losartan-potassium and Anemia

As a novel oral agent in treating anemia of chronic kidney disease (CKD), several clinical trials of vadadustat have been conducted to compare with darbepoetin alfa. This study systematically reviews and investigates the efficacy and safety of vadadustat in the anemia treatment with different duration in both nondialysis-dependent CKD (NDD-CKD) and dialysis-dependent CKD (DD-CKD).. Several main databases were searched for randomized controlled trials (RCTs) reporting vadadustat vs darbepoetin alfa for anemia patients with CKD. The outcome indicators were focused on hemoglobin (Hb), the percentage of patients within the target Hb, the need for RBC (Red Blood Cell) transfusions, and serious adverse events (SAEs).. Four eligible studies with 8,026 participants were included. The changes of Hb levels from the baseline in the darbepoetin alfa group were significantly higher than that in the vadadustat group with DD-CKD (mean difference (MD) - 0.19, [95% confidence interval (CI), - 0.21 to - 0.17], p < 0.0001). In NDD-CKD patients, the changes of Hb levels in the two groups are not significantly different (MD = - 0.06, [95% CI, - 0.18 to 0.05], p = 0.006), especially, during the treatment duration of 20-36 weeks (MD = 0.02, [95% CI, - 0.04 to 0.08], p = 0.51). The percentage of patients within the target Hb was significantly lower in the vadadustat group than that in the darbepoetin alfa group in DD-CKD patients (MD = 0.9, [95% CI, 0.86 to 0.94], p < 0.00001), while in NDD-CKD patients, there was no significant difference (MD = 1.05, [95% CI, 0.99 to 1.12], p < 0.00001). In terms of safety, the two agents had no significant difference in the incidence of RBC transfusions and SAEs (RR = 1.26 [95% CI, 0.99 to 1.61], p = 0.52; RR = 0.97, [95% CI, 0.94 to 1.01], p = 0.19; respectively).. Compared to darbepoetin alfa, vadadustat had the same effect in raising the hemoglobin level in NDD-CKD patients in the short term. Vadadustat may become an effective and safe alternative for the treatment of patients with anemia and CKD, especially in NDD-CKD patients. As the application of vadadustat is still under exploration, future research should compensate for the limitations of our study to estimate the vadadustat's value.

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Renal Insufficiency, Chronic

Erythropoiesis-stimulating agents (ESAs) have been reported to increase the risk of death in cancer patients. In this study, we selected breast cancer, which is currently the most prevalent cancer worldwide, for a meta-analysis to re-examine the advantages and disadvantages of using ESAs. All relevant studies were searched by PubMed, Embase, Web of science, and Cochrane Library. Endpoints including mortality, incidence of thrombo-vascular events, hemoglobin, and transfusion requirements were meta-analyzed based on random-effects model or fixed-effect model. 10 studies were finally included, with a total sample size of 6785 patients. The risk of mortality was higher in patients using ESA than in controls (RR 1.07, 95% CI 1.01-1.13, P = 0.03); subgroup analysis found that the mortality rate was higher in patients treating with ESA for > 6 months (RR 1.27, 95% CI 1.05-1.55, P = 0.01) and epoetin α (RR 1.07, 95% CI 1.01-1.14, P = 0.03). The incidence of thrombo-vascular adverse events was higher in patients using ESA than in controls (RR 1.53, 95% CI 1.27-1.86, P < 0.0001). The ESA group was more effective in improving anemia in cancer patients (MD 1.20, 95% CI 0.77-1.63, P < 0.00001). The blood transfusion needs of patients in the ESA group were significantly lower (RR 0.52, 95%CI 0.44-0.60, P < 0.00001). There was no statistically significant difference between the two groups in disease progression-related conditions (HR 1.03, 95%CI 0.95-1.12, P = 0.52). ESAs increase the risk of mortality and the incidence of thrombo-vascular adverse events in breast cancer patients, while reducing their anemia symptoms and transfusion requirements. Registration PROSPERO CRD42022330450.

Topics: Anemia; Breast Neoplasms; Erythropoiesis; Erythropoietin; Female; Hematinics; Humans

Biosimilars offer the potential to expand patient access and reduce healthcare costs. Therefore, it is of importance that clinicians and patients are reassured about their efficacy and safety in practice. In 2007, Binocrit® (HX575; Sandoz GmbH, Kundl, Austria) was the first epoetin alfa biosimilar approved for use in chemotherapy induced anaemia (CIA), chronic renal failure (CRF), and more recently myelodysplastic (MDS) anaemia. Since its approval, there has been a plethora of data demonstrating the well-tolerated safety profile of HX575. This review will outline the safety results collected from key studies that have added to the extensive HX575 (Binocrit® unless otherwise stated) clinical experience. With a focus on all approved indications, we will review the safety data collected across a range of study types, to further consolidate the reassurance for the use of HX575 in these indications.

Topics: Anemia; Biosimilar Pharmaceuticals; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Recombinant Proteins; Therapeutic Equivalency

The production of erythropoietin (EPO), the main regulator of erythroid differentiation, is regulated by hypoxia-inducible factor (HIF). HIF2α seems to be the principal regulator of EPO transcription, but HIF1α and 3α also may have additional influences on erythroid maturation. HIF is also involved in the regulation of iron, an essential component in erythropoiesis. Iron is essential for the organism but is also highly toxic, so its absorption and retention are strictly controlled. HIF also induces the synthesis of proteins involved in iron regulation, thereby ensuring the availability of iron necessary for hematopoiesis. Iron is a major component of hemoglobin and is also involved in erythrocyte differentiation and proliferation and in the regulation of HIF. Renal anemia is a condition in which there is a lack of stimulation of EPO synthesis due to decreased HIF expression. HIF prolyl hydroxylase inhibitors (HIF-PHIs) stabilize HIF and thereby allow it to be potent under normoxic conditions. Therefore, unlike erythropoiesis-stimulating agents, HIF-PHI may enhance iron absorption from the intestinal tract and iron supply from reticuloendothelial macrophages and hepatocytes into the plasma, thus facilitating the availability of iron for hematopoiesis. The only HIF-PHI currently on the market worldwide is roxadustat, but in Japan, five products are available. Clinical studies to date in Japan have also shown that HIF-PHIs not only promote hematopoiesis, but also decrease hepcidin, the main regulator of iron metabolism, and increase the total iron-binding capacity (TIBC), which indicates the iron transport capacity. However, concerns about the systemic effects of HIF-PHIs have not been completely dispelled, warranting further careful monitoring.

Topics: Anemia; Erythropoietin; Humans; Hypoxia; Hypoxia-Inducible Factor-Proline Dioxygenases; Iron; Procollagen-Proline Dioxygenase; Prolyl Hydroxylases; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

The important association of erythropoietin (EPO) serum levels and chronic obstructive pulmonary disease (COPD) with anemia has been inadequately studied and remains a controversial issue. We aimed to shed light on this matter by comparing EPO levels in anemic and non-anemic COPD patients, along with a review of published literature. This cross-sectional study was conducted on COPD patients referred to the pulmonary clinic of Shahid Faghihi Hospital and Motahari clinic, Shiraz, Iran, for one year. We measured complete blood count, red blood cell indices, serum iron, TIBC and ferritin levels, serum EPO levels, and body mass index. Among 35 patients in this study, 28 males and 7 females were enrolled with a mean age of 54.57 ± 8.07 years. The average Forced expiratory volume in first second (FEV1) was 37.26 ± 7.33% and FEV1/FVC was 0.46 ± 0.12. Mean EPO levels were 30.29 ± 2.066 mU/mL. No statistically significant association was observed among erythropoietin levels and Hb, COPD severity, and age. There was no significant difference in EPO levels between anemic and non-anemic patients. EPO level, against the traditional expectation, didn't increase in COPD patients. EPO production also didn't compensate for the anemia of chronic disease which considers as a common comorbid disorder in these patients.

Topics: Anemia; Chronic Disease; Cross-Sectional Studies; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive

Hypoxia-inducible factor (HIFs) is a new class of drug developed for the management of anemia in chronic kidney disease (CKD) patients. HIFs increase the production of erythropoietin in the kidney and liver, enhance the absorption and utilization of iron, and stimulate the maturation and proliferation of erythroid progenitor cells. Besides, HIFs regulate many physiologic processes by orchestrating the transcription of hundreds of genes. Essential hypertension (HT) is an epidemic worldwide. HIFs play a role in many biological processes involved in the regulation of blood pressure (BP). In the current review, we summarize pre-clinical and clinical studies investigating the relationship between HIFs and BP regulation in patients with CKD, conflicting issues, and discuss future potential strategies.

Topics: Anemia; Erythropoietin; Essential Hypertension; Humans; Hypoxia; Kidney; Renal Insufficiency, Chronic

Anemia of prematurity affects the majority of preterm infants, particularly extremely low birthweight infants. Anemia of prematurity arises from both innate and iatrogenic causes and results in more than 80% of extremely preterm infants receiving red blood cell transfusions during the first month after birth. Multiple randomized controlled trials were conducted to evaluate the effect of using lower versus higher transfusion thresholds based on hemoglobin levels. These trials showed no difference in the primary outcome of neurodevelopmental impairment at 2 years of age between lower and higher thresholds. However, some uncertainties about transfusion thresholds remain. This review elaborates the following: 1) the etiology, prevention, and treatment of anemia of prematurity with a focus on red blood cell transfusions, 2) the history of randomized controlled trials on the treatment of anemia of prematurity, and 3) limitations of the evidence and remaining questions about thresholds for red blood cell transfusions in preterm infants.

Topics: Anemia; Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Extremely Low Birth Weight; Infant, Extremely Premature; Infant, Newborn; Retinopathy of Prematurity

Renal anemia, a common complication and threat factor of chronic kidney disease (CKD), has long been treated with injectable erythropoietin-stimulating agents (ESAs). As concerns regarding cardiovascular safety and erythropoietin resistance to ESAs have emerged, alternative therapies are urgently needed. Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), an oral agent, has been proven to be effective in improving renal anemia. However, the effects of HIF-PHIs on nondialysis-dependent CKD (NDD-CKD) have yet to be supported by updated meta-analyses.. A meta-analysis of clinical randomized controlled trials (RCTs) on HIF-PHI treatment of NDD-CKD patients based on PubMed, EMBASE, and Cochrane databases as of July 16th, 2023, was conducted. The primary outcomes were the level of hemoglobin (Hb) postintervention and the ratio of Hb responses. Most of the analysis was conducted. Twenty-two studies with a total of 7178 subjects in the HIF-PHI group, 3501 subjects in the ESA group and 2533 subjects in the placebo group were enrolled. HIF-PHIs increased the level of Hb and improved iron metabolism but were not inferior to ESAs in terms of safety.. HIF-PHIs may be a convenient and safe alternative to ESAs in patients with NDD-CKD and anemia.

Topics: Anemia; Epoetin Alfa; Erythropoietin; Humans; Hypoxia; Prolyl Hydroxylases; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Although polycythemia has been considered a common adverse event in COPD, anemia is reported more often and has gained more importance than polycythemia over the last thirty years.. Factors considered to be associated with the development of anemia in COPD have included: Aging and kidney dysfunction with erythropoietin deficiency and bone marrow suppression due to uremic toxins; heart failure (HF), often encountered in COPD and accompanied by anemia in one-third of the cases; Low-grade chronic inflammation, directly suppressing bone marrow and diminishing iron absorption and utilization via increased hepcidin levels; long-term oxygen therapy (LTOT), ameliorating chronic hypoxia, and most important, RAS inhibitors, which are widely used for the comorbidities associated with COPD (hypertension, HF, CKD, diabetes) and have previously been shown to lower hematocrit values or cause anemia in various clinical conditions.. Introduction of LTOT in COPD and especially the established use of RAS inhibitors form the basis for the shift from polycythemia to anemia in COPD. Interestingly, when the SGLT2 inhibitors are introduced for cardiorenal protection in COPD, one could anticipate correction of anemia or even reemergence of polycythemia, since this new class of drugs can augment erythropoietin secretion and increase hematocrit values.

Topics: Anemia; Antihypertensive Agents; Erythropoietin; Humans; Polycythemia; Pulmonary Disease, Chronic Obstructive; Renin-Angiotensin System

Enarodustat, a newly developed hypoxia-inducible factor prolyl hydroxylase inhibitor, is used in clinical practice in Japan. Several clinical studies showed that enarodustat corrected and maintained hemoglobin (Hb) levels by stimulating endogenous erythropoietin production and improving iron utilization in anemic patients with chronic kidney disease, regardless of whether they were on dialysis. In addition, Phase III comparative studies demonstrated that enarodustat was noninferior to darbepoetin alfa in controlling Hb levels. Furthermore, enarodustat was well tolerated during the treatment. Enarodustat is currently being developed in the Republic of Korea and China and is expected to be developed worldwide. This article reviews the data on enarodustat, including the findings from preclinical studies, pharmacokinetics/pharmacodynamics, and efficacy and safety results of clinical studies.

Topics: Anemia; Erythropoietin; Hematinics; Humans; N-substituted Glycines; Prolyl-Hydroxylase Inhibitors; Pyridines; Renal Insufficiency, Chronic; Triazoles

Iron homeostasis and erythropoiesis are strongly interconnected. On one side iron is essential to terminal erythropoiesis for hemoglobin production, on the other erythropoiesis may increase iron absorption through the production of erythroferrone, the erythroid hormone that suppresses hepcidin expression Also erythropoietin production is modulated by iron through the iron regulatory proteins-iron responsive elements that control the hypoxia inducible factor 2-α. The second transferrin receptor, an iron sensor both in the liver and in erythroid cells modulates erythropoietin sensitivity and is a further link between hepcidin and erythropoiesis. When erythropoietin is decreased in iron deficiency the erythropoietin sensitivity is increased because the second transferrin receptor is removed from cell surface. A deranged balance between erythropoiesis and iron/hepcidin may lead to anemia, as in the case of iron deficiency, defective iron uptake and erythroid utilization or subnormal recycling. Defective control of hepcidin production may cause iron deficiency, as in the recessive disorder iron refractory iron deficiency anemia or in anemia of inflammation, or in iron loading anemias, which are characterized by excessive but ineffective erythropoiesis. The elucidation of the mechanisms that regulates iron homeostasis and erythropoiesis is leading to the development of drugs for the benefit of both iron and erythropoiesis disorders.

Topics: Anemia; Erythropoiesis; Erythropoietin; Hepcidins; Humans; Iron; Iron Deficiencies; Receptors, Transferrin; Signal Transduction

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

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

Desidustat (Oxemia™) is an orally bioavailable, small molecule, hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitor developed by Zydus Cadila for the treatment of anaemia associated with chronic kidney disease (CKD), COVID-2019 infections and chemotherapy induced anaemia. Desidustat inhibits prolyl hydroxylase domain enzymes, resulting in the stabilisation of hypoxia-inducible factor which stimulates erythropoietin production and erythropoiesis. In March 2022, desidustat received its first approval in India for the treatment of anaemia in adults with CKD who are either on dialysis or not on dialysis. Desidustat is in clinical development in China for the treatment of anaemia in patients with CKD, in Mexico for the management of COVID-2019 infections and in the USA for the treatment of chemotherapy induced anaemia. This article summarizes the milestones in the development of desidustat leading to this first approval for anaemia associated with CKD.

Topics: Adult; Anemia; Antineoplastic Agents; COVID-19 Drug Treatment; Erythropoietin; Humans; Hypoxia; Prolyl Hydroxylases; Prolyl-Hydroxylase Inhibitors; Quinolones; Renal Insufficiency, Chronic

The aging of the population has led to an increased prevalence of chronic diseases such as chronic kidney disease. Anemia is one of the most frequent complications of chronic kidney disease, with an impact not only on the quality of life but also on the patient's prognosis and associated costs. Knowledge in this therapeutic area has increased significantly: from the appearance of recombinant erythropoietin in 1989, through the use of increasing doses of parenteral iron and, more recently, to new molecules such as hypoxia-inducible factor inhibitors. The aim of this article is to present a pragmatic review of the state of the art in the epidemiology, pathophysiology, diagnosis and treatment of anemia associated with chronic kidney disease.. O envelhecimento populacional tem-se traduzido no aumento de prevalência de doenças crónicas como a doença renal crónica. A anemia é uma das complicações mais frequentes da doença renal crónica, com impacto não só na qualidade de vida como no prognóstico do doente e nos custos associados. O conhecimento nesta área terapêutica tem aumentado de forma significativa: desde o aparecimento da eritropoietina recombinante em 1989, passando pelo uso de doses crescentes de ferro parentérico e, mais recentemente, a novas moléculas como os inibidores do hypoxia-inducible factor. Os autores pretendem rever, de uma forma pragmática, o estado da arte da anemia associada à doença renal crónica, desde a epidemiologia, à fisiopatologia, ao diagnóstico e ao tratamento.

Topics: Anemia; Erythropoietin; Humans; Iron; Prolyl-Hydroxylase Inhibitors; Quality of Life; Renal Insufficiency, Chronic

Anaemia is a common complication of end-stage renal disease (ESRD) that relies on dialysis. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI) is a new class of small-molecule oral drugs for the treatment of anaemia in chronic kidney disease. They demonstrate several advantages over traditional exogenous erythropoietin (EPO). We conducted a meta-analysis of studies that compared the efficacy of HIF-PHI in erythropoiesis and iron metabolism, and its safety with EPO in maintenance dialysis patients.. A sensitive search strategy in the PubMed, EMBASE and Cochrane databases identified all citations for randomised controlled trials (RCTs) comparing HIF-PHI agents with EPO/placebo through December 2021.. Fourteen RCTs were identified, which included 2738 patients. No statistical difference was found in haemoglobin increase (p = 0.37) between HIF-PHI treatment and EPO using the random-effects model. HIF-PHI administration upregulated transferrin (MD 36.12, 95% CI 27.04-45.20) and soluble transferrin receptors (sTfR) (MD 1.28, 95% CI 0.44-2.13), but did not statistically reduce hepcidin level (p = 0.37). Total and LDL-cholestrol levels were suppressed by HIF-PHI (MD - 0.99, 95% CI - 1.34 to  - 0.63) (MD - 0.99, 95% CI - 1.34 to - 0.64), while triglyceride (TG) was not different between HIF-PHI and EPO (p = 0.74). The total incident rates of treatment-emergent adverse events (TEAE) (p = 0.20) from HIF-PHI treatment were not different from those of erythropoietin, while the treatment-emergent serious adverse events (TSAE) (p = 0.02) were higher in the HIF-PHI group than those in the EPO controls with the fixed-effect model.. HIF-PHI could effectively upregulate and maintain haemoglobin levels in patients with anaemia receiving maintenance dialysis. Furthermore, HIF-PHI could elevate iron metabolism activity and utility without inducing treatment-associated serious adverse events. Robust data from larger RCTs with longer treatment duration and follow-up are needed.

Topics: Anemia; Erythropoietin; Hepcidins; Humans; Hypoxia; Iron; Prolyl-Hydroxylase Inhibitors; Receptors, Transferrin; Renal Dialysis; Renal Insufficiency, Chronic; Transferrin; Triglycerides

Anemia is a common complication of chronic kidney disease; it is mainly treated with erythropoiesis-stimulating agents (ESAs) and iron. Experimental studies extensively investigated the mechanisms involved in the body's response to hypoxia and led to the discovery of the hypoxia-inducible factor (HIF) pathway and the enzymes regulating its function. HIF-prolyl-hydroxyl domain (PHD) inhibitors are a new class of oral drugs developed to treat anemia in chronic kidney disease. By inhibiting the function of PHD enzymes, they mimic the exposure to moderate hypoxia and stimulate the production of endogenous erythropoietin and very likely increase iron availability. Some data also suggest that their efficacy and, consequently, dose needs are less influenced by inflammation than ESAs. Overall, data from phases 2 and 3 clinical development showed efficacy in anemia correction and maintenance for all of the class molecules compared with placebo (superiority) or erythropoiesis-stimulating agents (noninferiority). Three molecules, roxadustat, vadadustat, and daprodustat, underwent extensive clinical investigation to assess their safety on hard cardiovascular end points, mortality, and special interest events (including cancer and thrombosis). Aside from vadadustat in the nondialysis population, at the prespecified primary analyses, all three molecules met the noninferiority margin for the risk of major cardiovascular events compared with erythropoiesis-stimulating agents or placebo. The reason for this discrepancy is difficult to explain. Other safety signals came from secondary analyses of some of the other randomized clinical trials, including a higher incidence of thrombosis. A more extensive clinical experience with post-marketing data on hard safety issues is needed to define better when and how to use HIF-PHD inhibitors compared with already available ESAs.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Hypoxia; Hypoxia-Inducible Factor-Proline Dioxygenases; Iron; Renal Insufficiency, Chronic

Anemia of chronic kidney disease (CKD) has traditionally been treated with recombinant human erythropoietin (rhEPO). Recently, daprodustat, a hypoxia-inducible factor prolyl-hydroxylase inhibitor, has also been shown to increase hematocrit. It remains unclear whether daprodustat or rhEPO should be the treatment of choice for anemia of CKD. We aimed to assess the efficacy and cardiovascular safety of daprodustat versus rhEPO in CKD patients.. Online databases were queried in April 2022 for articles comparing the efficacy and safety of daprodustat in DD-CKD and NDD-CKD subgroups. Results from trials were pooled using a random-effects model.. Data on 8245 CKD patients from eight clinical trials were included. Our results show that in comparison to rhEPO, daprodustat maintained the same efficacy in increasing hemoglobin levels in both the DD-CKD (MD: 0.10; 95% CI [- 0.13,0.34]; p = 0.50) and NDD-CKD (MD: - 0.01; 95% CI [- 0.38,0.35]; p = 0.95) subgroups. Daprodustat significantly lowered hepcidin levels and significantly increased TIBC in both subgroups. Additionally, daprodustat significantly reduced the incidence of major adverse cardiovascular events (MACE) (RR: 0.89; 95% CI: 0.89-0.98; p = 0.02) and its myocardial infarction (MI) component (RR: 0.74; 95% CI: 0.59-0.92; p = 0.006) in the DD-CKD subgroup.. Daprodustat has similar efficacy compared to rhEPO for the treatment of anemia of CKD. On treatment, the reduced experience of MACE was reported in DD-CKD patients as compared to rhEPO. Furthermore, effects on iron metabolism varied by parameter, with daprodustat being superior to rhEPO in some cases and inferior in others.

Topics: Anemia; Barbiturates; Erythropoietin; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic

Chronic kidney disease (CKD) affects approximately 10% of the worldwide population; anaemia is a frequent complication. Inadequate erythropoietin production and absolute or functional iron deficiency are the major causes. Accordingly, the current treatment is based on iron and erythropoiesis stimulating agents (ESAs). Available therapy has dramatically improved the management of anaemia and the quality of life. However, safety concerns were raised over ESA use, especially when aiming to reach near-to-normal haemoglobin levels with high doses. Moreover, many patients show hypo-responsiveness to ESA. Hypoxia-inducible factor (HIF) prolyl hydroxylase domain (PHD) inhibitors (HIF-PHIs) were developed for the oral treatment of anaemia in CKD to overcome these concerns. They simulate the body's exposure to moderate hypoxia, stimulating the production of endogenous erythropoietin. Some molecules are already approved for clinical use in some countries. Data from clinical trials showed non-inferiority in anaemia correction compared to ESA or superiority for placebo. Hypoxia-inducible factor-prolyl hydroxylase domain inhibitors may also have additional advantages in inflamed patients, improving iron utilisation and mobilisation and decreasing LDL-cholesterol. Overall, non-inferiority was also shown in major cardiovascular events, except for one molecule in the non-dialysis population. This was an unexpected finding, considering the lower erythropoietin levels reached using these drugs due to their peculiar mechanism of action. More data and longer follow-ups are necessary to better clarifying safety issues and further investigate the variety of pathways activated by HIF, which could have either positive or negative effects and could differentiate HIF-PHIs from ESAs.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Iron; Prolyl Hydroxylases; Prolyl-Hydroxylase Inhibitors; Quality of Life; Renal Insufficiency, Chronic

Anemia is a common feature and complication of chronic kidney disease (CKD). Erythropoiesis-stimulating agents (ESAs) and recombinant human erythropoietin have been used widely in renal anemia treatment. Recently, hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs) that may improve the treatment of renal anemia patients were launched. Previous studies indicated that HIF-PHIs may decrease hepcidin levels and modulate iron metabolism, thereby increasing total iron-binding capacity and reducing the need for iron supplementation. Furthermore, HIF-PHIs can reduce inflammation and oxidative stress in CKD. Recombinant erythropoietin has become a routine treatment for patients with CKD and end-stage renal disease with relatively few adverse effects. However, higher doses of recombinant erythropoietin have been demonstrated to be an independent predictor of mortality in patients under hemodialysis. Phase III clinical trials of HIF-PHIs in patients with anemia and dialysis-dependent CKD have shown their efficacy and safety in both non-dialysis and dialysis CKD patients. However, HIFα binds to specific hypoxia-response elements in the vascular endothelial growth factor or retinoic acid-related orphan receptor gamma t (RORγt) promoter, which may be involved in the progression of cancer, psoriasis, and rheumatoid arthritis. In this paper, we have summarized the mechanism, clinical application, and clinical trials of HIF-PHIs in the treatment of renal anemia and aimed to provide an overview of the new drugs in clinical practice, as well as reconsider the advantages and disadvantages of HIF-PHIs and ESAs. Presently, there are not enough clinical studies examining the effects of long-term administration of HIF-PHIs. Therefore, further studies will be needed.

Topics: Anemia; Animals; Basic Helix-Loop-Helix Transcription Factors; Cardiovascular Diseases; Enzyme Inhibitors; Erythropoietin; Hematinics; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Renal Insufficiency, Chronic

Anemia is a frequent comorbidity of chronic kidney disease (CKD) and is associated with a considerable burden because of decreased patient health-related quality of life and increased healthcare resource utilization. Based on observational data, anemia is associated with an increased risk of CKD progression, cardiovascular events, and all-cause mortality. The current standard of care includes oral or intravenous iron supplementation, erythropoiesis-stimulating agents, and red blood cell transfusion. However, each of these therapies has its own set of population-specific patient concerns, including increased risk of cardiovascular disease, thrombosis, and mortality. Patients receiving dialysis or those who have concurrent diabetes or high blood pressure may be at greater risk of developing these complications. In particular, treatment with high doses of erythropoiesis-stimulating agents has been associated with increased rates of hospitalization, cardiovascular events, and mortality. Resistance to erythropoiesis-stimulating agents remains a therapeutic challenge in a subset of patients. Hypoxia-inducible factor transcription factors, which regulate several genes involved in erythropoiesis and iron metabolism, can be stabilized by a new class of drugs that act as inhibitors of hypoxia-inducible factor prolyl-hydroxylase enzymes to promote erythropoiesis and elevate hemoglobin levels. Here, we review the burden of anemia of chronic kidney disease, the shortcomings of current standard of care, and the potential practical advantages of hypoxia-inducible factor prolyl-hydroxylase inhibitors in the treatment of patients with anemia of CKD.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Prolyl-Hydroxylase Inhibitors; Quality of Life; Renal Insufficiency, Chronic

Anaemia of chronic disease (ACD) is generated by the activation of the immune system by autoantigens, microbial molecules or tumour antigens resulting in the release of cytokines that cause an elevation of serum hepcidin, hypoferraemia, suppression of erythropoiesis, decrease in erythropoietin (EPO) and shortening of the half-life of red blood cells. Anaemia is usually normocytic and normochromic, which is the most prevalent after iron deficiency anaemia, and it is the most frequent in the elderly and in hospitalized patients. If the anaemia is severe, the patient's quality of life deteriorates, and it can have a negative impact on survival. Treatment is aimed at controlling the underlying disease and correcting anaemia. Sometimes intravenous iron and EPO have been used, but the therapeutic future is directed against hepcidin, which is the final target of anaemia.

