIF-alpha), an important transcription factor for several genes, can attenuate ischemic renal injury. We recently identified a novel WD-repeat protein designated Morg1 (MAPK organizer 1) that interacts with prolyl hydroxylase 3 (PHD3), an important enzyme involved in the regulation of HIF-1alpha and HIF-2alpha expression. While homozygous Morg1 -/- mice are embryonic lethal, heterozygous Morg1 +/- mice have a normal phenotype. We show here that Morg1 +/- were partially protected from renal ischemia-reperfusion injury compared with wild-type Morg1 +/+ animals. Morg1 +/- mice compared with wild-type animals revealed a stronger increase in HIF-1alpha and HIF-2alpha expression in the ischemic-reperfused kidney associated with enhanced serum erythropoietin levels. However, no significant expression of HIF-1alpha and HIF-2alpha was found in nonischemic kidneys without any difference between Morg1 +/- and Morg1 +/+ mice. Ischemic kidneys of Morg1 +/- mice expressed more erythropoietin mRNA than ischemic kidneys from wild-type animals. Renal ischemia in Morg1 +/- mice resulted in a decrease in renal inflammation and reduction of proinflammatory cytokines (MCP-1, IP-10, MIP-2) compared with wild-type mice. Furthermore, there was significantly less apoptosis and tubular damage in Morg1 +/- kidneys after ischemia-reperfusion, and this was also reflected in significantly improved renal function compared with wild-type. Thus Morg1 may be a novel therapeutic target to limit renal injury after ischemia-reperfusion.

Topics: Acute Disease; Adaptor Proteins, Signal Transducing; Animals; Apoptosis; Blotting, Western; DNA, Complementary; Electrophoretic Mobility Shift Assay; Erythropoietin; Female; Heterozygote; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; Kidney; Kidney Diseases; Kidney Function Tests; Mice; Mice, Inbred C57BL; Mice, Knockout; Pregnancy; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; RNA

Treatment with erythropoiesis-stimulating agents (ESA) is often associated with fluctuation in hemoglobin (Hb) levels that has been considered a factor that influences morbidity/mortality in hemodialysis patients. Our aim was to describe the hemoglobin variability during ESA treatment and to study associated factors in kidney transplants. Hb variability (defined as fluctuations of Hb +/- 1.5 g/dl) was assessed in 85 renal transplant patients treated with ESA for at least 3 months and with a minimum of 6 Hb measurements along 1 year. 58% of patients experienced Hb variability during follow-up. Although 71.3% of patients maintained Hb levels greater than 11 g/dl along the whole follow-up, only 3% of patients maintained stable Hb levels within the target range all the time (11 - 13 g/dl). By multivariate analysis, clinical factors associated with variability were changes in ESA dose (RR 2.92, p = 0.04), infectious events with hospitalization (RR 1.95, p = 0.03) and the use of sirolimus (RR 1.1, p < 0.05). Excluding dose changes and hospitalization in the analysis variability was an independent predictor of graft function deterioration. In conclusion, Hb variability is common in renal transplants treated with ESA. Only few patients maintained Hb levels in the therapeutic range (11 - 13 g/dl). Dose changes, inflammatory status and graft function deterioration are the determining factors.

Topics: Erythropoiesis; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Kidney Transplantation; Logistic Models; Male; Middle Aged

Topics: Adrenergic beta-Antagonists; Anemia; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Drug Resistance; Erythropoietin; Heart Failure; Humans; Kidney Diseases

Topics: Anemia; Chronic Disease; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Diseases; Kidney Transplantation; Meta-Analysis as Topic; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins

To determine the optimal range of increase in haemoglobin concentration with treatment with erythropoietins that is safe and is not associated with mortality.. Retrospective cohort study. The analysis was adjusted for several covariables with Cox regression analysis with spline functions. Use of erythropoietins, haemoglobin concentration, and covariables were included in a time varying manner; variable selection was based on the purposeful selection algorithm.. Transplantation centres in Austria.. 1794 renal transplant recipients recorded in the Austrian Dialysis and Transplant Registry who received a transplant between 1 January 1992 and 31 December 2004 and survived at least three months.. Survival time and haemoglobin concentration after treatment with erythropoietins.. The prevalence of use of erythropoietins has increased over the past 15 years to 25%. Unadjusted extended Kaplan-Meier analysis suggests higher mortality in patients treated with erythropoietins, in whom 10 year survival was 57% compared with 78% in those not treated with erythropoietins (P<0.001). In the treated patients there were 5.4 events/100 person years, compared with 2.6 events/100 person years in those not treated (P<0.001). After adjustment for confounding by indication, comorbidities, comedication, and laboratory readings, haemoglobin concentrations >125 g/l were associated with increased mortality in treated patients (hazard ratio 2.8 (95% confidence interval 1.0 to 7.9) for haemoglobin concentration 140 g/l v 125 g/l), but not in those not treated (0.7, 0.4 to 1.5). When haemoglobin concentrations were 147 g/l or above, patients treated with erythropoietins showed significantly higher mortality than those who were not treated (3.0, 1.0 to 9.4).. Increasing haemoglobin concentrations to above 125 g/l with erythropoietins in renal transplant recipients is associated with an increase in mortality. This increase was significant at concentrations above 140 g/l.

Topics: Anemia; Chronic Disease; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kaplan-Meier Estimate; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Quality of Life; Recombinant Proteins; Renal Dialysis; Retrospective Studies

Topics: Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Cholesterol; Erythropoietin; Hepcidins; Humans; Kidney Diseases; Molecular Weight; Regression Analysis; Renal Dialysis

Japanese haemodialysis (HD) patients not only have a very low mortality and hospitalization risk but also low haemoglobin (Hb) levels. Internationally, anaemia is associated with mortality, hospitalization and health-related quality of life (QoL) measures of HD patients.. Longitudinal data collected from 1999 to 2006 from 60 to 64 representative Japanese dialysis units participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS) were used to describe anaemia management practices and outcomes for Japanese HD patients.. From 1999 to 2006, patient mean Hb increased from 9.7 g/dl to 10.4 g/dl, and the percentage of facilities with median Hb >or=10 g/dl increased from 27% to 75%. Hb was measured in the supine position for 90% of patients, resulting in substantially lower reported Hb values than those seen in other countries. As of 2006, erythropoietin (Epo) was prescribed to 83% of HD patients; mean Epo dose was 5231 units/week; intravenous (IV) iron use was 33% and median IV iron dose was 160 mg/month. Many patient- and facility-level factors were significantly related to higher Hb. A consistent overall pattern of lower mortality risk with higher baseline Hb levels was seen (RR = 0.89 per 1 g/dl higher Hb, P = 0.003). Facilities with median Hb >or=10.4 displayed a lower mortality risk (RR = 0.77, P = 0.03) versus facility median Hb <10.4 g/dl. Lower Hb levels were not significantly related to hospitalization risk, but were associated with lower QoL scores.. These results provide detailed information on anaemia management practices in Japan and the relationships of anaemia control with outcomes, with implications of anaemia management worldwide.

Topics: Aged; Anemia; Erythropoietin; Female; Hemoglobins; Hospitalization; Humans; Iron; Japan; Kidney Diseases; Longitudinal Studies; Male; Middle Aged; Outcome Assessment, Health Care; Quality of Life; Renal Dialysis; Retrospective Studies; Risk Management; Treatment Outcome

Topics: Anemia; Chronic Disease; Drug Administration Schedule; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematinics; Hematocrit; Hemoglobins; Humans; Kidney Diseases; Patient Selection; Recombinant Proteins; Treatment Outcome

The aim of our study was to determine the effect of recombinant human erythropoietin (rhEPO) on cyclosporine (CsA) nephrotoxicity. Twenty-six female Wistar rats were injected with 15 mg/kg subcutaneous CsA and intraperitoneal saline/rhEPO for 28 days. Four groups were formed: Group 1 (n = 5), a control group; Group 2 (n = 7), CsA + saline; Group 3 (n = 7), CsA + low dose (20 U/kg per day) rhEPO; Group 4 (n = 7), CsA + high dose (100 U/kg per day) rhEPO. Body weights, creatinine clearance, urinary protein/creatinine, hematocrit, serum creatinine levels, histopathological parameters, apoptosis and lipid peroxidation tests were compared between the three groups. Body weights and renal functions were similar in Groups 2, 3 and 4 rats but significantly lower than the values found for the control group at the end of the study. The hematocrit was significantly different between the four groups, showing a positive association with the strength of the injected rhEPO doses. Tubular and arteriolar damage was significantly lower in Groups 3 and 4 rats than in Group 2 rats, while chronic changes were similar between the three groups. TUNEL-positive cells and thiobabarbituric acid reacting substance (TBARS) levels were significantly higher in Group 2 rats, whereas superoxide dismutase levels were significantly lower in Group 2 rats than in those of the other three groups. Low or high dose rhEPO had no significant protective effects on body weight, renal functions, chronic fibrotic changes, but both doses reduced tubular and arteriolar changes, apoptotis and oxidative stress.

Topics: Animals; Apoptosis; Body Weight; Cyclosporine; Dose-Response Relationship, Drug; Erythropoietin; Female; Hematopoiesis; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Function Tests; Lipid Peroxidation; Oxidative Stress; Rats; Rats, Wistar; Recombinant Proteins

High doses of human recombinant erythropoietin (rHuEPO) to achieve hemoglobin levels greater than 13 g/dL in patients with chronic kidney disease appear to be associated with increased mortality.. We conducted logistic regression and survival analyses in a retrospective cohort of long-term hemodialysis patients to examine the hypothesis that the induced iron depletion with resultant relative thrombocytosis may be a possible contributor to the link between the high rHuEPO dose-associated hemoglobin level of 13 g/dL or greater and mortality.. The national database of a large dialysis organization (DaVita) with 40,787 long-term hemodialysis patients during July to December 2001 and their survival up to July 2004 were examined.. Hemoglobin level, platelet count, and administered rHuEPO dose during each calendar quarter.. Case-mix-adjusted 3-year all-cause mortality and measures of iron stores, including serum ferritin and iron saturation ratio.. Higher platelet count was associated with lower iron stores and greater prescribed rHuEPO dose. Compared with a hemoglobin level of 12 to 13 g/dL, a hemoglobin level of 13 g/dL or greater was associated with increased mortality in the presence of relative thrombocytosis, ie, platelet count of 300,000/microL or greater (case-mix-adjusted death-rate ratio, 1.21; 95% confidence limits, 1.02 to 1.44; P = 0.03) as opposed to the absence of relative thrombocytosis (death-rate ratio, 1.04; 95% confidence limits, 0.98 to 1.08; P = 0.1). A prescribed rHuEPO dose greater than 20,000 U/wk was associated with a greater likelihood of iron depletion (iron saturation ratio < 20%) and relative thrombocytosis (case-mix-adjusted odds ratio, 2.53; 95% confidence limits, 2.37 to 2.69; and 1.36; 95% confidence limits, 1.30 to 1.42, respectively; P < 0.001) and increased mortality during 3 years (death-rate ratio, 1.59; 95% confidence limits, 1.54 to 1.65; P < 0.001).. Our results may incorporate uncontrolled confounding. Achieved hemoglobin level may have different mortality predictability than targeted hemoglobin level.. Iron depletion and associated relative thrombocytosis might contribute to increased mortality when administering high rHuEPO doses to achieve hemoglobin levels of 13 g/dL or greater in long-term hemodialysis patients. Randomized trials are needed to test these observational associations.

Topics: Adult; Aged; Anemia, Iron-Deficiency; Chronic Disease; Cohort Studies; Dose-Response Relationship, Drug; Erythropoietin; Female; Hemoglobins; Humans; Iron; Iron Deficiencies; Kidney Diseases; Logistic Models; Male; Middle Aged; Odds Ratio; Proportional Hazards Models; Recombinant Proteins; Renal Dialysis; Retrospective Studies; Risk Factors; Survival Analysis; Thrombocytosis

Topics: Anemia; Conflict of Interest; Erythropoietin; Hemoglobins; Humans; Kidney Diseases; Practice Guidelines as Topic; Recombinant Proteins

The aim of the present study was to evaluate the role of erythropoietin (EPO) in liver and renal injury following hemorrhagic shock (HS) after inhibition of tyrosine kinase activity in rats... Forty-eight Sprague-Dawley rats were assigned to six groups: (I) HS alone; (II) HS followed by retransfusion; (III) EPO and genistein followed by HS; (IV) EPO and genistein followed by HS, followed by retransfusion; (V) HS followed by EPO and genistein; and (VI) HS followed by EPO and genistein, followed by retransfusion. HS was induced for 60 minutes after withdrawal of 30% of the calculated total blood volume of each rat from the left femoral artery. Blood and tissue samples (from the kidney and liver) were obtained 60 minutes after HS in Group I, III, and V; blood and tissue samples were obtained 60 minutes after retransfusion in Group II, IV, and VI. In Group III and IV, EPO was given 60 minutes before HS, and genistein 30 minutes before HS. In Group V and VI, EPO and genistein were given 30 minutes after HS.. Liver and renal injury were significantly attenuated with EPO and genistein administration.. These results suggest that EPO is effective in attenuating liver and renal injury in HS, even with inhibition of tyrosine kinase activity with genistein.

Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Erythropoietin; Genistein; Interleukin-2; Kidney; Kidney Diseases; Liver; Liver Diseases; Male; Protein-Tyrosine Kinases; Rats; Rats, Sprague-Dawley; Shock, Hemorrhagic; Tumor Necrosis Factor-alpha

Treatment with erythropoiesis stimulating agents (ESA) is associated with fluctuations in hemoglobin (Hb) levels. Recently, variability of Hb has been considered a factor that influences comorbidity and mortality among hemodialysis patients. The purpose of this analysis was to describe the phenomenon of Hb variability during ESA treatment, to study associated factors among kidney transplant patients, and to assess the impact on patient and graft survivals.. Hb variability (defined as fluctuations of Hb +/- 1.5 g/dL) was assessed in 85 renal transplant patients treated with ESA for at least 3 months and with a minimum of 6 Hb measurements during 1 year.. Fifty-eight percent of the patients experienced Hb variability during follow-up. Only 3% of patients maintained stable Hb levels within the target range (11-13 g/dL), although 83% of patients maintained Hb levels >11 g/dL. Multivariate analysis showed that the clinical factors associated with variability were changes in ESA dose (relative risk [RR]: 2.92; 95% confidence interval [CI]: 1.0-8.5; P < .05), infectious events with hospitalization (RR: 1.95; 95% CI: 1.23-2.13; P < .05), and the use of sirolimus (RR: 1.1; 95% CI: 1.0-3.6; P < .05). When dose changes and hospitalization were excluded from the analysis, variability was an independent predictor of worsening graft function.. Hb variability is common in renal transplant patients treated with ESA. Only a few patients maintained Hb levels within the therapeutic range, although most had levels >11g/dL. Dose changes, inflammatory status, and worsening graft function are the determining factors of variability. Variability had no influence on patient survival, although it was a marker of worsening graft function.

Topics: Adult; Erythropoiesis; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Patient Selection

Topics: Anemia; Black or African American; Chronic Disease; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Diseases; Recombinant Proteins; White People

Although the results of Pizzi et al. point to the potential economic attractiveness of a ferric gluconate treatment strategy, they may not be sufficient to change public policy and reimbursement practices. What is required is a large, simple trial that will replicate the results of the DRIVE trial in a broader population with longer follow-up and a prospectively defined economic and quality-of-life study conducted from the societal perspective.

Topics: Drug Costs; Epoetin Alfa; Erythropoietin; Ferric Compounds; Health Care Costs; Humans; Kidney Diseases; Randomized Controlled Trials as Topic; Recombinant Proteins

A subgroup of hemodialysis patients experience high serum ferritin and low tansferrin saturation for reasons not clearly understood. Here we determined the economic impact of administering sodium ferric gluconate complex to patients with serum ferritin levels higher than 500 ng/ml and a transferrin saturation less than 25% based on the Dialysis Patients Response to IV Iron with Elevated Ferritin (DRIVE) study and its extension, DRIVE II. A cost effectiveness model was developed, consistent with the DRIVE studies, using decision analysis with a 12-week time horizon. The primary effectiveness measure was the mean hemoglobin increase in the intent to treat patient groups comparing epoetin with or without sodium ferric gluconate complex. Costs were computed using projected 2007 US Medicare reimbursements for the treatments and for serious adverse events, with the effectiveness factored by the increase in hemoglobin. The net savings for sodium ferric gluconate complex plus epoetin treatment was $1390 compared to epoetin alone for each g/dl hemoglobin increase over 12 weeks of study. Sensitivity analyses were performed to test the impact of change in the variables (using medians or means and actual 2005 or projected 2007 Medicare reimbursements) and these affirmed the robustness of the model. Our study shows that treatment of patients with high ferritin and low transferrin saturation levels, as defined in DRIVE, with sodium ferric gluconate complex and epoetin resulted in significant savings compared to epoetin alone.

Topics: Adult; Aged; Algorithms; Anemia; Cost Savings; Drug Costs; Epoetin Alfa; Erythropoietin; Ferric Compounds; Ferritins; Hematinics; Hemoglobins; Humans; Kidney Diseases; Medicare; Middle Aged; Recombinant Proteins; Renal Dialysis; United States

The response to erythropoietin-stimulating agents (ESA) can vary among different patients and according to the different circumstances over time within a given individual. The aim of this study was to analyze the factors that can modify the response to epoetin in patients on hemodialysis (HD) and its influence on early mortality. Prospective and observational study including 1710 patients from 119 HD units in Spain with a follow-up of 12 months. To evaluate the dose-response effect of EPO therapy, we used the erythropoietin resistance index (ERI), calculated as the weekly weight-adjusted dose of EPO divided by the hemoglobin level. Patients were stratified in three groups according to ERI: group A, ERI <5; group B, ERI=5-15; group C, ERI>15 U/kg/week/g per 100 ml. Mean ERI for the entire group was 10.2+/-7.3 U/kg/week/g per 100 ml. ERI was directly related with incident comorbidity (Charlson Index), age, female gender and low body mass index with no relationship with etiology of chronic kidney disease. Patients with antecedents of heart failure, acute infection or malignant neoplasm had significantly higher ERI than those without. Transferrin saturation index, but not serum ferritin, was inversely related with ERI. Serum levels of albumin and cholesterol were related with lower ERI, but no relation was found with normalized protein catabolic rate. Patients with a permanent catheter for HD had significant higher values of ERI than those with native fistula (P=0.012). One year survival in all three groups of patients according to ERI was 0.916 in group A, 0.877 in group B and 0.788 in group C (log-rank=20.7, P<0.001). The resistance to ESA is directly related with incident comorbidity in patients on hemodialysis and it can be interpreted as a useful marker of early mortality.

Topics: Aged; Biomarkers; Cholesterol; Chronic Disease; Dose-Response Relationship, Drug; Erythropoietin; Female; Ferritins; Follow-Up Studies; Humans; Kidney Diseases; Male; Middle Aged; Predictive Value of Tests; Prospective Studies; Renal Dialysis; Serum Albumin; Spain; Survival Analysis; Transferrin

Maintenance of target hemoglobin (Hb) values in hemodialysis patients treated with erythropoiesis-stimulating agents (ESAs) remains difficult. We examined Hb variability in the clinical setting in hemodialysis patients. Hemodialysis patients treated with ESAs who maintained the recommended Hb range of 11-13 g per 100 ml over 3 months and were not admitted to hospital, did not require transfusion, and did not experience any major clinical event during this period were followed prospectively for 1 year. Anemia events, Hb variation events (any value out of +/-1.5 g per 100 ml of the median Hb level in the total follow-up period for the individual patient), risk factors for anemia, and Hb variation events were assessed. We studied 420 patients (63% males, mean age 61 years), 222 received short-acting erythropoietin (EPO) and 198 long-acting darbepoetin. A total of 4654 blood samples (mean 11.1 per patient-year) were analyzed. Only 3.8% of patients were maintained within the target Hb levels (11-13 g per 100 ml) during 1 year. Hb variation events occurred in 20.8% of laboratory values and anemia events in 14.7%, with a median time to the first event of 3 months. Treatment with short-acting EPO (vs long-acting darbepoetin), change of ESA dose in the previous visit, resistance index, and hospitalization were significant risk factors for both anemia events and Hb variation events. Our results show that Hb values are rarely maintained within the recommended guidelines even in more stable hemodialysis patients. Hb variability is frequently associated with clinical events or ESA dose changes. Long-acting darbepoetin achieved better Hb stability than short-acting EPO.

Topics: Adult; Aged; Anemia; Chronic Disease; Cohort Studies; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hemoglobins; Humans; Kidney Diseases; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Renal Dialysis; Risk Factors; Spain

To investigate the effects of erythropoietin (EPO) on the expression of aquaporin 2 (AQP(2)) after renal ischemia/reperfusion (IR).. Twenty-four Wistar rats were randomly divided into 3 equal groups: IR group undergoing resection of the right kidney, closuring of the left renal artery, vein, and ureter, and un-closuring 40 min later; IR + EPO group undergoing the above mentioned procedures and then intraperitoneal injection of EPO 3000 U/kg on days 1 and 2 after the treatment; and control group undergoing resection of the right kidney only without IR of the left kidney. Urine volume and urine osmotic pressure were measured. Blood samples were collected to detect the serum blood urea nitrogen (BUN) and creatinine (Cr). Three days after the treatment the kidneys were taken out. RT-PCR and Western blotting were used to detect the mRNA and protein expression of AQP(2).. The urine volume of the IR + EPO group was (26.0 +/- 2.3) microl .min(-1).kg(-1), significantly lower than that of the IR group [(59.1 +/- 1.3) microl .min(-1) . kg(-1), P < 0.01]. The urine osmotic pressure of the IR + EPO group was (1508 +/- 121) mOsm/kg H(2)O, significantly higher than that of the IR group [(235 +/- 99) mOsm/kg H(2)O, P < 0.01]. The serum BUN and Cr levels of the IR + EPO group were (12.3 +/- 6.0) mmol/L and (51 +/- 5) micromol/L respectively, both significantly lower than those of the IR group [(29.9 +/- 3.7) mmol/L and (141 +/- 5) micromol/L respectively, both P < 0.01]. The mRNA and protein expression of AQP(2) were highly positive in the control group. The protein expression levels of AQP(2) of the IR + EPO group were not significantly different from those of the control group (both P > 0.05), and the protein expression levels of AQP(2) of the IR group were significantly lower than those of the control group (both P < 0.01).. EPO can inhibit the down-regulation of AQP(2) in response to IR and this may take part in the EPO protective mechanism of renal ischemia/reperfusion injury.