Topics: Aged; Anemia; Chronic Disease; Erythropoietin; Hepcidins; Humans; Iron; Quality of Life

Recombinant human erythropoietin (rHuEPO) has been used worldwide for treatment of renal anaemia due to its good curative effect. However, rHuEPO treatment is associated with a rare but severe complication because of the development of anti-EPO antibodies, which are difficult to treat. Currently, the main treatments for the anti-EPO antibodies include withdrawing the rHuEPO, providing blood transfusions and administrating steroid-based immunosuppressive agents. Although the above methods can alleviate anti-EPO-related anaemia, there are obvious side-effects such as decreased immunity and an increased risk of infection. Therefore, accurately identifying anti-EPO-related anaemia and effectively treating this complication is worth exploring. This current case report describes a 49-year-old female patient with chronic kidney disease that received rHuEPO subcutaneously and then developed anti-EPO antibody-mediated renal anaemia with her haemoglobin levels dropping to 37 g/l. The patient refused to be treated with steroids, so she received 120 mg roxadustat administered orally every 72 h and her Hb level increased to 110 g/l over a few months. This current case report demonstrates that roxadustat can be used to successfully treat anti-EPO antibody-mediated renal anaemia without the use of steroid-based immunosuppressants.

Topics: Anemia; Erythropoietin; Female; Glycine; Humans; Isoquinolines; Middle Aged; Recombinant Proteins

Erythropoiesis stimulating agents are exogenous erythropoietin medications that are used to stimulate the bone marrow red blood cells' production for the management of anemia of chronic kidney disease, some anticancer drugs, myelodysplastic syndrome, and others. Currently, there are different erythropoiesis stimulating agents accessible in the market. The objective of this narrative literature review is to summarize the role of some erythropoiesis stimulating agents in the treatment of anemia.. The following method was used to prepare this narrative literature review. The comprehensive computerized search of literatures was carried out using PubMed, Cochrane library, Google scholar, and Science direct. Keywords such as recombinant human erythropoietin, epoetin, darbepoetin, continuous erythropoietin receptor agonist, pegzyrepoetin alfa, erythropoiesis stimulating agents in combination with anemia/anaemia were used. The pertinent original and review full articles which are written in the English language were included in this narrative review.. From the discussions of the literature, erythropoiesis stimulating agents that are produced by different biosimilar manufacturers have different clinical characteristics and stabilities as a result of their chemical modifications. The chemical modifications of erythropoiesis stimulating agents like glycosylation and polyethylene glycosylation determine the half-life, affinity to erythropoietin receptor, and immune response of the agents. Erythro-poiesis stimulating agents are categorized as short-acting and long-acting agents due to their chemical structures that influence the clinical efficacy and safety of the agents.. The effectiveness of the agents is different in different patients depending on the individual characteristics and etiologies of anemia. The agents not only have the benefits but also, they have the risks for the patients. Hence, the risks and benefits of erythropoiesis stimulating agents must be given special consideration in the managements of anemia to get maximum efficacy for anemic patients. The treatment is dependent on hemoglobin levels of individual patients. The physician must follow the patients during and after therapy using erythropoiesis stimulating agents.

Topics: Anemia; Darbepoetin alfa; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematinics; Humans; Recombinant Proteins

In this review paper, we examine the latest evidence regarding the use of iron supplementation, erythropoiesis-stimulating agents (ESAs), and blood transfusions as therapeutic targets for anemia to mitigate morbidity and mortality in patients with cardiovascular disease.. Intravenous ferric carboxymaltose (FC) injections in heart failure (HF) have resulted in improved self-reported patient symptoms; higher exercise capacity, as measured by 6-min walk test distance in anemic patients; and lower re-hospitalization rates in iron deficient patients. Darbepoetin alfa has shown evidence of improved Kansas City Cardiomyopathy Questionnaire scores. No mortality benefits have been noted thus far with FC injections or darbepoetin in HF, with an increase in adverse events with darbepoetin. Aggressive transfusions (Hg < 10 g/dL) are not associated with improved outcomes in cardiovascular disease. Quality of life metrics, rather than mortality, appear to improve with IV FC and ESA use in HF. More studies are required to see if these treatments have a role in coronary artery disease. Current evidence suggests that anemia is a marker of underlying disease severity, with a limited role in disease modification. Further studies are required to solidify our understanding of this topic.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Humans; Quality of Life; Severity of Illness Index

Pre-term infants have one of the highest transfusion requirements within the hospital-setting. The vast majority of blood transfusions performed in Neonatal Intensive Care Units (NICUs) are for medically stable pre-term infants with anaemia of prematurity, with the aim of improving oxygen delivery to the vital organs during the crucial phase of growth and development. However, despite the frequency of transfusion in this population, the potential benefits and harms of 'top up' transfusion are not fully understood, leading to practice variation between clinicians, institutions and countries. Significant advances have been made in the prevention of anaemia of prematurity, with recent emphasis on optimising infants' circulatory volume at birth via placental transfusion and preserving infants' own blood volume through innovative minimal sampling techniques. More research is urgently needed to establish optimal transfusion thresholds for these high-risk pre-term infants, for whom benefits as well as adverse outcomes may have consequences that extend for decades throughout the recipients' life-course. In this review, we will discuss some of the consensus and controversies regarding optimal management of anaemia in pre-term infants and highlight potential areas for future research.

Topics: Anemia; Constriction; Delivery, Obstetric; Disease Management; Erythrocyte Transfusion; Erythropoietin; Fetal Blood; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Ligation; Risk Factors; Time Factors; Umbilical Cord

Cancer and chemotherapy-induced anemia (CIA) is commonly encountered among patients undergoing active chemotherapy with or without radiation therapy. Its pathogenesis is complex and is often difficult to identify. Symptoms related to CIA may have a negative impact on quality of life and may influence treatment efficacy, disease progression and even survival. The recent major setback of erythropoietin-stimulating agents (ESAs) and the reluctance to transfuse cancer patients with mild and even moderate anemia, had resulted in significant under-treatment of CIA. The discovery of hepcidin and its role in iron homeostasis has revolutionized our understanding of the pathogenesis of iron deficiency and iron overload states. In the present review we examine the multifactorial pathogenesis of CIA, addressing the main mechanisms by which the tumor and immune system affect anemia. Additionally, we discuss the treatment options with more focus on the utilization of the new intravenous iron formulations for this indication.

Topics: Anemia; Antineoplastic Agents; Erythropoietin; Hematinics; Humans; Neoplasms; Quality of Life

Topics: Anemia; Anemia, Iron-Deficiency; Erythropoietin; Humans; Renal Insufficiency, Chronic; Risk Factors

Anemia is frequently observed in the course of chronic kidney disease (CKD) and it is associated with diminishing the quality of a patient's life. It also enhances morbidity and mortality and hastens the CKD progression rate. Patients with CKD frequently suffer from a chronic inflammatory state which is related to a vast range of underlying factors. The results of studies have demonstrated that persistent inflammation may contribute to the variability in Hb levels and hyporesponsiveness to erythropoietin stimulating agents (ESA), which are frequently observed in CKD patients. The understanding of the impact of inflammatory cytokines on erythropoietin production and hepcidin synthesis will enable one to unravel the net of interactions of multiple factors involved in the pathogenesis of the anemia of chronic disease. It seems that anti-cytokine and anti-oxidative treatment strategies may be the future of pharmacological interventions aiming at the treatment of inflammation-associated hyporesponsiveness to ESA. The discovery of new therapeutic approaches towards the treatment of anemia in CKD patients has become highly awaited. The treatment of anemia with erythropoietin (EPO) was associated with great benefits for some patients but not all.

Topics: Anemia; Animals; Antioxidants; Cytokines; Erythropoietin; Humans; Inflammation; Renal Insufficiency, Chronic

Anaemia is a common finding in diabetes, particularly in those patients with albuminuria or renal dysfunction and is associated with impaired erythropoietin (EPO) secretion. This review focuses on mechanisms involved in the regulation of erythropoiesis in diabetic patients in an effort to elucidate the competing effects of the renin angiotensin system (RAS) blockade and sodium-glucose cotransporter-2 (SGLT2) inhibitors on haemoglobin concentration and hematocrit values.. The RAS shows significant activation in diabetic subjects. Angiotensin II, its active octapeptide, causes renal tubulointerstitial hypoxia, which stimulates hypoxia-inducible factors (HIF) and increases EPO secretion and erythropoiesis. As expected, drugs that inactivate RAS, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB) are associated with a significant hematocrit-lowering effect and/or anaemia in various clinical conditions, including diabetes. Dual blockade by a combination of ACEi and ARB in diabetic patients achieves a better RAS inhibition, but at the same time a worse drop of haemoglobin concentration. Increased glucose reabsorption by SGLTs in diabetic subjects generates a high-glucose environment in renal tubulointerstitium, which may impair HIF-1, damage renal erythropoietin-producing cells (REPs) and decrease EPO secretion and erythropoiesis. SGLT2 inhibitors, which inhibit glucose reabsorption, may attenuate glucotoxicity in renal tubulointerstitium, allowing REPs to resume their function and increase EPO secretion. Indeed, EPO levels increase within a few weeks after initiation of therapy with all known SGLT2 inhibitors, followed by increased reticulocyte count and a gradual elevation of haemoglobin concentration and hematocrit level, which reach zenith values after 2-3 months. Key Messages: The competing effects of RAS blockade and SGLT2 inhibitors on erythropoiesis may have important clinical implications. The rise of hematocrit values by SGLT2 inhibitors given on top of RAS blockade in recent outcome trials may significantly contribute to the cardiorenal protection attained. The relative contribution of each system to erythropoiesis and outcome remains to be revealed in future studies.

Topics: Anemia; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoiesis; Erythropoietin; Hematocrit; Hemoglobins; Humans; Hypertension; Kidney Tubules; Renal Reabsorption; Renin-Angiotensin System; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Prolyl hydroxylase (PHD) inhibitors, such as roxadustat, can stabilize hypoxia-inducible factor (HIF)-2α and induce erythropoietin (EPO) production under normal conditions. Roxadustat was recently approved as a first-in-class orally active drug for the treatment of renal anemia. In addition, it has garnered growing therapeutic interest for use against various diseases, such as carcinoma, neurological diseases, ocular diseases, and tissue and organ injuries. In this review, we systemically review target validation, hit identification, and further key clinical trials of roxadustat. The prospective clinical applications of PHD inhibitors are then discussed based on this marketed drug.

Topics: Anemia; Animals; Drug Discovery; Erythropoietin; Glycine; Humans; Isoquinolines; Prolyl-Hydroxylase Inhibitors

Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are orally active small molecules and are launched as novel therapeutic agents for anemia in chronic kidney disease (CKD). In contrast to conventional exogenous erythropoietin (EPO) administration, HIF-PHIs stimulate endogenous EPO production and improve iron metabolism via stabilization of hypoxia-inducible factor (HIF). This review summarizes the mechanism of action, the results of clinical trials, and future perspectives of HIF-PHIs.. Six HIF-PHIs are currently under phase III studies, some of which have been already completed. According to the results of clinical trials, HIF-PHIs increased and maintained hemoglobin levels in both nondialysis-dependent and dialysis-dependent CKD patients with physiological EPO concentrations. HIF-PHIs also improved iron utilization and were comparably effective regardless of underlying inflammation and iron status.. HIF-PHIs have several advantages including oral administration, physiological EPO secretion, and improved iron utilization. Undoubtedly, HIF-PHIs will pave the new way in the field of treatment of anemia in CKD, but it should be noted that HIFs have pleiotropic effects on a plethora of cellular functions, which might lead to either beneficial or undesirable off-target effects. Intensive postmarketing surveillance is crucially important to identify unexpected consequences.

Topics: Anemia; Erythropoietin; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Iron; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

The hypoxia-inducible factor prolyl hydroxylase (HIF-PH) pathway is responsible for regulating the biosynthesis of erythropoietin (EPO) and maintaining iron homeostasis. Investigational drugs that target the HIF-PH pathway are promising alternatives for treating anemia in Chronic Kidney Disease (CKD).. This review summarizes recent advances focused on the clinical development of HIF-PH inhibitors (HIF-PHIs) as potentially novel therapies in the treatment of anemia in CKD based on publications available on PubMed and restricted Google searches. We provide a comparison between HIF-PHIs regarding their pharmacokinetics, dosing regimens and safety concerns, structure-activity relationships, and alterations in key laboratory parameters observed in animal models and clinical trials.. HIF-PHIs may be advantageous in some aspects compared to the conventional erythropoiesis-stimulating agents (ESAs). While ESAs could increase the risk of cardiovascular events due to rapid rises in ESA blood levels, HIF-PHIs have been reported to maintain EPO concentrations at levels that are closer to the normal physiological ranges. Although HIF-PHIs have been demonstrated to be relatively safe and effective in clinical trials, long-term safety data are needed in order to establish whether these therapeutic agents will lead to a major paradigm change in the treatment of anemia of CKD.

Topics: Anemia; Animals; Drugs, Investigational; Erythropoietin; Hematinics; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

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

Anemia is a common finding in the perioperative setting with significant untoward consequences including worsening of outcomes and diminished quality of life as well as increased risk of allogeneic blood transfusions. Here, we present 3 cases that illustrate how anemia can be perioperatively managed in patients undergoing cardiac, orthopedic, and oncology surgeries. Timely detection of anemia prior to high-blood loss surgeries can allow clinicians to manage it and optimize hemoglobin level, making patients better prepared for the surgery. Treatment of anemia should be guided by the etiology and may include erythropoietic agents, folic acid, B12, and iron preparations. Other blood management strategies geared toward reducing surgical blood loss such as autologous transfusion techniques and agents to optimize hemostasis are used during surgery and in the immediate postoperative period. Patients should be closely monitored following surgery for signs of ongoing bleeding in need of control. Finally, screening for and management of anemia should continue in the postoperative and postdischarge period, as persistence and recurrence of anemia can further undermine patient's outcomes.

Topics: Anemia; Blood Loss, Surgical; Blood Transfusion, Autologous; Erythrocyte Transfusion; Erythropoietin; Humans; Iron; Perioperative Care; Postoperative Complications

Topics: Anemia; Betacoronavirus; Biomarkers; Clinical Laboratory Techniques; Coronavirus; Coronavirus Infections; COVID-19; COVID-19 Testing; Erythropoietin; Ferritins; Hemoglobins; Hepcidins; Humans; Iron; Pandemics; Pneumonia, Viral; Receptors, Transferrin; SARS-CoV-2; Transferrin

Hypoxia-inducible factor-prolyl hydroxylase inhibitors (HIF-PHIs) are orally active first-in-class new generation drugs for renal anemia. This extensive meta-analysis of randomized controlled trials (RCTs) was designed to provide clear information on the efficacy and safety of HIF-PHIs on anemia in chronic kidney disease (CKD) patients. Searches included PubMed, Web of Science, Ovid MEDLINE, and Cochrane Library database up to October 2019. RCTs of patients with CKD comparing HIF-PHIs with erythropoiesis-stimulating agents (ESAs) or placebo in the treatment of anemia. The primary outcome was hemoglobin change from baseline (Hb CFB); the secondary outcomes included iron-related parameters and the occurrence of each adverse event. 26 trials in 17 articles were included, with a total of 2804 dialysis or patients with CKD. HIF-PHIs treatment produced a significant beneficial effect on Hb CFB compared with the placebo group (MD, 0.69; 95% CI, 0.36 to 1.02). However, this favored effect of HIF-PHIs treatment was not observed in subgroup analysis among trials compared with ESAs (MD, 0.06; 95% CI, -0.20 to 0.31). The significant reduction in hepcidin by HIF-PHIs was observed in all subgroups when compared with the placebo group, whereas this effect was observed only in NDD-CKD patients when compared with ESAs. HIF-PHIs increased the risk of nausea (RR, 2.20; 95% CI, 1.06 to 4.53) and diarrhea (RR, 1.75; 95% CI, 1.06 to 2.92). We conclude that orally given HIF-PHIs are at least as efficacious as ESAs treatment to correct anemia short term in patients with CKD. In addition, HIF-PHIs improved iron metabolism and utilization in patients with CKD.

Topics: Anemia; Erythropoietin; Hematinics; Hepcidins; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Prolyl-Hydroxylase Inhibitors; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic

Anemia has and will continue to be a central theme in medicine particularly as clinicians are treating a burgeoning population of complex multi-organ system processes. As a result of multiple randomized controlled trials (RCTs), meta-analyses, and societal recommendations overly restrictive paradigms and under-administration of erythropoiesis stimulating agents (ESAs) have likely been followed by clinicians among all specialties.. A review of anemia in the context of chronic kidney disease, hematologic malignancies, and cancer is presented with focus on the establishment of ESAs as integral in the treatment of anemia. Multiple RCTs and meta-analyses studying the use of ESAs are presented with focus upon their application to clinical practice. A 'compendium' is proffered describing the evolution, establishment, and implications of ESA administration initially among those with CKD with rapid subsequent application to the Hematology-Oncology population of patients. Literature search methodologies have included MEDLINE (1985-2020), PubMed (1996-2020), Cochrane Central Trials (1985-2020), EMBASE (2000-2020), and ClinicalTrials.gov (2000-2020).. Upon evaluation of risks and benefits of ESAs focused opinion and commentary is made supporting more liberal use of these agents and strongly suggesting that the current underlying treatment 'pendulum' has perhaps shifted too far to the 'under-treatment' side in many cases.

Topics: Anemia; Blood Transfusion; Combined Modality Therapy; COVID-19; Epoetin Alfa; Erythropoietin; Expert Testimony; Forecasting; Guideline Adherence; Hematinics; Hematologic Neoplasms; Hematopoiesis; Humans; Iron; Medicine; Meta-Analysis as Topic; Multicenter Studies as Topic; Myocardial Ischemia; Neoplasms; Observational Studies as Topic; Pandemics; Practice Guidelines as Topic; Practice Patterns, Physicians'; Randomized Controlled Trials as Topic; Receptors, Erythropoietin; Renal Dialysis; Renal Insufficiency, Chronic; SARS-CoV-2; Venous Thromboembolism

Anemia is a common diagnosis in patients with cancer that may affect both quality of life and survival. Anemia in this patient population is often multifactorial, caused by direct effects of the malignancy, products secondary to the malignancy, the effects of treatment, or other factors. Therefore, a systematic approach is required to determine the true cause or causes of anemia. An appropriate workup of anemia in patients with cancer can lead to treatment with the potential to reduce transfusion needs and improve quality of life. The clinical benefit of these interventions for specific patients must be weighed against possible risk.

Topics: Anemia; Blood Transfusion; Erythropoietin; Humans; Neoplasms

Prolyl-hydroxylase (PHD) inhibitors (PHD-I) are the most appealing drugs undergoing clinical development for the treatment of anaemia in patients with chronic kidney disease. PHD inhibition mimics the exposure of the body to hypoxia and activates the hypoxia-inducible factor system. Among many other pathways, this activation promotes the production of endogenous erythropoietin (EPO) and the absorption and mobilization of iron. PHD-I are given orally and, differing from erythropoiesis-stimulating agents (ESAs), they correct and maintain haemoglobin levels by stimulating endogenous EPO production. Their efficacy and safety are supported by several Phases I and II studies with relatively short follow-up. This class of drugs has the potential to have a better safety profile than ESAs and there may be additional advantages for cardiovascular disease (CVD), osteoporosis and metabolism. However, possible adverse outcomes are feared. These span from the worsening or occurrence of new cancer, to eye complications or pulmonary hypertension. The data from the ongoing Phase III studies are awaited to better clarify the long-term safety and possible advantages of PHD-I.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Prognosis; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Anemia is the major complication resulting from chronic kidney disease (CKD) and also a risk factor for cardiovascular events and a poor quality of life (QoL). Diabetic kidney disease (DKD) is the major cause of CKD. Initially, insulin resistance has been reported to increase erythropoiesis, but it might be a minor issue. DKD-related anemia developed earlier and was more severe than non-DKD-related anemia based on more complicated mechanisms, including greater bleeding tendency associated with antiplatelet effect, less O2 sensing due to autonomic neuropathy or renin-angiotensin-aldosterone system inhibitor use, inhibitory effect of inflammatory cytokines, urinary loss of erythropoietin (EPO), and poor response to EPO. In DKD patients, prompt correction of anemia allows for a better cardiovascular outcome and QoL, which are similar to the promising effect of anemia correction in CKD patients. However, current evidence recommended that the avoidance of a high or normalized hemoglobin (Hb) level has been suggested in the treatment of anemia in DKD patients. Despite that EPO has a pleotropic effect on renal protection from animal studies, the renal benefit was less evident in CKD and DKD patients. Recently, the antidiabetic agent, sodium glucose cotransporter-2 inhibitors (SGLT2i), has been reported to exhibit the renal benefits due to the tubulo-glomerular feedback in addition to sugar control. It may also be due to less renal ischemic through higher EPO levels, followed by higher Hb levels. More studies are needed to clarify the link between the renal benefit of SGLT2i and EPO production.

Topics: Anemia; Diabetic Nephropathies; Erythropoietin; Humans; Renal Insufficiency, Chronic

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

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

Over the past two decades it has emerged that, in addition to erythropoietic activity, erythropoietin (EPO) has numerous other functions, including neuro-protective, anti-apoptotic, antioxidant, angiogenetic and immunomodulatory ones. EPO interacts with two different forms of its receptor (EPOR): a homodimer receptor, responsible for the erythropoietic effects, and a heterodimer receptor, responsible for the non-erythropoietic effects. The effects on the heterodimer receptor are responsible for EPO-induced prolongation of organ transplant survival in mice and humans. The development of new molecules that selectively target the heterodimer EPOR is allowing to test the effect of long-term treatments, without the possible complications related to the increased hematocrit.

Topics: Adaptive Immunity; Anemia; Animals; Cell Hypoxia; Erythropoiesis; Erythropoietin; Graft Survival; Heart; Humans; Immunity, Cellular; Immunity, Innate; Kidney; Mice; Nervous System; Organ Transplantation; Rats; Receptors, Colony-Stimulating Factor; Receptors, Erythropoietin; Recombinant Proteins; Renal Insufficiency, Chronic; Retina

Anemia is a common complication of chronic kidney disease (CKD) in adult and pediatric patients. It has traditionally been treated with erythropoietin therapy and iron supplementation, with great success. With the discovery of the major transcription factor hypoxia inducible factor (HIF) for the erythropoietin gene in 1992, molecules were created that inhibit the HIF prolyl-hydroxylase enzyme. This new class of drug-called HIF stabilizers, or HIF prolyl-hydroxylase inhibitors-prevents the proteasomal degradation of HIF-α, thereby inducing upregulation of the erythropoietin gene. This new strategy for treating CKD anemia is already in phase III clinical trials in adults, and the potential advantages of this therapy are that it is orally active (thereby avoiding injections), and patients are exposed to lower circulating levels of erythropoietin. The long-term safety of this strategy, however, requires elucidation in these trials, particularly since there are many other hypoxia-sensitive genes, notably, angiogenic factors such as vascular endothelial growth factors (VEGF), as well as glycolytic enzymes. As with all new therapies, it is only once a positive benefit: risk profile has been ascertained in adults that the treatment will translate across into pediatrics. Specific issues in the pediatric CKD population are discussed in this review.

Topics: Adult; Age Factors; Anemia; Animals; Child; Clinical Trials, Phase III as Topic; Disease Models, Animal; Erythropoiesis; Erythropoietin; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Prolyl-Hydroxylase Inhibitors; Proteolysis; Renal Insufficiency, Chronic; Signal Transduction; Treatment Outcome; Up-Regulation; Vascular Endothelial Growth Factor A; Von Hippel-Lindau Tumor Suppressor Protein

Erythropoiesis is the predominant consumer of iron in humans and other vertebrates. By decreasing the transcription of the gene encoding the iron-regulatory hormone hepcidin, erythropoietic activity stimulates iron absorption, as well as the release of iron from recycling macrophages and from stores in hepatocytes. The main erythroid regulator of hepcidin is erythroferrone (ERFE), synthesized and secreted by erythroblasts in the marrow and extramedullary sites. The production of ERFE is induced by erythropoietin (EPO) and is also proportional to the total number of responsive erythroblasts. ERFE acts on hepatocytes to suppress the production of hepcidin, through an as yet unknown mechanism that involves the bone morphogenetic protein pathway. By suppressing hepcidin, ERFE facilitates iron delivery during stress erythropoiesis but also contributes to iron overload in anemias with ineffective erythropoiesis. Although most of these mechanisms have been defined in mouse models, studies to date indicate that the pathophysiology of ERFE is similar in humans. ERFE antagonists and mimics may prove useful for the prevention and treatment of iron disorders.

Topics: Anemia; Bone Morphogenetic Proteins; Erythropoiesis; Erythropoietin; Hepatocytes; Hepcidins; Humans; Iron; Iron Overload; Macrophages; Peptide Hormones

Despite multiple factors correlating with the high prevalence of anaemia in heart failure, the prevailing mechanisms have yet to be established. The purpose of this study is to systematically review the literature and determine whether low circulating haemoglobin is primarily underlain by erythropoietin resistance or defective production in heart failure.. We conducted a systematic search of MEDLINE since its inception until May 2017 for articles reporting erythropoietin and haemoglobin concentrations in heart failure patients not treated with erythropoietin-stimulating agents. The primary outcome was the mean difference in observed/predicted (O/P) erythropoietin ratio between heart failure patients and normal reference values. Meta-regression analyses assessed the influence of potential moderating factors.. Forty-one studies were included after systematic review, comprising a total of 3137 stable heart failure patients with mean age and left ventricular ejection fraction ranging from 52 years to 80 years and 21% to 59%. The O/P erythropoietin ratio was below reference values in 24 of 25 studies in anaemic heart failure patients ( n = 1094, range = 0.49-1.05), whereas only one out of 16 studies in non-anaemic heart failure patients presented a low O/P erythropoietin ratio ( n = 2043, range = 0.91-1.97). In studies comparing anaemic versus non-anaemic heart failure patients ( n = 1531), the mean O/P erythropoietin ratio was consistently reduced in anaemic heart failure patients (mean difference = -0.68, 95% confidence interval = -0.78, -0.57; p < 0.001). In meta-regression, the O/P erythropoietin ratio was negatively associated with age, female sex, left ventricular ejection fraction, inflammation and disease severity.. Anaemia in heart failure is overwhelmingly characterized by impaired erythropoietin production, which is exacerbated with age, female sex, left ventricular ejection fraction, inflammation and disease severity.

Topics: Age Factors; Aged; Aged, 80 and over; Anemia; Biomarkers; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Male; Middle Aged; Prognosis; Risk Factors; Severity of Illness Index; Sex Factors; Stroke Volume; Ventricular Function, Left

Anemia can contribute negatively to a patient's morbidity and mortality. Which treatment options do exist and what role do anesthesiologists play in management of perioperative anemia treatment? This review gives an overview about recent findings.. Patient Blood Management and standards for the management and treatment of anemia have been established worldwide. Various logistic settings and approaches are possible. With a special focus on cardiovascular anesthesia, intravenous iron is a therapeutic option in the preoperative setting. Autologous blood salvage is a standard procedure during surgery. Restrictive transfusion triggers in adult cardiac surgery have been shown to be beneficial in the majority of studies. Elderly patients and defined comorbidities might require higher transfusion triggers. Both, intravenous and oral iron increase hemoglobin values when given prior to surgery. Oral iron is effective when given several weeks prior to elective surgery. Erythropoietin is a treatment decision individualized to each patient.. Within the previous 18 months, important publications have demonstrated the established role of anesthesiologists in managing perioperative anemia. A substantial pillar for anemia treatment is the implementation of Patient Blood Management worldwide.

Topics: Administration, Intravenous; Administration, Oral; Age Factors; Anemia; Anesthesiologists; Blood Loss, Surgical; Blood Transfusion, Autologous; Cardiac Surgical Procedures; Erythropoietin; Humans; Iron; Operative Blood Salvage; Perioperative Care; Professional Role

Erythropoietin (EPO) is a 34kD pleiotropic cytokine that was first identified as being essential for red blood cell (RBC) production. It is now recognized however that EPO is produced by many tissues. It plays a key role in the modulation of the response to injury, inflammation, and tissue hypoxia via the inhibition of apoptosis. Large clinical trials in the critically ill failed to demonstrate a role for EPO as an RBC transfusion sparing agent; however, improved clinical outcomes, attributable to EPO role in tissue protection are observed in critically ill trauma patients. Further research to confirm or refute these observations is required.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Apoptosis; Cell Proliferation; Critical Illness; Erythrocyte Transfusion; Erythropoietin; Female; Humans; Male; Middle Aged; Wounds and Injuries

Chronic kidney disease (CKD) is associated with several complications that worsen with progression of disease; anemia, disturbances in iron metabolism and inflammation are common features. Inflammatory response starts early, releasing pro-inflammatory cytokines, acute phase reactants and hepcidin. Hepcidin production is modulated by several factors, as hypoxia/anemia, erythropoietin and erythropoiesis products, transferrin saturation (TSAT) and liver iron levels, which are altered in CKD. Treatment of CKD anemia is based on pharmaceutical intervention, with erythropoietic stimulating agents and/or iron supplementation; however, in spite of the erythropoietic benefits, this therapy, on a regular basis, involves risks, namely iron overload. To overcome these risks, some therapeutic approaches are under study to target CKD anemia. Considering the actual alerts about risk of iron overload in dialysis patients, inhibition of hepcidin, the central key player in iron homeostasis, could be a pivotal strategy in the management of CKD anemia.

Topics: Anemia; Erythropoietin; Gene Expression Regulation; Hepcidins; Humans; Iron; Renal Insufficiency, Chronic

Roxadustat (Ai Rui Zhuo

Topics: Anemia; China; Drug Approval; Erythropoiesis; Erythropoietin; Glycine; Hepcidins; Humans; Isoquinolines; Prolyl-Hydroxylase Inhibitors; Renal Dialysis

Anemic patients with lower risk myelodysplastic syndromes are frequently treated with erythropoiesis stimulating agents (ESA), eventually in combination with granulocyte colony stimulating factor (G-CSF). However, the evidence for the efficacy of a combined treatment remains controversial. The goal of our analysis was to assess the available evidence for a combined treatment. We performed a systematic review and identified only nine eligible studies. In two randomized controlled trials (n = 98), erythroid response rates were 33% and 40% after low-/standard-doses of ESA alone (10,000-30,000 rHuEPO equivalents/week) versus 65% and 73% after combination treatment. In seven trials with sequential drug administration (n = 393), erythroid response rates ranged from 12% to 71% after full-doses of ESA alone (60,000-80,000 rHuEPO equivalents/week) and from 35% to 74% after combination therapy. Our analysis supports an additional efficacy of G-CSF added to low-/standard-dose ESA, but the available data remains controversial, if G-CSF is added to full-dose ESA.

Topics: Anemia; Drug Synergism; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Myelodysplastic Syndromes; Randomized Controlled Trials as Topic; Recombinant Proteins; Treatment Outcome

Iron restricted anemia is prevalent in surgical patients and is associated with an increased risk of allogeneic red blood cell (RBC) transfusion and adverse events. Treatment of anemia includes oral and intravenous iron and erythropoiesis stimulating agents (ESAs). More recent studies have focused on the use of intravenous iron as the primary approach to treating anemia. Nevertheless, the optimal treatment strategy for anemia remains to be established. Our primary objective was to evaluate the efficacy and safety of ESA and iron therapy relative to iron therapy alone in reducing RBC transfusion in surgical patients.. We searched the Cochrane Library, MEDLINE, EMBASE, and ClinicalTrials.gov from inception to May 2018. We included randomized-controlled trials in which adult surgical patients received an ESA and iron, vs iron alone, prior to cardiac and non-cardiac surgery. Our primary outcome was RBC transfusion rate. Secondary outcomes included hemoglobin concentration (post-treatment and postoperatively), number of RBC units transfused, mortality, stroke, myocardial infarction (MI), renal dysfunction, pulmonary embolism (PE), and deep vein thrombosis (DVT).. In total, 25 studies (4,719 participants) were included. Erythropoiesis stimulating agents and iron therapy reduced RBC transfusion relative to iron therapy (relative risk [RR] 0.57; 95% confidence interval [CI], 0.46 to 0.71) without any change in mortality (RR 1.31; 95% CI, 0.80 to 2.16), stroke (RR 1.91; 95% CI, 0.63 to 5.76), MI (RR 1.12; 95% CI, 0.50 to 2.50), renal dysfunction (RR 0.96; 95% CI, 0.72 to 1.26), PE (RR 0.92; 95% CI, 0.15 to 5.83), or DVT (RR 1.48; 95% CI, 0.95 to 2.31).. Administration of ESA and iron therapy reduced the risk for RBC transfusion compared with iron therapy alone in patients undergoing cardiac and non-cardiac surgery. Nevertheless, publication bias and heterogeneity reduces the confidence of the finding. Although the analysis was probably under-powered for some outcomes, no difference in the incidence of serious adverse events was observed with ESA and iron compared with iron alone. Further large prospective trials are required to confirm these findings.

Topics: Adult; Anemia; Erythrocyte Transfusion; Erythropoietin; Hematinics; Humans; Iron; Randomized Controlled Trials as Topic; Surgical Procedures, Operative

Anemia is a common comorbidity in patients with chronic kidney disease (CKD) and occurs due to diminished renal function. The main cause of such anemia is decreased erythropoietin (EPO) production and secretion from the kidney and a lower erythropoietic response to EPO. Treatment therefore involves erythropoiesis-stimulating agents (ESAs). Optimal erythropoietic response to ESA therapy also requires adequate iron management. However, iron metabolism is also dysregulated in CKD patients.. During erythropoiesis, biomarkers of iron metabolism are dramatically altered by ESA therapy. Hepcidin 25 is a key hormone of iron metabolism that regulates iron absorption from the gut and the release of stored iron out of reticuloendothelial system cells. Recently, erythroferrone has been identified as an erythroid suppressor of hepcidin 25 production. Because erythroferrone levels are significantly increased by ESA treatment in CKD patients, it may be a key factor in facilitating the release of stored iron into the circulation during erythropoiesis in these patients. In this review, we discuss the characteristics of the important biomarkers of iron metabolism in CKD patients and the changes in these biomarkers after ESA administration. Key Messages: In CKD patients, the management of anemia with ESA therapy requires comprehensive assessment of the levels of various biomarkers, with consideration of their optimal and physiological levels during erythropoiesis.

Topics: Anemia; Biomarkers; Erythropoiesis; Erythropoietin; Hematinics; Humans; Iron; Renal Insufficiency, Chronic

Several Erythropoiesis-stimulating agents (ESAs) are available to treat anemia in patients with chronic kidney disease (CKD). Questions about the comparability of such therapeutic options are not purely a regulatory or economical matter. Appropriate use of originator or biosimilar in these patients need to be supported by clinical data. Regarding the prevention of blood transfusion, reduction of fatigue, breathlessness and mortality or cardiovascular events, a summary of the comparative efficacy and safety data of these drugs is lacking.. We performed a systematic literature search of CENTRAL, PubMed, and Embase through November 11, 2015. Our inclusion criteria encompassed randomized, controlled clinical trials that evaluated the comparative effectiveness of different ESAs originators and/or biosimilar. The considered participants were adults aged 18 years or older with anemia due to CKD. The overall quality of evidence was assessed using the GRADE system.. We identified 30 eligible studies including 7843 patients with CKD, and 21/30 studies included patients using hemodialysis or peritoneal dialysis. Compared with ESA biosimilars, epoetin α did not statistically differ for any of the ten measured outcomes. The quality of evidence varied from low to very low. In the comparison between epoetin α vs. darbepoetin α, no differences were observed for all outcomes, but blood transfusions showed favorable results for darbepoetin α: RR 2.18 (1.31-3.62). The quality of evidence varied from low to very low. No differences were observed between epoetin β and methoxy polyethylene glycol-epoetin β, and between darbepoetin α and methoxy polyethylene glycol-epoetin β, the quality of evidence varied from moderate to very low.. Data from 31 included studies allowed to pool data in meta-analysis related to four different comparisons and eleven outcome measures. Nevertheless, only one result was statistically significant in favor of darbepoetin α in the comparison with epoetin α concerning blood transfusions. For all the other outcomes and comparisons, we did not find any differences in terms of efficacy and security between the EPO considered. The quality of evidence is quite low, and further research could change these results. Further high quality studies examining the comparative effectiveness of ESAs need to be conducted.

Topics: Adult; Anemia; Biosimilar Pharmaceuticals; Blood Transfusion; Comparative Effectiveness Research; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Polyethylene Glycols; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Insufficiency, Chronic

This article reviews an emerging therapeutic agent, which is currently in phase III development for the treatment of anemia secondary to chronic kidney disease, covering promising phase II results, drug characteristics, and the current phase III trials, which, if approved, may significantly impact the management of anemia in this patient population.

Topics: Anemia; Barbiturates; Clinical Trials, Phase III as Topic; Erythropoietin; Glycine; Humans; Renal Dialysis; Renal Insufficiency, Chronic; United States; United States Food and Drug Administration

Erythropoietin (EPO) is necessary and sufficient to trigger dynamic transcriptional patterns that drive the differentiation of erythroid precursor cells into mature, enucleated red cells. Because the molecular cloning and Food and Drug Administration approval for the therapeutic use of EPO over 30 years ago, a detailed understanding of how EPO works has advanced substantially. Yet, the precise epigenetic and transcriptional mechanisms by which EPO signaling controls erythroid expression patterns remains poorly understood. This review focuses on the current state of erythroid biology in regards to EPO signaling from human genetics and functional genomics perspectives.. The goal of this review is to provide an integrative view of the gene regulatory underpinnings for erythroid expression patterns that are dynamically shaped during erythroid differentiation. Here, we highlight vignettes connecting recent insights into a genome-wide association study linking an EPO mutation to anemia, a study linking EPO-signaling to signal transducer and activator of transcription 5 (STAT5) chromatin occupancy and enhancers, and studies that examine the molecular mechanisms driving topological chromatin organization in erythroid cells.. The genetic, epigenetic, and gene regulatory mechanisms underlying how hormone signal transduction influences erythroid gene expression remains only partly understood. A detailed understanding of these molecular pathways and how they intersect with one another will provide the basis for novel strategies to treat anemia and potentially other hematological diseases. As new regulators and signal transducers of EPO-signaling continue to emerge, new clinically relevant targets may be identified that improve the specificity and effectiveness of EPO therapy.

Topics: Anemia; Animals; Epigenesis, Genetic; Erythroid Cells; Erythropoietin; Humans; Mutation; Signal Transduction; Transcription, Genetic

Anemia is a common complication and contributes to increased morbidity and mortality in chronic kidney disease (CKD) patients. Whereas there has been a significant improvement of understanding the underlying mechanism of erythropoiesis, the treatment of renal anemia is still restricted to erythropoietin (EPO)-stimulating agents. The purpose of this article is to review the physiology of erythropoiesis, functional role of EPO and underlying molecular and cellular basis that regulate EPO production. Regulation of EPO production is at mRNA level. When anemia or hypoxia occurs, transcriptional factor, hypoxia-inducible factor (HIF), binds to EPO 5' hypoxic response element and EPO gene transcription increases. The renal EPO is mainly produced by pericytes. In CKD, pericytes transdifferentiate to myofibroblasts, and subsequently the ability of EPO production decreases, leading to renal anemia. Recent experimental and clinical studies show the promising efficacy of prolyl hydroxylase inhibitors in renal anemia through increasing EPO production by stabilizing HIF. Recent advances on epigenetics create a new field to study EPO gene expression at chromatin level. We will discuss the role of demethylating agent on restoring EPO expression, providing a novel approach to the treatment of renal anemia.

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Humans; Hypoxia-Inducible Factor 1; Myofibroblasts; Pericytes; Renal Insufficiency, Chronic

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

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

First generation erythropoiesis stimulating agents (ESAs) have short duration of action which requires administration once weekly or greater. Second generation ESAs were developed which have longer duration of action and can be administered one to two times monthly. Erythropoietin (EPO) mimetic peptides (EMPs) activate the EPO receptor but have no structural analogy to EPO, offering the potential for lower cost as they are not biologic drugs. The first approved EMP, peginesatide, was withdrawn from the market within a year of its approval because of fatal anaphylactic reactions. In this review, we summarize recent progress regarding the development of newer, possibly less toxic, EMPs. We also summarize the development of EPO fusion proteins which fuse EPO with a portion of an immunoglobulin molecule or another EPO molecule, achieving a longer duration of action and less frequent dosing.. AGEM400(hydroxyethyl starch) and pegolsihematide are EMPs in phase II clinical trials. Three EPO fusion proteins are under development, two in phase I and one in phase II.. The future success of EMPs is limited by the prior experience with peginesatide and EPO fusion proteins do not offer cost savings or longer duration of action than currently available ESAs.

Topics: Anemia; Biosimilar Pharmaceuticals; Erythropoiesis; Erythropoietin; Hematinics; Humans; Hydroxyethyl Starch Derivatives; Peptides; Polyethylene Glycols; Receptors, Erythropoietin; Recombinant Fusion Proteins; Renal Insufficiency, Chronic

Historically, the identity of O2-sensing renal erythropoietin (Epo)-producing (REP) cells was a matter of debate. This review summarizes how recent breakthroughs in transgenic mouse and in-situ hybridization techniques have facilitated sensitive and specific detection of REP cells and accelerated advancements in the understanding of the regulation of renal Epo production in health and disease.. REP cells are a dynamically regulated unique subpopulation of tubulointerstitial cells with features of fibroblasts, pericytes and neurons. Under normal conditions, REP cells are located in the corticomedullary border region within a steep decrement in O2 availability. During the progression of chronic kidney disease (CKD), REP cells cease Epo production, dedifferentiate and contribute to the progression of renal fibrosis. However, CKD patients with renal anaemia still respond with elevated Epo production following treatment with hypoxia-mimicking agents.. We hypothesize that REP cells are neuron-like setpoint providers and controllers, which integrate information about blood O2 concentration and local O2 consumption via tissue pO2, and combine these inputs with intrinsic negative feedback loops and perhaps tubular cross-talk, converging in Epo regulation.

Topics: Anemia; Animals; Cell Dedifferentiation; Erythropoietin; Fibrosis; Humans; Kidney; Mice, Transgenic; Oxygen; Renal Insufficiency, Chronic

To discuss if there will still be a role for the originator ESAs after the already available biosimilars and the approval of HIF stabilizers in the near future.. Current treatment with erythropoiesis-simulating agents (ESAs) is effective and generally well tolerated, but requires parenteral injections. It is also surrounded by safety concerns and is still expensive. Functional iron deficiency is the major obstacle for efficient ESA therapy. ESA resistance may develop, calling for high ESA doses, further increasing the side effects associated with ESA use. Biosimilars were introduced for reducing costs. In searching for an ideal antianemic drug, new investigational strategies have been proposed including the attractive alternative hypoxia-inducible factor (HIF) stabilizers, which stimulate endogenous EPO production. However, we should caution in translating the historical results referring to the side effects of ESAs to current clinical practice, considering that hemoglobin targets and ESAs doses are now much lower. We could anticipate that side effects will be much less.. According to preliminary data, orally administered HIF stabilizers could provide pharmacological advantages over the existing ESAs. These will need confirmation by the findings of large, phase-3, clinical trials. Finally, cost will be an important issue determining their future use.

Topics: Anemia; Basic Helix-Loop-Helix Transcription Factors; Biosimilar Pharmaceuticals; Drug Administration Routes; Erythropoiesis; Erythropoietin; Hematinics; Humans; Iron; Recombinant Proteins; Renal Insufficiency, Chronic

Small-molecule inhibitors of prolyl hydroxylase domain enzymes (PHD inhibitors) are novel renal anemia therapies that increase endogenous erythropoietin (EPO) production by stabilizing hypoxia-inducible factor (HIF). This review summarizes recent findings and future perspectives of PHD inhibitors (HIF stabilizers) in chronic kidney disease (CKD)-associated anemia.. Clinical trials have demonstrated that HIF stabilizers effectively increase hemoglobin levels of both nondialysis and dialysis CKD patients without causing serious adverse effects. HIF stabilizers not only restore EPO production but also optimize iron metabolism by reducing hepcidin levels. Considering the pleiotropic roles of the PHD-HIF pathway, HIF stabilizers might have both advantageous and disadvantageous effects in humans, in addition to erythropoiesis. Results of studies in animal models have suggested that HIF stabilizers alleviate ischemia-reperfusion injury and play protective roles against metabolic diseases. In contrast, a theoretical concern exists regarding the potential for tumorigenesis due to HIF stabilization.. At least five HIF stabilizers are now in phase III trials and may appear on the market in 1-2 years. The long-term effects and safety of HIF stabilization should be carefully examined in future basic and clinical studies.

Topics: Anemia; Animals; Basic Helix-Loop-Helix Transcription Factors; Erythropoietin; Humans; Kidney; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Orthopedic surgical procedures, especially in the lower limbs, are associated with a high risk of massive bleeding and, consequently, the development of anemia and the need for blood transfusions and its preparations. This creates the need to look for effective methods of prevention and treatment of anemia that will be safe for the patient and reduce the cost of treatment. One of the most common methods of limiting the allogenic blood usage in orthopedic procedures is the use of autologus transfusions. In addition to many benefits, they may contribute to the patient's anemia, which is a serious health problem in the post-operative period. Analyzed data from the literature indicate that the use of recombinant human erythropoietin significantly reduces the need for blood transfusion in the perioperative period and may reduce the cost of treatment.

Topics: Anemia; Erythropoietin; Hemorrhage; Humans; Orthopedic Procedures; Perioperative Period; Recombinant Proteins

A classic response to systemic hypoxia is the increase in red blood cell production. This response is controlled by the prolyl hydroxylase domain/hypoxia-inducible factor (HIF) pathway, which regulates a broad spectrum of cellular functions. The discovery of this pathway as a key regulator of erythropoiesis has led to the development of small molecules that stimulate the production of endogenous erythropoietin and enhance iron metabolism. This review provides a concise overview of the cellular and molecular mechanisms that govern HIF-induced erythropoietic responses and provides an update on clinical experience with compounds that target HIF-prolyl hydroxylases for anemia therapy.

Topics: Anemia; Barbiturates; Clinical Trials as Topic; Erythropoiesis; Erythropoietin; Glycine; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Iron; Isoquinolines; Picolinic Acids; Prolyl-Hydroxylase Inhibitors; Renal Dialysis

The 2009 NHS Blood and Transplant national comparative audit on blood use following primary total hip arthroplasty (THR) highlighted that preoperative anaemia was common and undertreated. They recommended that hospitals have a written policy for treating anaemia preoperatively. In our centre, we found that preoperative optimisation of anaemia, significantly reduced blood transfusion rate to <5%. The 2015 national audit showed that even though 48% of patients received tranexamic acid, 85% of patients required transfusion. By conducting a systematic review of literature on blood management for preoperative anaemia in primary THR; we aimed to validate the recommendations of the national audit and increase its awareness in the orthopaedic community.. A PubMed Search was performed to identify suitable literature limited to randomised controlled trials, cohort studies, meta-analyses and systematic reviews involving primary THR. We excluded any THRs performed for trauma and revision arthroplasty. Our exclusion criteria for the intervention was the use of autologous methods such as cell salvage techniques and preoperative autologous blood donation.. Analysis of 13 publications showed widespread study heterogeneity, which precluded meta-analysis. Preoperative blood management (PBM) interventions included the use of recombinant human erythropoietin and oral iron supplementation in 12/13 and 11/13 studies respectively. There were significant differences in transfusion rates between PBM and control groups in 12/13 studies.. The findings overwhelmingly support preoperative optimisation of anaemia. The main barrier to wider implementation remains the cost effectiveness. We recommend using our validated protocol, which has shown to significantly reduce transfusion rates, length of stay and remain cost effective.

Topics: Anemia; Antifibrinolytic Agents; Arthroplasty, Replacement, Hip; Blood Transfusion; Erythropoietin; Humans; Preoperative Care; Tranexamic Acid

Anemia is a common complication of chronic kidney disease and is mainly caused by the inability of injured kidneys to produce adequate amounts of erythropoietin. Studies elucidating the regulation of erythropoietin production led to the identification of hypoxia-inducible factor (HIF), which activates the transcription of genes that mediate adaptive responses to hypoxia. HIF is a heterodimer that consists of an α and β subunit. While HIF-β is constitutively expressed, HIF-α is subjected to ubiquitination and proteasomal degradation under normoxic conditions. This process is mediated by prolyl hydroxylase domain proteins, the inhibition of which results in an increased expression of hypoxia-induced genes, including erythropoietin. These findings led to the development of prolyl hydroxylase domain inhibitors as novel therapeutic agents against anemia in chronic kidney disease. Prolyl hydroxylase domain inhibition improves iron metabolism, which also contributes to erythropoiesis. To date, at least 6 small-molecule inhibitors of the prolyl hydroxylase domain have been tested in humans, and clinical trials have shown that they are effective without causing serious adverse events. However, there is a theoretical concern that the systemic activation of HIF could also induce deleterious effects such as tumorigenesis and severe pulmonary hypertension, which demands careful assessments in future clinical studies.

Topics: Anemia; Clinical Trials as Topic; Erythropoietin; Humans; Hypoxia-Inducible Factor 1; Iron; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Continuous erythropoiesis receptor activator (CERA) is a newer, longer acting ESA which might be preferred to other ESAs (epoetin or darbepoetin) based on its lower frequency of administration. Different dosing requirements and molecular characteristics of CERA compared with other ESAs may lead to different health outcomes (mortality, cardiovascular events, quality of life) in people with anaemia and chronic kidney disease (CKD).. To assess benefits and harms of CERA compared with other epoetins (darbepoetin alfa and epoetin alfa or beta) or placebo/no treatment or CERA with differing strategy of administration for anaemia in individuals with CKD.. We searched the Cochrane Kidney and Transplant Specialised Register to 13 June 2017 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.. We included randomised controlled trials (RCTs) of at least three months' duration, comparing CERA with a different ESA (darbepoetin alfa or epoetin alfa or beta) or placebo or standard care or versus CERA with different strategies for administration in people with any stage of CKD.. Data were extracted by two independent investigators. We summarised patient-centred outcomes (all-cause and cardiovascular mortality, major adverse cardiovascular events, red cell blood transfusion, iron therapy, cancer, hypertension, seizures, dialysis vascular access thrombosis, drug injection-related events, hyperkalaemia and health-related quality of life and haemoglobin levels) using random effects meta-analysis. Treatment estimates were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean differences or standardized mean difference with 95% CI for continuous outcomes.. We included 27 studies involving 5410 adults with CKD. Seven studies (1273 participants) involved people not requiring dialysis, 19 studies (4209 participants) involved people treated with dialysis and one study (71 participants) evaluated treatment in recipients of a kidney transplant. Treatment was given for 24 weeks on average. No data were available for children with CKD. Studies were generally at high or unclear risk of bias from allocation concealment and blinding of outcomes. Only two studies masked participants and investigators to treatment allocation. One study compared CERA with placebo, nine studies CERA with epoetin alfa or beta, nine studies CERA with darbepoetin alfa, and two studies compared CERA with epoetin alfa or beta and darbepoetin alfa. Three studies assessed the effects of differing frequencies of CERA administration and five assessed differing CERA doses.There was low certainty evidence that CERA had little or no effects on mortality (RR 1.07, 95% CI 0.73 to 1.57; RR 1.11, 95% CI 0.75 to 1.65), major adverse cardiovascular events (RR 5.09, 95% CI 0.25 to 105.23; RR 5.56, 95% CI 0.99 to 31.30), hypertension (RR 1.01, 95% CI 0.75 to 1.37; RR 1.00, 95% CI 0.79 to 1.28), need for blood transfusion (RR 1.02, 95% CI 0.72 to 1.46; RR 0.94, 95% CI 0.55 to 1.61), or additional iron therapy (RR 1.03, 95% CI 0.91 to 1.15; RR 0.99, 95% CI 0.95 to 1.03) compared to epoetin alfa/beta or darbepoetin alfa respectively. There was insufficient evidence to compare the effect of CERA to placebo on clinical outcomes. Only one low quality study reported that CERA compared to placebo might lead to little or no difference in the risk of major cardiovascular events (RR 2.97, 95% CI 0.31 to 28.18) and hypertension ((RR 0.73, 95% CI 0.35 to 1.52). There was low certainty evidence that different doses (higher versus lower) or frequency (twice versus once monthly) of CERA administration had little or no different effect on all-cause mortality (RR 3.95, 95% CI 0.17 to 91.61; RR 0.97, 95% CI 0.56 to 1.66), hypertension (RR 0.45, 95% CI 0.08 to 2.52; RR 0.85, 95% CI 0.60 to 1.21), and blood cell transfusions (RR 4.16, 95% CI 0.89 to 19.53; RR 0.91, 95% CI 0.51 to 1.62). No studies reported comparative treatment effects of different ESAs on health-related quality of life.. There is low certainty evidence that CERA has little or no effects on patient-centred outcomes compared with placebo, epoetin alfa or beta or darbepoetin alfa for adults with CKD. The effects of CERA among children who have CKD have not studied in RCTs.

Topics: Adult; Aged; Anemia; Cardiovascular Diseases; Cause of Death; Darbepoetin alfa; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Humans; Hypertension; Middle Aged; Polyethylene Glycols; Publication Bias; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Thrombosis

Anaemia is a commonly diagnosed complication among patients suffering with chronic kidney disease. If left untreated, it may affect patient quality of life. There are several causes for anaemia in this patient population. As the kidney function deteriorates, together with medications and dietary restrictions, patients may develop iron deficiency, resulting in reduction of iron supply to the bone marrow (which is the body organ responsible for the production of different blood elements). Chronic kidney disease patients may not be able to utilise their own body's iron stores effectively and hence, many patients, particularly those receiving haemodialysis, may require additional iron treatment, usually provided by infusion.With further weakening of kidney function, patients with chronic kidney disease may need additional treatment with a substance called erythropoietin which drives the bone marrow to produce its own blood. This substance, which is naturally produced by the kidneys, becomes relatively deficient in patients with chronic kidney disease. Any patients will eventually require treatment with erythropoietin or similar products that are given by injection.Over the last few years, several iron and erythropoietin products have been licensed for treating anaemia in chronic kidney disease patients. In addition, several publications discussed the benefits of each treatment and possible risks associated with long term treatment. The current guidelines provide advice to health care professionals on how to screen chronic kidney disease patients for anaemia, which patients to investigate for other causes of anaemia, when and how to treat patients with different medications, how to ensure safe prescribing of treatment and how to diagnose and manage complications associated with anaemia and the drugs used for its treatment.