Topics: Animals; Aquaporin 2; Disease Models, Animal; Erythropoietin; Female; Kidney; Kidney Diseases; Rats; Rats, Wistar; Reperfusion Injury

Erythropoietin is the treatment of the anaemia in chronic kidney disease. A target rate of haemoglobin higher than 11 g/dl was usually proposed, but recent recommendations stated that higher limit of haemoglobin was to be reached, with the aim to improve the quality of life of the patients and to reduce their risks of cardiovascular diseases. These objectives are to be revised, according to the results of recently published clinical trials.. Patients treated to reach a high rate of haemoglobin (between 13 and 14,5 g/dl) have an improved quality of life, but a 30% higher mortality rate, compared to patients treated with a lower objective of haemoglobin rate (10-12 g/dl). Hypertension and vascular access thromboses were also more frequent in the patients with the highest haemoglobin rate. Two to three times more erythropoietin was necessary to reach the higher rate of haemoglobin. These results favour a target rate of haemoglobin not higher than 12 g/dl. A polemic followed the results of these clinical trials, mostly in the United States, questioning the way in which the higher limit had been fixed whereas precise data were unavailable. The role of pharmaceutical industry and of for profit dialysis centres was underlined.. The next step is now to explain if the excess in cardiovascular morbimortality is related to the haemoglobin rate or to a direct effect of the erythropoietin. Such an understanding is important, the more so as new erythropoiesis-stimulating agents are being developed.

Topics: Anemia; Chronic Disease; Erythropoietin; Hemoglobins; Humans; Kidney Diseases; Recombinant Proteins; Renal Dialysis

Topics: Anemia; Conflict of Interest; Erythropoietin; Europe; Hemoglobins; Humans; Kidney Diseases; Practice Guidelines as Topic; Recombinant Proteins; United States

Study for influence of chronic hepatitis (CH) on anaemia in haemodialysis (HD) patients remains inconclusive. We aim to characterize the red cell status between CH and hepatitis-free groups among the HD population.. We retrospectively analysed 80 chronic HD patients from Taipei Medical University Hospital with monthly sampled biochemical study between December 2004 and December 2005. Data classified according to the hepatitis-free, chronic hepatitis B and C groups were expressed as mean +/- standard deviation. Student's t-test and anova were used to determine the mean difference for continuous variables.. Age, Kt/V, systolic or diastolic blood pressure, body mass index, total cholesterol and triglyceride were not different between CH and hepatitis-free groups. HD duration (P = 0.0002), aspartate (P < 0.0001), alanine aminotransferase (P < 0.0001), alkaline phosphatase (P = 0.04), haemoglobin (P = 0.0066) and haematocrit (P = 0.002) were significantly more elevated in the CH group demanding less erythropoietin dose than in the hepatitis-free group.. Our study demonstrated that lessened anaemia was observed in CH, which demanded less erythropoietin dose.

Topics: Aged; Alanine Transaminase; Anemia; Aspartate Aminotransferases; Erythropoietin; Female; Hematinics; Hematocrit; Hemoglobins; Hepatitis B, Chronic; Hepatitis C, Chronic; Humans; Injections, Intravenous; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Retrospective Studies

(1) Continuous erythropoietin receptor activator (CERA) is a third-generation erythropoiesis stimulating agent (ESA). CERA is used to correct anemia and maintain hemoglobin levels in patients with renal (kidney) failure. CERA is administered either once every two weeks (to correct anemia) or once per month (to maintain hemoglobin levels). This offers a potential advantage over other ESAs that require more frequent administration. (2) Two phase 3 trials involving erythropoietin-naïve patients found no difference between correcting renal anemia with CERA once every two weeks compared to results with other ESAs that were administered up to three times weekly. Four phase 3 trials reported that maintenance of stable hemoglobin levels in dialysis patients with once-monthly CERA was comparable to other agents that were administered up to three times weekly. Further clinical trials are needed to examine other important outcomes, such as mortality and major adverse effects. (3) The most common adverse effects with CERA were hypertension, diarrhea, headache, and upper respiratory tract infection. There was a higher risk of procedural hypotension (low blood pressure during administration), gastrointestinal hemorrhage, and tachycardia with CERA compared to other ESAs. (4) Administration of CERA at extended intervals may simplify anemia management, reduce the burden on patients, and decrease health care staff time spent administering the treatment.

Topics: Anemia; Canada; Clinical Trials, Phase III as Topic; Drug Approval; Erythropoietin; Humans; Kidney Diseases; Polyethylene Glycols; Receptors, Erythropoietin; Renal Dialysis; Time Factors; Treatment Outcome; United States; United States Food and Drug Administration

The aim of the present study was to analyze the relations between the serum anti-erythropoietin antibody (AEAb) levels and the antibodies' neutralizing activity in 20 patients with renal anemia and rhEPO-induced antibodies. AEAb levels were determined by the enzyme-linked immunosorbent assay (ELISA, double antigen-bridging) and by radioimmunoprecipitation assay (RIPA). The bone marrow neutralization test was used to determine the neutralizing activity of the antibodies. RIPA and ELISA data resulted in closely correlated measurements. The relations between AEAb levels and the neutralizing activity of the antibodies are variable as shown by follow-up and cross-sectional evaluations of the data. Serum samples with a high antibody level (>1000 ng/ml) are associated with 100% neutralizing activity, whereas serum samples with lower AEAb levels show partial neutralizing activities or have no effect. Determining the neutralizing activity might be helpful when it comes to deciding of whether or not rhEPO therapy should be continued, specifically in patients who have low antibody levels. The apparent affinity of the AEAb as defined by inhibition of the binding of rhEPO (IC(50)) did not change in the course of the disease, nor did it correlate to the AEAb levels or the neutralizing activities.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antibodies; Antibody Affinity; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Humans; Kidney Diseases; Male; Middle Aged; Neutralization Tests; Radioimmunoprecipitation Assay; Recombinant Proteins; Renal Insufficiency

To determine whether the administration of erythropoietin at the time of ischaemic renal injury (IRI) inhibits apoptosis, enhances tubular epithelial regeneration and promotes renal functional recovery, as it does in rodent models, in a higher mammalian model.. The model of IRI involved unilateral nephrectomy in pigs, followed a week later by renal artery occlusion for 1 h, followed by reperfusion for 5 days. Pigs were randomized to receive erythropoietin 5000 units/kg intravenously at the time of ischaemia, followed by 1000 units/kg subcutaneously daily, or no treatment (six pigs each). Renal function and structure were analysed; blood and urine were collected daily to determine serum creatinine level, blood urea nitrogen, and creatinine clearance. Animals were killed after 5 days to obtain the injured kidneys. The kidneys were examined histologically for evidence of cellular mitosis, apoptosis and necrosis.. Erythropoietin significantly abrogated renal dysfunction after IRI compared with controls at 12 h after injury; the mean (sem) creatinine clearance (as a percentage of baseline) for IRI was 68.2 (6)% vs erythropoietin-IRI 94.9 (8.9)% (P = 0.027), although by 36 h this was no longer significant, with values of 73.8 (12.7)% vs 95.9 (12)%, respectively (P = 0.23). Erythropoietin also significantly reduced the amount of cell death on histological analysis after 5 days of reperfusion, with a median (range) for IRI of 5.5 (1-45) vs erythropoietin-IRI of 1.5 (0-4) (P = 0.043).. This study confirms the potential clinical applications of erythropoietin as a novel therapeutic agent in patients at risk of IRI.

Topics: Animals; Cell Death; Creatinine; Erythropoietin; Immunohistochemistry; Kidney; Kidney Diseases; Reperfusion Injury; Swine; Treatment Outcome

Anaemia and hypertension are common in patients with chronic renal insufficiency. The correction of anaemia with erythropoiesis stimulating agents (ESA) can improve survival and decrease the decline of renal function. Angiotensin converting-enzyme inhibitors (ACEI) and angiotensin II receptor blockers (AIIRA) can also slow the progression of renal failure, but the blockade of the renin-angiotensin system can worsen anaemia. The aim of our study was to assess the impact of antihypertensive therapy (ACEI plus AIIRA) in the requirements of darbepoietin in a group of elderly predialysis patients. We included 71 patients (m = 39, f = 32), mean age of 76.3 years with a mean creatinine clearance of 17.5 ml/min. Patients were divided in two groups according to their antihypertensive therapy: G-I patients under ACEI or AIIRA therapy and G-II normotensive patients or hypertensive patients under antihypertensive drugs other than ACEI or AIIRA. The groups were compared regarding demographic, nutritional, biochemical and inflammatory parameters. We also compared the mean darbepoietin dose. In GI the mean dose of darbepoietin was higher than in GII (0.543 vs. 0.325 microg/kg/week, P = 0.032). We did not find any difference regarding other parameters analysed. We conclude that ACEI and AIIRA can increase the needs of darbepoietin in predialysis elderly patients. However, when formally indicated to treat hypertension in a specific patient, they should not be switched to another antihypertensive agent. Instead, in such cases, higher doses of ESA should be used, if necessary.

Topics: Aged; Aged, 80 and over; Anemia; Antihypertensive Agents; Chronic Disease; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Humans; Hypertension; Kidney Diseases; Male

Anaemia is a common complication of renal impairment. It has been suggested that renal failure secondary to diabetes is associated with more severe anaemia, but this has not been clearly substantiated in the published literature. To clarify this, we undertook a single centre, retrospective study to identify the impact of diabetes on anaemia associated with renal impairment.. Information on clinical, biochemical and haematological parameters of 2,052 stable ambulatory patients attending a single tertiary referral renal unit was collected. The impact of diabetic kidney disease on haemoglobin levels at all degrees of renal impairment was studied by comparison with patients with non-diabetic kidney disease after correcting for other commonly associated variables that influence anaemia in patients with renal impairment.. Linear regression analysis showed lower haemoglobin in patients with diabetic kidney disease (p < 0.01). At chronic kidney disease (CKD) stages 3, 4 and 5, mean haemoglobin levels in patients with diabetic kidney disease compared with those in patients with non-diabetic kidney disease were 129.5 vs 136.9 g/l (p < 0.001), 120.5 vs 126.9 g/l (p < 0.001) and 107.1 vs 115.9 g/l (p < 0.01), respectively. At CKD stage 4 and 5 the two groups were comparable for ferritin, plasma intact parathyroid hormone levels, ACE inhibitor use and length of follow-up by a nephrologist.. Diabetic kidney disease is associated with lower haemoglobin in comparison with non-diabetic kidney disease, especially at GFR <60 ml/min.

Topics: Anemia; Diabetes Mellitus; Diabetic Nephropathies; Disease Progression; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Regression Analysis; Retrospective Studies

Anaemia is prevalent in the chronic heart failure (CHF) population, but its cause is often unknown. The present study aims to investigate the relation between anaemia, renal perfusion, erythropoietin production, and fluid retention in CHF patients.. We studied 97 patients with CHF, of which 15 had anaemia (Hb<13.0 g/dL in men and Hb<12.0 g/dL in women), without haematinic deficiencies. Glomerular filtration rate (GFR) and extracellular volume (ECV) were measured as the clearance and the distribution volume of constantly infused 125I-iothalamate, respectively. Effective renal plasma flow (ERPF) was determined as the clearance of 131I-hippuran. Anaemic CHF patients displayed significantly reduced GFR (P=0.002), ERPF (P=0.005) and EPO production (P=0.001), and an elevated ECV (P=0.015). Multivariable analysis demonstrated that lower GFR (P=0.003), lower ERPF (P=0.004), lower EPO production (P=0.006), and a higher ECV (P=0.001) were significant independent predictors of lower haemoglobin levels.. Anaemia in CHF is not only independently associated with impaired renal perfusion and blunted EPO production, but to fluid retention as well.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Cell Size; Chronic Disease; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Renal Circulation; Renal Plasma Flow, Effective; Water-Electrolyte Imbalance

Several studies have shown that erythropoietin (EPO) can protect the kidneys from ischemia-reperfusion injury and can raise the hemoglobin (Hb) concentration. Recently, the EPO molecule modified by carbamylation (CEPO) has been identified and was demonstrated to be able to protect several organs without increasing the Hb concentration. We hypothesized that treatment with CEPO would protect the kidneys from tubular apoptosis and inhibit subsequent tubulointerstitial injury without erythropoiesis. The therapeutic effect of CEPO was evaluated using a rat ischemia-reperfusion injury model. Saline-treated kidneys exhibited increased tubular apoptosis with interstitial expression of alpha-smooth muscle actin (alpha-SMA), while EPO treatment inhibited tubular apoptosis and alpha-SMA expression to some extent. On the other hand, CEPO-treated kidneys showed minimal tubular apoptosis with limited expression of alpha-SMA. Moreover, CEPO significantly promoted tubular epithelial cell proliferation without erythropoiesis. In conclusion, we identified a new therapeutic approach using CEPO to protect kidneys from ischemia-reperfusion injury.

Topics: Animals; Apoptosis; Cell Proliferation; Erythropoiesis; Erythropoietin; Kidney; Kidney Diseases; Male; Nephritis, Interstitial; Phosphatidylinositol 3-Kinases; Proto-Oncogene Protein c-ets-1; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Signal Transduction

Patients with failed renal transplants represent an increasing proportion of the current dialysis population. Although their risk of anemia might be expected to be high, whether these patients receive adequate anemia therapy after returning to dialysis is unknown. We studied intravenous iron use, epoetin doses, and hemoglobin levels in patients with and without failed renal transplants who survived for 6 months after initiation of dialysis in the United States between 1996 and 2001. Of the study population (n=220 557), 9922 (4.5%) had failed renal transplants. In spite of a greater likelihood of receiving intravenous iron therapy (adjusted odds ratio (AOR) 1.47, P<0.0001) and epoetin (AOR 1.57, P<0.0001), patients with failed transplants were more anemic and had higher epoetin doses in each month of follow-up. During month 6, patients with failed transplants were more likely to have hemoglobin levels below 11 g/dl (AOR 1.50, P<0.0001) and to have epoetin-to-hemoglobin ratios above the population median of 1030 U/week per g/dl (AOR 1.73, P<0.0001). Patients who return to dialysis with failed transplants are at a higher risk of anemia than other patients who start dialysis; the pattern of lower hemoglobin levels and higher ratios of epoetin-to-hemoglobin suggests that relative epoetin resistance may be contributory.

Topics: Adolescent; Adult; Anemia; Epoetin Alfa; Erythropoietin; Graft Rejection; Hemoglobins; Humans; Kidney Diseases; Kidney Transplantation; Middle Aged; Recombinant Proteins; Renal Dialysis; Treatment Outcome

We aimed in this study to evaluate the attitude of physicians in the Kingdom of Saudi Arabia (KSA) towards strategies for treatment of anemia in patients with chronic kidney disease (CKD). A questionnaire was sent to 153 physicians in 148 active dialysis units in the KSA including centers under the Ministry of Health (MOH) (73.6%), centers in the governmental non-MOH sector (12.2%) and centers in private hospitals (14.2%) that together care for a population of more than 7900 chronic dialysis patients. The study was performed between April and June 2006. A total of 137 physicians (89.5%) answered the questionnaire from 129 (87.1%) dialysis centers that catered to 7052 (89.2%) dialysis patients. There were 104 respondents (75.9%) who staged their CKD patients according to the level of glomerular filtration rate (GFR). The estimated mean prevalence of each stage of CKD in the respondents' clinics was 15%, 19%, 29%, 22%, and 29% for the stages 1, 2, 3, 4, and 5, respectively. The estimated prevalence of anemia [hemoglobin (Hb) < 110 g/L] in the different stages of CKD were 11%, 17%, 38%, 59%, and 78% in stages 1, 2, 3, 4, and 5, respectively. However, only 69 respondents (48%) answered these two questions. Sixty-seven respondents (50.4 %) believed that any patient with Hb < 110 g/L should receive r-HuEPO irrespective of the CKD stage, and 133 (99.3%) believed that correction of anemia in the CKD patients has documented impact on morbidity and mortality. In case of availability of a long acting r-HuEPO such as darbepoetin, 88 (66.2%) respondents would use it as their first choice other than the current short acting drug. Our survey suggests that the current practices concerning anemia management in CKD patients in the KSA may not be satisfactory. There are many centers that do not have data on the prevalence of CKD or anemia in their units. More studies are required to explore the quality of services rendered to the CKD patients and guidelines need to be outlined for the management of anemia in the CKD patients.

Topics: Anemia, Hypochromic; Attitude of Health Personnel; Chronic Disease; Darbepoetin alfa; Drug Utilization; Erythropoietin; Glomerular Filtration Rate; Guideline Adherence; Health Care Surveys; Health Knowledge, Attitudes, Practice; Hematinics; Hemoglobins; Humans; Kidney Diseases; Practice Guidelines as Topic; Practice Patterns, Physicians'; Prevalence; Recombinant Proteins; Saudi Arabia; Severity of Illness Index; Surveys and Questionnaires

Topics: Aged; Anemia; Antibodies; Chronic Disease; Cyclophosphamide; Darbepoetin alfa; Erythropoietin; Fatal Outcome; Hematinics; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Opportunistic Infections; Prednisolone; Red-Cell Aplasia, Pure

Epidemiological studies report that a third of the cases of anaemia in older persons is unexplained. We compared erythropoietin (EPO), inflammatory markers and major comorbidities between older subjects with normal haemoglobin levels and those with different aetiologic forms of anaemia, including unexplained anaemia. Participants were a representative sample of 964 persons aged > or =65 years, with no evidence of bleeding, complete blood tests, and a complete blood count within 6 h of phlebotomy. Anaemia was defined as haemoglobin <130 g/l in men and 120 g/l in women, and classified as a result of chronic kidney disease, iron deficiency, chronic disease and B12/folate deficiency anaemia, or unexplained anaemia based on standard criteria. Of the 124 anaemic participants, 42 (36.8%) had unexplained anaemia. Participants with anaemia of chronic diseases had significantly higher interleukin-6 (IL-6) and C-reactive protein (CRP) levels, while those with unexplained anaemia had significantly lower CRP than non-anaemic controls. Iron deficiency anaemia was characterised by significantly higher EPO levels compared with other types of anaemia and normal haemoglobin, B12 and/or folate deficiency. Unexplained anaemia was characterised by unexpectedly low EPO and low lymphocyte count. Unexplained anaemia is associated with reduced kidney EPO response, low levels of pro-inflammatory markers and low lymphocyte counts.

Topics: Aged; Aging; Anemia; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Case-Control Studies; Diabetes Mellitus; Erythropoietin; Female; Health Surveys; Humans; Inflammation Mediators; Interleukin-6; Italy; Kidney Diseases; Lymphocyte Count; Male; Osteoarthritis; Parkinson Disease; Stroke; Tumor Necrosis Factor-alpha

Post-renal transplant anaemia is a potentially reversible cardiovascular risk factor. Graft function, immunosuppressive agents and inhibition of the renin-angiotensin system have been implicated in its aetiology. The evaluation of erythropoietin (EPO) levels may contribute to understanding the relative contributions of these factors.. Two-hundred and seven renal transplant recipients attending the Belfast City Hospital were studied. Clinical and laboratory data were extracted from the medical records and laboratory systems.. Of the 207 patients (126 male), 47 (22.7%) were found to be anaemic (males, haemoglobin (Hb)<12 g/dl, females Hb<11 g/dl). The anaemic group had a significantly higher mean serum creatinine level (162.8 micromol/l vs 131.0 micromol/l, P<0.001) and lower mean estimated glomerular filtration rate (eGFR) (41.5 ml/min vs 54.9 ml/min, P<0.001) than the non-anaemic group. Individual immunosuppressive regimens were comparable between those with and those without anaemia. Angiotensin converting enzyme inhibitor (ACE-I) or angiotensin receptor blocker (ARB) administration was not more prevalent in those with anaemia compared with those without (36.2 vs 38.8%, P=0.88). There was a significant inverse correlation between Hb levels and serum EPO levels (R=-0.29, P<0.001), but not between EPO levels and eGFR (R=0.02, P=0.74). Higher EPO levels were predictive of anaemia, independent of eGFR in multivariate analysis.. Anaemia is common in post-renal transplant patients. The levels of renal function and serum EPO and not immunosuppressive regimens or ACE-I/ARB use, are strong and independent predictors of anaemia.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Azathioprine; Erythropoietin; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Predictive Value of Tests

Correction of anemia by erythropoietin (EPO) is often associated with a rise in blood pressure (BP; EPO-induced hypertension). Most studies regarding EPO-induced hypertension have involved evaluation using office/clinic BP (OBP). However, recent investigations suggest that BP measured at home (HBP) may be of more importance for clinical practice in hypertension. In this context, the present study addressed whether or not HBP measured in the morning could be useful to predict EPO-induced hypertension.. The study involved patients with mild to moderate renal impairment who had renal anemia requiring EPO treatment. BP control was evaluated based on the relationship between OBP and HBP in the morning. The BP categories used were well-controlled BP, poorly controlled BP, hypertension with a white-coat effect (white-coat hypertension), and masked hypertension. Comparison was made of the BP categories before and after EPO treatment.. Before EPO treatment, 38% of patients had well-controlled BP, 30% had poorly controlled BP, 20% had masked hypertension, and 12% had white-coat hypertension, revealing a predominance of morning hypertension (poorly controlled BP plus masked hypertension). Following EPO treatment, the prevalence of morning hypertension in patients with masked hypertension and poorly controlled BP increased significantly, by 5% (HBP in those with masked hypertension increased from 152 +/- 18 mmHg to 162 +/- 25 mmHg, and HBP in those with poorly controlled BP increased from 157 +/- 18 mmHg to 168 +/- 25 mmHg; P < 0.05 by paired t-test). And there was a significant decrease in the prevalence of the well-controlled category, by 8%, with an increased level of morning HBP (from 128 +/- 14 mmHg to 137 +/- 16 mmHg; P < 0.05 by paired t-test). In contrast, OBP remained unchanged in all groups. The development of EPO-induced hypertension was effectively predicted by HBP in the morning (from 62% to 72% before and after EPO treatment; P = 0.0031 by Wilcoxon's analysis), but not by OBP (from 42% to 47% before and after treatment; P = 0.1399).. The present study indicates that, despite receiving concurrent antihypertensive therapy, the majority of patients with renal disease had morning hypertension. Furthermore, HBP in the morning can be more useful than OBP to predict the development of EPO-induced hypertension in patients with renal anemia.