Topics: Anemia; Erythropoietin; Humans; Practice Guidelines as Topic; Renal Dialysis; Renal Insufficiency, Chronic

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

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

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

Nephrotic syndrome is one of the most common glomerular diseases that affect in children. Complications may occur in nephrotic syndrome as a result of the disease itself as well as its treatment. Most of these complications result from excessive urinary protein losses, and control of proteinuria is the most effective treatment strategy. Anemia is one of the many complications seen in patients with persistent nephrotic syndrome and may occur as a result of excessive urinary losses of iron, transferrin, erythropoietin, transcobalamin and/or metals. This leads to a deficiency of substrates necessary for effective erythropoiesis, requiring supplementation in order to correct the anemia. Supplementation of iron and erythropoietin alone often does not lead to correction of the anemia, suggesting other possible mechanisms which need further investigation. A clear understanding of the pathophysiologic mechanisms of anemia in nephrotic syndrome is necessary to guide appropriate therapy, but only limited evidence is currently available on the precise etiologic mechanisms of anemia in nephrotic syndrome. In this review we focus on the current state of knowledge on the pathogenesis of anemia in nephrotic syndrome.

Topics: Anemia; Child; Epoetin Alfa; Erythropoiesis; Erythropoietin; Gluconates; Hematinics; Humans; Iron; Kidney; Nephrotic Syndrome; Proteinuria; Renal Elimination; Transferrin; Treatment Outcome; Vitamins

The benefits of erythropoiesis-stimulating agents (ESA) for chronic kidney disease (CKD) patients have been previously demonstrated. However, the efficacy and safety of short-acting epoetins administered at larger doses and reduced frequency as well as of new epoetins and biosimilars remains uncertain.. This review aimed to evaluate the benefits and harms of different routes, frequencies and doses of epoetins (epoetin alpha, epoetin beta and other short-acting epoetins) for anaemia in adults and children with CKD not receiving dialysis.. We searched the Cochrane Kidney and Transplant Specialised Register to 12 September 2016 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.. We included randomised control trials (RCTs) comparing different frequencies, routes, doses and types of short-acting ESAs in CKD patients.. Two authors independently assessed study eligibility and four authors assessed risk of bias and extracted data. Results were expressed as risk ratio (RR) or risk differences (RD) with 95% confidence intervals (CI) for dichotomous outcomes. For continuous outcomes the mean difference (MD) with 95% confidence intervals (CI) was used. Statistical analyses were performed using the random-effects model.. We identified 14 RCTs (2616 participants); nine studies were multi-centre and two studies involved children. The risk of bias was high in most studies; only three studies demonstrated adequate random sequence generation and only two studies were at low risk of bias for allocation concealment. Blinding of participants and personnel was at low risk of bias in one study. Blinding of outcome assessment was judged at low risk in 13 studies as the outcome measures were reported as laboratory results and therefore unlikely to be influenced by blinding. Attrition bias was at low risk of bias in eight studies while selective reporting was at low risk in six included studies.Four interventions were compared: epoetin alpha or beta at different frequencies using the same total dose (six studies); epoetin alpha at the same frequency and different total doses (two studies); epoetin alpha administered intravenously versus subcutaneous administration (one study); epoetin alpha or beta versus other epoetins or biosimilars (five studies). One study compared both different frequencies of epoetin alpha at the same total dose and at the same frequency using different total doses.Data from only 7/14 studies could be included in our meta-analyses. There were no significant differences in final haemoglobin (Hb) levels when dosing every two weeks was compared with weekly dosing (4 studies, 785 participants: MD -0.20 g/dL, 95% CI -0.33 to -0.07), when four weekly dosing was compared with two weekly dosing (three studies, 671 participants: MD -0.16 g/dL, 95% CI -0.43 to 0.10) or when different total doses were administered at the same frequency (four weekly administration: one study, 144 participants: MD 0.17 g/dL 95% CI -0.19 to 0.53).Five studies evaluated different interventions. One study compared epoetin theta with epoetin alpha and found no significant differences in Hb levels (288 participants: MD -0.02 g/dL, 95% CI -0.25 to 0.21). One study found significantly higher pain scores with subcutaneous epoetin alpha compared with epoetin beta. Two studies (165 participants) compared epoetin delta with epoetin alpha, with no results available since the pharmaceutical company withdrew epoetin delta for commercial reasons. The fifth study comparing the biosimilar HX575 with epoetin alpha was stopped after patients receiving HX575 subcutaneously developed anti-epoetin antibodies and no results were available.Adverse events were poorly reported in all studies and did not differ signif. Epoetin alpha given at higher doses for extended intervals (two or four weekly) is non-inferior to more frequent dosing intervals in maintaining final Hb levels with no significant differences in adverse effects in non-dialysed CKD patients. However the data are of low methodological quality so that differences in efficacy and safety cannot be excluded. Further large, well designed, RCTs with patient-centred outcomes are required to assess the safety and efficacy of large doses of the shorter acting ESAs, including biosimilars of epoetin alpha, administered less frequently compared with more frequent administration of smaller doses in children and adults with CKD not on dialysis.

Topics: Adult; Anemia; Child; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobin A; Humans; Injections, Intravenous; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

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

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

Chronic kidney disease (CKD) is an important health problem, because of unsuccessful outcomes such as CKD progression to end stage renal disease and high risk of cardiovascular disease (CVD). Anemia, associated with CKD, is considered a non-traditional risk factor for CVD which may contribute to faster CKD progression. Anemia treatment with erythropoiesis-stimulating agents (ESAs) seems to exert non-hematopoietic effects on different tissues and organs, including cardiovascular system and kidneys. On the other hand, clinical use of high doses of short-acting ESAs and higher target hemoglobin level were associated with higher risk of CVD. Literature data indicate the usefulness of long-acting ESAs in treatment of anemia in non-dialysis CKD patients. In particular, continuous erythropoietin receptor activator seems to be a good choice in these patients because of its efficiency, safety and monthly administration. Continuous but slower erythropoietin receptor activation, using methoxy polyethylene glycol-epoetin beta (MPG-EPO), administered once a month, slowly corrects anemia without exceeding the recommended hemoglobin level. An overview of the available literature may suggest nephroprotective and cardiovascular protective effects of MPG-EPO. It seems possible that anemia treatment with a novel ESAs, MPG-EPO in early stages of CKD may reduce CVD risk in these patients and delay CKD progression. This review of available literature evaluates the correlation between continuous erythropoietin receptor activation using MPG-EPO and CKD progression and CVD risk in non-dialysis CKD patients.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Hematinics; Humans; Kidney; Polyethylene Glycols; Renal Insufficiency, Chronic; Risk Factors

Erythropoiesis-stimulating agents (ESAs) increase hemoglobin levels, reduce transfusion requirements, and have been the standard of treatment for anemia in patients with chronic kidney disease (CKD) since 1989. Many safety concerns have emerged regarding the use of ESAs, including an increased occurrence of cardiovascular events and vascular access thrombosis. Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) enzyme inhibitors are a new class of agents for the treatment of anemia in CKD. These agents work by stabilizing the HIF complex and stimulating endogenous erythropoietin production even in patients with end-stage kidney disease. HIF-PH inhibitors improve iron mobilization to the bone marrow. They are administered orally, which may be a more favorable route for patients not undergoing hemodialysis. By inducing considerably lower but more consistent blood erythropoietin levels than ESAs, HIF-PH inhibitors may be associated with fewer adverse cardiovascular effects at comparable hemoglobin levels, although this has yet to be proved in long-term clinical trials. One significant concern regarding the long-term use of these agents is their possible effect on tumor growth. There are 4 such agents undergoing phase 2 and 3 clinical trials in the United States; this report provides a focused review of HIF-PH inhibitors and their potential clinical utility in the management of anemia of CKD.

Topics: Anemia; Barbiturates; Clinical Trials as Topic; Enzyme Inhibitors; Erythropoietin; Glycine; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Isoquinolines; Pyrazoles; Renal Insufficiency, Chronic; Triazoles

Recombinant human erythropoietin (rhEPO) is a first-line therapeutic for the anemia of chronic kidney disease, cancer chemotherapy, AIDS (Zidovudine therapy), and lower-risk myelodysplastic syndrome. However, rhEPO frequently elevates hypertension, is costly, and may affect cancer progression. Potentially high merit therefore exists for defining new targets for anti-anemia agents within erythropoietin (EPO) and EPO receptor (EPOR) regulatory circuits.. EPO production by renal interstitial fibroblasts is subject to modulation by several regulators of hypoxia-inducible factor 2a (HIF2a) including Iron Response Protein-1, prolyl hydroxylases, and HIF2a acetylases, each of which holds potential as anti-anemia drug targets. The cell surface receptor for EPO (EPOR) preassembles as a homodimer, together with Janus Kinase 2 (JAK2), and therefore it remains attractive to develop novel agents that trigger EPOR complex activation (activating antibodies, mimetics, small-molecule agonists). Additionally, certain downstream transducers of EPOR/JAK2 signaling may be druggable, including Erythroferrone (a hepcidin regulator), a cytoprotective Spi2a serpin, and select EPOR-associated protein tyrosine phosphatases.. While rhEPO (and biosimilars) are presently important mainstay erythropoiesis-stimulating agents (ESAs), impetus exists for studies of novel ESAs that fortify HIF2a's effects, act as EPOR agonists, and/or bolster select downstream EPOR pathways to erythroid cell formation. Such agents could lessen rhEPO dosing, side effects, and/or costs.

Topics: Anemia; Animals; Drug Design; Erythropoiesis; Erythropoietin; Hematinics; Humans; Molecular Targeted Therapy; Receptors, Erythropoietin; Recombinant Proteins

Chemotherapy-induced anaemia is frequent in cancer patients, with severity depending on the extent of the disease and intensity of treatment. Clinical guidelines recommend erythropoietin therapy to treat or prevent anaemia in some oncology/haematology patients being treated with chemotherapy. The patent expiry of the first-generation erythropoietins has led to the development of biosimilar products, i.e. therapeutic proteins exhibiting comparable quality, safety and efficacy to an existing reference biological medicine, the patent of which has expired. This review summarises the available data set supporting the use of one such biosimilar product, epoetin zeta (Retacrit™) in oncology/haematology. The body of evidence supporting the use of epoetin zeta continues to grow, with post-marketing clinical studies underway to evaluate its longer-term clinical efficacy and safety. Biosimilar medicines have the potential to offer cost savings to health care providers, with the assurance of ongoing risk management programmes to ensure patient safety.

Topics: Anemia; Biosimilar Pharmaceuticals; Erythropoietin; Humans; Neoplasms; Recombinant Proteins

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

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

Topics: Academies and Institutes; Anemia; Antineoplastic Agents; Blotting, Western; Consensus; Consensus Development Conferences, NIH as Topic; Drug Industry; Erythropoietin; Hematinics; Humans; Neoplasms; Observer Variation; Predictive Value of Tests; Receptors, Erythropoietin; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; Risk Assessment; United States

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

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

Small-molecule stabilizers of hypoxia inducible factor (HIF) are being developed for the treatment of renal anaemia. These molecules inhibit prolyl hydroxylase domain-containing (PHD) enzymes, resulting in HIF activation and increased production of erythropoietin. Currently, renal anaemia is treated with recombinant human erythropoietin or related analogues, referred to as conventional erythropoiesis stimulating agents (ESAs). Advantages of PHD enzyme inhibitors over conventional ESAs include their oral administration and their simpler - and potentially cheaper - production. Importantly, inhibition of PHD enzymes is likely to have a range of consequences other than increasing levels of erythropoietin, and these effects could be beneficial - for instance by reducing the need for parenteral iron - but might in some instances be harmful. Several companies are currently testing PHD enzyme inhibitors in patients with renal anaemia and have reported clear evidence of efficacy without serious safety concerns. A central question that current studies are beginning to address is whether using PHD enzyme inhibitors will influence hard end points, including mortality and the rate of cardiovascular events. In terms of approaches to therapy, the exquisite specificity of conventional ESAs is a striking contrast to the pleiotropic effects of activating HIF. Excitingly, PHD inhibitors could also be useful for conditions besides renal anaemia, such as protection from ischaemic injury.

Topics: Anemia; Erythropoietin; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases; Renal Insufficiency, Chronic

We conducted a systematic review and meta-analysis of observational studies in order to explore the relationship between erythropoietin (EPO) and hemoglobin in elderly individuals with anemia of unknown etiology (AUE) and other forms of anemia.. We searched Medline, EMBASE, Web of Science, Biosis Previews, Dissertations, and Theses in addition to meeting abstracts of the European Hematology Association and American Society of Hematology for relevant studies. The meta-analysis was conducted using pooled ratio of means (ROM) through the generic inverse variance method.. Six studies were included in the meta-analysis, which confirmed that EPO levels were significantly lower in AUE as compared to iron deficiency anemia (ROM 0.7210; random 95% CI 0.7052 to 0.7372; P-value < 0.00001) and anemia of chronic disease (ROM 0.8995; random 95% CI 0.8362 to 0.9677; P = 0.004). EPO levels in AUE were slightly higher than levels in anemia of chronic kidney disease (ROM 1.0940; random 95% CI 1.0557, 1.1337; P < 0.00001). The heterogeneity (I2) of all analyses was 100%.. Our findings suggest that erythropoietin levels in AUE, although elevated, remain inappropriately low, particularly when compared with other forms of anemia. This suggests a relative erythropoietin deficiency or a blunted erythroid cell response.

Topics: Anemia; Erythropoietin; Female; Humans; Male

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

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

Anemia and thrombocytopenia are frequent clinical manifestations of myelofibrosis as well as important prognostic factors of the disease. Concerning the treatment of anemia, the first step should be the correction of reversible contributing factors, such as possible iron, folate and vitamin B12 deficiency. Then, treatment options include erythropoiesis stimulating agents, androgens, immunomodulating drugs, corticosteroids, and splenectomy. Anemia responses may also be observed in some patients treated with JAK inhibitors. However, most patients eventually fail to such therapies and become transfusion dependent. Some of the aforementioned therapies can also improve thrombocytopenia, but the responses are usually observed in patients with moderate platelet count decrease. Allogeneic hematopoietic stem cell transplantation, the only curative treatment of myelofibrosis, can be an alternative for selected patients with cytopenias who are refractory to conventional therapies. However, for the majority of patients, the management of anemia and severe thrombocytopenia remains an unmet need.

Topics: Algorithms; Anemia; Disease Management; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Incidence; Primary Myelofibrosis; Protein Kinase Inhibitors; Risk Factors; Splenectomy; Thrombocytopenia; Transplantation, Homologous

Chronic kidney disease (CKD) anemia treatment was revolutionized in the late 1980s with the introduction of recombinant human erythropoietin. This and related erythropoiesis-stimulating agents (ESAs) greatly benefited patients by decreasing debilitating symptoms, improving their quality of life, and freeing them from dependence on blood transfusions with their associated complications such as infections, sensitization impeding transplantation, and secondary iron overload. However, even in the initial studies, untoward effects were noted in patients receiving ESAs, including worsening hypertension, seizures, and dialysis access clotting. Later, increased mortality, malignancy progression and even stroke were reported in renal patients. This review focuses on the safety issues of ESAs in CKD patients.

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Hematinics; Humans; Recombinant Proteins; Renal Insufficiency, Chronic

The main pillars for the treatment of chronic kidney disease (CKD) associated anemia are peptidic erythropoiesis stimulating agents (ESAs) and iron preparations. Both approaches benefit from long-term efficacy and safety data but are surrounded by clinical and economic concerns, driving the search for novel anti-anemic drugs.. By answering pivotal questions, the authors describe the recent developments of next generation ESAs, introduce cutting-edge iron formulations and focus on investigational approaches that interact with pathways involved in erythropoietin (Epo) synthesis and myeloid hematopoiesis. Finally, the challenges encountered with these drug candidates are discussed.. Current peptidic ESAs are effective and well-tolerated, but are costly, require parenteral application and iron supplementation. ESA resistance may develop calling for increased doses. Therefore, orally available hypoxia-inducible factor (HIF) stabilizing compounds are attractive alternatives, which may be approved in the near future. Prominent compounds are molidustat, daprodustat and roxadustat. HIF stabilizers suppress hepcidin production and improve iron balance as the present ESAs, but also raise safety concerns in association with their pleiotropic actions. Other investigational erythropoietic biologics are growth-differentiation factor-11 (GDF11) ligand traps (sotatercept, luspatercept), which are also well advanced in development. Possibly, they will provide an add-on for established therapies. However, immunogenicity of these compounds still needs to be carefully investigated.

Topics: Anemia; Animals; Biological Products; Drug Design; Drug Resistance; Drugs, Investigational; Erythropoietin; Hematinics; Humans; Peptides; Renal Insufficiency, Chronic

To assess the use of oral iron, intravenous (IV) iron, and erythropoiesis-stimulating agents (ESAs) for the prevention and management of perioperative anemia in elective orthopedic surgery patients, and to provide a clinical algorithm for use.. A PubMed and MEDLINE search was conducted from 1964 through March 2016 using the following search terms alone or in combination: orthopedic, surgery, elective, anemia, blood transfusion, iron, erythropoiesis-stimulating agents, and erythropoietin.. All English-language prospective and retrospective human studies and meta-analyses evaluating oral iron, IV iron, or ESA alone or in combination in elective orthopedic surgery patients were evaluated, provided they reported blood transfusion outcomes.. A total of 9 prospective and retrospective studies and 1 meta-analysis were identified and included. In the preoperative setting, administration of oral iron, IV iron, or ESA alone or in combination to correct underlying anemia led to significantly reduced transfusion rates. Transfusion requirements were generally less with combination therapy (ESA + oral or IV iron). In the short-term perioperative or postoperative period, use of oral or IV iron led to conflicting results, with some reporting a statistically significant reduction in blood transfusions, whereas others reported none.. In elective orthopedic surgery, IV or oral iron with or without an ESA may provide benefit in prevention of postoperative anemia and results in blood transfusion reduction without significantly increasing the risk of adverse events. These agents should be considered at the lowest effective dose with emphasis on administration prior to planned surgery.

Topics: Administration, Intravenous; Anemia; Blood Loss, Surgical; Blood Transfusion; Elective Surgical Procedures; Erythropoietin; Female; Hematinics; Humans; Iron; Orthopedic Procedures; Prospective Studies; Retrospective Studies

Erythropoiesis stimulating agents (ESA) are effective drugs, which have been used for decades in patients with chronic kidney disease (CKD) with few side effects. More recently, concern has been raised around their safety, from higher cardiovascular and thrombosis risk to cancer progression and increased mortality.. We made a literature search on PubMed looking for adverse effects of ESA in CKD patients. The topics covered are cardiovascular adverse events, thrombosis, increased mortality, hypertension, cancer progression, diabetic retinopathy, pure red cell aplasia and anaphylactic reactions.. Concerns around ESA therapy have questioned treatment indications in high-risk CKD patients (those with cancer, diabetes and cardiovascular comorbidities). A more cautious approach has then prevailed. In our opinion, intermediate Hb values (Hb 10-12 g/dl) should be aimed with ESA therapy, being more cautious in high-risk patients. As a consequence, IV iron is administered more frequently. However, excessive iron use may cause iron overload and in rare cases severe anaphylactic reactions. There are expectations of new erythropoietic agents, such as those manipulating the hypoxia-inducible transcription factors (HIF) system. Differing from ESAs, they stimulate the production of endogenous EPO, avoiding over-physiological plasmatic levels.

Topics: Anemia; Animals; Erythropoietin; Hematinics; Hemoglobins; Humans; Iron; Renal Insufficiency, Chronic; Risk Factors

What are the benefits and harms of iron supplementation alone and as an adjunct to erythropoiesis-stimulating agents (ESAs) compared with ESA alone in the treatment of chemotherapy-induced anemia?. Addition of iron to ESAs improves hematopoietic response, reduces the need for red blood cell transfusions, increases hemoglobin levels, and seems to be well tolerated. The subgroup analyses suggest the superiority of parenteral iron over oral iron supplementation in the treatment of chemotherapy-induced anemia.

Topics: Anemia; Antineoplastic Agents; Dietary Supplements; Erythropoiesis; Erythropoietin; Hematinics; Humans; Induction Chemotherapy; Iron; Randomized Controlled Trials as Topic

Red blood cell (RBC) transfusion is a common and lifesaving therapy for anemic neonates and infants, particularly among those born prematurely or undergoing surgery. However, evidence-based indications for when to administer RBCs and adverse effects of RBC transfusion on important outcomes including necrotizing enterocolitis, survival, and long-term neurodevelopmental impairment remain uncertain. In addition, blood-banking practices for preterm and term neonates and infants have been largely developed using studies from older children and adults. Use of and refinements in emerging technologies and advances in biomarker discovery and neonatal-specific RBC transfusion databases may allow clinicians to better define and tailor RBC transfusion needs and practices to individual neonates. Decreasing the need for RBC transfusion and developing neonatal-specific approaches in the preparation of donor RBCs have potential for reducing resource utilization and cost, improving outcomes, and assuring blood safety. Finally, large donor-recipient-linked cohort studies can provide data to better understand the balance of the risks and benefits of RBC transfusion in neonates. These studies may also guide the translation of new research into best practices that can rapidly be integrated into routine care. This review highlights key opportunities in transfusion medicine and neonatology for improving the preparation and transfusion of RBCs into neonates and infants. We focus on timely, currently addressable knowledge gaps that can increase the safety and efficacy of preterm and term neonatal and infant RBC transfusion practices.

Topics: Age Factors; Anemia; Birth Weight; Blood Banks; Clinical Trials as Topic; Erythrocyte Transfusion; Erythrocytes; Erythropoietin; Hematology; Humans; Infant, Newborn; Infant, Premature; Research Design; Time Factors; Treatment Outcome

Anemia of renal disease is common and is associated with significant morbidity and death. It is mainly caused by a decrease in erythropoietin production in the kidneys and can be partially corrected with erythropoiesis-stimulating agents (ESAs). However, randomized controlled trials have shown that using ESAs to target normal hemoglobin levels can be harmful, and have called into question any benefits of ESA treatment other than avoidance of transfusions.

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

Hospital-acquired anemia is common, especially in the most critically ill patients. It may be associated with poor patient outcomes. It may result from increased blood loss, impaired red cell production or reduced red cell life span. Multiple associated factors may contribute simultaneously or sequentially to the decrease in hemoglobin level. Some of them are related to the underlying disease and others are iatrogenic. Clinicians should be aware of the importance and consequences of iatrogenic anemia caused by diagnostic blood sampling. Strategies and measures to minimize iatrogenic blood loss should be prioritized. They may reduce the risk of developing anemia and then red blood cells transfusion requirement.

Topics: Adult; Anemia; Blood Transfusion; Child; Erythrocyte Aging; Erythropoietin; Ferritins; Health Services Needs and Demand; Hematinics; Hemodilution; Humans; Iatrogenic Disease; Inflammation; Iron; Multicenter Studies as Topic; Phlebotomy; Retrospective Studies; Vascular Access Devices

Cancer patients frequently present with anaemia that may result from the direct or indirect effects of the tumor or its treatment. Anaemia is an independent adverse prognostic factor that exerts negative influence on quality of life and survival of cancer patients. Anaemia in malignant disorders often arises from an interplay of multiple aetiological and pathophysiologic mechanisms. Understanding these mechanisms will help the oncologist identify and treat specific causes of the anaemia thereby minimizing the use of blood transfusion, which is associated with many adverse effects. This paper reviewed the various aetiological and pathophysiologic mechanisms of anaemia in cancer patients including direct and indirect tumour effects that lead to reduced red cell production or increased red cell destruction via a myriad of mechanisms ranging from marrow infiltration and cancer-associated acute myelonecrosis to chronic inflammation, blood loss, iron, folate, vitamin B12 and other nutrients deficiencies, malignancy related renal injury, pure red cell aplasia, hypersplenism, haemophagocytic syndrome, red cell autoantibody production, non-immune red cell fragmentation and cytotoxic therapy-induced erythroid cell apoptosis and eryptosis. Hence anaemia in cancer patients is attributable to a wide spectrum of aetiological factors with multiple and sometimes overlapping pathophysiologic mechanisms. It is therefore necessary for the oncologists to thoroughly investigate all cases of anaemia with the aim of identifying the actual causative factors in order to offer more sustainable cause-specific treatment modalities that will minimize the use of blood transfusion with its attendant adverse effects.

Topics: Anemia; Bone Marrow Transplantation; Erythropoietin; Humans; Neoplasms; Quality of Life; Syndrome

Backgroud. Anemia is one of the laboratory and clinical findings of chronic kidney diseases (CKD). The presence of anemia in patients with CKD has a wide range of clinically important consequences. Some of the symptoms that were previously attributed to reduced renal function are, in fact, a consequence of anemia. Anemia contributes to increased cardiac output, the development of left ventricular hypertrophy, angina, and congestive heart failure. According to current knowledge, anemia also contributes to the progression of CKD and is one of the factors that contribute to the high morbidity and mortality in patients with chronic renal failure and their reduced survival.. MEDLINE search was performed to collect both original and review articles addressing anemia in CKD, pathophysiology of renal anemia, erythropoiesis, erythropoietin, iron metabolism, inflammation, malnutrition, drugs, renal replacement therapy and anemia management. The present review summarized current knowledge in the field of the pathophysiology of renel anemia. Understanding the pathophysiology of anemia in CKD is crucial for the optimal treatment of anemia according to recent clinical practice guidelines and recommendation, and correct recognition of causes of resistence to treatment of erythropoietin stimulating agents (ESA).

Topics: Adult; Anemia; Erythropoiesis; Erythropoietin; Hemoglobins; Humans; Iron Deficiencies; Iron Metabolism Disorders; Renal Insufficiency, Chronic

Recombinant human erythropoietin (rhEpo, epoetin) has proved beneficial in preventing transfusion-dependent anaemia in patients with chronic kidney disease. Apart from copied epoetins distributed in less regulated markets, 'biosimilar' epoetins have gained currency in many regions, where they compete with the originals and with rhEpo analogues with prolonged survival in circulation ('biobetter'). Recombinant erythropoiesis stimulating agents are potent and well tolerated. However, their production is costly, and they must be administered by the parenteral route. Hence, other anti-anaemia treatments are being evaluated. Clinical trials are being performed with stabilizers of the hypoxia-inducible transcription factors (HIFs), which increase endogenous Epo production. HIF stabilizers are chemical drugs and they are active on oral administration. However, there is fear that they may promote tumour growth. Epo mimetic peptides have also raised expectations. Yet the prototype peginesatide was recalled after just 1 year of its widespread use in the USA because of serious side-effects including cases of death. Most recently, clinical trials have been initiated with sotatercept, a recombinant soluble activin receptor type 2A IgG-Fc fusion protein. Sotatercept binds distinct members of the transforming growth factor-β family, thereby preventing the inhibitory action of these factors in erythropoiesis. Taken together, rhEpo and its long-acting recombinant analogues will likely remain mainstay of anti-anaemia therapies in the near future.

Topics: Activins; Anemia; Biosimilar Pharmaceuticals; Erythropoietin; Hematinics; Humans

Renal fibrosis is a major hallmark of chronic kidney disease that is considered to be a common end point of various types of renal disease. To date, the biological meaning of fibrosis during the progression of chronic kidney diseases is unknown and possibly depends on the cell type contributing to extracellular matrix production. During the past decade, the origin of myofibroblasts in the kidney has been intensively investigated. Determining the origins of renal myofibroblasts is important because these might account for the heterogeneous characteristics and behaviors of myofibroblasts. Current data strongly suggest that collagen-producing myofibroblasts in the kidney can be derived from various cellular sources. Resident renal fibroblasts and cells of hematopoietic origin migrating into the kidney seem to be the most important ancestors of myofibroblasts. It is likely that both cell types communicate with each other and also with other cell types in the kidney. In this review, we will discuss the current knowledge on the origin of scar-producing myofibroblasts and cellular events triggering fibrosis.

Topics: Actins; Anemia; Animals; Cell Movement; Disease Progression; Epithelial-Mesenchymal Transition; Erythropoietin; Extracellular Matrix; Fibroblasts; Fibrosis; Humans; Kidney; Models, Biological; Myofibroblasts; Pericytes; Renal Insufficiency, Chronic

The myelodysplastic syndromes are characterized by refractory cytopenias that lead to symptomatic anemia, bleeding, and increased risk for infections. For almost two decades, the use of darbepoetin and other erythropoietin stimulating agents to treat symptomatic anemia in lower-risk myelodysplastic syndromes has been a standard of care. This practice is supported by numerous Phase I/II studies and one Phase III study demonstrating the benefit of using erythropoietin stimulating agents alone, or in combination with granulocyte colony stimulating factor, for treatment of symptomatic anemia with the goal of decreasing red blood cell transfusion requirements. This review summarizes the published experience regarding the use of erythropoietin stimulating agents, with a special focus on darbepoetin, in patients with myelodysplastic syndrome and symptomatic anemia.

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Hematinics; Humans; Myelodysplastic Syndromes

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

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

The association between chronic kidney disease (CKD) and cardiovascular disease (CVD) is well established, and there is mounting evidence of interorgan cross talk that may accelerate pathologic processes and the progression of organ dysfunction in both systems. This process, termed cardiorenal syndrome (CRS) by the Acute Dialysis Quality Initiative, is considered a major health problem: patients with CKD and CVD are at much higher risk of mortality than patients with either condition alone. To date, the majority of CRS research has focused on neurohormonal mechanisms and hemodynamic alterations. However, mounting evidence suggests that abnormalities in the normal pathophysiology of the bone-mineral axis, iron, and erythropoietin play a role in accelerating CKD and CVD. The goal of this article is to review the role and interrelated effects of the bone-mineral axis and anemia in the pathogenesis of chronic CRS.

Topics: Anemia; Bone and Bones; Calcifediol; Calcitriol; Calcium; Cardio-Renal Syndrome; Cardiovascular Diseases; Erythropoietin; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Iron; Parathyroid Hormone; Phosphates; Renal Insufficiency, Chronic

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

As essential mediators of red cell production, erythropoietin (EPO) and its cell surface receptor (EPO receptor [EPOR]) have been intensely studied. Early investigations defined basic mechanisms for hypoxia-inducible factor induction of EPO expression, and within erythroid progenitors EPOR engagement of canonical Janus kinase 2/signal transducer and activator of transcription 5 (JAK2/STAT5), rat sarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (RAS/MEK/ERK), and phosphatidylinositol 3-kinase (PI3K) pathways. Contemporary genetic, bioinformatic, and proteomic approaches continue to uncover new clinically relevant modulators of EPO and EPOR expression, and EPO's biological effects. This Spotlight review highlights such factors and their emerging roles during erythropoiesis and anemia.

Topics: Anemia; Animals; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation; Humans; Janus Kinase 2; MAP Kinase Signaling System; Phosphatidylinositol 3-Kinases; ras Proteins; Rats; Receptors, Erythropoietin; STAT5 Transcription Factor

Topics: Anemia; Disease Management; Drug Administration Routes; Erythropoietin; Humans; Iron; Iron Deficiencies; Renal Insufficiency, Chronic; Severity of Illness Index; Trace Elements

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Erythropoietin; Female; Hematinics; Hepcidins; Humans; Male; Multicenter Studies as Topic; Neoplasms; Randomized Controlled Trials as Topic

The European Medicines Agency (EMA), under a strictly regulated pathway, has approved several biosimilar products since 2005, including biosimilar versions of the erythropoiesis-stimulating agent (ESA) epoetin alfa since 2007. Subsequent to these approvals, the use of biosimilar epoetin alfa in the management of renal anemia has grown steadily throughout Europe. With the enactment of the US Biologics Price Competition and Innovation Act of 2009, a US Food and Drug Administration regulatory approval process for biosimilars was legalized. Thus, biosimilar erythropoietin products are expected to be available for prescription in the USA by mid-decade, presumably at a price that is competitive with the originator brand-name reference products. In this paper, we describe the status of originator and biosimilar ESAs, review the clinical development and regulatory approval of biosimilar erythropoietins in Europe, and summarize relevant efficacy and safety information of biosimilar erythropoietins in relation to their reference products to provide a background for US nephrologists as they appraise biosimilar erythropoietins as treatment options for renal anemia. Key lessons learned from Europe are that (a) EMA-approved biosimilar erythropoietins have comparable efficacy and safety profiles to their reference product erythropoietin; (b) pharmacovigilance preapproval and postapproval are critical, especially with regard to immunogenicity and vascular thromboembolic events; (c) strict preapproval and postapproval requirements must guide the regulatory pathway for biosimilars; and (d) high-quality manufacturing and production processes must be established to ensure quality biosimilar products. The availability of biosimilar erythropoietins in the USA will provide nephrologists with alternative effective, and potentially more affordable, treatment options for patients with renal anemia.

Topics: Anemia; Biosimilar Pharmaceuticals; Disease Management; Erythropoietin; Europe; Humans; Renal Insufficiency, Chronic; United States

Renal anemia is caused by the deficiency of endogenous erythropoietin (Epo) due to renal dysfunction. We think that it is possible to slow the progression of chronic kidney disease (CKD) in case we initiate Epo early in pre-dialysis patients, especially in the non-diabetic population. Erythropoiesis stimulating agent (ESA) treatments targeting mild anemia (10-12 g/dl) can decrease the risk of occurrence of cardiovascular disease (CVD) in patients with hypertension, diabetes mellitus and congestive heart failure. As the large randomized controlled trials such as 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 Thearpy in the Western countries suggested, we do not recommend high doses of ESA to achieve the target hemoglobin (Hb) level. The target Hb of >13 g/dl might lead to increase in the risk of CVD although maintaining a high Hb of >12 g/dl without ESA is not harmful for CKD patients. It is desirable to determine the target Hb in dialysis patients depending on their ages. Renal anemia should be monitored constantly to start ESA and iron replacement therapy at an appropriate time, while avoiding their excess in order to minimize the occurrence of CVD and other complications. Taken all the international guidelines and our clinical experiences together, we should consider administration of ESA when the Hb level becomes <11 g/dl in pre-dialysis patients and <10 g/dl in dialysis patients.

Topics: Anemia; Erythropoietin; Hemoglobins; Humans; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic

Anemia is a global public health problem affecting both developing and developed countries at all ages. According to the World Health Organization (WHO), anemia is defined as hemoglobin (Hb) levels <12.0 g/dL in women and <13.0 g/dL in men. However, normal Hb distribution varies not only with sex but also with ethnicity and physiological status. New lower limits of normal Hb values have been proposed, according to ethnicity, gender, and age. Anemia is often multifactorial and is not an independent phenomenon. For the classification and diagnosis the hematologic parameters, the underlying pathological mechanism and patient history should be taken into account. The aging of population, especially in Western countries, causes an increase of anemia in elderly people. In this population, anemia, recently defined by levels of Hb <12 g/dL in both sexes, is mostly of mild degree (10-12 g/dL). Understanding the pathophysiology of anemia in this population is important because it contributes to morbidity and mortality. In one third of the patients, anemia is due to nutritional deficiency, including iron, folate, or vitamin B12 deficiency; moreover, anemia of chronic disease accounts for about another third of the cases. However, in one third of patients anemia cannot be explained by an underlying disease or by a specific pathological process, and for this reason it is defined "unexplained anemia". Unexplained anemia might be due to the progressive resistance of bone marrow erythroid progenitors to erythropoietin, and a chronic subclinical pro-inflammatory state.

Topics: Aging; Anemia; Biomarkers; Cellular Senescence; Erythropoietin; Humans; Prevalence; Stem Cells

Anemia in the setting of chronic inflammatory disorders is a very frequent clinical condition, which is, however, often neglected or not properly treated given the problems often caused by the diseases underlying the development of anemia. Mechanistically, anemia is mainly caused by inflammation-driven retention of iron in macrophages making the metal unavailable for heme synthesis in the course of erythropoiesis, and further by impaired biological activity of the red blood cell hormone erythropoietin and the reduced proliferative capacity of erythroid progenitor cells. Anemia can be aggravated by chronic blood loss, as found in subjects with gastrointestinal cancers, inflammatory or infectious bowel disease, or iatrogenic blood loss in the setting of dialysis, all resulting in true iron deficiency. The identification of such patients is a clinical necessity because these individuals need contrasting therapies in comparison to subjects suffering from only classical anemia of chronic disorders. The diagnosis is challenging because no state of the art laboratory test is currently available that can clearly separate patients with inflammatory anemia from those with additional true iron deficiency. However, based on our expanding knowledge on the pathophysiology of inflammatory anemia, new diagnostic markers, including the iron-regulatory hormone hepcidin, and hematologic parameters emerge. Apart from traditional anemia treatments such as blood transfusions, recombinant erythropoietin, and iron, including new high-molecular-weight formulations, new therapeutics are currently under preclinical and clinical evaluation. These novel compounds aim at correcting anemia by multiple pathways, including antagonizing the inflammation- and hepcidin-driven retention of iron in the monocyte-macrophage system and thereby promoting the supply of iron for erythropoiesis or by stimulating the endogenous formation of erythopoietin via stabilization of hypoxia-regulated factors.

Topics: Anemia; Animals; Chronic Disease; Erythropoietin; Hepcidins; Humans; Iron

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

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

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

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

Erythropoiesis-stimulating agents (ESAs) are widely used in treating anemia associated with renal failure. They are also now used perioperatively to reduce the use of allogeneic blood transfusions (ABTs) in patients undergoing surgery with anticipated high blood loss. Although they can reduce the risks associated with ABT and improve quality of life, the use of ESAs is still associated with adverse effects.. A narrative review is provided on ESAs and a systematic review has been conducted to examine the current evidence for the efficacy and safety of perioperative ESAs use. A search of PubMed and Medline databases has been performed using a combination of search terms including erythropoietin, perioperative, surgical, safety and efficacy.. Current evidence supports the use of perioperative ESAs to reduce the need for ABT. However, large studies assessing safety in anemic patients with chronic renal disease have found adverse effects including cardiovascular, stroke and thromboembolic events. However, whether these concerns can be conferred onto the surgical population remains to be seen as the perioperative dosing strategies have been more variable in timing, dose and duration in comparison with those used for chronic diseases. Future research needs to address the questions of optimal dosing strategies in order to maximize the positive effects and minimize adverse events.

Topics: Anemia; Animals; Blood Loss, Surgical; Blood Transfusion; Drug Administration Schedule; Erythropoiesis; Erythropoietin; Hematinics; Humans; Perioperative Care; Postoperative Hemorrhage; Recombinant Proteins; Risk Factors; Time Factors; Treatment Outcome

Treatment of anemia remains an important component in the care of patients with nondialysis chronic kidney disease (CKD) and end-stage renal disease (ESRD). Erythropoietin-stimulating agents (ESAs) remains a key anemia treatment strategy in this patient population. However, anemia management in this group can become more complicated by prior or current history of malignancy. There has been a great deal of work both scientifically and in clinical trials in oncology that have revealed certain concerns and risks of ESA use in patients with cancer. In this review, we will bring together knowledge from nephrology and oncology literature to help nephrologists understand the implications for ESA treatment when CKD/ESRD is complicated by cancer. We also suggest an approach to the management of anemia in this patient group with active or previous malignancy.

Topics: Anemia; Contraindications; Erythropoietin; Female; Hematinics; Humans; Male; Neoplasms; Receptors, Erythropoietin; Renal Insufficiency, Chronic; Risk Factors

The concept of patient blood management is such that if a patient with anemia can be identified in the pre-operative period, therapeutic modalities can be targeted to that patient who might benefit from such treatment. Management strategies include the optimization of preoperative hemoglobin by maximizing hemopoiesis and RBC mass. This can best be achieved with the use of iron supplementation, either oral or intravenous, with or without the use of erythrocyte stimulating agents (ESAs) such as erythropoietin. The use of i.v. iron and ESAs is reviewed. Different i.v. iron formulations available are discussed along with current indications and contraindications for the use of ESAs.

Topics: Administration, Intravenous; Anemia; Blood Preservation; Blood Transfusion; Dietary Supplements; Erythrocytes; Erythropoietin; Hematinics; Humans; Iron; Preoperative Period

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

Cancer-related anemia (CRA) is due to multiple etiologies, including chemotherapy-induced myelosuppression, blood loss, functional iron deficiency, erythropoietin deficiency due to renal disease, marrow involvement with tumor as well as other factors. The most common treatment options for CRA include iron therapy, erythropoietic-stimulating agents (ESAs), and red cell transfusion. Safety concerns as well as restrictions and reimbursement issues surrounding ESA therapy for CRA have resulted in suboptimal treatment. Similarly, many clinicians are not familiar or comfortable using intravenous iron products to treat functional iron deficiency associated with CRA. This article summarizes our approach to treating CRA and discusses commonly encountered clinical scenarios for which current clinical guidelines do not apply.

Topics: Anemia; Erythrocyte Transfusion; Erythropoietin; Humans; Iron; Malnutrition; Neoplasms; Prevalence; Treatment Outcome

Erythropoiesis, the bone marrow production of erythrocytes by the proliferation and differentiation of hematopoietic cells, replaces the daily loss of 1% of circulating erythrocytes that are senescent. This daily output increases dramatically with hemolysis or hemorrhage. When erythrocyte production rate of erythrocytes is less than the rate of loss, chronic anemia develops. Normal erythropoiesis and specific abnormalities of erythropoiesis that cause chronic anemia are considered during three periods of differentiation: a) multilineage and pre-erythropoietin-dependent hematopoietic progenitors, b) erythropoietin-dependent progenitor cells, and c) terminally differentiating erythroblasts. These erythropoietic abnormalities are discussed in terms of their pathophysiological effects on the bone marrow cells and the resultant changes that can be detected in the peripheral blood using a clinical laboratory test, the complete blood count.

Topics: Anemia; Animals; Blood Cell Count; Blood Platelets; Cell Differentiation; Chronic Disease; Erythrocytes; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Humans; Leukocytes

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

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

Anemia, usually due to iron deficiency, is highly prevalent among patients with colorectal cancer. Inflammatory cytokines lead to iron restricted erythropoiesis further decreasing iron availability and impairing iron utilization. Preoperative anemia predicts for decreased survival. Allogeneic blood transfusion is widely used to correct anemia and is associated with poorer surgical outcomes, increased post-operative nosocomial infections, longer hospital stays, increased rates of cancer recurrence and perioperative venous thromboembolism. Infections are more likely to occur in those with low preoperative serum ferritin level compared to those with normal levels. A multidisciplinary, multimodal, individualized strategy, collectively termed Patient Blood Management, minimizes or eliminates allogeneic blood transfusion. This includes restrictive transfusion policy, thromboprophylaxis and anemia management to improve outcomes. Normalization of preoperative hemoglobin levels is a World Health Organization recommendation. Iron repletion should be routinely ordered when indicated. Oral iron is poorly tolerated with low adherence based on published evidence. Intravenous iron is safe and effective but is frequently avoided due to misinformation and misinterpretation concerning the incidence and clinical nature of minor infusion reactions. Serious adverse events with intravenous iron are extremely rare. Newer formulations allow complete replacement dosing in 15-60 min markedly facilitating care. Erythropoiesis stimulating agents may improve response rates. A multidisciplinary, multimodal, individualized strategy, collectively termed Patient Blood Management used to minimize or eliminate allogeneic blood transfusion is indicated to improve outcomes.

Topics: Algorithms; Anemia; Blood Transfusion; Colorectal Neoplasms; Erythropoietin; Europe; Female; Humans; Iron; Male; Oxygen; Perioperative Care; Perioperative Period; Quality of Life

Anemia is fairly common in lung neoplasms and adequate management can influence both the prognosis and the quality of life of patients. Anemia can stem from diverse mechanisms, and its management must include the search for correctable causes (iron deficiency, inflammation, disease- or treatment-related), and their subsequent treatment. Use of erythropoiesis stimulating agents, namely recombinant erythropoietin, results in hemoglobin increase, fewer blood transfusions, and better quality of life. However, there is also a significant increase in thromboembolic risk associated with this treatment, and their effect on overall survival is still debated. Thus, their use must be restricted to patients treated with palliative intent, receiving chemotherapy but no radiotherapy, with a baseline hemoglobin level under 100 g/L, and target hemoglobin level must not exceed 120 g/L.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Hematinics; Humans; Lung Neoplasms; Practice Guidelines as Topic

Erythropoiesis-stimulating agents (ESAs) increase red blood cell production in patients with chemotherapy-induced anemia (CIA). In Europe, short-acting ESAs (epoetin alfa, epoetin beta, epoetin zeta, and epoetin theta) and a long-acting ESA (darbepoetin alfa) are available to treat CIA.. This systematic review aimed to determine potential dose efficiency associated with the use of different ESAs for the treatment of CIA according to European labeling.. A systematic review of ESA studies with starting doses according to European labeling was conducted according to published methodology. Measures of dose efficiency were defined as mean weekly doses to achieve target hemoglobin level or final dose and dose adjustments (dose increase, decrease, or withheld). Electronic databases and grey literature sources were searched up to July 2012. Data were selected for analysis using an evidence hierarchy and quantitatively analyzed to assess statistical homogeneity. Where pooling of data was not appropriate, a narrative summary with descriptive statistics (medians and ranges) was reported.. Fifty-five studies met the inclusion criteria. Twenty-five studies considered to represent the highest level of evidence were extracted and included in the analysis. The analysis showed a high degree of statistical heterogeneity, often precluding meta-analysis. The patients included in the analysis were representative of those encountered in clinical practice, and patient characteristics were similar between the short-acting and the darbepoetin alfa groups. Mean weekly doses appeared ~30% lower with darbepoetin alfa versus short-acting ESAs (median, 136.5 μg or 27,300 IU [range, 21,560-38,260 IU] vs 38,230 IU [range, 31,634-42,714 IU], respectively), resulting in a mean weekly dose ratio of 1:280. Darbepoetin alfa patients appeared to need fewer dose increases compared with short-acting ESAs (pooled, 0.75%; I(2) = 21% vs median 26.6% [range, 7.6%-44.6%]) and more dose decreases (median, 74% [range, 57%-75%] vs 22% [range, 2.8%-59%]). A similar percentage of darbepoetin alfa and short-acting ESA patients required a dose to be withheld (20% and 33% [2 studies] vs median 33.2% [range, 12.6%-51.1%]).. Statistical heterogeneity between studies was high, although clinically the studies represented medical practice. Without randomized clinical trials directly comparing darbepoetin alfa and short-acting ESAs, these findings are tentative and future research is warranted. This review shows that good-quality, reliable data from head-to-head trials are lacking. The best available evidence comes from prospective ESA-arm data. Mean weekly doses, dose increases, and dose decreases suggest a dose efficiency for darbepoetin alfa compared with short-acting ESAs.

Topics: Anemia; Darbepoetin alfa; Databases, Factual; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematinics; Humans; Middle Aged; Prospective Studies; Recombinant Proteins

Anemia is frequently observed in cancer patients and can cause symptoms and result in red cell transfusions. The erythropoiesis stimulating agents (ESAs) have been shown to increase hemoglobin levels and reduce transfusion requirements in anemic subjects with cancer who are receiving chemotherapy. Initially, these benefits motivated broad use of the ESAs in oncology. Over the past 10 years, recognition of the adverse events that can be associated with ESA use in these patients, particularly venous thrombosis, has resulted in a rethinking of the issue of who are the correct candidates for treatment. Different health care systems have come to different conclusions based upon the available data and additional data are still being generated. This article will review the data concerning the safety of ESAs in cancer patients, including the results of additional trials published in the past 2 years. This will include a discussion of the potential of ESAs to impact tumor progression or survival. Thrombosis remains the most important and best documented adverse event associated with ESA therapy in oncology. The mechanism(s) through which ESAs alter thrombosis risk are still very poorly understood.

Topics: Anemia; Disease Progression; Erythropoietin; Hematinics; Humans; Neoplasms

Erythropoiesis-stimulating agents are used to treat anaemia in people with chronic kidney disease (CKD). Several agents are available including epoetin alfa or beta as well as agents with a longer duration of action, darbepoetin alfa and methoxy polyethylene glycol-epoetin beta.. To assess the benefits and harms of darbepoetin alfa to treat anaemia in adults and children with CKD (stages 3 to 5, 5D, and kidney transplant recipients).. We searched the Cochrane Renal Group's Specialised Register (to 13 January 2014) through contact with the Trials' Search Co-ordinator using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE and EMBASE.. We included randomised controlled trials of any darbepoetin alfa treatment of at least three months duration in adults or children with CKD (any stage).. Data were extracted by two independent investigators. Patient-centred outcomes (need for blood transfusion, iron therapy, progression of kidney disease, total and cardiovascular mortality, cardiovascular events, cancer, hypertension, seizures, and health-related quality of life) and other outcomes (haemoglobin levels) were assessed using random effects meta-analysis. We calculated risk ratios for dichotomous outcomes and mean differences for continuous outcomes, both with 95% confidence intervals.. We identified 32 studies comprising 9414 participants; 21 studies in 8328 participants could be included in our meta-analyses. One study (4038 participants) compared darbepoetin alfa to placebo, 16 studies (2955 participants) compared darbepoetin alfa to epoetin alfa or beta, four studies (1198 participants) compared darbepoetin alfa to methoxy polyethylene glycol-epoetin beta, three studies (420 participants) compared more frequent with less frequent darbepoetin alfa administration and four studies (303 participants) compared intravenous with subcutaneous darbepoetin alfa administration.In a single large study, darbepoetin alfa reduced the need for blood transfusion and iron therapy compared with placebo in adults with CKD stage 3 to 5, but had little or no effect on survival, increased risks of hypertension, and had uncertain effects on quality of life. Data comparing darbepoetin alfa with epoetin alfa or beta or methoxy polyethylene glycol-epoetin beta were sparse and inconclusive. Comparisons of differing dosing schedules and routes of administration were compared in small numbers of participants and studies. Evidence for treatment effects of darbepoetin alfa were particularly limited for children with CKD, adults with CKD stage 5D, and recipients of a kidney transplant.Studies included in this review were generally at high or unclear risk of bias for all items (random sequence generation, allocation concealment, incomplete outcome data, blinding of participants and personnel, blinding of outcome assessment, selective outcome reporting, intention to treat analysis and other sources of bias). One large study comparing darbepoetin alfa with placebo was at low risk of bias for most items assessed.. Data suggest that darbepoetin alfa effectively reduces need for blood transfusions in adults with CKD stage 3 to 5, but has little or no effect on mortality or quality of life. The effects of darbepoetin alfa in adults with CKD stage 5D and kidney transplant recipients and children with CKD remain uncertain as do the relative benefits and harms of darbepoetin alfa compared with other ESAs (epoetin alfa or beta and methoxy polyethylene glycol-epoetin beta).

Topics: Adult; Anemia; Child; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Transplantation; Polyethylene Glycols; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Insufficiency, Chronic

Erythropoiesis stimulating agents [erythropoietin (EPO)] have been recommended to treat anaemic patients who cannot receive or refuse blood tranfusion ('untransfusable' patients).. The objective of the study was to quantify the association of EPO use with haemoglobin (Hgb) recovery in anaemic untransfusable hospitalised patients.. EPO treated anaemic untransfusable patients were identified through the combination of a retrospective case review and a systematic review of the medical literature. Literature reports of untransfusable patients not treated with any EPO were used as a comparator group. Hgb concentrations before and following EPO use were abstracted and used to determine the rate of Hgb recovery for each case. Multilevel mixed effects modelling was used to determine the association of Hgb recovery with EPO use.. A total of 76 EPO treated cases (19 cases from the retrospective hospital case review and 57 from the literature), and 33 non-EPO treated comparator patients from the literature were included in the study. Hgb increased similarly over time in all groups at an overall mean standard error (SE) rate of 0·13 (0·01) g dL(-1)  day(-1) . The Hgb recovery rate was higher in patients with lower baseline Hgb, regardless of EPO use. No association was found between the rate of Hgb recovery and EPO use, dose or therapy duration.. In anaemic, 'untransfusable' hospitalised patients, EPO use was not associated with increased Hgb recovery at anytime within 28 days.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Models, Biological; Recombinant Proteins; Recovery of Function; Retrospective Studies

Chronic Kidney Disease (CKD) has adverse consequences on almost all body systems. The kidney does not function merely as an excretory organ, but participates in normal erythropoiesis, normal bone mineral deposition and blood pressure regulation.. Anemia is prevalent in CKD with known deleterious effects on the car diovascular system. It is mostly due to erythropoietin deficiency, inhibition of erythropoiesis by uremic solutes, and reduction in red blood cell life span. Other possible causes include iron, B12 or folic acid deficiency or blood loss. Dysfunction of the endogenous erythropoietin is usually clinically evident once the glomerular filtration rate (GFR) falls below 20-25 ml/min. Treating anemia of CKD is based on correction of iron deficiency and replacement of decreased erythropoietin production by erythropoietin stimulating agents (ESA). Guidelines recommend targeting hemoglobin levels of no more than 10-12 g/dl since there is evidence of increased mortality and morbidity in patients with higher levels. Increased level of pro-coagulant biomarkers cause enhanced thrombotic activity in CKD patients which promotes ischemic cardiac events while platelet dysfunction leads to bleeding diathesis. If anticoagulation is indicated, low molecular weight heparins (LMWHs) offer certain advantage sbut the dosage needs to be adjusted with increasing grade of renal insufficiency. Antiplatelet agents are effective in averting shunt and catheter thrombosis, but not for avoiding the thrombosis of arteriovenous grafts.. Health related quality of life in CKD patients can be improved by treating anemia. Newly available ESAs and the entry into the market of epoetinbiosimilars are expected to lead to improvements in the management of CKD and its complications.