Topics: Aged; Aged, 80 and over; Anemia; Blood Pressure Determination; Erythropoietin; Female; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Time Factors

The inhibitory effects of recombinant human erythropoietin (rhEPO) were examined against (1) the progression of renal fibrosis in mice with complete unilateral ureteral obstruction and (2) the TGF-beta1-induced epithelial-to-mesenchymal transition (EMT) in MDCK cells. Unilateral ureteral obstruction was induced in BALB/c mice and rhEPO (100 or 1000 U/kg, intraperitoneally, every other day) or vehicle was administered from day 3 to day 14. Immunoblotting and immunohistochemistry revealed increased expressions of TGF-beta1, alpha-smooth muscle actin (alpha-SMA), and fibronectin and decreased expression of E-cadherin in the obstructed kidneys. In contrast, rhEPO treatment significantly attenuated the upregulation of TGF-beta1 and alpha-SMA and the downregulation of E-cadherin. MDCK cells were treated with TGF-beta1 (5 ng/ml) for 48 h to induce EMT, and the cells were then co-treated with TGF-beta1 and rhEPO for another 48 h. Increased expressions of alpha-SMA and vimentin and decreased expressions of zona occludens-1 and E-cadherin were observed after TGF-beta1 treatment, and these changes were markedly attenuated by rhEPO co-treatment. TGF-beta1 increased phosphorylated Smad-2 expression in MDCK cells, which was decreased by rhEPO co-treatment. In conclusion, rhEPO treatment inhibits the progression of renal fibrosis in obstructed kidney and attenuates the TGF-beta1-induced EMT. It is suggested that the renoprotective effects of rhEPO could be mediated, at least partly, by inhibition of TGF-beta1-induced EMT.

Topics: Actins; Animals; Cells, Cultured; Disease Progression; Dogs; Epithelial Cells; Erythropoietin; Fibronectins; Fibrosis; Humans; Kidney; Kidney Diseases; Male; Mesoderm; Mice; Mice, Inbred BALB C; Recombinant Proteins; Transforming Growth Factor beta1; Ureteral Obstruction

Sepsis has a high mortality (50-80%) when associated with acute renal failure (ARF). Oxidant injury and proinflammatory cytokines and chemokines have been shown to increase with endotoxaemia-related ARF. Since erythropoietin (EPO) has been demonstrated to possess anti-oxidant and anti-inflammatory properties, EPO may have therapeutic efficacy for treating ARF associated with endotoxaemia.. Wild-type mice were given 2.5 mg/kg of intraperitoneal (i.p.) endotoxin, lipopolysaccharide (LPS), and studied 16 h later. Thirty minutes prior to LPS, the mice were given either EPO or vehicle.. During endotoxaemia, EPO was found to significantly attenuate the renal dysfunction, as assessed by glomerular filtration rate (48.1 +/- 12.4 microl/min vs 136.7 +/- 30.2, P < 0.05). Renal blood flow and mean arterial pressure were not significantly different between the two groups. The renal dysfunction during endotoxaemia was associated with a decrease in renal superoxide dismutase (SOD). The EPO-related renal protection was associated with reversal of the effects of endotoxin on renal SOD.. This is the first demonstration of a renal protective effect of EPO on endotoxin-related renal dysfunction.

Topics: Animals; Cytokines; Endotoxemia; Erythropoietin; Glomerular Filtration Rate; Inflammation; Kidney; Kidney Diseases; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Sepsis; Tumor Necrosis Factor-alpha

Topics: Amides; Anemia; Antihypertensive Agents; Benzazepines; Drug Administration Schedule; Drug Approval; Drug Combinations; Drug Delivery Systems; Erythropoietin; Ferrosoferric Oxide; Fumarates; Humans; Hyponatremia; Immunosuppressive Agents; Kidney Diseases; Nanoparticles; Nephrology; Renal Dialysis; Renin; Tacrolimus; Tolvaptan

Topics: Anemia; Clinical Trials as Topic; Erythropoietin; Humans; Kidney Diseases; Neoplasms; Premedication; Preoperative Care

Topics: Anemia; Clinical Trials as Topic; Erythropoietin; Humans; Influenza A Virus, H5N1 Subtype; Influenza Vaccines; Influenza, Human; Kidney Diseases; Polyethylene Glycols; Recombinant Proteins

Recent studies have established that erythropoietin (EPO) is a pleiotropic cytokine. In this study we investigated whether pleiotropic effects of EPO may involve regulation of heme oxygenase (HO)-1, an anti-oxidative stress protein. A stimulatory effect of EPO on HO-1 expression was demonstrated in cultured renal endothelial cells, in which EPO decreased intracellular oxidative stress and provided cytoprotection against H(2)O(2). These beneficial effects were partially reversed by a HO-1 inhibitor. We then evaluated whether EPO induces HO-1 and ameliorates renal injury in vivo. Administration of EPO to Dahl salt-sensitive (DS) rats with low salt diet, a model of chronic tubulointerstitial injury, reduced proteinuria, and renal injury including peritubular capillaries rarefaction as compared to vehicle-treated DS rats. This renoprotection was associated with up-regulation of HO-1 in the kidney. In conclusion, EPO-induced HO-1 expression is likely to provide cytoprotection against oxidative stress.

Topics: Animals; Cells, Cultured; Dose-Response Relationship, Drug; Endothelial Cells; Erythropoietin; Gene Expression Regulation, Enzymologic; Heme Oxygenase (Decyclizing); Kidney Diseases; Male; Oxidative Stress; Rats; Rats, Inbred Dahl; Treatment Outcome

Topics: Anemia; Chronic Disease; Erythropoietin; Hematinics; Humans; Kidney Diseases; Legislation, Drug; Neoplasms; Recombinant Proteins; United States; United States Food and Drug Administration

Topics: Anemia; Animals; Cell Line; Chemistry, Pharmaceutical; Cricetinae; Drug Design; Erythropoietin; Glycosylation; Humans; Kidney Diseases; Nephrology; Recombinant Proteins

In contrast to other sympathetic outflow tracts, renal sympathetic nerve activity (RSNA) decreases in response to hypotensive hemorrhage. The functional significance of this "paradox" is not known. We tested the hypothesis that RSNA modulates renal perfusion and thus erythropoietin (EPO) release after transient hypotensive hemorrhage in anesthetized rats. Plasma EPO was measured before and after 30 min of transient hypotensive hemorrhage (i.e., -40 mmHg from mean baseline blood pressure, followed by reinfusion of shed blood) and 120 min thereafter in sham-denervated rats, and after renal denervation (DNX) or bilateral cervical vagotomy (VX) to abolish/blunt the RSNA decrease mediated by a cardiopulmonary reflex. RSNA, renal Doppler flow, renal vascular resistance (RVR), resistance index, and oxygen delivery/uptake (Do(2)/Vo(2)) were measured. RSNA decreased in intact animals (-40 +/- 5% from baseline, P < 0.05). This was blunted by VX. With intact nerves, EPO level did not increase. In DNX rats, EPO was increased at minute 120 (49 +/- 3 vs. 74 +/- 2 mU/ml; P < 0.05), in VX rats this (47 +/- 2 vs. 62 +/- 4 mU/ml; P < 0.05) was less pronounced. Do(2) in DNX rats was lower compared with intact and VX rats (0.25 +/- 0.04 vs. 0.51 +/- 0.06 and 0.54 +/- 0.05 ml O(2)/min; P < 0.05) due to lower Doppler flow and increased RVR. RVR and Do(2) were similar in intact and VX rats, but resistance index differed between all groups (0.70 +/- 0.02 vs. 0.78 +/- 0.02 vs. 0.85 +/- 0.02; P < 0.05, intact vs. VX vs. DNX), indicating differential reactivity of renal vasculature. Vo(2) was unaffected by VX and DNX. Renal sympathoinhibition during hypotensive hemorrhage might help to preserve sufficient oxygenation of renal tissue by modulation of hemodynamic mechanisms that act to adapt renal oxygen availability to demand.

Topics: Animals; Blood Pressure; Erythropoietin; Hemorrhage; Hypotension; Kidney; Kidney Diseases; Lactic Acid; Male; Oxygen; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Sympathetic Nervous System; Vascular Resistance

1. Erythropoietin (EPO) is a hormone regulating the proliferation and differentiation of erythroid precursor cells. The hypothesis that haematopoietic and endothelial cells share a common haemanglioblast progenitor among others is based on the finding that both cell lineages express cell surface antigens, such as CD31 and CD34. 2. In the present study, we investigated the angiogenic potential of recombinant human erythropoietin on cyclosporine A (CsA)-induced nephrotoxicity in the rat kidney and compared it with the effect of basic fibroblast growth factor (bFGF), a well-known angiogenic factor. 3. Rats were divided into five groups: A (control), B (EPO treated), C (CsA treated), D (CsA + EPO treated) and E (CsA + bFGF treated). Mouse anti-human CD31 and CD34 antibodies were used to evaluate the kidney vessels present in histological preparations. 4. Glomerular and peritubular capillaries in Group B (EPO) were increased compared with the control (Group A; P < 0.05). Reduction of the same kidney vessels (glomerular and peritubular capillaries) in Group C (CsA; P < 0.05) compared with controls was observed, whereas in Groups D (CsA + EPO treated) and E (CsA + bFGF treated), capillaries were increased compared with Group C (CsA; P < 0.05). 5. Erythropoietin has a significant angiogenic effect in rat kidney with CsA-induced nephrotoxicity, similar to the effect of the other angiogenic factor bFGF.

Topics: Angiogenic Proteins; Animals; Cyclosporine; Disease Models, Animal; Erythropoietin; Fibroblast Growth Factor 2; Humans; Kidney; Kidney Diseases; Male; Neovascularization, Physiologic; Rats; Rats, Sprague-Dawley; Recombinant Proteins

Patients with chronic kidney disease (CKD) are frequently complicated by renal anemia as renal function declines. However, clinical guidelines on erythrocyte stimulating agents (erythropoietin : EPO) for such patients have not been established. Current clinical practice for EPO administration is based on the recommendations of the Japanese health insurance regulations, which have not always been supported by clinical evidence.. The study subjects were 49 patients with CKD staged above 3 who had developed renal anemia requiring EPO. These patients were treated with EPO S. C. at the dose of 6,000 IU/week together with iron supplementation as deemed necessary for more than 24 weeks.. The hemoglobin (Hb) value was 9.2 +/- 1.0 g/dL at the start, 10.9 +/- 1.6 g/dL at the peak (n = 49, p < 0.001 the start vs. the peak), and 9.0 +/- 1.6 g/dL at the commencement of dialysis (n = 49, p < 0.001 the peak vs. the commencement of dialysis). Seventy-one percent (35/49) of the patients achieved Hb levels over 10 g/dL, and 51% (25/49) achieved Hb levels over 11 g/dL. Conversely, 28% (14/49) of the patients failed to reach an Hb level over 10 g/dL. Factors explaining the good response to EPO (good responders were defined as those achieving Hb levels over 11 g/dL) had shown high Hb levels at the start (Logistic multiple regression analysis, p = 0.03) along with low creatinine concentration at the start (Cox's proportional hazard models, p = 0.015). Transferrin saturation (TSAT) at the start was 33.6 +/- 13.6%, 34.0 +/- 19.9% at the peak, and 24.7 +/- 11.6% at the commencement of dialysis, showing a significant reduction in TSAT at the commencement of dialysis compared to that at the start (n = 49, p = 0.0383, the start vs. the commencement of dialysis). Serum ferritin concentration was 140.7 +/- 139.5 pg/mL at the start, 107.9 +/- 110.8 pg/mL at the peak, and 131.9 +/- 112.4 pg/mL at the commencement of dialysis, indicating an absence of significant differences among the three time points.. The current health insurance regulations in Japan seem to be inappropriate in that the permitted EPO dosage of 6,000 IU/week might not be sufficient to achieve the target Hb level of more than 11 g/dL in most patients with CKD. To more efficiently achieve renoprotection, both early and timely initiation of EPO and reconsideration of the recommended EPO dosage appear to be warranted.

Topics: Aged; Anemia; Chronic Disease; Dialysis; Erythropoietin; Female; Humans; Kidney Diseases; Male; Middle Aged

There are limited data suggesting that initiation of epoetin alfa at extended dosing intervals of every 2, 3, or 4 wk may be efficacious for treating anemia in patients who have chronic kidney disease and are not on dialysis (CKD-NOD). This open-label, multicenter, single-arm study investigated the efficacy of administration of 20,000 IU of epoetin alfa once every 2 wk as initiation therapy in these patients. Adults with CKD-NOD were eligible when they had hemoglobin (Hb) <11 g/dl, GFR of 10 to 60 ml/min per 1.73 m2, and stable serum creatinine for the past 6 mo. Patients received 20,000 IU of epoetin alfa subcutaneously every 2 wk for up to 27 wk, with dosage adjustments permitted after 4 wk of treatment. The primary efficacy end point was the proportion of patients with Hb response, defined as achievement of the target Hb range of 11 to 12 g/dl for at least two consecutive visits. Sixty-seven patients were enrolled; >88% (59 of 67) of patients achieved an Hb response. Mean Hb increased to the targeted range by week 6 and remained in the range through week 28. Hb increases of 1 and 2 g/dl were observed in 91 and 78% of patients, respectively. Epoetin Alfa was well tolerated; most adverse events were mild or moderate in nature and typical of the CKD patient population. In this study, results demonstrated that epoetin alfa can be initiated safely and effectively at an extended dosing interval of 20,000 IU every 2 wk in patients with CKD-NOD.

Topics: Aged; Anemia; Chronic Disease; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Kidney Diseases; Male; Recombinant Proteins

Forty-one percent of UK patients commence RRT with an Hb < 10.0 g/dl. The mean Hb at commencement of RRT is 10.3 g/dl. Eighty-five percent of patients on dialysis in the UK have an Hb > or = 10.0 g/dl by 6 months after commencement of RRT. The median Hb on haemodialysis in the UK is 11.8 g/dl with an IQR of 10.7-12.8 g/dl. Eighty-six percent of haemodialysis patients in the UK have a Hb > or = 10.0 g/dl. The median Hb on peritoneal dialysis in the UK is 12.0 g/dl with an IQR of 11.0-12.9 g/dl. Ninety percent of peritoneal dialysis patients in the UK have an Hb > or = 10.0 g/dl. In the UK, 49% of patients on PD and 48% of patients on haemodialysis have an Hb between 10.5-12.5 g/dl. The median ferritin in UK haemodialysis patients is 413 microg/l (IQR 262-623), 95% of UK haemodialysis patients have a ferritin > or =100 microg/l. The median ferritin in UK PD patients is 256 microg/l (IQR 147-421), 86% of UK peritoneal dialysis patients have a ferritin > or = 100 microg/l. A higher proportion of HD patients than PD patients receive ESA therapy (88% vs 76%). The ESA dose is higher for HD than PD patients (9204 vs 6080 IU/week).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Chronic Disease; Erythropoietin; Female; Ferritins; Guideline Adherence; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Peritoneal Dialysis; Registries; Renal Dialysis; United Kingdom

Instability of hemoglobin levels during epoetin therapy is a new problem in hemodialysis. We evaluated extent and correlates of time in target, that is, the time spent with hemoglobin > or = 11 g/dl during the first year of epoetin and its association with renal survival.. Data were collected in 917 visits for 12.0 mo in 119 patients with chronic kidney disease; thereafter, patients started renal survival analysis for 10.1 mo. At baseline, hemoglobin was 10.0 +/- 0.8 g/dl and GFR was 22.1 +/- 14.2 ml/min per 1.73 m2.. Hemoglobin target, reached in 1.5 mo, was steadily maintained in only 24% of patients. Time in target was not merely due to differences in time to target; after first achievement of target, in fact, a reduction of hemoglobin < 11 g/dl occurred in 51% of patients. At multivariate analysis, male gender, basal GFR and hemoglobin levels, first epoetin dose, and iron supplementation were directly associated with length of time in target. A lower risk for renal death (dialysis n = 53; death n = 8) was detected in the higher tertile of time in target (11.3 mo) versus lower tertile (3.2 mo). This difference persisted at Cox analysis after adjustment for age, gender, GFR, BP, and proteinuria.. In chronic kidney disease, time in target during the first year of epoetin therapy is frequently short depending not only on time to target but also on post-target hemoglobin reductions, correlates with male gender, timing, and intensity of initial therapy and is coupled with better renal survival.

Topics: Anemia; Chronic Disease; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Time Factors

The inpatient dosing patterns and treatment costs in cancer and predialysis chronic kidney disease (CKD) patients treated with erythropoietic agents from a hospital pharmacy perspective were studied.. An analysis of electronic inpatient records from the Premier Perspective comparative hospital database was conducted. Study participants were identified through hospitalizations recorded between July 2002 and March 2005 from over 500 hospitals nationwide. Adult patients with an admitting diagnosis of cancer or predialysis CKD and treated with epoetin alfa or darbepoetin alfa during hospitalization were included. Patients who had received renal dialysis or both agents during a hospitalization were excluded. Wholesale acquisition costs from September 2006 were used to calculate drug costs.. A total of 25,645 hospitalized patients with cancer (22,873 received epoetin alfa; 2,772 received darbepoetin alfa) and 66,822 hospitalized patients with CKD (60,079 received epoetin alfa; 6,743 received darbepoetin alfa) were identified. The mean cumulative dose per hospitalization resulted in dose ratios of 245:1 and 242:1 (units epoetin alfa:micrograms darbepoetin alfa) for cancer and CKD patients, respectively. On the basis of the cumulative dose per hospitalization, drug costs for darbepoetin alfa-treated patients were approximately 50% higher than drug costs for epoetin alfa-treated patients for both oncology and CKD patients.. Epoetin alfa was associated with less cost compared with darbepoetin alfa for treating inpatients with cancer or CKD. Further research including the patients' clinical outcomes is necessary to determine the true pharmacoeconomic differences between the two agents.

Topics: Adult; Aged; Anemia; Cohort Studies; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Female; Health Care Costs; Humans; Inpatients; Kidney Diseases; Male; Middle Aged; Neoplasms; Pharmacy Service, Hospital; Recombinant Proteins; Retrospective Studies

1. The aim of the present study was to investigate the role of oxidative stress in renal injury and to determine whether erythropoietin (EPO) acts as an anti-oxidant in vancomycin (VCM)-induced renal impairment. 2. Twenty-four rats were divided into three groups as follows: (i) control (Group 1); (ii) VCM treated (Group 2); and (iii) VCM + EPO treated (Group 3). Vancomycin (200 mg/kg, i.p.) was administered to Groups 2 and 3 for 7 days. Erythropoietin (150 IU/kg, i.p.) treatment was started 24 h before VCM and lasted for 7 days. On Day 8, renal tissues were excised and blood samples were collected. Serum creatinine and blood urea nitrogen were measured, along with renal malondialdehyde (MDA) levels, superoxide dismutase (SOD) and catalase (CAT) activity and tissue VCM levels. The kidneys were examined for any histopathological changes. 3. Renal MDA levels were found to be increased, whereas SOD and CAT activity was decreased, in the VCM-treated group compared with the control group. There was a marked decrease in MDA levels and an increase in SOD activity, but not CAT activity, after VCM + EPO treatment. Marked histopathological alterations, including interstitial oedema, tubular dilatation, tubular epithelial cell desquamation and vacuolization, were observed in VCM-treated rats. Histopathological changes were significantly improved after EPO administration. 4. In conclusion, the present data suggest that oxidative stress plays an important role in VCM-induced nephrotoxicity. Erythropoietin seems to act as an anti-oxidant, diminishing the toxic oxidative effects of VCM on renal tissues.

Topics: Animals; Anti-Bacterial Agents; Antioxidants; Blood Urea Nitrogen; Catalase; Creatinine; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Kidney; Kidney Diseases; Male; Malondialdehyde; Oxidative Stress; Rats; Rats, Wistar; Recombinant Proteins; Superoxide Dismutase; Vancomycin

While hospitalization is common for hemodialysis patients, perihospitalization associations between hemoglobin levels and epoetin doses are not well characterized. U.S. Medicare claims were used to identify 71,360 hemodialysis patients hospitalized from 1998 to 2003. Hemoglobin levels, epoetin doses, and epoetin responsiveness index (ERI) were compared by calendar year. In the prehospitalization month, the mean hemoglobin levels increased from 10.96 g/dL in 1998 to 11.76 in 2003 and the mean epoetin doses from 63,715 to 75,012 U; corresponding values in the hospitalization month were 10.53 and 11.19 g/dL, and 66,623 and 80,569 U. In each year, prehospitalization hemoglobin levels were achieved within 2 months, but ERI declined to prehospitalization levels within 12 months only in 2000. With mixed models, hemoglobin declines in the 3 prehospitalization months grew between 1998 (-0.1362 g/dL/month) and 2003 (-0.2003 g/dL/month). Epoetin responsiveness index slopes were J-shaped, with values of 287.9, 221.1, and 356.5U/month per g/dL in 1998, 2000, and 2003. In the 3 postadmission months, a modest increase in the rapidity of hemoglobin recovery was seen (+0.2538 g/dL/month in 1998, +0.2743 in 2003), with increasing rates of ERI change (+8.7 U/month/g/dL in 1998, +146.8 in 2003). While time to recovery of prehospitalization hemoglobin levels remained constant year to year, epoetin doses and ERI did not, suggesting that optimum perihospitalization anemia management practices have yet to be determined.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Child; Child, Preschool; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hemoglobins; Hospitalization; Humans; Infant; Infant, Newborn; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Renal Replacement Therapy; Treatment Outcome; United States

A statistical survey conducted at the end of 2005 covered 3985 medical facilities across Japan, and 3940 facilities (98.87%) responded. The dialysis population in Japan at the end of 2005 was 257,765, which showed an increase of 9599 patients (3.87%) from the end of the previous year. The number of patients per million was 2017.6. The crude death rate for one year (from the end of 2004 to the end of 2005) was 9.5%. The mean age of the patients who began dialysis (in 2005) was 66.2 years, and the mean age of the entire dialysis population was 63.9 years. The primary diseases of the patients who began dialysis were diabetic renal disease (42.0%) and chronic glomerulonephritis (27.3%). The mean (+/-SD) serum ferritin concentration of all the dialysis patients was 191 (+/-329) ng/mL. The percentages of antihypertensive agents administered to the hemodialysis patients were as follows: calcium-channel blocker, 50.3%; angiotensin-converting enzyme inhibitor, 11.5%; and angiotensin II-receptor blocker, 33.9%. Of the peritoneal dialysis patients, 33.4% used automated peritoneal dialysis devices. Moreover, 7.3% of the peritoneal dialysis patients received dialysis treatment only in the daytime, and 15% received the treatment only at night. Icodextrin solution was used by 37.2% of the peritoneal dialysis patients. The average amount of dialysis solution used by the peritoneal dialysis patients was 7.43 (+/-2.52) L/day and the average amount of removal fluid was 0.81 (+/-0.60) L/day. A peritoneal equilibration test was conducted on 67% of the patients, and the mean dialysate to plasma creatinine ratio was 0.65 (+/-0.13). The annual incidence of peritonitis in the peritoneal dialysis patients was 19.7%. Of the 126 040 patients who responded to the inquiry of the therapeutic situation of peritoneal dialysis, 676 (0.7%) had a history of encapsulated peritoneal sclerosis and 66 (0.1%) were treated for encapsulated peritoneal sclerosis. The mean life expectancy of the dialysis population in 2003 was calculated according to sex and age. Results showed that the mean life expectancy of the dialysis population was approximately 40-60% of that of the general population of the same sex and age.