Topics: Anemia; Erythropoiesis; Erythropoietin; Glomerular Filtration Rate; Hematinics; Humans; Quality of Life; Renal Insufficiency, Chronic

Anemia, a common complication associated with inflammatory bowel disease (IBD), is frequently overlooked in the management of IBD patients. Unfortunately, it represents one of the major causes of both decreased quality of life and increased hospital admissions among this population. Anemia in IBD is pathogenically complex, with several factors contributing to its development. While iron deficiency is the most common cause, vitamin B12 and folic acid deficiencies, along with the effects of pro-inflammatory cytokines, hemolysis, drug therapies, and myelosuppression, have also been identified as the underlying etiology in a number of patients. Each of these etiological factors thus needs to be identified and corrected in order to effectively manage anemia in IBD. Because the diagnosis of anemia in IBD often presents a challenge, combinations of several hematimetric and biochemical parameters should be used. Recent studies underscore the importance of determining the ferritin index and hepcidin levels in order to distinguish between iron deficiency anemia, anemia due to chronic disease, or mixed anemia in IBD patients. With regard to treatment, the newly introduced intravenous iron formulations have several advantages over orally-administered iron compounds in treating iron deficiency in IBD. In special situations, erythropoietin supplementation and biological therapies should be considered. In conclusion, the management of anemia is a complex aspect of treating IBD patients, one that significantly influences the prognosis of the disease. As a consequence, its correction should be considered a specific, first-line therapeutic goal in the management of these patients.

Topics: Anemia; Anemia, Iron-Deficiency; Cytokines; Dietary Supplements; Erythropoietin; Ferritins; Folic Acid Deficiency; Hemolysis; Hepcidins; Humans; Inflammatory Bowel Diseases; Iron; Prognosis; Quality of Life; Vitamin B 12 Deficiency

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

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

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

Anaemia is a common finding at diagnosis in myelofibrosis, and becomes a symptomatic problem in most patients with time. There are several treatment options for specific anaemia treatment, none of which has been tested in large, randomized, controlled trials. However, as myelofibrosis is not a disease with spontaneous remissions, even non-randomized trials carry weight. In this survey, the existing evidence will be analysed, both for the commonly used treatments like erythropoiesis-stimulating agents, androgens and thalidomide and for the new drugs in the area, and conclusions will be drawn concerning standard clinical anaemia treatment in myelofibrosis, which according to evidence from studies has a 40-50% chance of response in patients with not too advanced disease.

Topics: Androgens; Anemia; Blood Transfusion; Erythropoietin; Hematinics; Humans; Immunosuppressive Agents; Interferons; Lenalidomide; Nitriles; Oxymetholone; Primary Myelofibrosis; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Thalidomide

Anemia management in non-dialysis-dependent chronic kidney disease (CKD) patients is associated with cardiovascular and cost benefits, slows decline in renal function, and prevents mortality. Different reviews have focused on evaluating the safety and efficacy of methoxy polyethylene glycol-epoetin beta (MPG-EPO), a continuous erythropoietin receptor activator, in CKD patients regardless of dialysis dependency and others have studied this novel agent exclusively in CKD patients receiving dialysis.. To evaluate the efficacy and tolerability of MPG-EPO compared with other erythropoiesis stimulating agents (in particular darbepoetin alfa) for the treatment of anemia in non-dialysis-dependent CKD patients.. A systematic review of original studies published mainly in MEDLINE, Cochrane Database, ScienceDirect, ProQuest, clinical trials registries, and Google Scholar was carried out to identify randomized controlled trials (RCTs) comparing MPG-EPO with other erythropoiesis stimulating agents or placebo among patients with anemia of CKD who were not yet receiving dialysis. Data were independently extracted by two reviewers using standardized data abstraction tool.. Four trials involving 1,155 patients were included in the review. The changes in hemoglobin level from the baseline reported by the reviewed studies demonstrate that MPG-EPO was clinically non-inferior to darbepoetin alfa. In addition, the studies documented that MPG-EPO-treated patients experienced a lower rate of hemoglobin level above the target range of 12-13 g/dL than darbepoetin-treated patients. The proportion of patients requiring RBC transfusion was higher among patients who received darbepoetin alfa than those who received MPG-EPO. However, the time to hemoglobin response was longer with MPG-EPO than with darbepoetin. Finally, the incidences of serious adverse events were similar between the two therapeutic agents.. There are currently only few well-designed head-to-head RCTs investigating the efficacy and safety of MPG-EPO compared with other ESAs in non-dialysis-dependent patients. MPG-EPO therapy compared with darbepoetin alfa has demonstrated favorable effects of increasing and maintaining hemoglobin concentrations to recommended target levels. This mini-review is not conclusive due to limited number of studies. Therefore, the beneficial effects and tolerability of MPG-EPO among non-dialysis-dependent CKD patients should be further investigated, given the economic and clinical benefits of managing anemia in this population.

Topics: Anemia; Clinical Trials as Topic; Darbepoetin alfa; Erythropoietin; Hematinics; Humans; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic

Anaemia occurs when blood contains fewer red blood cells and lower haemoglobin levels than normal, and is a common complication among adults with chronic kidney disease (CKD). Although a number of approaches are applied to correct anaemia in adults with CKD, the use of androgen therapy is controversial.. The aim of this review was to determine the benefits and harms of androgens for the treatment of anaemia in adult patients with CKD.. We searched CENTRAL, the Cochrane Renal Group's Specialised Register, the Chinese Biomedicine Database (CBM), CNKI, VIP and reference lists of articles without language restriction. The most recent search was conducted in August 2014.. All randomised controlled trials (RCTs) that assessed the use of androgens for treating anaemia of CKD in adults were eligible for inclusion.. Two authors independently extracted data and assessed risk of bias in the included studies. Meta-analyses were performed using relative risk (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, with 95% confidence intervals (CI).. We included eight studies that reported data from 181 participants. Study quality was assessed as moderate in six studies, one was low quality, and one was high quality. The small number of included studies, and low participant numbers adversely influenced evidence quality overall.We found limited evidence (1 study, 24 participants) to indicate that oxymetholone can increase haemoglobin (Hb) (MD 1.90 g/dL, 95% CI 1.66 to 2.14), haematocrit (HCT) (MD 27.10%, 95% CI 26.49 to 27.71), change in albumin (MD 4.91 g/L, 95% CI 3.69 to 6.13), alanine aminotransferase (ALT) (MD 54.50 U/L, 95% CI 43.94 to 65.06), and aspartate aminotransferase (AST) (MD 47.33 U/L, 95% CI 37.69 to 56.97); and decrease high-density lipoprotein (HDL) (MD -15.66 mg/dL, 95% CI -24.84 to -6.48). We also found that compared with erythropoietin alone, nandrolone decanoate plus erythropoietin may increase HCT (3 studies, 73 participants: MD 2.54%, 95% Cl 0.96 to 4.12). Compared with erythropoietin (1 study, 27 participants), limited evidence was found to suggest that nandrolone decanoate can increase plasma total protein (MD 0.40 g/L, 95% CI 0.13 to 0.67), albumin (MD 0.20 g/L, 95% CI 0.01 to 0.39), and transferrin (MD 45.00 mg/dL, 95% CI 12.61 to 77.39) levels. Compared with no therapy (remnant kidney), evidence was found to suggest that nandrolone decanoate can increase Hb (2 studies, 33 participants: MD 1.04 g/dL, 95% Cl 0.66 to 1.41) and HCT (1 study, 24 participants: MD 3.70%, 95% Cl 0.68 to 6.72). Compared with no therapy (anephric), evidence was found (1 study, 5 participants) to suggest that nandrolone decanoate can increase Hb (MD 1.30 g/dL, 95% Cl 0.57 to 2.03), but nandrolone decanoate did not increase HCT (MD 2.00%, 95% Cl -0.85 to 4.85).However, oxymetholone was not found to reduce blood urea nitrogen (BUN), serum creatinine (SCr), cholesterol, or triglycerides; or increase plasma total protein, prealbumin, or transferrin. No evidence was found to indicate that nandrolone decanoate increased prealbumin or decreased BUN, SCr, AST, ALT, cholesterol, triglycerides, HDL or low-density lipoprotein (LDL). Adverse events associated with androgen therapy were reported infrequently.. We found insufficient evidence to confirm that use of androgens for adults with CKD-related anaemia is beneficial.

Topics: Adult; Androgens; Anemia; Cholesterol; Erythropoietin; Hematocrit; Humans; Nandrolone; Nandrolone Decanoate; Oxymetholone; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Triglycerides

There is a well-documented association between erythropoiesis-stimulating agents (ESAs) and hypertension in chronic kidney disease. Studies suggest that the mechanism for this is multifactorial. First, some chronic kidney disease patients may have a limited ability to accommodate a rapid increase in red cell volume because of a decreased glomerular filtration rate, left ventricular hypertrophy, and decreased arterial compliance. Second, there is likely a direct vasoconstrictor effect of ESAs. Although no large randomized controlled trials of ESAs have been designed with blood pressure as an a priori outcome, several meta-analyses have explored this relationship and generally support the existence of ESA-induced hypertension. There are as of yet no data directly linking ESA-induced hypertension with increased cardiovascular morbidity and mortality. Despite this, clinicians should be vigilant for ESA-induced hypertension, use caution when using ESAs in patients with resistant hypertension, and be attentive to the rate of hemoglobin increase in patients with poorly controlled blood pressure.

Topics: Anemia; Blood Pressure; Drug Resistance; Endothelin-1; Erythropoietin; Hematinics; Humans; Hypertension; Nitric Oxide; Recombinant Proteins; Renal Insufficiency, Chronic; Renin-Angiotensin System

Several erythropoiesis-stimulating agents (ESAs) are available for treating anaemia in people with chronic kidney disease (CKD). Their relative efficacy (preventing blood transfusions and reducing fatigue and breathlessness) and safety (mortality and cardiovascular events) are unclear due to the limited power of head-to-head studies.. To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, or methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs, against each other, placebo, or no treatment) to treat anaemia in adults with CKD.. We searched the Cochrane Renal Group's Specialised Register to 11 February 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review.. Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, or biosimilar ESA) with another ESA, placebo or no treatment in adults with CKD and that reported prespecified patient-relevant outcomes were considered for inclusion.. Two independent authors screened the search results and extracted data. Data synthesis was performed by random-effects pairwise meta-analysis and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore for sources of heterogeneity or inconsistency. We assessed our confidence in treatment estimates for the primary outcomes within network meta-analysis (preventing blood transfusions and all-cause mortality) according to adapted GRADE methodology as very low, low, moderate, or high.. We identified 56 eligible studies involving 15,596 adults with CKD. Risks of bias in the included studies was generally high or unclear for more than half of studies in all of the risk of bias domains we assessed; no study was low risk for allocation concealment, blinding of outcome assessment and attrition from follow-up. In network analyses, there was moderate to low confidence that epoetin alfa (OR 0.18, 95% CI 0.05 to 0.59), epoetin beta (OR 0.09, 95% CI 0.02 to 0.38), darbepoetin alfa (OR 0.17, 95% CI 0.05 to 0.57), and methoxy polyethylene glycol-epoetin beta (OR 0.15, 95% CI 0.03 to 0.70) prevented blood transfusions compared to placebo. In very low quality evidence, biosimilar ESA therapy was possibly no better than placebo for preventing blood transfusions (OR 0.27, 95% CI 0.05 to 1.47) with considerable imprecision in estimated effects. We could not discern whether all ESAs were similar or different in their effects on preventing blood transfusions and our confidence in the comparative effectiveness of different ESAs was generally very low. Similarly, the comparative effects of ESAs compared with another ESA, placebo or no treatment on all-cause mortality were imprecise.All proprietary ESAs increased the odds of hypertension compared to placebo (epoetin alfa OR 2.31, 95% CI 1.27 to 4.23; epoetin beta OR 2.57, 95% CI 1.23 to 5.39; darbepoetin alfa OR 1.83, 95% CI 1.05 to 3.21; methoxy polyethylene glycol-epoetin beta OR 1.96, 95% CI 0.98 to 3.92), while the effect of biosimilar ESAs on developing hypertension was less certain (OR 1.18, 95% CI 0.47 to 2.99). Our confidence in the comparative effects of ESAs on hypertension was low due to considerable imprecision in treatment estimates. The comparative effects of all ESAs on cardiovascular mortality, myocardial infarction (MI), stroke, and vascular access thrombosis were uncertain and network analyses for major cardiovascular events, end-stage kidney disease (ESKD), fatigue and breathlessness were not possible. Effects of ESAs on fatigue were described heterogeneously in the available studies in ways that were not useable for analyses.. In the CKD setting, there is currently insufficient evidence to suggest the superiority of any ESA formulation based on available safety and efficacy data. Directly comparative data for the effectiveness of different ESA formulations based on patient-centred outcomes (such as quality of life, fatigue, and functional status) are sparse and poorly reported and current research studies are unable to inform care. All proprietary ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, and methoxy polyethylene glycol-epoetin beta) prevent blood transfusions but information for biosimilar ESAs is less conclusive. Comparative treatment effects of different ESA formulations on other patient-important outcomes such as survival, MI, stroke, breathlessness and fatigue are very uncertain.For consumers, clinicians and funders, considerations such as drug cost and availability and preferences for dosing frequency might be considered as the basis for individualising anaemia care due to lack of data for comparative differences in clinical benefits and harms.

Topics: Adult; Anemia; Biosimilar Pharmaceuticals; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Hypertension; Polyethylene Glycols; Recombinant Proteins; Renal Insufficiency, Chronic

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

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

Anemia is a frequent comorbidity of heart failure and is associated with poor outcomes. Anemia in heart failure is considered to develop due to a complex interaction of iron deficiency, kidney disease, and cytokine production, although micronutrient insufficiency and blood loss may contribute. Currently, treatment of anemia of heart failure lacks clear targets and specific therapy is not defined. Intravenous iron use has been shown to benefit anemic as well as nonanemic patients with heart failure. Treatment with erythropoietin-stimulating agents has been considered alone or in combination with iron, but robust evidence to dictate clear guidelines is not currently available. Available and emerging new agents in the treatment of anemia of heart failure will need to be tested in randomized, controlled studies.

Topics: Age Factors; Aged; Anemia; Anemia, Iron-Deficiency; Chronic Disease; Erythropoietin; Female; Heart Failure; Hematinics; Humans; Incidence; Inflammation Mediators; Iron; Male; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Renin-Angiotensin System; Sex Factors

Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disorder that mainly affects the small joints of the hands and feet. Erythropoiesis-stimulating agents have been used to treat anemia, one of the extra-articular manifestations of RA. Although anemia is less of a problem now because of the reduction in inflammation due to disease-modifying antirheumatic drugs (DMARDs), it could still be an issue in countries where DMARDs are not yet accessible.. We assessed the clinical benefits and harms of erythropoiesis-stimulating agents for anemia in rheumatoid arthritis.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (issue 7 2012), Ovid MEDLINE and Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations (1948 to 7 August 2012), OVID EMBASE (1980 to 7 August 2012), LILACS (1982 to 7 August 2012), the Clinical Trials Search Portal of the World Health Organization, reference lists of the retrieved publications and review articles. We did not apply any language restrictions.. We included randomized controlled trials (RCTs) in patients aged 16 years or over, with a diagnosis of rheumatoid arthritis affected by anemia. We considered health-related quality of life, fatigue and safety as the primary outcomes.. Two authors independently performed trial selection, risk of bias assessment, and data extraction. We estimated difference in means with 95% confidence intervals (CIs) for continuous outcomes. We estimated risk ratios with 95% CIs for binary outcomes.. We included three RCTs with a total of 133 participants. All trials compared human recombinant erythropoietin (EPO), for different durations (8, 12 and 52 weeks), versus placebo. All RCTs assessed health-related quality of life. All trials had high or unclear risk of bias for most domains, and were sponsored by the pharmaceutical industry. Two trials administered EPO by a subcutaneous route while the other used an intravenous route.We decided not to pool results from trials, due to inconsistencies in the reporting of results.Health-related quality of life: subcutaneous EPO - one trial with 70 patients at 52 weeks showed a statistically significant difference in improvement of patient global assessment (median and interquartile range 3.5 (1.0 to 6.0) compared with placebo 4.5 (2.0 to 7.5) (P = 0.027) on a VAS scale (0 to 10)). The other shorter term trials (12 weeks with subcutaneous EPO and eight weeks with intravenous administration) did not find statistically significant differences between treatment and control groups in health-related quality of life outcomes.Change in hemoglobin: both trials of subcutaneous EPO showed a statistically significant difference in increasing hemoglobin levels; (i) at 52 weeks (one trial, 70 patients), intervention hemoglobin level (median 134, interquartile range 110 to 158 g/litre) compared with the placebo group level (median 112, interquartile range; 86 to 128 g/litre) (P = 0.0001); (ii) at 12 weeks (one trial, 24 patients) compared with placebo (difference in means 8.00, 95% CI 7.43 to 8.57). Intravenous EPO at eight weeks showed no statistically significant difference in increasing hematocrit level for EPO versus placebo (difference in means 4.69, 95% CI -0.17 to 9.55; P = 0.06).Information on withdrawals due to adverse events was not reported in two trials, and one trial found no serious adverse events leading to withdrawals. None of the trials reported withdrawals due to high blood pressure, or to lack of efficacy or to fatigue.. We found conflicting evidence for erythropoiesis-stimulating agents to increase quality of life and hemoglobin level by treating anemia in patients with rheumatoid arthritis. However, this conclusion is based on randomized controlled trials with a high risk of bias, and relies on trials assessing human recombinant erythropoietin (EPO). The safety profile of EPO is unclear. Future trials assessing erythropoiesis-stimulating agents for anemia in rheumatoid arthritis should be conducted by independent researchers and reported according to the CONSORT statements. Trials should be based on Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) and The Patient-Centered Outcomes Research Institute (PCORI) approaches for combining both clinician and patient perspectives.

Topics: Anemia; Arthritis, Rheumatoid; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobin A; Humans; Randomized Controlled Trials as Topic; Recombinant Proteins

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

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

Resistance to erythropoiesis-stimulating agents (ESAs) has been observed in a considerable proportion of patients with chronic kidney disease (CKD) and it is reportedly associated with adverse outcomes, such as increased cardiovascular morbidity, faster progression to end-stage renal disease (ESRD) and all-cause mortality. The major causes of ESA resistance include chronic inflammation producing suppressive cytokines of early erythroid progenitor proliferation. In addition, pro-inflammatory cytokines stimulate hepcidin synthesis thus reducing iron availability for late erythropoiesis. Recent studies showing an association in deficiencies of the vitamin D axis with low haemoglobin (Hb) levels and ESA resistance suggest a new pathophysiological co-factor of renal anaemia. The administration of either native or active vitamin D has been associated with an improvement of anaemia and reduction in ESA requirements. Notably, these effects are not related to parathyroid hormone (PTH) values and seem to be independent on PTH suppression. Another possible explanation may be that calcitriol directly stimulates erythroid progenitors; however, this proliferative effect by extra-renal activation of 1α-hydroxylase enzyme is only a hypothesis. The majority of studies concerning vitamin D deficiency or supplementation, and degree of renal anaemia, point out the prevalent role of inflammation in the mechanism underlying these associations. Immune cells express the vitamin D receptor (VDR) which in turn is involved in the modulation of innate and adaptive immunity. VDR activation inhibits the expression of inflammatory cytokines in stromal and accessory cells and up-regulates the lymphocytic release of interleukin-10 (IL-10) exerting both anti-inflammatory activity and proliferative effects on erythroid progenitors. In CKD patients, vitamin D deficiency may stimulate immune cells within the bone marrow micro-environment to produce cytokines, inducing impaired erythropoiesis. Immune activation involves the reticuloendothelial system, increasing hepcidin synthesis and functional iron deficiency. Consequences of this inflammatory cascade are erythropoietin (EPO) resistance and anaemia. Given the key role of inflammation in the response to EPO, the therapeutic use of agents with anti-cytokines properties, such as vitamin D and paricalcitol, may provide benefit in the prevention/treatment of ESA hyporesponsiveness.

Topics: Anemia; Animals; Cytokines; Erythropoietin; Humans; Inflammation; Renal Insufficiency, Chronic; Vitamin D Deficiency

This article describes the incidence and etiology of anemia in critically ill children. In addition, the article details the pathophysiology and clinical ramifications of anemia in this population. The use of transfused packed red blood cells as a therapy for anemia in critically ill patients is also discussed, including the indications for and complications associated with this practice as well as potential reasons for these complications. Finally, the article lists some therapeutic practices that may lessen the risks associated with transfusion, and briefly discusses the use of blood substitutes.

Topics: Acute Lung Injury; Anemia; Blood Substitutes; Blood Transfusion; Child; Child, Preschool; Critical Illness; Erythropoietin; Hemodilution; Humans; Immunomodulation; Infant; Infant, Newborn; Infant, Premature; Iron; Phlebotomy; Risk Factors; Transfusion Reaction; Treatment Outcome

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

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

Anemia is common among patients with malignant tumors, due to the disease and chemotherapy. Active oncotherapy, combination chemotherapy of lung cancer is accompanied with many side effects which may impair the patient's quality of life and compromise the effectiveness of chemotherapy, the most frequent one of them being chemotherapy-induced anemia. Anemia decreases not only the patient's quality of life, but also worsens the dose-intensity of chemotherapy. One of the potential treatments of chemotherapy-induced anemia is erythropoietin-stimulating agents (ESAs) for the appropriate indications. Several national and international studies have shown that ESA therapy effectively increases hemoglobin level. However, more recently, contradictory results were published on ESA treatment in terms of survival and tumor progression. The reason for this may be that the tumor cells and endothelial cells may as well express erythropoietin receptor, the role of which has not yet been fully elucidated in tumor progression.. Daganatos betegek körében gyakori szövõdmény az anémia, amelyet maga a betegség vagy az onkológiai kezelés okozhat. A tüdõrák kezelése során az aktív kombinált kemoterápia mellett számos, a beteg életminõségét és az onkoterápia sikerességét rontó mellékhatással kell számolni, ezek közül az egyik leggyakoribb a kemoterápia indukálta anémia. A vérszegénység nemcsak a betegek életminõségét rontja, hanem a citotoxikus kezelés dóziscsökkentéséhez, illetve késleltetéséhez vezethet. A kemoterápia indukálta anémia kezelésének egyik lehetséges útja, az eritropoetin-stimuláló szerek (ESA) használata a megfelelõ indikációval. Számos nemzetközi és hazai tanulmány bizonyította, hogy az ESA-kezelés hatékonyan emeli a hemoglobinszintet. Az utóbbi idõben azonban ellentmondásos eredményeket olvashattunk az ESA-kezelésrõl a túlélés és a daganat progressziója tekintetében. Ennek a hátterében az állhat, hogy a tumorsejtek és az endothelsejtek is kifejezhetnek eritropoetinreceptort, amelynek a szerepe még nem teljesen tisztázott a daganatok progressziójában.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Disease Progression; Endothelial Cells; Erythrocyte Transfusion; Erythropoietin; Hematinics; Hemoglobins; Humans; Hypertension; Lung Neoplasms; Quality of Life; Receptors, Erythropoietin; Severity of Illness Index; Venous Thromboembolism

EPO is an autologous hormone, which is known to regulate erythropoiesis. For 30 years it has been used for the therapy of diverse forms of anaemia, such as renal anaemia, tumour-related anaemias, etc. Meanwhile, a multitude of scientific publications were able to demonstrate its pro-regenerative effects after trauma. These include short-term effects such as the inhibition of the "primary injury response" or apoptosis, and mid- and long-term effects for example the stimulation of stem cell recruitment, growth factor production, angiogenesis and re-epithelialisation. Known adverse reactions are increases of thromboembolic events and blood pressure, as well as a higher mortality in patients with tumour anaemias treated with EPO. Scientific investigations of EPO in the field of plastic surgery included: free and local flaps, nerve regeneration, wound healing enhancement after dermal thermal injuries and in chronic wounds.Acute evidence for the clinical use of EPO in the field of plastic surgery is still not satisfactory, due to the insufficient number of Good Clinical Practice (GCP)-conform clinical trials. Thus, the initiation of more scientifically sound trials is indicated.

Topics: Anemia; Chronic Disease; Clinical Trials as Topic; Erythropoietin; Graft Survival; Humans; Nerve Regeneration; Plastic Surgery Procedures; Regenerative Medicine; Skin; Surgical Flaps; Wound Healing; Wounds and Injuries

Topics: Anemia; Erythrocyte Transfusion; Erythropoietin; Heart Failure; Hematinics; Humans; Iron

Chronic obstructive pulmonary disease (COPD) is one of the most prevalent chronic diseases, with an increasing rate in morbidity and mortality. In recent years, there has been a greater awareness about the clinical importance of systemic effects and other chronic conditions associated with COPD, as these significantly impact on the course of disease. The most studied extrapulmonary manifestations in COPD include the presence of concomitant cardiovascular disease, skeletal muscle wasting, osteoporosis and lung cancer. Anaemia is a recognised independent marker of mortality in several chronic diseases. Recent studies have shown that anaemia in patients with COPD may be more frequent than expected, with a prevalence ranging from 5% to 33%. Some evidence suggests that systemic inflammation may play an important pathogenic role, but anaemia in COPD is probably multifactorial and may be caused by others factors, such as concealed chronic renal failure, decreased androgenic levels, iron depletion, angiotensin-converting enzyme inhibitor treatment and exacerbations. Low levels of haemoglobin and haematocrit in COPD patients have been associated with poor clinical and functional outcomes as well as with mortality and increased healthcare costs. Despite the potential clinical benefit of successfully treating anaemia in these patients, evidence supporting the importance of its correction on the prognosis of COPD is uncertain.

Topics: Acute Disease; Androgens; Anemia; Chronic Disease; Erythropoiesis; Erythropoietin; Exercise Tolerance; Glomerular Filtration Rate; Health Resources; Hemoglobins; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Renal Insufficiency, Chronic; Renin-Angiotensin System

Blood management is a system-based comprehensive approach that uses evidence-based medicine to facilitate an environment to encourage an appropriate use of blood products in the hospital setting. The ultimate goal of a blood-management program is to improve patient outcomes by integrating all available techniques to ensure safety, availability, and appropriate allocation of blood products. It is a patient-centered, multidisciplinary, multimodal, planned approach to the management of patients and blood products.

Topics: Anemia; Blood Transfusion; Data Collection; Erythropoietin; Evidence-Based Medicine; Humans; Iron; Preoperative Care; Thrombelastography

Topics: Anemia; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Iron; Recombinant Proteins; Renal Insufficiency, Chronic

The addition of protease inhibitors, boceprevir or telaprevir, to peginterferon+ribavirin (PegIFN/RBV) increases the frequency as well as the severity, and hence, clinical relevance of anemia, which has now become one of the major complications associated with triple therapy. Most significant factors associated with anemia in patients receiving triple therapy include older age, lower body mass index (BMI), advanced fibrosis, and lower baseline hemoglobin. The variability in inosine triphosphate pyrophosphatase (ITPA) gene, which encodes a protein that hydrolyses inosine triphosphate (ITP), has been identified as an essential genetic factor for anemia both in dual and triple therapy. The correct management of anemia is based on anticipation, characterization and therapeutic management. Basically, anemia can be characterized in 3 types: ferropenic (mostly in fertile women), thalassemic type hemolytic anemia, and anemia from chronic processes. Functional deficit of iron should also be excluded in patients with normal ferritin and lower saturation of transferrin. Ribavirin dose reduction and epoetin, sequentially, are indicated in the management of anemia. Epoetin non-response can be caused by lack of time, type of anemia, functional iron deficit or erythropoietin resistance. In the transplantation setting, adding a protease inhibitor to PegIFN/RBV results in a significant increase in the incidence and severity of anemia and, as a consequence, a greater need for epoetin, transfusions, and ribavirin dose reductions. Packed red cell transfusions are utilized when hemoglobin decreases to less than 7.5g/dl and/or there are clinical symptoms and/or there is no response to other therapeutic measures.

Topics: Anemia; Drug Therapy, Combination; Erythrocyte Transfusion; Erythropoietin; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Liver Transplantation; Polyethylene Glycols; Protease Inhibitors; Recombinant Proteins; Ribavirin

Renal anemia has been recognized as a characteristic complication of chronic kidney disease. Although many factors are involved in renal anemia, the predominant cause of renal anemia is a relative deficiency in erythropoietin (EPO) production. To date, exogenous recombinant human (rh)EPO has been widely used as a powerful drug for the treatment of patients with renal anemia. Despite its clinical effectiveness, a potential risk for increased mortality has been suggested in patients who receive rhEPO, in addition to the economic burden of rhEPO administration. The induction of endogenous EPO is another therapeutic approach that might have advantages over rhEPO administration. However, the physiological and pathophysiological regulation of EPO are not fully understood, and this lack of understanding has hindered the development of an endogenous EPO inducer. In this review, we will discuss the current treatment for renal anemia and its drawbacks, provide an overview of EPO regulation in healthy and diseased conditions, and propose future directions for therapeutic trials that more directly target the underlying pathophysiology of renal anemia.

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Humans; Recombinant Proteins; Renal Insufficiency, Chronic

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

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

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

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

Erythropoiesis-stimulating agents (ESAs) prevent transfusions among anemic patients with chronic kidney disease (CKD). Clinical trials, meta-analyses, and guidelines identify arterial and venous thromboembolism as well as myocardial event risks with the traditional ESAs, erythropoietin (EPO), and darbepoietin. Side effects of anemia treatment, considering frequency and dosage of treatment as well as targeted hemoglobin levels when utilizing ESAs, greatly impact overall well-being and the quality of life. There is a need for less frequent but equally effective ESAs in this setting.. The three generations of ESAs used in CKD-associated anemia are described. Cost effectiveness of the utilization of these therapies, in addition to emerging therapies, is also presented. The few clinical and controlled trials only highlight the need for clarity in molecular biology surrounding the components that control EPO levels and utilization.. Anemia associated with CKD is an important area for development of newer therapies which are potentially safer and more convenient to administer.

Topics: Anemia; Darbepoetin alfa; Drug Discovery; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Quality of Life; Recombinant Proteins; Renal Insufficiency, Chronic

Topics: Anemia; Animals; Clinical Trials as Topic; Erythropoietin; Hepcidins; Humans; Inflammation; Iron

Total hip arthroplasty is associated with marked blood loss, with the potential for up to 90% of patients requiring allogeneic transfusions. Also, perioperative-induced anemia is associated with lower postoperative functional scores, increased mortality, increased cardiovascular risks, longer hospital stays, and postoperative infections. The purpose of this review was to analyze the recent evidence on preoperative blood management strategies utilized for total hip arthroplasty. Specifically, we evaluated the use of preoperative iron therapy, intravenous erythropoietin, and autologous blood donation. No single strategy was shown to be superior over another in reducing the need for allogeneic transfusions; however, a combination of these blood management strategies may result in improved blood loss outcomes. Larger prospective randomized studies comparing the individual strategies, as well as combination therapies, are needed to develop a concise statement on the most effective and efficient preoperative blood management treatment algorithms for total hip arthroplasty.

Topics: Anemia; Arthroplasty, Replacement, Hip; Blood Loss, Surgical; Blood Transfusion, Autologous; Causality; Combined Modality Therapy; Erythropoietin; Evidence-Based Medicine; Humans; Injections, Intravenous; Iron; Preoperative Care; Prevalence; Risk Factors; Treatment Outcome

Elective total knee arthroplasty is frequently associated with considerable blood loss and a concomitant decline in hemoglobin postoperatively. This often leads to high rates of allogeneic transfusions, with reports of up to 69%, to treat postoperative anemia. Allogeneic blood transfusions have been shown to be an independent risk factor for increased adverse outcomes, such as prolonged length of hospital stay and postoperative infections. Although multiple preoperative blood management strategies have been proposed, there are no concise guidelines, as few studies have compared the relative efficacy of these techniques. The aim of this review was to evaluate current evidence on the various preoperative blood management strategies for patients undergoing total knee arthroplasty and to provide an overview of the safety and efficacy of these practices. Specifically, we evaluated preoperative autologous blood donation, iron therapy, and intravenous erythropoietin. Current evidence suggests that these techniques independently may be effective at reducing the incidence of allogeneic blood transfusions, correcting preoperative, and preventing postoperative anemia. However, more studies are necessary to evaluate combination protocols, as well as the cost-effectiveness and safety of these practices as part of routine preoperative blood management for total knee arthroplasty.

Topics: Algorithms; Anemia; Arthroplasty, Replacement, Knee; Blood Loss, Surgical; Blood Transfusion, Autologous; Erythropoietin; Humans; Injections, Intravenous; Iron; Postoperative Complications; Preoperative Care; Trace Elements

Pure red cell aplasia (PRCA) is a rare adverse effect of recombinant erythropoietin (rEPO). Affected patients rapidly become transfusion-dependent, with many requiring immunosuppressive therapy for remission. We report a confirmed case in an elderly female, possibly the first of its kind in New Zealand, who was started on rEPO for anaemia of chronic kidney disease. We also briefly review current literature on rEPO-associated PRCA.

Topics: Aged, 80 and over; Anemia; Erythropoietin; Female; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

Erythropoiesis-stimulating agents can reduce red blood cell transfusion rates in patients developing anemia while receiving chemotherapy. We investigated potential cost savings from reduced transfusion rates in patients starting darbepoetin alfa (DA) at higher versus lower hemoglobin (Hb) levels.. Two systematic literature reviews were performed: transfusion outcomes in patients receiving DA stratified by baseline Hb level and costs of transfusion in Europe. Potential cost savings were calculated by multiplying the difference in transfusion rates between Hb levels by the midpoint of transfusion costs.. Despite differences in baseline characteristics, treatment duration and analysis technique, the clinical studies (n = 8) showed that fewer transfusions were required when DA was initiated at higher versus lower Hb levels. The economic studies (n = 9) showed that 1 unit of transfusion ranged from 130 to 537 (2010-adjusted values). Cost savings from initiating DA at higher versus lower Hb levels were 503-2,226 (2 units transfused) and 880-3,895 (3.5 units) per ten patients.. Transfusion incidence increases with DA initiation at lower Hb levels. Potential cost savings depend on the number of units transfused and cost items included. DA initiation according to guidelines can reduce transfusions and potentially reduce transfusion-associated costs.

Topics: Anemia; Antineoplastic Agents; Cost Savings; Darbepoetin alfa; Erythrocyte Transfusion; Erythropoietin; Hematinics; Hemoglobins; Humans; PubMed

Targeting higher hemoglobin levels with erythropoiesis-stimulating agents (ESAs) to treat the anemia of chronic kidney disease (CKD) is associated with increased cardiovascular risk.. Metaregression analysis examining the association of ESA dose with adverse outcomes independent of target or achieved hemoglobin level.. Patients with anemia of CKD irrespective of dialysis status.. We searched MEDLINE (inception to August 2010) and bibliographies of published meta-analyses and selected randomized controlled trials assessing the efficacy of ESAs for the treatment of anemia in adults with CKD, with a minimum 3-month duration. Two authors independently screened citations and extracted relevant data. Individual study arms were treated as cohorts and constituted the unit of analysis.. ESA dose standardized to a weekly epoetin alfa equivalent, and hemoglobin levels.. All-cause and cardiovascular mortality, cardiovascular events, kidney disease progression, or transfusion requirement.. 31 trials (12,956 patients) met the criteria. All-cause mortality was associated with higher (per epoetin alfa-equivalent 10,000-U/wk increment) first-3-month mean ESA dose (incidence rate ratio [IRR], 1.42; 95% CI, 1.10-1.83) and higher total-study-period mean ESA dose (IRR, 1.09; 95% CI, 1.02-1.18). First-3-month ESA dose remained significant after adjusting for first-3-month mean hemoglobin level (IRR, 1.48; 95% CI, 1.02-2.14), as did total-study-period mean ESA dose adjusting for target hemoglobin level (IRR, 1.41; 95% CI, 1.08-1.82). Parameter estimates between ESA dose and cardiovascular mortality were similar in magnitude and direction, but not statistically significant. Higher total-study-period mean ESA dose also was associated with increased rate of hypertension, stroke, and thrombotic events, including dialysis vascular access-related thrombotic events.. Use of study-level aggregated data; use of epoetin alfa-equivalent doses; lack of adjustment for confounders.. In patients with CKD, higher ESA dose might be associated with all-cause mortality and cardiovascular complications independent of hemoglobin level.

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

Anemia is common in patients with aneurysmal subarachnoid hemorrhage (SAH), but these patients have constituted only a small fraction of those studied in large trials of anemia and transfusion. Unlike other critically ill patients, those with SAH face a well-defined risk of vasospasm and cerebral ischemia in the weeks after their hemorrhage. The risk of ongoing ischemia may make them less able to tolerate anemia and more likely to benefit from blood transfusion. The available data show that anemia is associated with poor outcomes after SAH but that blood transfusion does not consistently improve physiological markers, and it may be associated with poor outcomes. Most of these data are observational in nature, although 1 recent study demonstrated the safety and feasibility of maintaining relatively high transfusion thresholds in patients with SAH. Larger, randomized trials are needed to determine at what levels of anemia patients with SAH might benefit from transfusion, the optimal timing of transfusion, and how to identify those patients who are most likely to benefit.

Topics: Anemia; Blood Transfusion; Erythrocyte Aging; Erythropoietin; Hemodilution; Humans; Intraoperative Care; Oxygen Consumption; Preoperative Care; Recombinant Proteins; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Iron is an important mineral element required for diverse life processes. Its metabolism is almost synonymous to erythrocyte maintenance, erythropoiesis and erythrophagocytosis. Consequently, exercise exertion impacts significantly on red cell haematology. Here, the interactions between exercise and erythropoiesis are explored. Hepcidin, the peptide hormone that regulates systemic iron metabolism, decreases in response to erythropoiesis by facilitating increased iron efflux from ferroportin into circulation. However, during exercise, there is an alarming increase in the expression of hepcidin resulting in a negative iron balance in athletes. In this review, the confounding cause and effect scenarios of exercise, athlete training and haematology and hepcidin interactions are discussed.

Topics: Anemia; Antimicrobial Cationic Peptides; Athletes; Erythropoiesis; Erythropoietin; Exercise; Hemolysis; Hepcidins; Humans; Hypoxia; Iron

Erythropoietin (EPO) is a frequently prescribed drug for treatment of cancer-related and chemotherapy-induced anemia in cancer patients. Paradoxically, recent preclinical and clinical studies indicate that EPO could potentially accelerate tumor growth and jeopardize survival in cancer patients. In this review I critically discuss the current knowledge and broad biological functions of EPO in association with tumor growth, invasion, and angiogenesis. The emphasis is focused on discussing the complex interplay between EPO and other tumor-derived factors in angiogenesis, tumor growth, invasion, and metastasis. Understanding the multifarious functions of EPO and its reciprocal relation with other signaling pathways is crucial for developing more effective agents for cancer therapy and for minimizing risks for cancer patients.

Topics: Anemia; Animals; Erythropoietin; Humans; Neoplasms

Patient blood management(1,2) incorporates patient-centered, evidence-based medical and surgical approaches to improve patient outcomes by relying on the patient's own (autologous) blood rather than allogeneic blood. Particular attention is paid to preemptive measures such as anemia management. The emphasis on the approaches being "patient-centered" is to distinguish them from previous approaches in transfusion medicine, which have been "product-centered" and focused on blood risks, costs, and inventory concerns rather than on patient outcomes. Patient blood management(3) structures its goals by avoiding blood transfusion(4) with effective use of alternatives to allogeneic blood transfusion.(5) These alternatives include autologous blood procurement, preoperative autologous blood donation, acute normovolemic hemodilution, and intra/postoperative red blood cell (RBC) salvage and reinfusion. Reviewed here are the available pharmacologic tools for anemia and blood management: erythropoiesis-stimulating agents (ESAs), iron therapy, hemostatic agents, and potentially, artificial oxygen carriers.

Topics: Anemia; Blood Loss, Surgical; Blood Substitutes; Blood Transfusion; Blood Transfusion, Autologous; Blood Volume; Case Management; Drug Therapy; Erythropoiesis; Erythropoietin; Hematinics; Hemodilution; Hemostatics; Humans; Iron; Operative Blood Salvage; Patient-Centered Care

Biosimilars have been developed for several biologic therapeutic agents, including erythropoiesis-stimulating agents (ESAs). However, biosimilars cannot be assumed to be completely identical to the reference product, nor can two different biosimilars of the same reference product be considered equivalent. Accordingly, standards for approving biosimilars are distinct from those for generic versions of conventional pharmaceuticals.By late 2007, two biosimilar epoetins (HX575 and SB309) had been approved by the European Medicines Agency (EMA), following a series of pharmacokinetic and pharmacodynamic equivalence studies, as well as phase 3 clinical comparability evaluations. Additionally, the results of a limited number of postauthorization interventional or observational studies and quality comparisons were published subsequently on both products.The reported differences in glycosylation profiles between these epoetin biosimilars and their reference product, as well as the lack of long-term safety and efficacy evaluation, could indicate a need to develop a more comprehensive analysis of the available data, and to evaluate the post-authorization real-life data, in order to gain a better understanding of any potential implications of molecular structural or formulation differences on longterm safety and effectiveness.Switching between an original reference ESA and a biosimilar (and possibly also switching between biosimilar versions of the same product) should be regarded as a change in clinical management. Clinicians need to be fully involved in such decisions. Prescribing by brand name will prevent unintentional substitution by pharmacists and allow for effective pharmacovigilance, in accordance with recent EU directives. In this review, the authors have analyzed most of the published information on the two epoetin biosimilars, HX575 and SB309, to highlight the points that healthcare providers may need to consider when assessing an epoetin biosimilar.

Topics: Anemia; Biosimilar Pharmaceuticals; Epoetin Alfa; Erythropoietin; Europe; Hematinics; Humans; Pharmacovigilance; Recombinant Proteins; Therapeutic Equivalency

Topics: Acute Lung Injury; Adult; Anemia; Blood Preservation; Blood Specimen Collection; Brain Injuries; Critical Illness; Erythrocyte Transfusion; Erythropoietin; Hemorrhage; Humans; Myocardial Ischemia; Nervous System Diseases; Sepsis; Shock; Stroke; Subarachnoid Hemorrhage

One of the molecules regulated by the transcription factor, hypoxia inducible factor (HIF), is the hypoxia-responsive hematopoietic factor, erythropoietin (EPO). This may have relevance to the development of renal cell carcinoma (RCC), where mutations of the von Hippel-Lindau (VHL) gene are major risk factors for the development of familial and sporadic RCC. VHL mutations up-regulate and stabilize HIF, which in turn activates many downstream molecules, including EPO, that are known to promote angiogenesis, drug resistance, proliferation and progression of solid tumours. HIFs typically respond to hypoxic cellular environment. While the hypoxic microenvironment plays a critical role in the development and progression of tumours in general, it is of special significance in the case of RCC because of the link between VHL, HIF and EPO. EPO and its receptor, EPOR, are expressed in many cancers, including RCC. This limits the use of recombinant human EPO (rhEPO) to treat anaemia in cancer patients, because the rhEPO may be stimulatory to the cancer. EPO may also stimulate epithelial-mesenchymal transition (EMT) in RCC, and pathological EMT has a key role in cancer progression. In this mini review, we summarize the current knowledge of the role of EPO in RCC. The available data, either for or against the use of EPO in RCC patients, are equivocal and insufficient to draw a definitive conclusion.

Topics: Anemia; Animals; Carcinoma, Renal Cell; Erythropoietin; Hematinics; Humans; Hypoxia-Inducible Factor 1; Kidney Neoplasms; Receptors, Erythropoietin; Recombinant Proteins; Risk Factors; Signal Transduction; Tumor Microenvironment; Von Hippel-Lindau Tumor Suppressor Protein

Prior to the approval of the first erythropoiesis-stimulating agent (ESA) in the early 1990s, red blood cell transfusions were the primary means of treating severe chemotherapy-induced anemia (CIA), with little recourse for those with more mild forms of the condition. The introduction of the ESAs allowed treatment of mild-to-moderate CIA in patients with cancer. It has been a decade since darbepoetin alfa (DA), a second-generation ESA with a longer half-life, became available to patients with CIA.. We present a review of studies on DA in CIA, from its development through to the present day. Medline was searched for randomized clinical trials on DA. Additional trials and meta-analyses on ESAs were incorporated into this review when relevant.. The first publications on DA generally focused on optimal dosing, efficacy and tolerability. In these, it was shown that DA is an effective and well tolerated treatment option to achieve hematopoietic response, regardless of dosing interval. Subsequently, the focus shifted towards meta-analyses on survival data of all ESAs. These reported conflicting results regarding mortality and/or disease progression. However, guidelines for ESA use were updated and, when followed, these make ESAs a well tolerated and effective tool for managing CIA.. As the past decade has broadened our knowledge on the benefits and risks of CIA management, continued high-quality studies will help to optimize treatment with ESAs in order to maximize quality of life for these patients. The limitation of a literature review of this nature is the complete reliance on previously published research and the availability of these studies using the methodology outlined above.

Topics: Anemia; Antineoplastic Agents; Blood Transfusion; Darbepoetin alfa; Erythropoietin; Hematinics; Humans; Meta-Analysis as Topic; Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Venous Thromboembolism

Erythropoiesis-stimulating agents (ESA) reduce the need for transfusions and improve the quality of life in patients receiving chemotherapy, but several clinical trials have suggested that ESA might have a negative impact on survival. To evaluate the efficacy and safety of ESA, epoetin beta and darbepoetin alfa, including their impact on overall survival and thromboembolic events, we conducted an individual data-based meta-analysis of three randomized, placebo-controlled trials studying Japanese patients with chemotherapy-induced anemia. All trials were conducted in compliance with Good Clinical Practice. A total of 511 patients with solid tumor or lymphoma (epoetin beta or darbepoetin alfa, n = 273; placebo, n = 238) were included. The ESA significantly reduced the risk of transfusion (relative risk, 0.47; 95% confidence interval, 0.29-0.76). No significant effect of the ESA on overall survival was observed (unadjusted hazard ratio, 1.00; 95% confidence interval, 0.75-1.34). A prespecified subgroup analysis showed no strong interaction between the baseline hemoglobin concentration and the effect of ESA on overall survival. Among the ESA-treated patients, the highest hemoglobin achieved during the treatment period in each patient had no impact on mortality. No increase in thromboembolic events was observed in the ESA-treated patients (0.7% vs 1.7% placebo). The ESA reduced the risk of transfusion without a negative impact on the survival of patients with chemotherapy-induced anemia.

Topics: Anemia; Antineoplastic Agents; Asian People; Darbepoetin alfa; Erythropoietin; Hematinics; Humans; Randomized Controlled Trials as Topic; Recombinant Proteins

Erythropoiesis-stimulating agents (ESAs) have become a hallmark of anaemia therapy in patients with chronic kidney disease (CKD). Although different ESAs are available for the treatment of renal anaemia, each nephrologist should select a single ESA for an individual patient. Epoetin alfa and epoetin beta have been used 1-3 times weekly but extended-interval dosing up to every 4 weeks is also effective in a substantial majority of CKD patients. However, the epoetin dose necessary to achieve or maintain target haemoglobin (Hb) levels increases substantially as the dosing interval increases. Subcutaneous administration of short-acting ESAs is more effective than the intravenous route of administration. Darbepoetin alfa and the continuous erythropoietin receptor activator (CERA) have been developed as a treatment for anaemia with extended administration intervals (every 2 weeks and every 4 weeks, respectively). Dose requirements for these long-acting ESAs are independent of the route of administration. Patents of short-acting ESAs have expired, which has opened the field for biosimilars. Epoetin biosimilars approved by the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA) have been shown to have a comparable efficacy and safety profile to their originators. An alarming increase in pure red cell aplasia (PRCA) in Thailand with follow-on epoetins manufactured in Asia (but also those manufactured in Latin America) indicates that stringent country-specific approval and pharmacovigilance protocols for ESAs manufactured in non-North American and non-EU European countries are urgently needed. Two PRCA cases occurring with subcutaneous HX575 (one certain, one likely) indicate that chances of inducing a more immunogenic product are unpredictable, even with a biosimilar epoetin approved under the EMA biosimilar approval pathway. Phase III clinical trials with peginesatide, a pegylated synthetic peptide-based ESA without any homology to erythropoietin raised safety concerns in non-dialysis CKD patients but not in dialysis patients.

Topics: Anemia; Biosimilar Pharmaceuticals; Darbepoetin alfa; Erythropoiesis; Erythropoietin; Hematinics; Humans; Injections, Intravenous; Injections, Subcutaneous; Peptides; Polyethylene Glycols; Randomized Controlled Trials as Topic; Red-Cell Aplasia, Pure; Renal Insufficiency, Chronic; Time Factors

To review the literature regarding current strategies for the management of anemia associated with treatment for chronic viral hepatitis C (HCV) in adults.. The MEDLINE/PubMed, EMBASE, and Cochrane databases were searched (January 1980-October 2012) for articles in English using the search terms anemia, ribavirin, dose reduction, erythropoietin stimulating agents, hepatitis C, HIV, liver transplant, telaprevir, and boceprevir.. All relevant original studies, meta-analyses, systematic reviews, guidelines, and review articles were assessed for inclusion. References from pertinent articles were examined for additional content not found during the initial search.. Standard of care for patients infected with HCV genotype 1 now requires a triple therapy regimen including an HCV NS3 protease inhibitor. These regimens lead to significantly higher rates of anemia compared to prior dual therapy regimens. Development of an optimal management strategy should begin with risk stratification. Ribavirin dose reductions have been recommended in the package inserts for the pegylated interferon products and studies have demonstrated the need for maintenance of 80% of the initial ribavirin dose to achieve optimal sustained virologic response (SVR) with dual therapy. The use of erythropoietin-stimulating agents has been shown to be effective for anemia caused by peginterferon and ribavirin without compromising SVR rates. Limited data have been published regarding the management of anemia with triple therapy; however, efficacy studies for boceprevir and telaprevir have used ribavirin dose reduction and erythropoietin-stimulating agents to successfully manage anemia.. Anemia is a common adverse event associated with the use of ribavirin, and, more recently, the new HCV protease inhibitors. Ribavirin dose reduction should continue to be used as an initial anemia management strategy, with the use of erythropoietin alfa 40,000 units once weekly reserved for patients whose hemoglobin does not adequately respond to initial management strategies.

Topics: Anemia; Antiviral Agents; Drug Monitoring; Drug Therapy, Combination; Erythropoietin; Hematinics; Hepacivirus; Hepatitis C, Chronic; Humans; Oligopeptides; Proline; Ribavirin; Risk Factors; Serine Proteinase Inhibitors; Viral Nonstructural Proteins

Even though anemia is a significant comorbidity regularly observed in patients with chronic heart failure (HF), only in recent years systematic therapeutic research has been started. This article aims to review the aspects of anemia in chronic HF that are relevant for making treatment decisions, beginning with the definition of anemia and its incidence and prevalence of anemia in patients with chronic HF. Considering the etiology and prognostic impact of anemia in chronic HF, several treatment options will be considered. The latter are the application of erythropoiesis-stimulating agents (erythropoietin or darbepoetin alfa) or in the application of intravenous iron (e.g., iron carboxymaltose). According to the results seen in the FAIR-HF trial, iron supplementation should be particularly considered to improve symptoms and quality of life. Intravenous iron application may result in higher compliance and much faster treatment response than oral iron. The RED-HF study will show whether use of darbepoetin alfa in anemic patients with chronic HF will reduce the combined endpoint of death for any reason or hospitalization for heart failure.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Iron; Prognosis

Recently, it has been suggested that erythropoietin may be useful in the treatment of cardiovascular disease, particularly heart failure. This may be by improving microvascular blood supply and ventricular function through prevention of apoptosis and angiogenesis. Promising results were seen in animals but the few, limited clinical trials have shown modest benefits. Additionally, concerns exist regarding potential serious adverse effects of erythropoietin. Our current understanding of the non-haematopoietic mechanisms of erythropoietin is presented here, with a review of trials to date, and a discussion of the questions that remain over the use of this drug in heart failure.

Topics: Anemia; Animals; Erythropoietin; Heart Failure; Humans; Signal Transduction

Advances in renal transplantation management have proven to be beneficial in improving graft and patient survival. One of the properties of a well-functioning renal allograft is the secretion of adequate amounts of the hormone erythropoietin to stimulate erythropoiesis. Posttransplantation anemia (PTA) may occur at any point in time following transplantation, and the cause is multifactoral. Much of our understanding of PTA is based on studies of adult transplant recipients. The limited number of studies that have been reported on pediatric renal transplant patients appear to indicate that PTA is prevalent in this patient population. Erythropoietin deficiency or resistance is commonly associated with iron deficiency. An understanding of the risk factors, pathophysiology and management of PTA in the pediatric renal transplant population may provide guidelines for clinicians and researchers in the pursuit of larger prospective randomized control studies aimed at improving our limited knowledge of PTA. Recognition of PTA through regular screening and evaluation of the multiple factors that may contribute to its development are recommended after transplantation.

Topics: Anemia; Child; Erythropoietin; Humans; Kidney Transplantation; Postoperative Complications; Risk Factors

Complex intracellular signalling networks integrate extracellular signals and convert them into cellular responses. In cancer cells, the tightly regulated and fine-tuned dynamics of information processing in signalling networks is altered, leading to uncontrolled cell proliferation, survival and migration. Systems biology combines mathematical modelling with comprehensive, quantitative, time-resolved data and is most advanced in addressing dynamic properties of intracellular signalling networks. Here, we introduce different modelling approaches and their application to medical systems biology, focusing on the identifiability of parameters in ordinary differential equation models and their importance in network modelling to predict cellular decisions. Two related examples are given, which include processing of ligand-encoded information and dual feedback regulation in erythropoietin (Epo) receptor signalling. Finally, we review the current understanding of how systems biology could foster the development of new treatment strategies in the context of lung cancer and anaemia.

Topics: Anemia; Antineoplastic Agents; Cell Survival; Cytokines; Erythropoietin; Forecasting; Humans; Likelihood Functions; Lung Neoplasms; Mathematics; Models, Biological; Receptors, Erythropoietin; Recombinant Proteins; Risk Factors; Signal Transduction; Systems Biology; Transcription Factors

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

Combined pegylated interferon (PegIFN) and ribavirin represents the standard therapy for patients with chronic hepatitis C (CHC), which allows for sustained viral response (SVR) in up to 90% of patients depending on certain viral and host factors. Clinical studies have demonstrated the importance of adherence to therapy, that is, the ability of patients to tolerate and sustain a fully dosed therapy regimen. Adherence is markedly impaired by treatment-related adverse effects. In particular, haemolytic anaemia often requires dose reduction or termination of ribavirin treatment, which compromises treatment efficacy. Recent evidence points to a beneficial role of recombinant erythropoietin (EPO) in alleviating ribavirin-induced anaemia thereby improving quality of life, enabling higher ribavirin dosage and consequently improving SVR. However, no general consensus exists regarding the use of EPO for specific indications: its optimal dosing, treatment benefits and potential risks or cost efficiency. The Swiss Association for the Study of the Liver (SASL) has therefore organized an expert meeting to critically review and discuss the current evidence and to phrase recommendations for clinical practice. A consensus was reached recommending the use of EPO for patients infected with viral genotype 1 developing significant anaemia below 100 g/L haemoglobin and a haematocrit of <30% during standard therapy to improve quality of life and sustain optimal ribavirin dose. However, the evidence supporting its use in patients with pre-existing anaemia, non-1 viral genotypes, a former relapse or nonresponse, liver transplant recipients and cardiovascular or pulmonary disease is considered insufficient.