Topics: Aged; Antihypertensive Agents; Blood Pressure; C-Reactive Protein; Cause of Death; Erythropoietin; Female; Ferritins; Health Care Surveys; Humans; Iron; Japan; Kidney Diseases; Life Expectancy; Male; Middle Aged; Peritoneal Dialysis; Peritonitis; Renal Dialysis; Survival Rate

Anemia is a common complication of chronic kidney disease (CKD). The approved dosing interval for currently available erythropoiesis-stimulating agents (ESAs) is 2 to 3 times weekly for epoetin alfa (EPO) and every 1 to 2 weeks for darbepoetin alfa (DARB). However, clinicians sometimes use less frequent dosing in the interest of convenience.. This study investigated patterns of actual ESA use (doses and dosing intervals) and hemoglo- bin (Hb) control in adult outpatients with CKD not requiring dialysis at the Cleveland Clinic Foundation anemia clinic. The distribution of and variability in Hb levels in these patients were also examined.. The clinical charts and electronic records of adult outpatients with CKD who initiated ESA therapy before March 2005 were reviewed to identify the initial, dominant (used for the longest consecutive period), and final dosing intervals and mean weekly doses of EPO and DARB. Hb control was examined in terms of maximum deviations >12 g/dL and <11 g/dL, and the proportions of measurements outside these values.. The analysis included data from 111 outpatients (mean [SD] age, 65.9 [14.4] years; 53.2% male; 66.7% white, 29.7% black, 2.7% other, 0.9% unknown ethnicity). Twenty-one patients received EPO only, 74 received DARB only, and 16 switched ESAs. The mean duration of follow-up was 20.5 months. The most common initial dosing intervals were qwk for EPO (66.7%) and q2wk for DARB (90.5%). The dominant dosing intervals were q2wk in 61.9% of EPO patients and q3wk in 62.3% of DARB patients. However, 80.0% of those who received EPO q2wk and 63.2% of those who received DARB q3wk eventually returned to their initial dosing intervals. The largest proportions of Hb mea- surements <11 g/dL occurred at dominant dosing intervals of qwk for EPO and q2wk for DARB (both, 46.0%; 11 and 26 patients, respectively), whereas the largest proportions of measurements >12 g/dL occurred with EPO dosed at q2wk (44.0%; 5 patients) and DARB dosed at >q4wk (62.0%; 5 patients).. The patterns of ESA usage in adult outpatients with CKD at this center indicated that clinicians extended dosing intervals beyond those in the approved prescribing information. However, variations in Hb concentrations occurred during maintenance therapy administered at extended dosing intervals, resulting in the resumption of shorter dosing intervals in the majority of patients.

Topics: Aged; Anemia; Chronic Disease; Cohort Studies; Darbepoetin alfa; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Diseases; Male; Recombinant Proteins; Retrospective Studies

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Erythropoietin; Goals; Hemoglobins; Humans; Kidney Diseases; Kidney Failure, Chronic; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Thrombophilia

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Diseases; Practice Guidelines as Topic; Recombinant Proteins

Our aim is to study the effect of improvement in anemia on event-related potentials (ERPs; P300) as markers of cognitive dysfunction in predialysis and dialysis patients of chronic kidney disease (CKD). Thirty anemic patients of CKD (hemoglobin [Hb] < 9 g%), 15 in the predialysis group (Group A), and 15 patients on biweekly hemodialysis (Group B) were recruited for the study. Patients of uremic encephalopathy, dyselectrolytemia, and those with hearing problems were excluded. Both groups were given recombinant human erythropoietin (rhuEPO) 100 IU/kg biweekly for 6 weeks by the subcutaneous route. No intervention was performed in the third control group (Group C), which consisted of 30 normal healthy volunteers. The improvement in Hb was assessed every 2 weeks, and the amplitude and latency of the P300 component of the ERPs were studied before initiating treatment and after 6 weeks of rhuEPO administration. There was a significant increase in Hb in both the study groups without any significant alteration in kidney functions. A significant reduction in P300 latency was noted in both the study groups after intervention. Similarly, the amplitude of P300 also increased in both study groups, but attained statistical significance for the dialysis group only. No significant changes were observed in the control group. Administration of EPO in patients of anemia with CKD resulted in a significant improvement in the electrophysiological markers of cognitive function in the form of increased amplitudes and decreased latencies of P300 in both predialysis and dialysis patients.

Topics: Anemia; Chronic Disease; Cognition Disorders; Erythropoietin; Event-Related Potentials, P300; Hemoglobins; Humans; Kidney Diseases; Reaction Time; Recombinant Proteins

Anaemia is aggravated by the coexistence of chronic kidney disease (CKD) in patients infected with human immunodeficiency virus (HIV). Darbepoetin alfa effectively alleviates CKD-associated anaemia with less frequent dosing than recombinant human erythropoietin (EPO). The current study aimed to determine the efficacy, safety and cost-effectiveness of darbepoetin alfa compared with erythropoietin alfa (EPO-alfa) for treatment of anaemia in HIV-infected subjects receiving haemodialysis.. An open label, single arm, prospective study of 12 haemodialysis subjects with HIV infection was conducted for a duration of 6 months after switching from intravenous (i.v.) EPO-alfa two/three times weekly to i.v. darbepoetin alfa once weekly. The primary end point was the proportion of patients maintaining haemoglobin (Hb) levels>or=11 g/dl while a weekly dose of darbepoetin alfa was a secondary end point.. Darbepoetin alfa, as effectively as EPO-alfa maintained the proportion of the subjects having Hb levels>or=11 g/dl at an average weekly dose of 40.60 microg compared with an equivalent dose of 51.84 microg for EPO-alfa. Antiretroviral therapy and HIV infection stage remained the same for each specific patient throughout the study period, including the last 6 months of EPO-alfa therapy. No difference in the incidence of adverse effects was observed after switching from EPO-alfa to darbepoietin alfa.. Lower doses of darbepoetin alfa at extended dosing interval is as safe and effective as EPO-alfa for treating anaemia, suggesting that darbepoetin alfa is a more cost-effective therapeutic alternative to EPO-alfa in the management of anaemia associated with HIV infection in subjects receiving haemodialysis.

Topics: Adult; Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Hematinics; HIV Infections; Humans; Injections, Intravenous; Kidney Diseases; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis

Due to its strong intra- and inter-individual variability, predicting the ideal erythropoietin dose is a difficult task. The aim of this study was to re-evaluate the impact of the main parameters known to influence the responsiveness to epoetin beta and to test the performance of artificial neural networks (ANNs) in predicting the dose required to reach the haemoglobin target and the monthly dose adjustments.. We did a secondary analysis of the survey on Anaemia Management in dialysis patients in Switzerland; a prospective, non-randomized observational study, enrolling 340 patients of 26 centres and in order to have additional information about erythropoietin responsiveness, we included a further 92 patients from the Renal Services of the Ente Ospedaliero Cantonale, Bellinzona, Switzerland. The performance of ANNs in predicting the epoetin dose was compared with that of linear regressions and of nephrologists in charge of the patients.. For a specificity of 50%, the sensitivity of ANNs compared with linear regressions in predicting the erythropoietin dose to reach the haemoglobin target was 78 vs. 44% (P < 0.001). The ANN built to predict the monthly adaptations in erythropoietin dose, compared with the nephrologists' opinion, allowed to detect 48 vs. 25% (P < 0.05) of the patients treated with an insufficient dose with a specificity of 92 vs. 83% (P < 0.05).. In predicting the erythropoietin dose required for an individual patient and the monthly dose adjustments ANNs are superior to nephrologists' opinion. Thus, ANN may be a useful and promising tool that could be implemented in clinical wards to help nephrologists in prescribing erythropoietin.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Computer Simulation; Decision Support Systems, Clinical; Drug Therapy, Computer-Assisted; Erythropoietin; Expert Systems; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Models, Biological; Nephrology; Neural Networks, Computer; Point-of-Care Systems; Renal Dialysis; Reproducibility of Results; Sensitivity and Specificity; Switzerland; Treatment Outcome

To evaluate the relationship between hemoglobin (Hb) level and quality of life (QOL) in anemic patients with non-dialysis chronic kidney disease receiving epoetin alfa.. A post-hoc analysis using data from a multicenter, open-label, prospective study of epoetin alfa for anemia in patients with chronic kidney disease not on dialysis was conducted. The relationship between Hb and QOL was analyzed using correlation and longitudinal analyses, the latter adjusting for sample selection bias. The Linear Analog Scale Assessment (LASA) and the Kidney Disease Questionnaire (KDQ) subscales were used to measure QOL. The impact of an incremental 1 g/dL increase in Hb level on LASA and KDQ scores was determined using an incremental analysis.. A total of 1183 and 1044 patients formed the study populations for the LASA and KDQ analyses, respectively. There was a positive and significant relationship between Hb levels and QOL (p < 0.05). Using non-linear regression analysis, we characterized the sigmoid-shape of the relationship between Hb levels and QOL scores. Hemoglobin change was a statistically significant determinant of QOL improvement for both LASA and KDQ scales (p < 0.05). The model predicted that, based on a 2 unit change in Hb, the greatest incremental QOL improvement per unit of Hb increase occurred when Hb was in the range of 11 to 12 g/dL.. This study demonstrates that, beyond the well-known relationship between Hb increases and QOL improvements, the maximal incremental gain in QOL occurred when Hb reached 11 to 12 g/dL. This suggests that treating anemic patients with non-dialysis chronic kidney disease until their Hb level reaches 12 g/dL will result in the greatest QOL improvement per Hb unit increase. The analyses were conducted based on an open-label study of epoetin alfa and could be further validated using a randomized, controlled trial, comparing incremental gains in QOL associated with treatment initiation at varying levels of Hb across arms.

Topics: Aged; Anemia; Chronic Disease; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Quality of Life; Recombinant Proteins

Topics: Animals; Epoetin Alfa; Erythropoietin; Humans; Incidence; Kidney Diseases; Mice; Ovalbumin; Recombinant Proteins; Red-Cell Aplasia, Pure; Structure-Activity Relationship

The prevalence of iron deficiency and its contribution to the anemia of end stage renal disease has been extensively studied, but much less is known about the role of iron deficiency in the pathogenesis of the anemia of chronic kidney disease in predialysis patients. All new hemodialysis patients entering a single hemodialysis unit between July 1999 and April 2002 were included in the study. The admission laboratory tests and the Health Care Financing Administration (HCFA) 2728 form were examined to determine the prevalence of erythropoietin use, anemia (Hb<11 g/dl), and iron deficiency (ferritin<100 ng/ml and transferrin saturation %<20%). In a second part of the study, the effect of intravenous iron gluconate replacement in patients with stage III & IV chronic kidney disease was examined. Anemia was present in 68% of all patients starting hemodialysis. Iron deficiency was a common feature occurring in 29% of patients taking erythropoietin (49% of all patients) and 26% of patients without erythropoietin (51% of all patients). Following the administration of intravenous iron gluconate to four patients, there was a significant rise in hemoglobin levels from 10.6+/-0.19 to 11.7+/-g/dl (p=0.02).. Iron deficiency is common in predialysis patients. Replenishing iron stores in anemic patients with chronic kidney disease significantly increases hemoglobin levels and should be considered as an integral part of the therapy for treating anemia in the predialysis population.

Topics: Anemia, Iron-Deficiency; Chronic Disease; Erythropoietin; Ferric Compounds; Gluconates; Humans; Kidney Diseases

To demonstrate the efficacy and safety of once-monthly (QM) darbepoetin alfa administration in maintaining haemoglobin (Hb) 11.0-13.0 g dL(-1) in subjects with chronic kidney disease (CKD) not receiving dialysis and previously treated with darbepoetin alfa every other week (Q2W).. This open-label study enrolled subjects > or =18 years of age who had glomerular filtration rate > or =15 and < or =60 mL min(-1)/1.73 m(2), had Hb 11.0-13.0 g dL(-1), and were receiving Q2W darbepoetin alfa.. Subjects were switched to QM darbepoetin alfa therapy for 28 weeks; the QM dose was titrated to maintain Hb levels. Primary end-point: proportion of subjects maintaining Hb > or =11.0 g dL(-1) during the final 8 weeks of the study (evaluation phase). Secondary end-points: Hb concentration during evaluation, darbepoetin alfa dose during the study, adverse events, laboratory parameters, and blood pressure.. The study enrolled 152 subjects (female 52%, white 64%). Mean Hb > or =11.0 g dL(-1) during evaluation was achieved by 76% of the 150 subjects who received at least one dose of darbepoetin alfa [95% confidence interval (CI): 68%, 83%]. Mean (SD) Hb during evaluation was 11.71 (0.92) g dL(-1). Eighty-five per cent of 129 subjects who completed the study (95% CI: 78%, 91%) had Hb > or =11.0 g dL(-1) during evaluation. The dose of darbepoetin alfa over the study period was median (95% CI) 124.4 mug (106.2, 140.0). Darbepoetin alpha administered QM was well tolerated in study subjects.. Darbepoetin alpha administered QM maintained Hb in study subjects with CKD not receiving dialysis.

Topics: Administration, Oral; Aged; Anemia; Chronic Disease; Colony-Stimulating Factors; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Injections, Intravenous; Iron; Kidney Diseases; Male; Middle Aged; Treatment Outcome

Anaemia is frequently found in patients with chronic heart failure (CHF) and has been associated with an increase in mortality and morbidity, impaired cardiac and renal function and a reduced quality of life (QoL) compared with non-anaemic CHF patients. Correction of anaemia with recombinant human erythropoietin (epoetin) has been associated with an improvement in CHF in both controlled and uncontrolled studies. The present study describes our findings in a series of 78 consecutive patients with symptomatic CHF and anaemia (haemoglobin (Hb) level <12.0 g/dl) treated with epoetin beta and, if necessary, intravenous iron sucrose. Over a mean observation period of 20.7 +/- 12.1 months, mean Hb levels increased from 10.2 +/- 1.1 to 13.5 +/- 1.2 g/dl, p < 0.01. New York Heart Association (NYHA) functional class, left ventricular ejection fraction (LVEF) were significantly improved and the number of hospitalizations was significantly reduced with the period before treatment (all p < 0.01). Serum creatinine and creatinine clearance (CCr) were 2.2 +/- 0.9 mg/dl and 32.5 +/- 26.5 ml/min, respectively, at baseline, and remained stable over the observation period. Interestingly, >90% of the patients had concomitant mild-to-moderate chronic kidney disease at baseline and study end (CKD), as defined by the accepted diagnostic criterion of a CCr <60 ml/min.. The correction of the anaemia with epoetin beta together with initial intravenous iron supplementation, resulted in significant improvements in NYHA class and cardiac function, and a reduction in hospitalization rate. Moreover, renal function was maintained stable in most patients.

Topics: Aged; Aged, 80 and over; Anemia; Case-Control Studies; Chronic Disease; Erythropoietin; Female; Heart Failure; Hospitalization; Humans; Kidney Diseases; Male; Recombinant Proteins

Despite an increase in the use and average dose of recombinant human EPO (rh-EPO) over the last 15 years, a substantial percentage of patients still do not achieve hemoglobin targets recommended by international guidelines. The definition of rh-EPO resistance has been introduced to identify those patients in whom the target hemoglobin level is not attained despite a greater-than-usual dose of erythropoietin-stimulating agent (ESA). In recent years, increasing attention has been paid to the relationship between dialysis, increased inflammatory stimulus, malnutrition, and ESA response. About 35% to 65% of hemodialysis patients show signs of inflammation that could be a cause of anemia through the suppression of bone marrow erythropoiesis by a number of cytokines. A large proportion of chronic kidney disease patients also have protein-energy malnutrition and wasting; low serum albumin levels, together with other more specific nutritional markers, are predictors of rh-EPO response. A diminished nutritional state could then be a feature of patients who are resistant to ESA treatment, with malnutrition probably being a consequence of a chronic inflammatory state. Starting from the hypothesis that anemia, partially attributable to a reduced response to ESA, could be the link among malnutrition, inflammation, and the poor outcome of chronic kidney disease patients, we designed a multicenter observational study, the Malnutrition-Inflammation-Resistance-Treatment Outcome Study (MIRTOS), aimed at evaluating the impact and possible causes of resistance to ESA in a large sample of hemodialysis patients. We hope the results of MIRTOS will represent a step forward toward a better understanding of the factors influencing the response to ESA in hemodialysis patients.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Drug Resistance; Epoetin Alfa; Erythropoietin; Hemoglobins; Humans; Inflammation; Kidney Diseases; Kidney Failure, Chronic; Malnutrition; Protein-Energy Malnutrition; Recombinant Proteins; Renal Dialysis

Patients with chronic kidney disease (CKD) stages 2-5 are known to suffer numerous complications and co-morbidities associated with kidney disease. The medication prescription patterns in this population are not well understood. We report on prescription data collected as part of a multicentre longitudinal study in patients with CKD, with a focus on medications with cardiovascular or cardioprotective effects.. Patients were recruited from four academic nephrology centres in the USA, with patient recruitment from June 2000 to March 2002. Medication data were captured at the time of first enrollment into the study. Individual medications were classified into medication groups, and those with predominant cardioprotective effects or for prevention of progression of kidney disease (e.g. medications for treatment of anaemia, lipid-lowering agents, antihypertensives, statins, etc.) were recorded for analysis. Descriptive statistics were used for medication prescription according to baseline demographics and co-morbidities. Predictors of epoetin and iron use were determined by logistic regression adjusting for age, race, sex, diabetes, glomerular filtration rate (GFR), haemoglobin and serum albumin.. Medication data were available for 619 patients with stages 2-5 CKD. Patients were 60.6+/-16.0 years of age, and were prescribed 8+/-4 (range 1-28) medications. Overall, the proportion of patients prescribed different classes of medications included epoetin (20%), intravenous iron (13%), HMG-CoA reductase inhibitors (16%), angiotensin-converting enzyme (ACE) inhibitors (44%), angiotensin receptor blockers (13%), beta-blockers (46%), calcium channel blockers (52%) and aspirin (37%). There was a low use of epoetin (45%) and iron (20%) in patients with anaemia. Only 24% of patients with coronary artery disease were prescribed statins, and ACE inhibitors and angiotensin receptor blockers were used in only 58 and 23% of diabetic patients with proteinuria. Positive predictors of epoetin and iron therapy included white race and diabetes. Higher GFR and higher serum albumin were associated with lower odds of being prescribed epoetin. White race and diabetics were more likely to be prescribed iron.. This study provides an overview of prescription practices in a cohort of CKD patients. Substantial underutilization of certain classes of cardioprotective medications is apparent, and systematic educational efforts in this direction may well prove worthwhile to impact outcomes.

Topics: Aged; Cardiovascular Diseases; Chronic Disease; Drug Utilization; Epoetin Alfa; Erythropoietin; Glomerular Filtration Rate; Hematinics; Humans; Kidney Diseases; Logistic Models; Middle Aged; Recombinant Proteins

Health-related quality of life (QOL) is an important measure of how disease affects patients' lives. Dialysis patients have decreased QOL relative to healthy controls. Little is known about QOL in patients with chronic kidney disease (CKD) before renal replacement therapy.. The Medical Outcomes Study Short Form-36 (SF-36), a standard QOL instrument, was used to evaluate 634 patients (mean glomerular filtration rate [GFR], 23.6 +/- 9.6 mL/min/1.73 m2 [0.39 +/- 0.16 mL/s/1.73 m2]) enrolled in a 4-center, prospective, observational study of CKD. SF-36 scores in these patients were compared with those in a prevalent cohort of hemodialysis (HD) patients and healthy controls (both from historical data). QOL data also were analyzed for correlations with GFR and albumin and hemoglobin levels in multivariable analyses.. Patients with CKD had higher SF-36 scores than a large cohort of HD patients (P < 0.0001 for 8 scales and 2 summary scales), but lower scores than those reported for the US adult population (P < 0.0001 for 7 of 8 scales and 1 of 2 summary scales). Patients with CKD stage 4 had lower QOL scores than patients with CKD stage 5, although differences were not significant. Hemoglobin level was associated positively with higher mental and physical QOL scores (P < 0.05) in all individual and component scales except Pain.. SF-36 scores were higher in this CKD cohort compared with HD patients, but lower than in healthy controls. GFR was not significantly associated with QOL. Hemoglobin level predicted both physical and mental domains of the SF-36. Longitudinal studies are needed to define at-risk periods for decreases in QOL during progression of CKD.

Topics: Aged; Anemia; Black or African American; Cardiovascular Diseases; Cohort Studies; Comorbidity; Cross-Sectional Studies; Diabetes Complications; Erythropoietin; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Obesity; Prospective Studies; Quality of Life; Renal Dialysis; Serum Albumin; Socioeconomic Factors; Surveys and Questionnaires; United States; White People

Patients with chronic kidney disease (CKD) have a high burden of mortality and cardiovascular morbidity. Additional strategies to modulate cardiovascular risk in this population are needed. Data suggest that anemia is a potent and potentially modifiable risk factor for cardiovascular disease in patients with CKD, but these data remain unsubstantiated by any randomized controlled trial (RCT). Furthermore, the clinical practice guidelines for anemia management in patients with CKD are based on limited data. The need for new RCTs to address critical knowledge deficits, particularly with regard to the impact of anemia therapy on cardiovascular disease and survival, is recognized within the guidelines and independent comprehensive reviews of the existing published trial data.. The Trial to Reduce Cardiovascular Events with Aranesp (Amgen Inc, Thousand Oaks, Calif) (darbepoetin alfa) Therapy (TREAT) is a 4000-patient, multicenter, double-blind RCT, designed to determine the impact of anemia therapy with darbepoetin alfa on mortality and nonfatal cardiovascular events in patients with CKD and type 2 diabetes mellitus. Subjects will be randomized in a 1:1 manner to either darbepoetin alfa therapy to a target hemoglobin (Hb) of 13 g/dL or control, consisting of placebo for Hb > or =9 g/dL or darbepoetin alfa for Hb <9 g/dL until Hb is again Hb > or =9 g/dL. TREAT is event-driven and has a composite primary end point comprising time to mortality and nonfatal cardiovascular events, including myocardial infarction, myocardial ischemia, stroke, and heart failure. TREAT will provide data that are critical to evolution of the management of cardiovascular risk in this high-risk population.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Darbepoetin alfa; Diabetes Mellitus, Type 2; Double-Blind Method; Erythropoietin; Humans; Kidney Diseases; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Research Design; Risk Assessment; Risk Reduction Behavior

Since its introduction in 1988, recombinant human erythropoietin (epoetin) has been standard treatment for patients with anemia due to chronic kidney disease. From 1998 to 2004, nearly 200 epoetin-treated persons with chronic kidney disease developed antibodies to epoetin, resulting in pure red cell aplasia (PRCA). The majority of these patients received Eprex, an epoetin alfa product marketed exclusively outside the United States. Herein, we report on the long-term outcome of these individuals. For 170 chronic kidney disease patients who developed epoetin-associated PRCA and had 3 months or more follow-up information available, case reports from the Food and Drug Administration and epoetin manufacturers were reviewed for information on clinical characteristics of the patients, immunosuppressive treatments, epoetin responsiveness, and hematologic recovery. Overall, 64% of the PRCA patients received immunosuppressive therapy, including 19 who also underwent a renal transplantation. Thirty-seven percent experienced a hematologic recovery, with higher hematologic recovery rates among PRCA patients who received immunosuppressive therapy (57% vs 2%, P < .001). Among 34 patients who received epoetin after the onset of PRCA, 56% regained epoetin responsiveness. The highest rates of epoetin responsiveness were observed among persons whose antierythropoietin antibodies were undetectable when epoetin was administered (89%). Among chronic kidney disease patients with epoetin-associated PRCA, epoetin discontinuation and immunosuppressive therapy or renal transplantation is necessary for hematologic recovery. Reinitiation of epoetin therapy among individuals could be considered if antierythropoietin antibodies are undetectable.

Topics: Autoantibodies; Chronic Disease; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hematinics; Humans; Immunosuppression Therapy; Kidney Diseases; Kidney Transplantation; Male; Recombinant Proteins; Red-Cell Aplasia, Pure; Retrospective Studies; Treatment Outcome; United States; United States Food and Drug Administration

Erythropoiesis-stimulating proteins, such as erythropoietin alfa and darbepoetin alfa, have positively impacted anemia management. These medications improve patient outcomes and quality of life. Their costs, however, remain a major barrier for health systems.. To evaluate the development, implementation, and cost-effectiveness of an inpatient therapeutic interchange protocol for erythropoiesis-stimulating proteins at a large, tertiary care, university-affiliated health system.. Virginia Commonwealth University Health System (VCUHS) developed and implemented a therapeutic interchange program to convert therapy for all inpatients undergoing dialysis from erythropoietin alfa to darbepoetin alfa for treatment of chronic kidney disease-related anemia. An evaluation of the economic impact of this program on drug expenditures over a fiscal quarter (2003) was conducted using historical comparator data (2002).. Preliminary evaluation of the program demonstrated cost-savings and reduced drug utilization of erythropoiesis-stimulating proteins in hospitalized dialysis patients. For the first quarter of 2003 compared with the first quarter of 2002, VCUHS realized a cost-savings of nearly 10,000 US dollars, which was related to the program's aggressive screening procedure. When these data were normalized for equal numbers of patients in each group receiving one of the drugs, the actual cost-savings was over 2000 US dollars. These cost-savings are largely due to reduced utilization of these expensive biotechnology products with implementation of a dosing protocol.. VCUHS has successfully developed and implemented a darbepoetin alfa therapeutic interchange protocol for hospitalized dialysis patients. This has translated into reduced use of erythropoiesis-stimulating proteins, resulting in cost-savings for the health system.

Topics: Anemia; Chronic Disease; Clinical Protocols; Costs and Cost Analysis; Darbepoetin alfa; Drug Administration Schedule; Drug Utilization Review; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Hospitals, University; Humans; Injections, Intravenous; Kidney Diseases; Length of Stay; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Therapeutic Equivalency; Virginia

Topics: Anemia; Bias; Biomarkers; Chronic Disease; Epoetin Alfa; Erythropoietin; Goals; Hemoglobins; Humans; Hypertrophy, Left Ventricular; Kidney Diseases; Randomized Controlled Trials as Topic; Recombinant Proteins; Reference Values; Research Design; Treatment Outcome

The BEACH program, a continuous national study of general practice activity in Australia, gives us an overview of consultations involving the management of renal problems. In this analysis, we have included renal failure, glomerulonephritis/nephrosis (all forms of nephritis and nephrotic syndrome), renal insufficiency, nephropathy (including diabetic and analgesic), and uraemia and nephrosclerosis grouped as 'other'. This synopsis provides a backdrop against which articles in this issue of Australian Family Physician can be further considered.

Topics: Adult; Age Distribution; Aged; Antacids; Australia; Calcium Carbonate; Diuretics; Erythropoietin; Family Practice; Female; Furosemide; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Referral and Consultation; Sex Distribution; Ultrasonography

The cost of darbepoetin alfa versus that of epoetin alfa in a hospital setting was studied.. The study was an observational, retrospective review of the hospitalwide use of darbepoetin and epoetin during hospital admissions beginning in the period from January 2003 through April 2003. After the identification from daily charge reports of patients who used at least one of the study drugs during an admission, charts were requested for review. Drug product costs were determined from hospital purchasing information. Material and labor costs were combined to estimate drug administration costs. Total costs were calculated as the sum of drug product costs and administration costs.. A total of 429 epoetin records and 80 darbepoetin records were included. The two cohorts were similar with respect to demographic characteristics. With respect to costs, the only significant difference between cohorts was in daily administration costs, which were lower for patients receiving darbepoetin. Sensitivity analysis found lower costs for darbepoetin only after the dose-conversion ratio (DCR) was increased to above 256.74 units:1 microg. The overall DCR based on the median daily dose of each drug was 244.90 units:1 microg.. A cost-minimization study in a hospital showed no cost difference between treatment with epoetin and darbepoetin.

Topics: Anemia; Darbepoetin alfa; Drug Costs; Epoetin Alfa; Erythropoietin; Hemoglobins; Hospital Costs; Hospitals; Humans; Kidney Diseases; Length of Stay; Neoplasms; Recombinant Proteins

Topics: Acute Disease; Coronary Artery Disease; Erythropoietin; Humans; Insulin-Like Growth Factor I; Kidney Diseases; Myocardial Infarction; Myocardial Ischemia; Syndrome

The National Kidney Foundation has developed guidelines for the diagnosis and classification of chronic kidney disease (CKD) but it is not known whether these are applicable to renal transplant recipients. This study determined the prevalence of CKD according to the stages defined in the guidelines, the complications related to CKD and whether the prevalence of complications was related to CKD stage in 459 renal transplant recipients. CKD was present in 412 patients (90%) and 60% were in CKD Stage 3 with a glomerular filtration rate (GFR) between 30 and 59 mL/min/1.73 m2. The prevalence of anemia increased from 0% in Stage 1 to 33% in Stage 5 (p<0.001). Hypertension was present in 86% and increased from 60% in Stage 1 to 100% in Stage 5 (p=0.02). The number of anti-hypertensives per patient increased from 0.7 in Stage 1 to 2.3 in Stage 5 (p<0.001). The number of CKD complications per patient increased from 1.1 in Stage 1 to 2.7 in Stage 5 (p<0.001). We conclude that CKD and the complications of CKD are highly prevalent in renal transplant recipients. The classification of renal transplant patients by CKD stage may help clinicians identify patients at increased risk and target appropriate therapy to improve outcomes.

Topics: Blood Pressure; Chronic Disease; Creatinine; Cross-Sectional Studies; Erythropoietin; Ferritins; Glomerular Filtration Rate; Hemoglobins; Humans; Hypocalcemia; Kidney Diseases; Kidney Transplantation; Ontario; Postoperative Complications; Prevalence; Renal Replacement Therapy; Retrospective Studies; Transferrin

Erythropoietin (EPO) is upregulated by hypoxia and causes proliferation and differentiation of erythroid progenitors in the bone marrow through inhibition of apoptosis. EPO receptors are expressed in many tissues, including the kidney. Here it is shown that a single systemic administration of EPO either preischemia or just before reperfusion prevents ischemia-reperfusion injury in the rat kidney. Specifically, EPO (300 U/kg) reduced glomerular dysfunction and tubular injury (biochemical and histologic assessment) and prevented caspase-3, -8, and -9 activation in vivo and reduced apoptotic cell death. In human (HK-2) proximal tubule epithelial cells, EPO attenuated cell death in response to oxidative stress and serum starvation. EPO reduced DNA fragmentation and prevented caspase-3 activation, with upregulation of Bcl-X(L) and XIAP. The antiapoptotic effects of EPO were dependent on JAK2 signaling and the phosphorylation of Akt by phosphatidylinositol 3-kinase. These findings may have major implications in the treatment of acute renal tubular damage.

Topics: Animals; Apoptosis; Blood Proteins; Caspase 3; Caspase Inhibitors; Caspases; Cell Line, Transformed; Creatinine; Disease Models, Animal; Erythropoietin; Humans; Kidney Diseases; Kidney Tubules; Male; Oxidative Stress; Phosphorylation; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Reperfusion Injury

Erythropoietin (EPO) is the principal factor regulating red blood cell production in humans. It has been shown that EPO gradually decreases with the progression of diabetic nephropathy and may be used as a marker of severity of disease. In vitro studies have shown that interleukin-10 (IL-10) acts synergistically with EPO to increase stimulation of erythroid differentiation and proliferation. We evaluate serum levels of EPO and IL-10 in children with reflux nephropathy (RN).. Serum level of EPO and IL-10 were measured in 32 girls and 22 boys with RN, and in 22 boys and 10 girls who served as healthy controls. Renal scarring was evaluated with Technetium dimercapto-succinic acid scan. RN was severe (less than 20% uptake) in 16 children, moderate (20% to 40% uptake) in 25 and mild RN (greater than 40% uptake) in 13. Because anemia may further stimulate EPO production we also compared the index Hb (hemoglobin) x EPO in all patients. IL-10 and EPO were measured with standard enzyme-linked immunosorbent assay technique. The unpaired t test was used for statistical analysis.. There were no statistically significant differences in the serum levels of EPO in children with RN (6.11 +/- 0.51 mIU/ml) compared to controls (6.42 +/- 0.46 mIU/ml) (p >0.5). Similarly the index Hb x EPO was 75.25 +/- 5.65 in children with RN compared to 73.76 +/- 5.48 in controls. Mean EPO levels were similar for mild, moderate and severe RN. There was no difference in the serum levels of IL-10 in children with RN (23.14 +/- 2.32 pg/ml) compared to controls (22.67 +/- 4.13 pg/ml) (p >0.5).. Although EPO has been reported to be a marker of progressive renal disease in diabetic nephropathy, our data indicate that serum levels of EPO do not reflect the severity of renal parenchymal damage in children with RN.

Topics: Child; Erythropoietin; Female; Humans; Kidney Diseases; Male; Severity of Illness Index; Vesico-Ureteral Reflux

Darbepoetin alfa, a novel erythropoiesis-stimulating protein, is a glycosylation analog of recombinant human erythropoietin (rHuEPO) with two additional N-linked carbohydrates. Used to treat anemia of cancer, chemotherapy, and kidney disease, it has a three-fold longer serum half-life and increased in vivo activity, but decreased receptor-binding activity. Glycosylation analogs with altered N-linked carbohydrate content were compared with rHuEPO to elucidate the relationship between carbohydrate content and activity.. EPO glycosylation analogs and rHuEPO were expressed and, in some cases, purified from Chinese hamster ovary cells and carbohydrate characterized by Western blotting. Assays were performed to compare in vitro receptor binding and in vivo activity of rHuEPO, darbepoetin alfa, and analogs.. Reduced receptor binding of darbepoetin alfa could be accounted for entirely by increased sialic acid content and not by carbohydrate-related stearic hindrance or by amino acid differences. Shapes of dose-response curves, maximal responses in proliferation and colony assays, and magnitude and duration of downstream signaling events were comparable in vitro for rHuEPO and darbepoetin alfa. The in vivo response correlated with the number of N-linked carbohydrates. The number of carbohydrates was a more significant determinant for in vivo activity than position. The differences in in vivo erythropoietic activity among glycosylation analogs were more evident with increased time following administration in exhypoxic polycythemic mice.. Carbohydrate increases persistence of EPO, resulting in a prolonged and increased biological response in vivo, and overcoming reduced receptor-binding activity.

Topics: Anemia; Animals; Carbohydrate Metabolism; Carbohydrates; Cell Proliferation; CHO Cells; Colony-Forming Units Assay; Cricetinae; Darbepoetin alfa; Dose-Response Relationship, Drug; Erythropoietin; Female; Gene Expression; Glycosylation; Half-Life; Hematopoietic Stem Cells; Humans; Kidney Diseases; Mice; Neoplasms; Polycythemia; Protein Binding; Protein Processing, Post-Translational; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction

The Predialysis Survey on Anemia Management was designed to assess the care given to predialysis patients within 3 months of the start of hemodialysis or peritoneal dialysis (PD) therapy. In this presentation, we focus on demographic data and patient referral practices of patients who enter kidney centers.. We conducted a retrospective chart review of patients who had started hemodialysis or PD therapy between August 1999 and April 2000. All patients (age, 16 to 99 years) who entered 1 of the 779 centers in 21 European countries, Israel, or South Africa were included, except those for whom dialysis therapy was only started during an acute episode. Demographic characteristics, referral to kidney centers, comorbidities, drug treatments, major clinical events, and use of epoetin were documented.. Mean creatinine clearance rate at the first visit to the kidney center was 18.2 mL/min (0.303 mL/s). Of all patients, greater than 35% had a creatinine clearance less than 10.0 mL/min (<0.167 mL/s) at their first visit. Overall, 87% of patients were initiated on hemodialysis therapy, and 13% were started on PD therapy. PD was used more often the longer a patient was under the care of a nephrologist. Of 4,333 new dialysis patients, 68% had a hemoglobin concentration of 11.0 g/dL or less (< or =110 g/L) at the first visit.. The majority of patients in the survey had been under the care of a nephrologist for more than 12 months before the start of dialysis therapy. Nevertheless, most of these patients were anemic, and only a minority were on epoetin treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Chronic Disease; Epoetin Alfa; Erythropoietin; European Union; Female; Health Care Surveys; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Peritoneal Dialysis; Practice Guidelines as Topic; Recombinant Proteins; Referral and Consultation; Renal Dialysis; Retrospective Studies

Topics: Clinical Trials as Topic; Confounding Factors, Epidemiologic; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Hematocrit; Humans; Kidney Diseases; Recombinant Proteins; Selection Bias

Topics: Anemia; Chronic Disease; Contraindications; Darbepoetin alfa; Erythropoietin; Humans; Kidney Diseases

Topics: Anemia; Autoimmune Diseases; Clinical Trials as Topic; Doping in Sports; Erythropoietin; Humans; Kidney Diseases; Myelodysplastic Syndromes; Neoplasms; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome; Uremia

Patients undergoing chronic hemodialysis have an increased risk of acquiring hepatitis B infection. Only 43-66% of dialysis patients develop effective anti-HBs titers after vaccination.. To evaluate the effect of recombinant erythropoietin (rEPO) therapy and basal hemoglobin levels on the outcome of the immune response to four doses of IM 40 microg Engerix-B vaccination in hemodialysis and chronic kidney disease (CKD) patients before starting replacement therapy.. One hundred and three patients were included in the study: 34 hemodialysis patients treated with rEPO (Group A), 36 predialytic patients who did not treated with rEPO (Group B) and 33 predialytic patients treated with rEPO (Group C). Plasma creatinine in predialytic patients was 2-7 mg/dL. All patients' HBsAg and anti-HBs antibodies were negative. Patients were immunized with IM 40 microg Engerix-B at 0, 1, 3, and 6 months. Anti-HBs titers were measured at 7th month.. Eighty seven point one percent of patients from group C developed protective anti-HBs titers compared with 69.4% from group B and 44.1% from group A (p = 0.001). Patients from all groups with baseline hemoglobin levels above 11 gr/dL developed protective anti-HBs titers significantly more than patients with baseline hemoglobin levels below 11 gr/dL (p < 0.05).. Predialytic patients treated with rEPO and with hemoglobin levels higher than 11 gr/dL had significantly better immune response outcomes to Engerix-B vaccination. Immunization against hepatitis B infection should be considered at early stages of CKD prior to the deterioration in kidney functions and the development of renal anemia.

Topics: Aged; Chronic Disease; Complement Hemolytic Activity Assay; Erythropoietin; Female; Hemoglobins; Hepatitis B Vaccines; Hepatitis C Antibodies; Humans; Immunity; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Statistics as Topic; Treatment Outcome; Vaccination; Vaccines, Synthetic

Improving the ability of the kidney to tolerate ischemic injury has important implications. We investigated the effect of recombinant human erythropoietin (rHuEPO) treatment on subsequent ischemia/reperfusion (I/R) injury and evaluated the role of heat shock protein (HSP) 70 in rHuEPO-induced renal protection. rHuEPO (3000 U/kg) was administered 24 h before I/R injury, and rats were killed at 24, 48, and 72 h after I/R injury. Pretreatment of rHuEPO resulted in the following: i) decreased serum creatinine level; ii) decreased tubular cell apoptosis and necrosis, measured by DNA fragmentation analysis and TUNEL staining and histomorphological criteria; iii) decreased tubular cell proliferation as determined by proliferating cell nuclear antigen expression; iv) increased bcl-2 protein and decreased caspase 3 activity; and v) decreased JNK expression. rHuEPO treatment increased HSP70 expression in a dose-dependent manner in normal rat kidneys, and inhibition of HSP70 expression by quercetin eliminated the renoprotective effect of rHuEPO in ischemic kidneys. Our study demonstrates that rHuEPO has a protective effect on subsequent I/R injury and that this effect is associated with induction of HSP70. Our study provides a new avenue for therapy to prevent renal damage after I/R injury.

Topics: Animals; Apoptosis; Erythropoietin; HSP70 Heat-Shock Proteins; Ischemic Preconditioning; Kidney; Kidney Diseases; Mitogen-Activated Protein Kinases; Models, Biological; Rats; Recombinant Proteins; Reperfusion Injury; Signal Transduction

To study iron metabolism in patients on programmed hemodialysis (PH) in oral and intravenous administration of iron drugs; to compare clinical and financial results of using such drugs.. A two-stage trial studied iron metabolism in 158 PH patients on replacement therapy with erythropoetin. They received correction of iron deficiency with oral drugs (stage I) and venofer (stage II).. The study of iron metabolism has found its deficiency in 2/3 patients receiving oral iron: absolute (48%) and relative (20%). Administration of venofer led to a 2-fold increase in the number of patients with normal iron metabolism. The target Hb and Ht were achieved in 2.5 times more patients than before venofer treatment. The dose of erythpoetin in such cases was reduced by 40%. Side effects were not observed. The week cost of venofer treatment per patient was lower by 22.5$ than the cost of treatment with oral iron drugs.. Venofer correction of iron deficiency in PH patients is more effective both clinically and financially than use of oral iron preparations.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anemia, Iron-Deficiency; Drug Costs; Erythropoietin; Female; Ferric Compounds; Ferric Oxide, Saccharated; Glucaric Acid; Hemoglobins; Humans; Injections, Intravenous; Kidney Diseases; Male; Middle Aged; Renal Dialysis; Sucrose; Treatment Outcome

Cardiovascular disease is a leading cause of death among kidney transplant recipients. Anemia, a risk factor for cardiovascular complications among patients with chronic kidney disease, has not been well characterized in kidney transplant recipients. We performed a retrospective cohort study of the prevalence of and factors associated with anemia among 240 patients who underwent kidney transplantation at our institution. The mean hematocrit (Hct) rose from 33% at 1 month after transplantation to 40% at 12 months after transplantation. The proportion of patients with Hct < 36% was 76% at transplantation and 21% and 36%, 1 year and 4 years after transplantation, respectively. Six months after transplantation, women had higher likelihood (OR = 3.61) of Hct < 36%, while higher Hct at 3 months (OR = 0.67 for 1% higher Hct) and diabetes (OR = 0.14) were associated with a lower likelihood of Hct < 36%. Similar associations were seen 12 months after transplantation. Even among patients with Hct < 30%, only 36% had iron studies, 46% received iron supplementation and 40% received recombinant human erythropoietin. Awareness of factors associated with a lower Hct may prompt better anemia screening and management, potentially improving cardiovascular outcomes among kidney transplant recipients.

Topics: Adolescent; Adult; Anemia; Cohort Studies; Erythropoietin; Female; Glomerular Filtration Rate; Hematocrit; Humans; Iron; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Retrospective Studies; Sex Factors; Time Factors

The introduction of recombinant erythropoietin (rHu-EPO) has been shown to reverse anemia of chronic renal failure and was able to almost completely obviate the need for repeated blood transfusions (BT), the most potent cause of allostimulation in renal transplant candidates. The series describes single center experience of the pretransplant BT and rHu-EPO therapy effects on late outcomes of cadaveric renal transplantation.. We retrospectively analyzed data of 502 adult recipients of primary renal allograft between 1990-1997 whose graft survived > 6 months. In the study group 51 patients were treated prior to transplantation with de novo rHu-EPO therapy, 207 patients received BT, 184 patients were switched from BT to rHu-EPO therapy, and 60 patients did not require treatment. The groups were compared in respect to pretransplant % PRA, frequency of acute rejections and graft survival.. At one-year graft survival was similar between groups, however at five years recipients of de novo rHu-EPO and those who have converted from BT to rHu-EPO experienced only 7% graft loss, as compared to 22% of patients treated with BT, and 18% of patients who did not require treatment, p < 0.001. The pretransplant therapy with rHu-EPO was associated with decreased frequency of late episodes of rejection from 0.42 to 0.27, p = 0.03. There were no differences between groups in the number of highly sensitized (PRA > 20%) at the time of transplantation.. The use of rHu-EPO as de novo therapy or conversion from BT treatment to rHu-EPO prior to transplantation was associated with a decline in late posttransplant alloreactivity and improved late renal graft survival.

Topics: Adult; Blood Transfusion; Erythropoietin; Female; Humans; Kidney Diseases; Kidney Transplantation; Major Histocompatibility Complex; Male; Preoperative Care; Recombinant Proteins; Regression Analysis; Reoperation; Retrospective Studies; Treatment Outcome

Recent American and European guidelines recommend that epoetin therapy should be considered whenever the blood haemoglobin (Hb) level is <10-11 g/dl in dialysis patients and in pre-dialysis patients. Thus, data on the current prevalence of anaemia with respect to the degree of chronic renal insufficiency are needed in order to determine the potential indications of epoetin therapy in the pre-dialysis period.. We prospectively studied 403 consecutive ambulatory pre-dialysis patients whose serum creatinine (Scr) was 200 micro mol/l or more at their first passage at our out-patient clinic between January 1 and June 30, 1999. Hb and Scr values were determined at each visit until June 30, 2000, or until the start of maintenance dialysis. Patients had a clinical and laboratory evaluation every 2-3 months, and monthly when treated with epoetin.. The mean (+/-SD) age of patients was 60.9+/-17.2 years at presentation. The Hb level was <11 g/dl in 62% of patients with Scr > or =400 micro mol/l, and in 58% of patients with an estimated creatinine clearance (Ccr) <20 ml/min/1.73 m(2). The proportion of anaemic patients was higher for any given Ccr value in females than in males. A total of 136 patients were treated with epoetin during the observation period. At the start of epoetin, their mean Hb value was 9.5+/-0.6 g/dl and Ccr level 13.9+/-4.9 ml/min/1.73 m(2). Among the 123 patients who began maintenance dialysis therapy during the observation period, 85 (or 69%) received epoetin therapy before the start of dialysis. Their mean Hb value at the start of dialysis was 10.8+/-1 g/dl compared with 10.5+/-1.1 g/dl in the 41 dialysed patients who did not require epoetin therapy during the pre-dialysis period.. Based on the data gained in a large cohort of patients receiving regular pre-dialysis nephrological care, the proportion of subjects with a Hb level <11 g/dl may be estimated at approximately 60% when the Ccr is <20 ml/min/1.73 m(2). If the Hb level is to be maintained at no less than 11 g/dl, at least two-thirds of patients at this advanced stage of chronic renal failure should require pre-dialysis epoetin therapy.

Topics: Anemia; Creatinine; Cross-Sectional Studies; Epoetin Alfa; Erythropoietin; Female; France; Hemoglobins; Humans; Incidence; Kidney Diseases; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Regression Analysis; Renal Replacement Therapy; Sex Characteristics; Uremia; White People

The 35th Annual Meeting of the American Society of Nephrology, held in Philadelphia, Pennsylvania, United States (October 30 to November 4, 2002) presented the newest advances in basic and clinical nephrology science. Several presentations and symposia discussed the effects of various interventions and risk factors in clinical outcomes in dialysis patients. The recent evidences of pure red cell aplasia secondary to neutralizing antibodies against erythropoietin were also extensively discussed in a special symposium. Recent advances in the management of calcium phosphorus metabolism and secondary hyperparathyroidism, such as the clinical efficacy and safety of AMG-073, a new calcimimetic agent in the control of hyperparathyroidism in chronic kidney disease patients, or the use of sevelamer or lanthanum carbonate as phosphate binders, were presented. The results in animal models on improved sparing of renal function with rapamycin versus cyclosporin A represent a promising advance in renal transplantation. Finally, the recent discoveries with the newly identified disease gene PKHD1, which causes autosomal recessive polycystic kidney disease, were also presented at the meeting.

Topics: Anemia; Calcium; Chelating Agents; Erythropoietin; Humans; Kidney Diseases; Kidney Transplantation; Nephrology; Phosphorus; Recombinant Proteins; Renal Dialysis

Topics: Anemia, Iron-Deficiency; Ascorbic Acid; Bacteremia; Chronic Disease; Drug Hypersensitivity; Erythropoietin; Ferritins; Humans; Injections, Intravenous; Iron; Kidney Diseases; Predictive Value of Tests; Recombinant Proteins; Renal Dialysis

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Humans; Kidney Diseases

Topics: Anemia; Combined Modality Therapy; Epoetin Alfa; Erythropoietin; Female; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Peritoneal Dialysis; Recombinant Proteins; Renal Dialysis

Chronic hepatitis C virus (HCV) infection is quite prevalent in long-term hemodialysis (HD) patients. Patients who are candidates for renal transplantation might be treated, before grafting, with interferon-alpha (IFN-alpha). Among 39 HCV-positive long-term HD patients treated with IFN-alpha, we observed three cases of reversible posterior leukoencephalopathy syndrome (PLES). PLES included headaches in three patients, confusion in three patients, cortical blindness in two patients, visual hallucinations in one patient, seizures in three patients, and respiratory distress in one patient in a context of fluid overload and severe hypertension in all cases. The three patients were receiving IFN-alpha and recombinant erythropoietin therapies simultaneously for de novo anemia. Contrast-enhanced computed tomography scan or magnetic resonance imaging showed low-density areas in the occipital lobes (in three patients), frontal lobes (in one patient), and temporal lobes (in one patient). After withdrawal of IFN-alpha and recombinant erythropoietin therapies, hemodiafiltration, and symptomatic treatment of seizures and hypertension, PLES was reversible within 1 week in one patient, 10 days in one patient, and 2 months in the third patient. Our case reports show the occurrence of reversible PLES in HCV-positive long-term HD patients treated with IFN-alpha. Physicians caring for HCV-positive long-term HD patients treated with IFN-alpha need to be particularly cautious when these patients receive simultaneously recombinant erythropoietin and when IFN-alpha therapy induces a weight loss, which indicates a reduction in dry weight.

Topics: Adult; Anemia; Brain Diseases; Comorbidity; Erythropoietin; Hepatitis C; Humans; Hypertension; Interleukin-1; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Syndrome

Topics: Aldosterone; Anemia, Sickle Cell; beta-Thalassemia; Erythropoietin; Humans; Kidney Diseases; Kidney Function Tests; Kidney Glomerulus; Kidney Tubules, Proximal; Proteinuria

The observation that antiplatelet therapy may decrease the incidence of Epo-induced hypertension in dialysis patients remains a subject of particular interest. The aim of the present study was to test this hypothesis in patients at the predialysis stage. Predialysis patients with renal anemia were treated with EPO (6000 IU/week) for 6-12 months. Patients were divided into two groups, one of which received antiplatelet therapy and the other did not, and a comparison was made between them with respect to the incidence of EPO-induced hypertension. Logistic regression analysis was used to determine the risk factors for developing hypertension during the EPO therapy. Such predictors included age, gender, antecedent of hypertension, antiplatelet drugs and diabetes mellitus. Overall, 66 patients were enrolled in the study and 18 developed hypertension (27%). Out of the 35 patients not receiving antiplatelet therapy, 15 developed hypertension (43%). In contrast, out of the 31 patients receiving antiplatelet therapy, only 3 (10%) developed hypertension (p=0.003 by Chi square test). Multiple regression analysis showed that the best predictive variables for the development of hypertension were antecedent of hypertension (odds ratio: 0.064, p=0.0118), and use of antiplatelet drugs (odds ratio: 5.081, p=0.0295). The present data provide evidence that antiplatelet therapy may prevent EPO-induced hypertension in predialysis patients. However, the mechanism to explain such an effect still remains to be elucidated.

Topics: Adult; Aged; Anemia; Dilazep; Dipyridamole; Erythropoietin; Female; Hematocrit; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Platelet Aggregation Inhibitors; Recombinant Proteins; Renal Dialysis; Risk Factors

Intravenous iron supplementation is often necessary in recombinant human erythropoietin (r-HuEPO)-treated haemodialysis (HD) patients, but rarely in r-HuEPO-treated peritoneal dialysis (PD) patients. This may be due to differences in iron absorption or blood loss.. Iron absorption (whole-body counting after ingestion of a radiolabelled iron test dose) and iron metabolism were compared in eight iron-replete rHuEPO-treated PD patients (serum ferritin 100-500 microg/l) and 68 healthy iron-replete controls (sufficient iron in bone marrow specimen).. Mucosal uptake (13.4+/-9.8%), mucosal transfer (0.34+/-0.18) and iron retention (4.9+/-4.0) in PD patients was significantly lower than in controls (42.9+/-18.8%, P < 0.0001, 0.63+/-0.18, P < 0.0001, and 28.0+/-16.7%, P<0.0001).. Iron absorption is impaired in PD patients, as we have shown previously for HD patients. One reason for higher iron needs in HD patients may be higher blood losses due to the dialysis procedure and blood sampling for laboratory tests.

Topics: Absorption; Adolescent; Adult; Anemia, Iron-Deficiency; Erythropoiesis; Erythropoietin; Female; Ferritins; Follow-Up Studies; Hemorrhage; Humans; Infusions, Intravenous; Iron; Iron Compounds; Iron Deficiencies; Kidney Diseases; Male; Peritoneal Dialysis; Receptors, Transferrin; Recombinant Proteins

Topics: Drug Interactions; Erythropoietin; Ferritins; Humans; Injections, Intravenous; Iron; Kidney Diseases; Recombinant Proteins; Renal Dialysis

Keeping in mind the renal origin of erythropoietin (EPO), we designed our study in order to estimate the role of kidney damage in the development of bone marrow erythropoiesis in erythroblastic islands (EI). The experiment was performed comparing intact rats with untreated and gentamicin-pretreated rats (50 mg/kg/15 days) exposed to hypobaric pressure (42.55 kPa/6 h) to stimulate hypoxia. Blood samples were taken following a 2-week period. The study included an estimation of plasma EPO levels by RIA, the number of peripheral blood parameters and bone marrow EI (classes I to V/femur), the rate of erythroid differentiation into erythroblasts, and the rate of repeated participation of macrophages in new EI reconstruction. Plasma EPO increased to 52.88 mU/ml (p < 0.01) and 23.45 mU/ml at 0 h immediately following hypobaric exposure in untreated and gentamicin-treated rats, respectively, as compared to 14.25 mU/ml in intact animals. Bone marrow recovery patterns were markedly expressed in untreated hypoxic animals throughout the observed period. The rate of erythroid differentiation into erythroblasts in EI was increased (p < 0.01) while the number of maturing EI decreased (p < 0.01); increased reconstruction was observed in involuted EI. Less pronounced stimulation of erythropoiesis was observed in hypoxic gentamicin-treated rats. The direct impact of the hypoxic stimulus on the erythropoietic bone marrow tissue was considered significant for the erythropoietic response via activation of macrophages. These data support the hypothesis that EI central macrophages play an important role as local regulators of bone marrow erythropoiesis.

Topics: Animals; Bone Marrow; Creatinine; Erythroblasts; Erythropoietin; Gentamicins; Hypoxia; Kidney Diseases; Kidney Tubules; Linear Models; Male; Rats; Rats, Wistar

There is accumulating evidence from in vitro studies suggesting that the genes of endothelin-1, PDGF, and VEGF are, like the erythropoietin gene, regulated by oxygen tension and by divalent cations. Hypoxia-induced stimulation of, such as endothelin-1, PDGF or VEGF might be involved in the pathogenesis of acute or chronic renal failure, and in renal "inflammatory" diseases (glomerulonephritis, vasculitis, allograft rejection). Hypoxia (8% O2) for six hours caused a 55-fold/1.6-fold increase of renal erythropoietin/endothelin-1 gene expression, whereas endothelin-3, PDGF-A, PDGF-B, and VEGF gene expression was unchanged. Carbon monoxide (0.1%) treatment for six hours stimulated renal erythropoietin gene expression 140-fold; however, endothelin-1, endothelin-3, PDGF-A, PDGF-B, and VEGF gene expression was not affected. Finally, cobalt treatment (60 mg/kg CoCl2) increased only renal erythropoietin/PDGF-B gene expression 5-fold/1.65-fold. These findings suggest that hypoxia is a rather weak stimulus for renal endothelin-1 gene expression, and that renal PDGF and VEGF gene expression in vivo is not sensitive to tissue hypoxia, in contrast to cell culture experiments. The in vivo regulation of endothelin-1, PDGF, and VEGF differs substantially from that of erythropoietin, suggesting that the basic gene regulatory mechanisms may not be the same.

Topics: Animals; Endothelial Growth Factors; Endothelin-1; Endothelin-3; Erythropoietin; Gene Expression; Growth Substances; Hypoxia; Kidney; Kidney Diseases; Lymphokines; Male; Platelet-Derived Growth Factor; Rats; Rats, Sprague-Dawley; RNA, Messenger; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

To define the potential for erythropoietin gene expression in injured kidneys, marker gene expression was examined in transgenic mice bearing a homologously recombined erythropoietin--simian virus 40 T antigen (Epo-TAg) transgene. Three types of renal injury were studied: ureteric obstruction, global ischemia following clamping of the renal pedicle, and focal needlestick injury. All modes of injury were associated with an expansion of the interstitial space, which contained an increased number of cells. Alterations observed in the interstitial fibroblast-like cells included an increased number and complexity of cellular processes, enhanced expression of contractile elements, particularly of the intermediate filament desmin, and reduced expression of ecto-5'-nucleotidase. Following each type of injury there was a focal or general reduction in the proportion of such cells that could be stimulated to express Epo-TAg. However, some positively staining cells were present even in severely injured regions and more could be recruited to express Epo-TAg by severe anemic or hypoxic stimulation, indicating that cells with the potential for erythropoietin gene expression were neither absent nor completely refractory to stimulation in these regions. In all injured kidneys, Epo-TAg expression was limited to the fibroblast-like population. Double labeling experiments showed that cells expressing Epo-TAg also expressed increased amounts of desmin, demonstrating that the myofibroblast features which develop in response to injury and the capacity for erythropoietin gene expression are not mutually exclusive.

Topics: Animals; Antigens; Antigens, Viral, Tumor; Erythropoietin; Fibroblasts; Gene Expression; Ischemia; Kidney; Kidney Diseases; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; Microscopy, Electron; Needlestick Injuries; Phenotype; Renal Circulation; Simian virus 40; Ureteral Obstruction

Cadmium (Cd) chloride was intravenously injected at doses of 0.05 and 0.5 mg/kg/day in ovariectomized rats for 50 weeks, and the chronic Cd exposure-induced nephrotoxicity and anemia were investigated. The rats treated with 0.05 mg/kg Cd showed no apparent hematological, urinary, and histopathological abnormalities. In the 0.5-mg/kg group, renal tubular disorders became marked at 16 weeks, and cortical fibrosis with glomerular dysfunction appeared at 50 weeks. Anemia occurred at 12 weeks in the 0.5-mg/kg group and became increasingly marked with time. The mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were decreased at 12 and 25 weeks; however, the decreases of MCV and MCH disappeared at 50 weeks. A slight decrease in mean corpuscular hemoglobin concentration was noted at 50 weeks. The blood chemistry from the same group revealed a decrease in plasma iron levels and an increase in total iron binding capacity throughout the administration period. The erythropoietin (EPO) level was increased as the hemoglobin level decreased at 12 weeks, whereas the EPO level was not elevated even when the hemoglobin level was decreased at 50 weeks. These findings showed that renal anemia also occurred in addition to the iron deficiency anemia at 50 weeks.

Topics: Anemia; Animals; Body Weight; Cadmium; Cadmium Poisoning; Drinking; Erythropoietin; Female; Ferritins; Hemoglobins; Injections, Intravenous; Kidney; Kidney Diseases; Liver; Metallothionein; Ovariectomy; Rats; Rats, Sprague-Dawley; Urine

The use of recombinant human erythropoietin in pregnancy has been described in patients with renal impairment. We present a patient with a hypoproliferative anemia with low serum erythropoietin levels and no renal disease or other known cause for this type of anemia, who was treated with recombinant human erythropoietin.. A 29-year-old white woman who became pregnant after leuprolide acetate and menopausal gonadotropin therapy developed a moderate anemia (hemoglobin 8.5 g/dL) in early pregnancy. The only important laboratory findings were a hypoproliferative marrow and a low serum erythropoietin level. She was treated successfully with injections of recombinant human erythropoietin. Her pregnancy was otherwise uncomplicated and her pre-delivery hemoglobin level was 12 g/dL.. Hypoproliferative anemia in pregnancy with low erythropoietin levels and no renal disease can be treated successfully with recombinant human erythropoietin.

Topics: Adult; Anemia; Erythropoietin; Female; Humans; Infant, Newborn; Kidney Diseases; Pregnancy; Pregnancy Complications, Hematologic; Pregnancy Outcome; Recombinant Proteins

Topics: Adult; Anemia; Blood Pressure; Erythropoietin; Female; Hematocrit; Humans; Kidney Diseases; Middle Aged; Nephrectomy; Recombinant Proteins; Renal Dialysis

The effects of cisplatin on erythropoietin (EPO) production were investigated in comparison with the effects of phenylhydrazine in rats. Cisplatin (4.5 mg/kg i.p. bolus) decreased red blood cell count (RBC), hematocrit (Hct) and hemoglobin concentration (Hgb) for 14 days after dosing. These decreases were accompanied with increases of blood urea nitrogen (BUN) and serum creatinine (s-CRE). Both serum EPO concentration and kidney EPO mRNA content were significantly decreased in cisplatin-treated rats. On the other hand, phenylhydrazine (10 mg/kg p.o. once a day for 8 days) decreased RBC, Hct and Hgb, and increased serum EPO concentration and kidney EPO mRNA content. Phenylhydrazine had little effect on BUN or s-CRE. These results suggest that a suppression of EPO production is involved in the pathophysiology of cisplatin-induced renal anemia and that measurement of serum EPO concentration and kidney EPO mRNA content is available for distinguishing renal anemia from hemolytic anemia.

Topics: Anemia; Animals; Antineoplastic Agents; Blood Urea Nitrogen; Cisplatin; Creatinine; Erythrocyte Count; Erythropoietin; Hematocrit; Hemoglobins; Immunoenzyme Techniques; Kidney; Kidney Diseases; Male; Phenylhydrazines; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; RNA, Messenger; Transcription, Genetic

Angiotensin-converting enzyme (ACE) inhibitor therapy has recently been shown to be effective in the treatment of post-renal transplant erythrocytosis (PTE). In an attempt to assess the effect of drug treatment on serum erythropoietin level, glomerular filtration rate, and urinary protein excretion, we prospectively evaluated 8 consecutive cadaveric renal transplant recipients with PTE treated with ACE inhibitor therapy for 3 months. In response to ACE inhibition, the mean hematocrit (HCT) value decreased from 53.7 +/- 0.6% before treatment to 42.7 +/- 2.2% at the conclusion of the study (p = 0.03). However, 1 patient failed to respond to ACE inhibition (HCT > 50%), and 2 patients with PTE developed anemia (HCT < 35%) while maintained on drug treatment. Although the mean serum erythropoietin level decreased during ACE inhibition (from 22.8 +/- 8.4 to 9.4 +/- 5.3 mU/ml; p = 0.06), a consistent change in individual erythropoietin levels was not identified. At the conclusion of the study, the serum erythropoietin levels were undetectable in 4 patients, decreased in 1, unchanged in 2, and increased in the only patient with PTE who failed to respond to drug treatment. All patients tolerated the ACE inhibitor therapy without developing cough or hyperkalemia. In addition, serum creatinine levels, 125I-iothalamate clearances, and mean arterial blood pressures were unchanged throughout the study. Microalbuminuria (spot urinary albumin/creatinine ratio between 30 and 200 mg/g) developed in 5 patients with PTE and coincided with the onset of erythrocytosis (25.2 +/- 7 mg/g before PTE and 76.3 +/- 36.7 mg/g at the time of PTE detection).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Contrast Media; Erythropoietin; Female; Glomerular Filtration Rate; Humans; Iodine Radioisotopes; Iothalamic Acid; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Polycythemia; Prospective Studies

Topics: Cholesterol, LDL; Erythrocyte Count; Erythropoietin; Humans; Interleukins; Kidney Diseases; Lipid Metabolism; Renal Dialysis

Topics: Anemia; Child; Child, Preschool; Drug Administration Schedule; Erythropoietin; Female; Humans; Infant; Injections, Jet; Injections, Subcutaneous; Kidney Diseases; Male; Peritoneal Dialysis, Continuous Ambulatory

Renal endothelin-1 (ET-1) production is diminished in spontaneously hypertensive rats. An increase has been reported of renal ET-1 production associated with progression of renal disease in rats with reduced renal mass. The purpose of the present study was to investigate the evolution over time of the urinary ET-1 excretion in an experimental model of renal mass reduction not caused by renal infarction. Rats were subjected to 2/3 nephrectomy (right nephrectomy and resection of the lower left renal pole) and thereafter randomly assigned to a no-treatment control group or to treatment with recombinant erythropoietin, recombinant erythropoietin plus verapamil, or recombinant erythropoietin plus enalapril. The urinary ET-1 excretion was decreased by week 16 after nephrectomy as compared with healthy animals and with the levels 6 weeks after nephrectomy. The temporal evolution of urinary ET-1 excretion in the various groups of rats showed a trend toward decrease in all groups except the one receiving enalapril. The urinary ET-1 excretion correlated directly with creatinine clearance and inversely with tubulointerstitial damage. We observed an inverse correlation between urinary ET-1 excretion and arterial blood pressure 16 weeks after nephrectomy. These results indicate that renal ET-1 production decreases with the progression of renal disease and in relation with the severity of tubulointerstitial damage. The decrease in renal ET-1 production might contribute to the development and perpetuation of renal disease-associated arterial hypertension; this situation may be favorably modified by the use of enalapril.

Topics: Animals; Enalapril; Endothelins; Erythropoietin; Hypertension, Renal; Kidney; Kidney Diseases; Male; Nephrectomy; Radioimmunoassay; Rats; Rats, Wistar; Recombinant Proteins; Verapamil

Twenty chronic hemodialysis patients with renal anemia (hematocrit < 25%) received recombinant human erythropoietin (40 IU/kg body weight 3 x weekly) intravenously after each dialysis. Prior to and at 4, 8 and 12 weeks after commencement of erythropoietin therapy, hematocrit together with hemostasis and microhemolysis parameters were determined. There were significant increases in hematocrit, platelet count and platelet retention, but a significant fall in the initial clearly prolonged bleeding time. Free plasma hemoglobin likewise increased. Conversely, lactate dehydrogenase, prothrombin time, fibrinogen, antithrombin III activity, protein C activity and protein S concentration were all unaltered. The positive effect on bleeding time and platelet retention is most probably caused by an increase in adenosine diphosphate due to the hematocrit-dependent rise in the blood shear stress via physiologic microhemolysis (raised free plasma hemoglobin).

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Hematocrit; Hemostasis; Humans; Injections, Intravenous; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Plasma lipid disturbances are common among patients on maintenance haemodialysis and it seems to be important to evalate lipid status on r-Epo since this treatment of anemia is becoming substantial and so often used in that population. It appears more valuable because there are controversial data in the literature concerning this problem. The aim of the present study was to measure changes in serum lipid concentration in two comparable groups: I--11 patients (7f, 4m) aged 47 +/- 8 years receiving r-Epo s.c. during at least 6 months before HD and 2 years of HD with initial dose 3 x 50 u/kg b.w. and II--18 patients (7f, 11m) aged 45 +/- 8 years without r-Epo in that period of time. Following parameters were estimated every two months: total cholesterol (CH-C), HDL cholesterol (HDL-CH), LDL cholesterol (LDL-CH), triglycerides (TG), apolipoprotein B (Apo B).. 1. Subcutaneous therapy with r-Epo is an effective method of treatment of anemia in dialysis patients. 2. Long-term r-Epo treatment does not permanently influence the blood lipid profile in hemodialysed patients.

Topics: Adult; Anemia; Apolipoproteins B; Chronic Disease; Erythropoietin; Female; Humans; Hyperlipidemias; Injections, Subcutaneous; Kidney Diseases; Lipids; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Topics: Anemia; Erythropoietin; Humans; Kidney Diseases

A patient with a 15 year history of secondary polycythaemia due to renal erythropoietin hypersecretion is presented. Subsequent spontaneous development of bilateral renal lymphocoeles, which contained high erythropoietin levels, was shown by computerized tomography. The lymphocoeles were successfully treated by bilateral peritoneal marsupialization. No cause for the persistent polycythaemia or lymphocoeles was found at laparotomy or on renal biopsy.

Topics: Adult; Erythropoietin; Follow-Up Studies; Humans; Kidney; Kidney Diseases; Lymphocele; Male; Polycythemia

Predialysis plasma endothelin (ET) values were followed during the first 8 weeks of rHuEpo treatment in 12 patients on routine haemodialysis. Mean plasma ET was significantly increased in uraemic patients before rHuEpo (27.9 +/- 11.4 pmol/l), as compared to 40 healthy controls (16.5 +/- 5.7 pmol/l) (P < 0.0001). Under rHuEpo treatment, predialysis values remained unchanged although diastolic blood pressure increased after 2 and 6 weeks. We found no correlation between ET and haemoglobin or blood pressure before or under rHuEpo treatment. These results confirmed the high levels of plasma ET in haemodialysis patients, but no increase was observed during rHuEpo treatment.

Topics: Adult; Aged; Blood Pressure; Endothelins; Erythropoietin; Female; Humans; Kidney Diseases; Male; Middle Aged; Radioimmunoassay; Recombinant Proteins; Renal Dialysis

Topics: Erythropoietin; Ferritins; Humans; Iron Deficiencies; Kidney Diseases; Renal Dialysis

Topics: Bone Marrow Transplantation; Cyclosporine; Depression, Chemical; Erythropoietin; Humans; Infusions, Intravenous; Kidney Diseases; Kidney Function Tests; Prospective Studies; Secretory Rate

The dialysis adequacy was considered as the treatment method which eradicated the symptoms and signs of uremia and led to the full rehabilitation of treated patients. The chronic renal failure patients substitutional treatment using both peritoneal dialysis and hemodialysis assures correction of biochemical disturbances but only 33% of dialyzed patients are fully rehabilitated. Such situation is caused by the uremic anemia. The erythropoietin deficit is the main reason of the uremic anemia. The clinical effects of the erythropoietin treatment in hemodialyzed, peritoneal dialyzed and pre-dialyzed patients were proved. The erythrocytes increment to the normal or almost normal levels may caused the dialysis kinetics changes. During the r-Hu EPO treatment in both hemodialyzed and peritoneal dialyzed patients the dialysis effectiveness changes occurred. The dialysis therapy adequacy is mainly caused by the dialysis efficiency and additionally by the residual renal function and metabolism state. Taking into account own peritoneal dialysis kinetics parameters research results during the r-Hu EPO treatment the dialysis adequacy was evaluated. The aim of this study was the optimal dialysis scheme definition when the peritoneal transfer changes occurred as the r-Hu EPO treatment effect.

Topics: Adult; Erythropoietin; Female; Glomerulonephritis; Hematocrit; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Peritoneal Dialysis; Recombinant Proteins

Several factors may contribute to the pathogenesis of uraemic anaemia but there is general agreement that inadequate secretion of erythropoietin is the main cause. Recombinant human erythropoietin (r-Hu EPO) is today widely used in the treatment of patients with renal anaemia. Initial studies were conducted on patients receiving haemodialysis (HD) using intravenous dosing, and number of reports have confirmed the efficacy and safety of the hormone. However, there is still limited information on the use of r-Hu EPO in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). The cost of this treatment was initially very high. The optimal way of administration of the drug and optimal dosage is still under discussion. More studies are needed to optimize treatment from a clinical as well as an economic point of view. We therefore present our result on the efficacy and safety of low dose r-Hu EPO given subcutaneously in th treatment of anemia in CAPD patients.

Topics: Adult; Anemia; Chronic Disease; Erythrocyte Count; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Quality of Life; Recombinant Proteins; Reticulocyte Count; Treatment Outcome

We studied 38 patients (9 haemodialysis, 18 peritoneal dialysis, 11 advanced renal failure) over the first 12 weeks of erythropoietin therapy. In 14 iron-overloaded patients (ferritin > 500 micrograms/l the haemoglobin (+/- SEM) increased from 6.74 +/- 0.27 to 9.85 +/- 0.36 g/dl (P < 0.0001) entirely by mobilizing iron reserves (reduced from 1,220 +/- 73 to 739 +/- 111 mg, P < 0.0001). In the 24 non-overloaded patients (ferritin < 500 micrograms/l) the haemoglobin rose similarly from 7.04 +/- 0.18 to 10.70 +/- 0.36 g/dl (P < 0.0001), partly from iron reserves (depleted from 200 +/- 74 to -44 +/- 77 mg, P = 0.016) and partly from oral iron supplements (305 +/- 110 mg). In the overloaded patients the ferritin declined from 1057 micrograms/l (geometric mean, range 504-3699) to 317 micrograms/l (42-1505, P < 0.0001). In the non-overloaded patients it declined from 82 micrograms/l (8-461) to 45 micrograms/l (5-379, P = 0.016). The transferrin saturation (TS) in the overloaded patients appeared to decline from 38.3 +/- 7.2% to 24.0 +/- 3.7% but this was not statistically significant. In the non-overloaded the TS was unchanged (23.3 +/- 2.4 before and 28.1 +/- 3.6% after treatment). Considering all 38 patients together, the haemoglobin correlated negatively with the ferritin (r = 0.3731, P < 0.001) but not with the TS. The TS correlated with the serum ferritin initially (r = 0.75, P < 0.001) but not after the first 4 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Erythropoietin; Female; Ferritins; Humans; Iron; Kidney Diseases; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Transferrin

Topics: Adult; Aged; Erythropoiesis; Erythropoietin; Female; Glomerular Filtration Rate; Glomerulonephritis; Hemoglobinometry; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Nephritis, Interstitial; Polycystic Kidney Diseases

The effects of treating the anaemia of end-stage renal failure with erythropoietin were studied in nine dialysis patients. The increase in haemoglobin concentration (by 59% from 7.0 +/- 1.2 to 11.1 +/- 1.1 g dl-1) was associated with increases in exercise duration (by 41%) and maximum oxygen consumption (by 34%). Treatment reduced resting heart rate but did not significantly alter heart rate at maximum exercise, nor resting or exercise blood pressure. Resting arterial potassium concentrations were slightly increased after treatment, but they increased similarly in relation to minute ventilation during exercise. Lactic acidaemia developed during exercise at both levels of haemoglobin, and was accompanied by similar reductions in arterial pH and bicarbonate levels but constant PaO2 and PaCO2. Ventilation was coupled to the metabolic rate of carbon dioxide production, ventilatory dead-space and arterial PCO2 before and after treatment of anaemia, the ventilatory requirement for carbon dioxide elimination being unchanged. Treatment of anaemia did not alter resting arterial lactate concentration; the concentration of lactate at maximum exercise was increased slightly following treatment but this increase did not reach statistical significance. The rate of increase in arterial lactate concentration as a function of oxygen consumption, assessed both with respect to the 'lactate threshold' and 'lactate slope index', was significantly delayed by treatment. Treatment of anaemia also delayed the 'anaerobic threshold', and there was good correlation between lactate and anaerobic thresholds. Treatment of renal anaemia by erythropoietin thus results in improved tissue oxygen supply during exercise, reflected by delay in the onset of lactic acidaemia.

Topics: Adolescent; Adult; Aged; Anemia; Bicarbonates; Erythropoietin; Exercise Tolerance; Female; Humans; Kidney Diseases; Lactates; Lactic Acid; Male; Middle Aged; Oxygen Consumption; Renal Dialysis; Renal Insufficiency

Topics: Aged; Anemia; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Kidney Diseases; Male; Middle Aged; Recombinant Proteins

Biotechnology products signify a major advancement in our world today. Products resulting from biotechnology will revolutionize how health care is delivered. One of these technologic breakthroughs is recombinant human erythropoietin (epoetin). Its impact on the delivery of care to the anemic renal patient is changing the roles of nurses who provide care for these patients. Epoetin alfa has virtually eliminated the necessity of transfusions in the renal patient population, while simultaneously improving the quality of life for those patients and their families. To appropriately monitor the patient receiving epoetin therapy, the nurse must understand iron physiology and metabolism, factors that influence blood pressure, and factors that can blunt the response to epoetin therapy, and still appreciate the individual nursing requirements of each patient. Such juggling of information demands that the critical care nurse be alert to the subtle changes occurring within the patient, thereby allowing sound decisions based on astute nursing assessment.

Topics: Anemia; Critical Care; Erythropoietin; Humans; Kidney Diseases; Male; Middle Aged

Pharmacokinetics and distribution were studied following intravenous administration of recombinant human erythropoietin (rh-EPO, CAS 11096-26-7) to 5/6-nephrectomized rats. 5/6-Nephrectomy caused a significant decrease of total body clearance of rh-EPO. Renal function, therefore, is thought to affect the metabolism in extrarenal tissues. The metabolism of EPO might be indirectly associated with renal function. There were no differences of the concentration in the bone marrow and spleen between 5/6-nephrectomized rats and non-nephrectomized rats, suggesting that 5/6-nephrectomy does not cause a change in the affinity of rh-EPO for target tissues. Repeated administration of rh-EPO caused a slight reduction of the biological half-life in 5/6-nephrectomized rats as well as in non-nephrectomized rats, suggesting stimulation of a compensatory metabolism in extrarenal tissues.

Topics: Animals; Erythropoietin; Half-Life; Humans; Iodine Radioisotopes; Kidney Diseases; Male; Nephrectomy; Radioimmunoassay; Rats; Rats, Inbred Strains; Recombinant Proteins

Topics: Arthritis, Rheumatoid; Erythropoietin; Humans; Kidney Diseases; Quality of Life

Topics: Deferoxamine; Erythropoietin; Humans; Kidney Diseases; Male; Middle Aged; Plasma Exchange; Porphyrias; Porphyrins; Recombinant Proteins; Renal Dialysis; Skin Diseases

Topics: Clinical Protocols; Erythropoietin; Humans; Kidney Diseases

Topics: Aged; Amyloidosis; Anticoagulants; Chronic Kidney Disease-Mineral and Bone Disorder; Dialysis Solutions; Erythropoietin; Heart Failure; Humans; Hypotension; Kidney Diseases; Membranes, Artificial; Middle Aged; Renal Dialysis; Survival Rate

Topics: Anemia; Erythropoietin; Half-Life; Humans; Kidney Diseases; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Renal Dialysis

Topics: Anemia; Collagen Diseases; Erythropoiesis; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins

In order to investigate the clinical usage of SNB-5001 (recombinant human erythropoietin), two types of anemic models induced by drugs were prepared. One group of rats was intravenously injected with 8 mg/kg of cisplatin. These rats temporarily showed leucopenia and thrombocytopenia. Since 2 weeks after the cisplatin injection, rats chronically showed renal failure and moderate anemia. Another group was subcutaneously injected with 15 mg/kg of puromycin, 4 times a week, for 3 weeks. These rats showed hypercholesteremia and hypoalbuminemia, and they showed chronic renal failure and severe progressive anemia. Anemic rats received SNB-5001 (50 or 500 U/kg) once a day for 7 days. In the anemic rats induced by cisplatin, more than 50 U/kg of SNB-5001 dose-dependently increased reticulocytes, red blood cells (RBC), hemoglobin (HGB) and hematocrits (HCT). SNB-5001 apparently improved the anemia induced by cisplatin. On the other hand, in anemic rats induced by puromycin, 50 U/kg of SNB-5001 increased reticulocytes, but did not increase RBC, HGB and HCT. SNB-5001 at the dose of 500 U/kg stopped the progress of anemia in puromycin treated rats. It was suggested that SNB-5001 is useful for the improvement of renal anemia induced by drugs, but the effects are affected by the uremic condition and the stage of renal anemia.

Topics: Anemia; Animals; Cisplatin; Erythrocyte Count; Erythropoietin; Hematocrit; Hemoglobins; Kidney Diseases; Male; Puromycin; Rats; Rats, Inbred Strains; Recombinant Proteins

The haemodynamic effects of recombinant human erythropoietin (rHuEpo) on anaemic haemodialysis patients suffering from chronic hypotension were examined. rHuEpo increased the haematocrit to around 30% and increased diastolic blood pressure by 12.4%, statistically significant. Correspondingly, the total peripheral resistance index increased 42.3% while the cardiac index decreased 24.4% (P less than 0.05) respectively. Blood volume, plasma renin activity and plasma noradrenaline did not change significantly. The extent of blood pressure elevation and haemodynamic alteration did not differ from our previous report on anaemic haemodialysis patients without hypotension. The incidence of hypotensive episodes and fluid supplementation did not change significantly after rHuEpo treatment. In conclusion, by using rHuEpo, approximately a 10% increase of blood pressure can be expected. However no substantial improvement in hypotensive episodes can be expected in chronic haemodialysis patients suffering from hypotension.

Topics: Adult; Blood Volume; Erythropoietin; Female; Hemodynamics; Humans; Hypotension; Kidney Diseases; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

The results of estimating blood plasma erythropoietic activity in patients with polycythemia of unclear genesis, in 95% of cases coincided with the clinical diagnosis proved during further follow up. These data have permitted recommendation of estimating blood plasma erythropoietic activity in patients to verify the diagnosis of polycythemic states.

Topics: Adult; Child; Diagnosis, Differential; Erythropoietin; Female; Humans; Kidney Diseases; Male; Middle Aged; Polycythemia; Polycythemia Vera

Fifteen severely anaemic patients receiving CAPD were treated with subcutaneous recombinant human erythropoietin (Epo). Ten subjects had a good response with the haemoglobin concentration increasing from less than 8 g/dl to greater than 10 g/dl within 16 weeks. Four patients had a poor response, which was due to infection in two, myelofibrosis in one and unknown cause in another. Epo was ineffective in the remaining individual, probably due to the presence of occult metastatic carcinoma. Iron supplementation in the form of intravenous iron dextran was given to 12 patients when transferrin saturation decreased below 20%. There was a significant increase in red cell volume (P less than 0.005), with a decrease in plasma volume (P less than 0.005). Red cell iron turnover increased (P less than 0.05) but there was no change in red cell lifespan or deformability. Biochemical parameters remained unaltered, as did peritoneal function. Exercise duration improved (P less than 0.001), as did maximal oxygen consumption (P less than 0.01). Four patients required an increased dose of hypotensive drugs. Epo is a safe effective therapy for the anaemia of CAPD subjects.

Topics: Adult; Aged; Anemia; Erythropoietin; Female; Humans; Kidney Diseases; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins

Recombinant human erythropoietin was administered to an anemic patient with multiple myeloma (IgD, lambda type) and renal dysfunction who had been dependent on blood transfusions. Three thousand units of the recombinant human erythropoietin was given intravenously three times a week. Thereafter transfusion requirements, hemoglobin level, and reticulocyte responses have been monitored. An increase in hemoglobin level and reticulocyte counts was observed within 10 days and then further blood transfusion was not necessary. Neither organ dysfunction nor toxic effects were observed. The administration of recombinant human erythropoietin can be a new method to treat anemia associated with multiple myeloma and renal dysfunction.

Topics: Anemia, Refractory; Erythropoietin; Female; Humans; Kidney Diseases; Middle Aged; Multiple Myeloma; Recombinant Proteins

Serum immunoreactive erythropoietin (siEPO) was determined in cord serum from neonates (n = 97, gestational age 36-43 weeks), in healthy children from birth to adolescence (n = 260) and in children with haematological (n = 30), renal (n = 10) and congenital heart diseases (n = 70). In healthy children siEPO levels decreased after birth (geometric mean cord siEPO 35.6 mU/ml with 95% range of 17-56 mU/ml in eutrophic, nondistressed fetuses) and reached lowest values during the first 2 months (geometric mean siEPO 11.5 mU/ml). Thereafter siEPO levels increased slightly and were constant between 2 months and adolescence. The geometric mean siEPO for healthy children after birth was 18.8 mU/ml with 95% range of 7-47 mU/ml. These estimates were not significantly different from normal adult values. In newborns with fetal distress (n = 15) cord siEPO was significantly elevated (geometric mean 63.0 mU/ml; P less than 0.001). In children with haematological disease, siEPO and Hb concentration were inversely correlated (log siEPO (mU/ml) = 4.1-0.20 x Hb (g/dl); r = -0.62; P less than 0.0005). This relationship was significantly different in children with chronic renal failure (log siEPO (mU/ml) = 0.67 + 0.035 x Hb (g/dl); r = 0.50; P = 0.1). In children with heart disease the geometric mean siEPO was 19.2 mU/ml with 95% range 8-65 mU/ml for cyanotic (SaO2 less than 94%) and 17.7 mU/ml with 95% range of 12-36 mU/ml for acyanotic patients. In this group siEPO values were inversely correlated to the arterial oxygen content (log siEPO (mU/ml) = 1.61-2.04 x oxygen content (l/l); r = -0.28; P less than 0.02).

Topics: Adolescent; Adult; Analysis of Variance; Anemia; Child; Child, Preschool; Erythropoietin; Female; Fetal Distress; Heart Defects, Congenital; Hemoglobins; Humans; Infant; Infant, Newborn; Infant, Small for Gestational Age; Kidney Diseases; Male; Normal Distribution; Oxygen; Pregnancy; Reference Values; Regression Analysis

Topics: Erythropoiesis; Erythropoietin; Female; Fetal Blood; Hematocrit; Humans; Infant, Newborn; Kidney; Kidney Diseases; Male; Tissue Distribution

Topics: Amino Acid Sequence; Anemia; Base Sequence; Cloning, Molecular; DNA; Erythropoietin; Humans; Kidney; Kidney Diseases; Molecular Sequence Data

Topics: Adult; Aged; Aged, 80 and over; Erythropoietin; Female; Humans; Injections, Intravenous; Injections, Subcutaneous; Kidney Diseases; Male; Middle Aged; Renal Dialysis

Topics: Adult; Aged; Anemia; Blood Viscosity; Erythropoietin; Female; Hematocrit; Humans; Kidney Diseases; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Recombinant Proteins; Ultrafiltration

Serum from dogs with surgically induced renal impairment was incorporated into the medium for erythroid bone marrow cultures. A significant correlation was found between serum activities of erythropoietin and numbers of erythroid colony-forming units grown in culture. Serum creatinine concentrations had no correlation, and serum parathyroid hormone activities had a negative correlation with numbers of erythroid colony-forming units that was below the level of significance. Purified 1-84 parathyroid hormone added to bone marrow cultures was found to be stimulatory to erythroid colony-forming unit growth in higher concentrations, but decreased the number of burst-forming units. Unmeasured substances in the canine serum appeared to have a greater effect on the canine erythroid bone marrow cultures than did creatinine or parathyroid hormone values.

Topics: Animals; Bone Marrow Cells; Cells, Cultured; Creatinine; Culture Media; Dog Diseases; Dogs; Erythroid Precursor Cells; Erythropoietin; Kidney Diseases; Parathyroid Hormone

The accurate radioimmunological measurement of serum erythropoietin (EPO) levels has only been possible since the development of highly specific antibodies directed against recombinant human EPO. In the present study, we determined the serum EPO levels in 100 healthy volunteers and in over 300 patients with anemias and hyperglobulinemia of various causes. In the healthy group, the females had levels of 11.3 +/- 3.4 mU/ml, while the males had levels of 8 +/- 3.2 mU/ml. The serum EPO concentrations were inversely related to the degree of anemia in patients with nonrenal anemias, while predialysis patients with renal anemias showed only partially such a tendency. Hemodialysis patients exhibited EPO-levels that were inadequately low relative to the degree of anemia. Patients with hyperglobulinemia had significantly higher serum EPO-levels than healthy individuals and polycythemia vera patients, the latter having particularly low serum EPO levels. Our results show that the determination of serum EPO levels can be of value in the differential diagnosis of hyperglobulinemia. Finally, sequential measurements document fluctuating serum EPO-levels after gastrointestinal hemorrhages and in patients with iron deficiency anemias receiving iron substitution. The probable reason for this phenomenon seems to be the intermittent utilisation of the hormone by EPO-sensitive erythropoietic precursor cells.

Topics: Acquired Immunodeficiency Syndrome; Anemia; Anemia, Hypochromic; Erythropoietin; Female; Gastrointestinal Diseases; Hemoglobins; Humans; Hypergammaglobulinemia; Kidney Diseases; Male; Myelodysplastic Syndromes; Polycythemia Vera; Renal Dialysis

Topics: Anemia, Aplastic; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins

Topics: Anemia; Animals; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins

Topics: Anemia; Erythropoietin; Humans; Kidney Diseases; Recombinant Proteins

The normal response to anemic or hypoxic hypoxia is synthesis and release of erythropoietin in accord with the concept that erythropoietin production is controlled by a renal oxygen sensor. In this study, erythropoietin production, as predicted, was abrogated in patients with renal impairment (55 cases), but normal in nonuremic individuals. Specifically, patients with rheumatoid arthritis (34 cases), sickle cell anemia (25 cases), aregenerative anemia (27 cases), and aplastic anemia (13 cases) had erythropoietin titers overlapping with those observed in simple anemia (61 cases) at corresponding hematocrits. The response of polycythemic laboratory animals to hypoxia is more difficult to fit within the concept of an oxygen sensor responsive both to anemic and hypoxic hypoxia. If the polycythemia was induced by hypertransfusion, erythropoietin production in response to hypoxia was, as predicted, less than that observed in normal animals. If, however the polycythemia was induced by previous exposure to hypoxia, the animals responded to hypoxia as though they were not polycythemic. An explanation for this challenging observation may provide a clue as to the operation of the oxygen sensor.

Topics: Anemia; Animals; Arthritis, Rheumatoid; Erythropoietin; Feedback; Humans; Hypoxia; Kidney; Kidney Diseases; Mice; Oxygen; Polycythemia

Topics: Anemia; Erythropoiesis; Erythropoietin; Humans; Kidney Diseases

We have studied serum immunoreactive erythropoietin (SIE) levels in 28 patients with sickle cell anemia (SCA) without renal insufficiency and in 17 patients with nonhemoglobinopathy anemias of comparable severity using a sensitive radioimmunoassay procedure. An exponential relationship between SIE level and degree of anemia was noted in all patients. However, in nonhemoglobinopathy anemia, a sharp rise in the SIE level occurred as hemoglobin (Hb) levels fell below about 12 g/dL, whereas in sickle cell patients the increase was not marked until hemoglobin fell to about 9 g/dL. The response was more blunted in older SCA patients than in younger ones. A linear regression model relating SIE level to Hb level, presence/absence of SCA, and age explained 63% of the variation in SIE. We conclude that the serum erythropoietin levels in SCA increased at a lower hemoglobin concentration and are of a lower magnitude than that of the other anemias.

Topics: Adolescent; Adult; Age Factors; Anemia, Sickle Cell; Child; Child, Preschool; Erythropoietin; Hemoglobins; Humans; Infant; Kidney Diseases

Serum erythropoietin levels were randomly collected and measured by a sensitive radioimmunoassay in a hemodialysis population. For analysis, the patients were divided into two groups: those with polycystic kidney disease and those with other kidney diseases. In 12 polycystic kidney disease patients, serum erythropoietin was 22.6 +/- 2.4 mU/ml, hematocrit 29.7 +/- 1.0%, and absolute reticulocyte count 17.0 +/- 4.1 X 10(4)/microliters. In 24 other kidney disease patients, serum erythropoietin was 12.4 +/- 0.7 mU/ml, hematocrit 21.2 +/- 0.8%, and reticulocyte count 7.5 +/- 1.5 X 10(4)/microliters. Serum erythropoietin was 18.5 +/- 0.7 mU/ml in normal controls. Polycystic kidney disease patients manifested higher hematocrit, reticulocyte counts, and serum erythropoietin levels when compared to other kidney disease patients (p less than 0.01). The data suggest (1) an inappropriately low serum erythropoietin level for the severity of anemia in uremic hemodialysis patients and (2) that greater availability of erythropoietin results in more effective erythropoiesis, even in the uremic environment.

Topics: Adolescent; Adult; Anemia; Erythropoietin; Humans; Kidney Diseases; Kidney Failure, Chronic; Middle Aged; Polycystic Kidney Diseases; Renal Dialysis

The relative importance of erythropoietin (Ep) and inhibition of erythropoiesis in the anemia of chronic renal insufficiency has been investigated. Sixty patients with varying degrees of renal insufficiency, 40 normal subjects and 40 patients with anemia and normal renal function, were studied. Erythroid (CFU-E) and granulocytic (CFU-GM) progenitor cell colony formation were assayed in fetal mouse liver and human bone marrow cultures, respectively. Erythropoietin was measured by radioimmunoassay. Hematocrit and plasma creatinine concentration correlated with the degree of serum inhibition of CFU-E formation (r = 0.69, P less than 0.001, and r = 0.62, P less than 0.001, respectively). Serum erythropoietin levels in patients with renal insufficiency (34.4 +/- 6.7 mU/ml) were slightly higher than normal values (23.1 +/- 0.98 mU/ml), but showed no relationship to plasma creatinine, hematocrit, or inhibition of CFU-E formation. In contrast, serum erythropoietin concentrations increased exponentially as the hematocrit decreased below 32% (r = 0.61, P less than 0.001), and CFU-E formation was stimulated by serum in anemia patients with normal renal function. Studies of granulopoiesis showed uremic sera supported in vitro CFU-GM growth more efficiently than sera from normal subjects. These results suggest that inhibition of erythroid, but not granulocytic, progenitor cell formation, in addition to a relative erythropoietin deficiency, are the primary factors responsible for the anemia of chronic renal failure.

Topics: Adolescent; Adult; Aged; Anemia; Animals; Bone Marrow Cells; Cells, Cultured; Creatinine; Erythropoiesis; Erythropoietin; Female; Fetus; Granulocytes; Hematocrit; Hematopoietic Stem Cells; Humans; Kidney Diseases; Liver; Male; Mice; Middle Aged; Radioimmunoassay

Topics: Blood Cell Count; Bloodletting; Diagnosis, Differential; Erythropoiesis; Erythropoietin; Hematocrit; Humans; Kidney Diseases; Lung Diseases; Oxygen; Phosphorus Radioisotopes; Polycythemia; Polycythemia Vera

Topics: Animals; Erythropoietin; Female; Heparin; Hydrocortisone; Kidney; Kidney Diseases; Male; Rats

Determinations of immuno-detectable Erythropoietin (idEP), haematocrit (Hct), reticulocyte counts (RC) and serum iron (SI) in uraemic patients with different kidney diseases (KD) and various lengths of chronic haemodialysis treatment (HDT) revealed firstly that all patients had normal idEP, except for analgesic nephropathies who had significantly higher idEP levels; secondly that over six years of haemodialysis idEP increased by about 40% but without concomitant Hct improvement and thirdly that there were no clear interdependencies between Hct, SI, RC and idEP in uraemic patients. In conclusion, inhibitors of erythropoiesis seem to be a major pathogenetic factor in renal anaemia besides a relative deficit in idEP.

Topics: Analgesics; Blood Cell Count; Erythropoietin; Hematocrit; Humans; Iron; Kidney Diseases; Renal Dialysis; Reticulocytes; Time Factors; Uremia

So far the question has not been elucidated whether latent ESF-deficiency exists in patients with chronic renal disease during initial development of renal anemia. Therefore, ESF was determined in urine and serum of non anemic patients being exposed to acute hypoxia: 8 healthy volunteers and 8 patients who had a Ccreat below 48 ml/min were studied while in a hypobaric chamber for 4 subsequent periods of 10 h each (simulated maximal altitude 4000 m INA = 462 mm Hg). We also determined plasma iron turnover and reticulocyte counts. 10 h after the study began, the patients showed a significantly higher ESF-level than the normal volunteers. In the course of 48 h collection periods of urine under hypoxic conditions the mean ESF excretion in patients corresponded to 9.9 and in healthy persons to 7.3 Units. With regard to plasma iron turnover and reticulocyte count an increase was shown, but no significant differences existed between the two groups. A latent ESF-deficiency as the initial cause of renal anemia does not exist.

Topics: Adult; Chronic Disease; Deficiency Diseases; Erythrocyte Count; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Hypoxia; Iron; Kidney Diseases; Male; Middle Aged

The question of a latent erythropoietin (ESF)-deficiency was studied in incipient renal anemia using a double stimulation technique for ESF. After a 4-week stimulation of ESF production with oral administration of fluoxymesterone (flu) intermittent hypoxic ESF stimulation was performed corresponding to a maximum altitude of 4000 m in 7 patients with chronic renal disease without or with incipient renal anemia (mean hematocrit 40%) and in 11 normal subjects (mean hematocrit 46%). Double stimulation in patients was compared with hypoxic stimulation alone and both were compared with controls. After flu alone only ESF excretion was increased in patients and in normal subjects. After flu plus 10 h of hypoxia serum ESF--titers were higher in healthy subjects than in the patients. The mean ESF titer after double stimulation was 81 mU/ml in patients and 115 mU/ml in normal persons. Forty-eight hour ESF excretion was 11 U and 43 U respectively. Compared to hypoxic stimulation alone double stimulation increased serum ESF titers in patients by 5% versus 80% in controls. Correspondingly, ESF excretion was enhanced by 19% and 49%, respectively. Finally, renal ESF clearance was increased by 42% versus 200%. After hypoxia alone non-anemic patients had higher serum ESF titers than healthy controls excluding a latent ESF deficiency in incipient renal anemia. It is concluded that decreased ESF production after double stimulation in patients was due to a nephrotoxic effect of flu followed by a decreased excretory and ESF-producing function of the damaged kidneys.

Topics: Adult; Anemia; Chronic Disease; Erythropoiesis; Erythropoietin; Female; Fluoxymesterone; Hematocrit; Humans; Hypoxia; Kidney; Kidney Diseases; Male; Reticulocytes

Marver & Gurney ((1968)Ann.N.Y.Acad.Sci. 149, 570-575) reported that the erythropoietin excretion in two anaemic patients increased 17 and 3.5-fold, respectively, during the production of alkaline urine by the administration of NaHCO3. We have studied the excretion of erythropoietin in 6 persons, following the daily administration of 3.5 g of NH4Cl, which resulted in an average urine pH of 5.9; and following the administration of hexapotassium hexasodium pentacitrate, which increased the urine pH TO 7.5. In the alkaline urine, erythropoietin excretion showed an average, but non-significant, two-fold increase. The increase was significant in only two experimental persons.

Topics: Adult; Aged; Ammonium Chloride; Anemia, Aplastic; Citrates; Erythropoietin; Female; Humans; Hydrogen-Ion Concentration; Kidney Diseases; Male

The Diaflo-ultrafiltration process with polyion membranes, UM 10, PM 10, and PM 30 for the determination of erythropoietin concentration in urine is compared with the method of urine dialysis in Visking tubes against Carbowax. The aberage regain of animal erythropoietin in human urine by ultrafiltration with the UM 10-membrane is 84%, with the PM 10-membrane 62%,with the PM 30-membrane 17% and with urine dialysis 71%. Mice show a lower toleration for the UM 10 concentrates than for the concentrates prepared by urine dialysis. The concentrates of kidney patients also cause a higher mortality in the animals. The concentrates are tolerated when equal amounts of urine components are incorporated in a three times larger volume and this is divided into three separate injections. Mice with polyglobulia tolerate urine concentrates when not more than 6% of a whole contrate of a 24-hours-urine per mouse is injected in the peritoneum. There is a low iron incorporation rate in the mice that show a strongly toxic reaction.

Topics: Animals; Biological Assay; Dialysis; Erythropoietin; Humans; Kidney Diseases; Membranes, Artificial; Mice; Polycythemia; Polyethylene Glycols; Ultrafiltration

Topics: Age Factors; Anemia, Hemolytic; Animals; Child; Chronic Disease; Erythropoietin; Female; Humans; Kidney Diseases; Leukemia; Male; Mice; Mice, Inbred BALB C

Topics: Anemia; Animals; Bone Marrow; Bone Marrow Cells; Cell Division; Cell Survival; Cells, Cultured; Erythrocytes; Erythropoiesis; Erythropoietin; Heme; Humans; Iron; Kidney; Kidney Diseases; Rabbits; Uremia

Topics: Anemia; Animals; Erythrocyte Aging; Erythropoietin; Female; Hematopoiesis; Hemoglobins; Humans; Iron; Kidney; Kidney Diseases; Kidney Failure, Chronic; Male; Rats; Uremia

Topics: Anemia, Hemolytic; Diet Therapy; Erythropoietin; Humans; Kidney Diseases; Kidney Transplantation; Renal Dialysis; Transplantation, Homologous

Topics: Adenocarcinoma; Aged; Erythropoietin; Female; Humans; Kidney Diseases; Kidney Failure, Chronic; Kidney Neoplasms; Kidney Transplantation; Male; Middle Aged; Polycystic Kidney Diseases

Topics: Anemia; Anemia, Hemolytic; Bone Marrow; Erythropoietin; Hemolysis; Humans; Kidney; Kidney Diseases; Uremia

Topics: Adenocarcinoma; Aged; Erythropoietin; Female; Humans; Kidney Diseases; Kidney Diseases, Cystic; Kidney Neoplasms; Male; Middle Aged; Polycythemia; Radionuclide Imaging

Topics: Acute Kidney Injury; Adult; Anemia; Animals; Blood Platelets; Disseminated Intravascular Coagulation; Erythropoietin; Female; Folic Acid; Hemolysis; Humans; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Polycythemia; Pre-Eclampsia; Pregnancy; Rabbits; Renal Dialysis; Transplantation, Homologous

Topics: Anemia, Hemolytic; Anemia, Hemolytic, Autoimmune; Anemia, Myelophthisic; Anemia, Sickle Cell; Bone Marrow; Erythropoietin; Heart Diseases; Hematocrit; Humans; Hypoxia; Kidney Diseases; Reticulocytes; Spherocytosis, Hereditary

Topics: Aminohippuric Acids; Child; Erythropoietin; Humans; Kidney; Kidney Diseases; Kidney Function Tests; Male; Polycythemia; Radiography; Renal Artery; Renal Veins; Renin; Vena Cava, Inferior

Topics: Androgens; Blood Urea Nitrogen; Erythropoietin; Female; Hematocrit; Hemoglobinometry; Humans; Iron Isotopes; Kidney Diseases; Lymph; Male; Nephrectomy; Pyelonephritis; Renal Dialysis; Testosterone; Thoracic Duct; Uremia

Topics: Animals; Cells, Cultured; Erythropoietin; Hematopoietic Stem Cells; Hemoglobins; Humans; Kidney Diseases; Sheep; Uremia

Topics: Alanine Transaminase; Anemia; Animals; Aspartate Aminotransferases; Bilirubin; Blood Cell Count; Blood Chemical Analysis; Blood Urea Nitrogen; Chemical and Drug Induced Liver Injury; Dogs; Erythropoietin; Female; Haplorhini; Hematocrit; Iron; Iron Isotopes; Kidney Diseases; Liver; Male; Mice; Necrosis; Nitrosamines; Polycythemia; Species Specificity

Topics: Acute Kidney Injury; Adult; Animals; Dogs; Erythropoietin; Female; Haplorhini; Humans; Kidney; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Renal Dialysis; Transplantation, Homologous

Topics: Animals; Erythropoiesis; Erythropoietin; Hematocrit; Hemoglobinometry; Hydronephrosis; Ischemia; Kidney Diseases; Male; Rabbits; Renal Artery Obstruction

Topics: Anemia, Aplastic; Animals; Ascites; Blood Transfusion; Chronic Disease; Erythropoietin; Female; Glomerulonephritis; Humans; Hydronephrosis; Immune Sera; Iron Isotopes; Kidney Diseases; Kidney Failure, Chronic; Male; Mice; Phenacetin; Pyelonephritis; Renal Dialysis; Uremia

Topics: Animals; Atmospheric Pressure; Blood Cell Count; Blood Pressure; Blood Volume; Carotid Arteries; Chemoreceptor Cells; Erythrocyte Count; Erythropoiesis; Erythropoietin; Hematocrit; Hemoglobinometry; Hemoglobins; Hypoxia; Ischemia; Kidney Diseases; Male; Rabbits; Rats; Renal Artery Obstruction; Time Factors; Urea

Topics: Adult; Blood Urea Nitrogen; Bone Marrow Examination; Erythropoiesis; Erythropoietin; Female; Hematocrit; Humans; Iron Isotopes; Kidney; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Renal Dialysis; Transplantation Immunology; Transplantation, Homologous; Uremia; Veins

Topics: Androgens; Child; Erythropoietin; Humans; Kidney; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Transplantation, Homologous

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Animals; Brain Neoplasms; Child; Child, Preschool; Dogs; Electric Stimulation; Erythropoiesis; Erythropoietin; Ethacrynic Acid; Haplorhini; Humans; Hydronephrosis; Hypertension; Hypothalamus; Infant; Iron Isotopes; Kidney Diseases; Kidney Neoplasms; Lung Neoplasms; Male; Mice; Middle Aged; Polycythemia Vera; Rats; Testicular Neoplasms; Testosterone; Urinary Calculi; Urologic Diseases; Wilms Tumor; Wounds and Injuries

Topics: Adult; Aged; Animals; Biological Assay; Electric Stimulation; Erythrocytes; Erythropoietin; Female; Haplorhini; Humans; Hypophysectomy; Hypothalamus; Hypoxia; Iron; Iron Isotopes; Kidney; Kidney Diseases; Kidney Diseases, Cystic; Male; Middle Aged; Neoplasms, Experimental; Polycythemia Vera; Rats; Wilms Tumor

Topics: Acute Kidney Injury; Anemia; Animals; Blood Urea Nitrogen; Dogs; Erythropoiesis; Erythropoietin; Female; Humans; Hydronephrosis; Hypoxia; Iron Isotopes; Kidney Diseases; Kidney Failure, Chronic; Kidney Neoplasms; Kidney Transplantation; Mice; Nephrectomy; Peritoneal Dialysis; Polycythemia; Rabbits; Testosterone; Transplantation, Homologous; Uremia

Topics: Adrenal Gland Neoplasms; Animals; Carcinoma; Cerebellar Neoplasms; Erythropoietin; Female; Hemangiosarcoma; Humans; Hypertension, Renal; Kidney; Kidney Diseases; Kidney Neoplasms; Liver Neoplasms; Neoplasms; Pheochromocytoma; Polycythemia; Polythiazide; Rats; Renin; Uterine Neoplasms

Topics: Adenosine Triphosphate; Animals; Erythropoietin; Folic Acid; Guanine Nucleotides; Ischemia; Kidney; Kidney Diseases; Liver Regeneration; Mice; Nephrectomy; Rats; Tissue Extracts; Xanthopterin

Topics: Adult; Animals; Biological Assay; Blood Cell Count; Bone Marrow; Erythropoiesis; Erythropoietin; Humans; Iron; Iron Isotopes; Kidney Diseases; Mice; Nephrectomy; Renal Dialysis; Renin; Splenectomy; Transplantation, Homologous

Topics: Endocrine System Diseases; Erythropoietin; Humans; Hypoxia; Kidney Diseases; Neoplasms; Polycythemia

Topics: Anemia; Animals; Biological Assay; Erythropoietin; Humans; Kidney Diseases; Liver Diseases; Rats

Topics: Anemia; Animals; Dogs; Erythropoiesis; Erythropoietin; Humans; Hypoxia; Juxtaglomerular Apparatus; Kidney; Kidney Diseases; Kidney Neoplasms; Polycythemia; Rats

Topics: Animals; Erythropoietin; Hypertrophy; Kidney; Kidney Diseases; Nephrectomy; Postoperative Complications; Rats; Tissue Extracts

Topics: Adult; Anemia; Animals; Child; Erythropoietin; Fasting; Female; Hemoglobinometry; Humans; Hyperthyroidism; Iron Isotopes; Kidney Diseases; Leukemia; Liver Diseases; Rabbits; Rats; Staphylococcal Infections; Streptococcal Infections

Topics: Animals; Erythropoietin; Female; Hematocrit; Hemorrhage; Hydronephrosis; Hypotension; Iron Isotopes; Kidney Diseases; Male; Primates; Renal Artery Obstruction; Uremia

Topics: Adolescent; Anemia, Aplastic; Anemia, Hemolytic, Autoimmune; Anemia, Hypochromic; Child; Child, Preschool; Erythroblastosis, Fetal; Erythropoietin; Female; Humans; Infant; Infant, Newborn; Kidney Diseases; Male; Pregnancy; Wilms Tumor

Topics: Adenocarcinoma; Animals; Erythropoietin; Hypertension, Renal; Ischemia; Kidney Diseases; Kidney Neoplasms; Male; Mercury; Nitrosamines; Radioisotopes; Rats

Topics: Anemia; Erythrocyte Aging; Erythropoietin; Heme; Hemoglobins; Hemolysis; Humans; Iron; Kidney Diseases; Kidney Failure, Chronic; Metabolic Diseases; Porphyrins; Uremia

Topics: Animals; Dogs; Epoetin Alfa; Erythropoietin; Hypoxia; Iron Isotopes; Ischemia; Kidney; Kidney Diseases; Physiology; Research

Topics: Animals; Blood Urea Nitrogen; Epoetin Alfa; Erythropoietin; Hypoxia; Iron Isotopes; Kidney Diseases; Mice; Pathology; Polycythemia; Rabbits; Radiometry; Renal Artery Obstruction; Research; Reticulocytes; Urea

Following the successful replacement of diseased kidneys by renal homotransplants, regression of the anemia of chronic renal disease was found in five patients. Increased erythropoietic-stimulating activity was demonstrated in the serum of one patient seven weeks after renal transplantation when he suffered a severe hemorrhage. It is postulated that a renal homotransplant can produce enough erythropoietin to maintain a normal hemoglobin value and to respond to the stimulus of a sudden hemorrhage.

Topics: Anemia; Epoetin Alfa; Erythrocyte Count; Erythropoiesis; Erythropoietin; Hemoglobins; Hemorrhage; Humans; Kidney Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Postoperative Complications; Reticulocytes; Transplantation, Homologous

Topics: Erythropoietin; Humans; Kidney Diseases; Kidney Failure, Chronic; Nephrectomy

Topics: Adolescent; Adult; Anemia; Erythropoietin; Female; Humans; Kidney Diseases; Male; Middle Aged

Topics: Erythropoietin; Humans; In Vitro Techniques; Kidney Diseases; Neoplasms; Polycythemia

Topics: Animals; Blood Volume; Epoetin Alfa; Erythrocyte Count; Erythropoietin; Hemoglobinometry; Hydronephrosis; Kidney Diseases; Physiology; Polycythemia; Rabbits; Renal Artery Obstruction; Renal Veins; Research

Topics: Epoetin Alfa; Erythropoietin; Gout; Humans; Kidney Diseases; Liver Diseases; Neoplasms; Polycythemia Vera; Thyroid Diseases

Topics: Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematologic Diseases; Humans; Kidney Diseases

Topics: Erythropoiesis; Erythropoietin; Humans; Kidney Diseases

Topics: Epoetin Alfa; Erythropoiesis; Erythropoietin; Humans; Kidney Diseases

Topics: Biological Assay; Epoetin Alfa; Erythrocytes; Erythropoiesis; Erythropoietin; Humans; Hydronephrosis; Kidney; Kidney Diseases; Kidney Diseases, Cystic; Kidney Neoplasms; Physiology; Polycythemia

Topics: Anemia; Animals; Bone Marrow; Culture Media; Epoetin Alfa; Erythropoietin; Humans; Kidney Diseases; Rabbits; Research; Tissue Culture Techniques

Topics: Epoetin Alfa; Erythropoietin; Humans; Hydronephrosis; Kidney Diseases; Plasma; Polycystic Kidney Diseases; Polycythemia