Topics: Anemia; Antiviral Agents; Erythropoietin; Hepatitis C, Chronic; Humans; Interferons; Ribavirin; Treatment Outcome

Anaemia is a common complication of antiviral therapy for chronic hepatitis C virus (HCV) infection that necessitates dose reductions or therapy discontinuation. Administration of erythropoietin (EPO) is an alternative to ribavirin (RBV) dose reduction, but its advantage in terms of sustained virological response (SVR) has not been determined yet. In a systematic way, randomized studies were identified that evaluated the effect of EPO administration vs RBV dose reduction on virological response in patients who developed anaemia during anti-HCV therapy. The random-effects model was employed to run meta-analysis. SVR was set as the end point of interest. Data were abstracted from four studies containing 257 patients who developed anaemia during therapy. One hundred and twenty six subjects underwent RBV dose reduction. Patients who received EPO in response to haemoglobin drop had a significantly higher probability of achieving SVR compared with those who underwent RBV dose reduction because of anaemia (relative risk = 1.83 95% CI; 1.41-2.37). No heterogeneity was observed across study results (I(2) = 0). Publication bias assessment was nonsignificant. Our meta-analysis indicates that administration of EPO in patients who develop anaemia during anti-HCV therapy can considerably enhance SVR. Moreover, no adverse event of EPO administration was reported among included subjects.

Topics: Anemia; Antiviral Agents; Erythropoietin; Hepatitis C, Chronic; Humans; Interferons; Ribavirin; Treatment Outcome

Anemia is common in the intensive care unit, and may be associated with adverse consequences. However, current options for correcting anemia are not without problems and presently lack convincing efficacy for improving survival in critically ill patients. In this article we review normal red blood cell physiology; etiologies of anemia in the intensive care unit; its association with adverse outcomes; and the risks, benefits, and efficacy of various management strategies, including blood transfusion, erythropoietin, blood substitutes, iron therapy, and minimization of diagnostic phlebotomy.

Topics: Anemia; Critical Care; Critical Illness; Erythrocyte Transfusion; Erythrocytes; Erythropoietin; Hematinics; Humans; Intensive Care Units; Iron; Trace Elements

Fever during neutropenia may be a symptom of severe life threatening infection, which must be treated immediately with antibiotics. If signs of infection persist, therapy must be modified. Diagnostic measures should not delay treatment. If the risk of febrile neutropenia after chemotherapy is ≥ 20%, then prophylactic therapy with G-CSF is standard of care. After protocols with a risk of febrile neutropenia of 10-20%, G-CSF is necessary, in patients older than 65 years or with severe comorbidity, open wounds, reduced general condition. Anemia in cancer patients must be diagnosed carefully, even preoperatively. Transfusions of red blood cells are indicated in Hb levels below 7-8 g/dl. Erythropoiesis stimulating agents (ESA) are recommended after chemotherapy only when hemoglobin levels are below 11 g/dl. The Hb-level must not be increased above 12 g/dl. Anemia with functional iron deficiency (transferrin saturation < 20%) should be treated with intravenous iron, as oral iron is ineffective being not absorbed. Therapy of pain must follow diagnostic and treatment standards. Nausea or emesis following chemotherapy can be classified as minimal, low, moderate and high. The antiemetic prophylaxis should be escalated accordingly. In chemotherapy with low emetogenic potential steroids are sufficient, in the moderate level 5-HT3 receptor antagonists (setrons) are added, and in the highest level Aprepitant as third drug.

Topics: Anemia; Anti-Bacterial Agents; Antineoplastic Agents; Diarrhea; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Nausea; Neutropenia; Opportunistic Infections; Otorhinolaryngologic Neoplasms; Pain Management; Palliative Care; Pneumonia; Vomiting

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

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

Erythropoiesis stimulating agents (ESAs) have been used widely for anemic patients, especially those on dialysis and with cancer. However, reports have suggested shorter survival in erythropoietin (EPO)-treated cancer patients. The purpose of this review is to summarize and evaluate critically the current information about ESA treatment and its possible association with mortality in cancer patients. The pendulum that initially swung in the direction of widespread ESA treatment, and then in the direction of no treatment, is swinging back toward a stable position. This review also provides tools to decide how and when to use ESAs safely, according to accepted guidelines.

Topics: Anemia; Clinical Trials as Topic; Erythropoietin; Hematinics; Humans; Medical Oncology; Neoplasms; Practice Guidelines as Topic; Societies, Medical; United States; United States Food and Drug Administration

The Fc fusion technology has been introduced to generate long-acting antagonistic drugs such as Enbrel, Orencia and Amevive. Here, Genexine created a novel noncytolytic hybrid Fc (hyFc) as a carrier of agonistic protein drugs using naturally existing IgD and IgG4 Fcs without any mutation in the hyFc region. The erythropoietin (EPO) fused with hyFc exhibited little binding activity to FcγR and C1q molecules that are main mediators for death of target cells. The EPO-hyFc showed higher in vitro and in vivo bioactivities than EPOIgG1 Fc and highly glycosylated EPO (Aranesp). Phase I clinical trial with EPO-hyFc is currently undergoing in Korea.

Topics: Alefacept; Anemia; Animals; Darbepoetin alfa; Delayed-Action Preparations; Erythropoietin; Humans; Protein Binding; Receptors, Fc; Recombinant Fusion Proteins; Time Factors; Treatment Outcome; X-Ray Diffraction

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

Cardio-renal-anemia syndrome is a combination of heart failure, kidney failure, and anemia. Many advanced chronic kidney disease patients have both anemia and chronic heart failure. They have often hyperhomocysteinemia, high dimethylarginine values and low erythropoietin levels. Nephrologists treat advanced chronic kidney disease patients with erythropoiesis stimulating agents to improve anemia, renal and heart disease. Erythropoiesis stimulating agents, though considered essential to improve anemia in chronic kidney disease patients, have shown no significant protective effect on cardiovascular disease when used in large clinical trials targeting normal hemoglobin levels. It is possible that the high amounts of these drugs, given to reach normal hemoglobin values, may have counterbalanced the positive effect on endothelium obtained with low doses. Many studies have shown that erythropoietin improves endothelial function in animals with high dimethylarginine levels, lowering asymmetric dimethylarginine and increasing nitric oxide synthesis. Advanced chronic kidney disease patients have also high homocysteine levels which further reduce endothelial function by increasing asymmetric dimethylarginine. Homocysteine-lowering vitamin B treatment has been associated to a significant reduction of cardiovascular disease in advanced chronic kidney disease patients. Low doses of epoetin and B vitamins may improve cardiovascular morbidity by reducing asymmetric dimethylarginine and by increasing nitric oxide synthase activity. This review analyses the interaction between erythropoietin, dimethylarginine and homocysteine, and their role in cardio-renal-anemia syndrome.

Topics: Anemia; Animals; Arginine; Cardio-Renal Syndrome; Erythropoietin; Homocysteine; Humans; Nitric Oxide Synthase; Vitamin B Complex

Anemia is common in critically ill patients, but treatment with red blood cell transfusions can have unwanted effects. Limiting the occurrence and severity of anemia by using erythropoietic agents (iron and/or recombinant erythropoietin), therefore, remains an attractive option during the intensive care unit stay but also after hospital discharge. Moreover, these agents may have additional beneficial properties. In this article the authors review the rationale for the administration of iron and/or erythropoietin in critically ill patients.

Topics: Anemia; Critical Care; Drug Therapy, Combination; Erythropoietin; Hematinics; Humans; Intensive Care Units; Iron; Randomized Controlled Trials as Topic; Treatment Outcome

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematologic neoplasms characterized by morphologic dysplasia, aberrant hematopoiesis and peripheral blood refractory cytopenias. MDS is recognized to be associated with an increased risk of symptomatic anemia, infectious complications and bleeding diathesis, as well as a risk of progression to acute myeloid leukemia, particularly in patients with a high IPSS score. The advent of use of hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) and recombinant erythropoietin (EPO) has improved symptoms in MDS patients in addition to some data that suggest there might be an improvement in survival. G-CSF is an effective therapeutic option in MDS patients, and it should be considered for the management of refractory symptomatic cytopenias. G-CSF and EPO in combination can improve outcomes in appropriate MDS patients such as those with lower-risk MDS and refractory anemia with ring sideroblasts (RARS) . This article reviews use of growth factors for lower-risk MDS patients, and examines the data for G-CSF, EPO and thrombopietic growth factors (TPO) that are available or being developed as therapeutic modalities for this challenging disease.

Topics: Anemia; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Myelodysplastic Syndromes; Neutropenia; Receptors, Fc; Recombinant Fusion Proteins; Thrombocytopenia; Thrombopoietin

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

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

Anemia is a common feature of CKD associated with poor outcomes. The current management of patients with anemia in CKD is controversial, with recent clinical trials demonstrating increased morbidity and mortality related to erythropoiesis stimulating agents. Here, we examine recent insights into the molecular mechanisms underlying anemia of CKD. These insights hold promise for the development of new diagnostic tests and therapies that directly target the pathophysiologic processes underlying this form of anemia.

Topics: Anemia; Anemia, Iron-Deficiency; Antimicrobial Cationic Peptides; Erythropoiesis; Erythropoietin; Hepcidins; Homeostasis; Humans; Iron, Dietary; Models, Biological; Renal Insufficiency, Chronic

Anemia is a common comorbidity in heart failure (HF), and is associated with increased morbidity and mortality. However, it remains unclear whether anemia is merely a marker of poor prognosis or whether anemia itself confers risk. The pathogenesis of anemia in HF is multifactorial. Iron deficiency also confers risk in HF, either with or without associated anemia, and treatment of iron deficiency improves the functional status of patients with HF. An ongoing large clinical trial studying the use of darbepoetin-alfa in patients with anemia and systolic HF is expected to provide information that should improve our understanding of anemia in HF.

Topics: Anemia; Comorbidity; Erythropoietin; Heart Failure; Hematinics; Humans; Iron; Iron Deficiencies; Prognosis; Randomized Controlled Trials as Topic

Topics: Anemia; Erythrocyte Transfusion; Erythropoietin; Humans; Infant Nutritional Physiological Phenomena; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Recombinant Proteins; Transfusion Reaction

Red blood cell (RBC) transfusions convey benefits but they also carry risks. Among NICU patients, some transfusion risks are well defined and their occurrence odds can be estimated and weighed against benefits. However other risks are poorly defined and it is not currently possible to estimate their occurrence adds or weigh these against benefits.. We reviewed publications in the past 15 years, listed in PubMed, dealing with risks and benefits of RBC transfusions to newborn infants.. Risks of RBC transfusion to adult patients decreased significantly with the advent of nucleic acid testing for viral pathogens. However, new or previously unknown risks of transfusions have been suggested for neonatal recipients. These include developmental delay, intraventricular hemorrhage, and necrotizing enterocolitis. These potential transfusion risks are all currently in the form of statistical associations, and cause-and-effect relationships have not been proven. Mean of reducing transfusions, tested during the past 15 years, include adopting transfusions guidelines, erythropoietic stimulating agents, delayed cord clamping, cord stripping, drawing all NICU admission blood tests from the placenta, and limiting phlebotomy losses for blood testing.. We advocate always attempt to weigh benefits and risks when ordering a transfusion for a neonatal patient. Certainly some such are life-saving or otherwise clearly beneficial. Perhaps others carry risks unbalanced by meager benefit. Efforts to improve NICU transfusion practice have been proposed and appear to be working to diminish costs and improve outcomes.

Topics: Adult; Anemia; Blood Transfusion, Autologous; Cerebral Hemorrhage; Developmental Disabilities; Enterocolitis, Necrotizing; Erythrocyte Transfusion; Erythropoietin; Fetal Blood; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Intensive Care Units, Neonatal; Risk Assessment; Risk Factors; Umbilical Cord

To review causes of anemia in preterm infants and to suggest potential preventive measures.. Data for this review is obtained from review of the literature.. An approach to investigating and treating causes of neonatal anemia is outlined.. Clinical practices can significantly impact anemia in premature infants. Delayed cord clamping, decreasing phlebotomy loss and optimizing nutritional support are practices that may decrease the severity of anemia, thereby decreasing the need for transfusions or erythropoietin treatment.

Topics: Anemia; Blood Specimen Collection; Constriction; Erythrocyte Transfusion; Erythropoiesis; Erythropoietin; Humans; Infant Nutritional Physiological Phenomena; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Nutritional Support; Time Factors; Umbilical Cord

Adaptive responses to hypoxia, including hypoxia-inducible factor signaling, allow the cell to satisfy its basal metabolic demand and avoid death, but these responses can also be deleterious by promoting inflammation, cell dedifferentiation and fibrogenesis. Therefore, targeting hypoxia constitutes a promising therapeutic avenue. Recombinant human erythropoietin (rhEPO) appeared as a good candidate therapy because its hematopoietic properties could reverse anemia, and its tissue-protective properties could reduce cell death and limit maladaptive cellular responses to hypoxia. Despite experimental evidence on the nephroprotecive properties of rhEPO, recent clinical trials provided evidence that rhEPO was ineffective in preventing delayed graft function after ischemic acute injury but that the normalization of hemoglobin values preserved kidney function deterioration and reduced graft loss. Our aim here is to provide a survey of the rationale for evaluating the administration of rhEPO in the setting of kidney transplantation. We will discuss the intriguing findings that emerged from the clinical trials and the discrepancies between promising experimental results and negative clinical studies, as well as the differences in terms of the benefits and safety profiles of the normalization of hemoglobin values in chronic kidney disease patients and kidney transplant patients.

Topics: Anemia; Animals; Erythropoietin; Humans; Kidney Transplantation; Neuroprotective Agents; Recombinant Proteins

For years, the treatment of chemotherapy-induced anemia (CIA) consisted of red blood cell transfusions. Major disadvantages of transfusions are their temporary effect and limitation to treatment of severe anemia. In an extensive clinical trial program in patients with CIA, darbepoetin alfa (DA) - a long-acting recombinant human erythropoietin - was proven to be very effective in reducing transfusion needs in patients developing CIA. The administration is suitable with most chemotherapy schemes. Caution is needed in patients with a history of thrombo-embolic events, as a slightly higher incidence of these events is noted in patients treated with darbepoetin alfa or erythropoietin substitution agents (ESAs) in general. In recent years, concerns have been raised about a potential negative influence of these agents on survival. In this respect, it is important to make the distinction between studies on the treatment of existing CIA versus treatment with ESAs outside this indication. On the other hand, it has always been assumed that transfusions were a completely safe treatment, but concerns about a potential negative effect on survival have been raised for transfusions as well. The safety concerns with DA and ESAs in general led to a pharmacovigilance program and an adaptation of the guidelines for treatment of CIA, focusing on treatment of moderate CIA but no longer on mild CIA. Now that the most recent safety data of the pharmacovigilance program of ESAs is almost completed, the clinical impact of the shift to the treatment of only moderate anemia is discussed in this review, which provides a critical view on the indications of DA and the benefit-risk assessment, in order to provide good supportive care without harm to the patient.

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Erythrocyte Transfusion; Erythropoietin; Hematinics; Humans; Neoplasms; Practice Guidelines as Topic; Thromboembolism

Interpretation of the results of earlier meta-analyses in chronic kidney disease (CKD) patients on the impact of anaemia treatment with erythropoiesis-stimulating agents (ESAs) on clinical outcomes has been hampered by the inclusion of small trials and trials of short duration. We re-evaluated the benefits and harms of treating anaemia, including only relevant clinical trials.. We conducted a systematic review and meta-analysis of randomised controlled trials performed in adults with CKD which allocated patients to different doses of ESAs, and we compared the effect of these interventions on vascular access thrombosis, stroke, risk of end-stage renal disease (ESRD) and all-cause mortality. Additional inclusion criteria were studies with a duration of at least 1 year and enrolling more than 500 participants.. Five trials (7,902 participants) met the inclusion criteria and were included in the meta-analysis. The number of patients enrolled in each trial ranged from 596 to 4,038. The mean/median duration of follow-up ranged from 14 to 36 months. A higher haemoglobin target was associated with increased risk of vascular access thrombosis (RR 1.343; 95% CI 1.162-1.554; p = 0.0005) and stroke (RR 1.735; 95% CI 1.323-2.275; p = 0.0005), and no effect on risk of ESRD (RR 1.089; 95% CI 0.986-1.203; p = 0.094) or all-cause mortality (RR 1.148; 95% CI 0.977-1.350; p = 0.093).. In CKD patients, treatment of anaemia with ESAs targeting a higher haemoglobin value does not lower mortality or reduce the risk of ESRD, and may increase cardiovascular risk.

Topics: Adult; Anemia; Cardiovascular Diseases; Comorbidity; Erythropoietin; Hematinics; Humans; Incidence; Renal Insufficiency, Chronic; Risk Factors; Survival Analysis; Survival Rate; Treatment Outcome

Topics: Anemia; Antibodies, Monoclonal, Humanized; Antimicrobial Cationic Peptides; Arthritis, Rheumatoid; Erythropoiesis; Erythropoietin; Hepcidins; Humans; Inflammation; Interleukin-6; Iron; Vitamin D; Vitamins

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

Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoiesis stimulating agents (ESAs) and red blood cell transfusions.. To assess the effects of ESAs to either prevent or treat anaemia in cancer patients.. This is an update of a Cochrane review first published in 2004. We searched the Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE and other databases. Searches were done for the periods 01/1985 to 12/2001 for the first review, 1/2002 to 04/2005 for the first update and to November 2011 for the current update. We also contacted experts in the field and pharmaceutical companies.. Randomised controlled trials on managing anaemia in cancer patients receiving or not receiving anti-cancer therapy that compared the use of ESAs (plus transfusion if needed).. Several review authors assessed trial quality and extracted data. One review author assessed quality assessment and extracted data, a second review author checked for correctness.. This update of the systematic review includes a total of 91 trials with 20,102 participants. Use of ESAs significantly reduced the relative risk of red blood cell transfusions (risk ratio (RR) 0.65; 95% confidence interval (CI) 0.62 to 0.68, 70 trials, N = 16,093). On average, participants in the ESAs group received one unit of blood less than the control group (mean difference (MD) -0.98; 95% CI -1.17 to -0.78, 19 trials, N = 4,715). Haematological response was observed more often in participants receiving ESAs (RR 3.93; 95% CI 3.10 to 3.71, 31 trials, N = 6,413). There was suggestive evidence that ESAs may improve Quality of Life (QoL). There was strong evidence that ESAs increase mortality during active study period (hazard ratio (HR) 1.17; 95% CI 1.06 to 1.29, 70 trials, N = 15,935) and some evidence that ESAs decrease overall survival (HR 1.05; 95% CI 1.00 to 1.11, 78 trials, N = 19,003). The risk ratio for thromboembolic complications was increased in patients receiving ESAs compared to controls (RR 1.52, 95% CI 1.34 to 1.74; 57 trials, N = 15,498). ESAs may also increase the risk for hypertension (fixed-effect model: RR 1.30; 95% CI 1.08 to 1.56; random-effects model: RR 1.12; 95% CI 0.94 to 1.33, 31 trials, N = 7,228) and thrombocytopenia/haemorrhage (RR 1.21; 95% CI 1.04 to 1.42; 21 trials, N = 4,507). There was insufficient evidence to support an effect of ESA on tumour response (fixed-effect RR 1.02; 95% CI 0.98 to 1.06, 15 trials, N = 5,012).. ESAs reduce the need for red blood cell transfusions but increase the risk for thromboembolic events and deaths. There is suggestive evidence that ESAs may improve QoL. Whether and how ESAs affects tumour control remains uncertain. The increased risk of death and thromboembolic events should be balanced against the potential benefits of ESA treatment taking into account each patient's clinical circumstances and preferences. More data are needed for the effect of these drugs on quality of life and tumour progression. Further research is needed to clarify cellular and molecular mechanisms and pathways of the effects of ESAs on thrombogenesis and their potential effects on tumour growth.

Topics: Anemia; Cause of Death; Darbepoetin alfa; Erythrocyte Transfusion; Erythropoietin; Humans; Hypertension; Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Thromboembolism

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

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

Anemia is common in Congestive Heart Failure (CHF) and is associated with an increased mortality, morbidity and progressive renal failure. The most common causes of the anemia in CHF are (1) the associated Chronic Kidney Disease (CKD), which causes depression of erythropoietin (EPO) production in the kidney, and (2) excessive cytokine production in CHF, which can cause both depression of erythropoietin production in the kidney and depression of erythropoietin response in the bone marrow. The cytokines can also induce iron deficiency by increasing hepcidin production from the liver, which both reduces gastrointestinal iron absorption and reduces iron release from iron stores located in the macrophages and hepatocytes. It appears that iron deficiency is very common in CHF and is rarely recognized or treated. The iron deficiency can cause a thrombocytosis that might contribute to cardiovascular complications in both CHF and CKD and is reversible with iron treatment. Thus, attempts to control this anemia in CHF will have to take into consideration both the use of both Erythropoiesis Stimulating Agents (ESA) such as EPO and oral and, probably more importantly, intravenous (IV) iron. Many studies of anemia in CHF with ESA and oral or IV iron and even with IV iron without ESA have shown a positive effect on hospitalization, New York Heart Association functional class, cardiac and renal function, quality of life, exercise capacity and reduced Beta Natriuretic Peptide and have not demonstrated an increase in cardiovascular damage related to the therapy. However, adequately powered long-term placebo-controlled studies of ESA and of IV iron in CHF are still needed and are currently being carried out.

Topics: Anemia; Bone Marrow; Cardiovascular System; Clinical Trials as Topic; Erythropoietin; Heart Failure; Hematinics; Humans; Infusions, Intravenous; Iron; Iron Deficiencies; Kidney; Outcome Assessment, Health Care; Renal Insufficiency, Chronic; Syndrome; Trace Elements

Anemia is a common comorbidity in heart failure (HF) patients. Its occurrence and severity are associated with worse prognosis. Although the etiology of anemia is multifactorial, inappropriate erythropoietin (EPO) production and/or bone-marrow resistance to EPO appear crucial in majority of anemic HF patients. Consequently, treatment based on this pathophysiological background may prove to be most effective and beneficial. In a number of smaller clinical studies, administration of erythropoiesis-stimulating agents (ESAs) to anemic HF patients improved a number of surrogate endpoints, including left ventricular function, exercise capacity, renal function, and different quality of life parameters. However, two larger, phase II studies, did not fully confirm these promising results. Furthermore, many concerns have been raised on the safety of ESAs after the recent publication of studies correcting anemia in patients with chronic kidney disease (CKD). On the other hand, chronic HF population varies significantly from CKD patients, with different comorbidities, renal function, and etiology of anemia. Moreover, ESAs have been shown to possess robust nonhematopoietic effects in the heart, namely inhibition of apoptosis and stimulation of neovascularization. Therefore, large-scale trials with ESAs are required to examine the effect and safety of anemia treatment in HF patients.

Topics: Anemia; Erythropoietin; Heart Failure; Hematinics; Humans; Randomized Controlled Trials as Topic; Renal Insufficiency

Chronic heart failure is a substantial public health problem. Anemia is an important comorbidity frequently observed in patients with the disease and, in heart failure, anemia has only recently started to attract systematic epidemiological and therapeutical research endeavor. This article describes the many aspects of anemia in chronic heart failure, starting with the ongoing discussion of how to define anemia, which has important consequences for the estimation of its prevalence and incidence. Further, we discuss prognostic implications of anemia in patients with chronic or acute heart failure, the etiology of anemia in heart failure and treatment possibilities. Such therapeutic avenues embrace intravenous iron preparations and subcutaneous administration of erythropoietin and its derivatives, all of which have been extensively studied over the last several years. Finally, this article describes the potential costs incurred by treating anemic patients with heart failure.

Topics: Anemia; Comorbidity; Darbepoetin alfa; Erythropoietin; Ferric Compounds; Heart Failure; Hematinics; Humans; Injections, Intravenous; Iron Compounds; Maltose; Prognosis; Risk Assessment; Risk Factors; United States

Anemia is a disease that is often associated with heart failure (HF) and renal insufficiency (RI). This unfavorable triad of conditions has been called Cardio-Renal-Anemia Syndrome (CRS). The association of HF, RI, and anemia is poorly reported in multicenter clinical trials, so the pathophysiologic mechanisms and treatment options need to be better defined. When CRS patients develop anemia, a "perfect storm" often occurs: HF and RI cause anemia which will worsen the first two conditions. Anemia appears to be the result of complex interactions between cardiac performance, bone marrow homeostasis, renal dysfunction, and various drug side effects. However, neurohormonal and inflammatory activities play a key role in the beginning and progression of the disease. As a consequence, endogenous erythropoietin activity dysfunction with inadequate production and tissue resistance occurs. Despite the advances of therapy in the neurohormonal activation blockade, mortality and hospitalization in HF still remain unacceptably high, suggesting that specific comorbidity treatments could have a significant positive prognostic impact. Anemia should be recognized as one of the novel targets in HF treatment.

Topics: Anemia; Bone Marrow; Cardiovascular System; Clinical Trials as Topic; Disease Progression; Drug Therapy, Combination; Erythropoietin; Heart Failure; Hemoglobins; Humans; Iron; Patient Selection; Prognosis; Renal Insufficiency; Risk Factors; Severity of Illness Index; Syndrome; Water-Electrolyte Balance

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

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

Recombinant human erythropoietin (rhEPO), the prototype erythropoiesis-stimulating agent developed in the 1980s, was among the first recombinant human proteins to be marketed for clinical use in the oncology setting. Anemia is a frequent concern in patients with cancer receiving myelosuppressive chemotherapy and the availability of rhEPO as an alternative to red blood cell transfusions to treat symptomatic anemia created excitement among clinicians, particularly during an era of mounting concern for transfusion-transmissible infections. Early studies of rhEPO for chemotherapy-induced anemia in patients with non-myeloid malignancies showed these agents improved hemoglobin levels and reduced transfusion rates. rhEPO therapy was reported to decrease fatigue and improve quality of life, although the magnitude and clinical meaningfulness of these effects have been debated. More recent clinical trials since 2003 linking rhEPO therapy to increased risk of tumor progression, thrombo-vascular events and mortality prompted implementation of use restrictions to minimize potential for harm. Scientific research to understand the basic mechanisms of the biologic effects of erythropoietin at the cellular receptor and signaling level has revealed pleiotropic cytokine effects extending beyond erythropoiesis regulation. The importance of erythropoietin receptor signaling in normal, non-erythroid tissues and in pre-clinical tumor models has been under intense investigation and scrutiny, as potential mechanisms of the adverse outcomes associated with rhEPO therapy have been debated. Further research will be required to clarify the complex interplay between the diverse hematopoietic and non-hematopoietic effects of erythropoietin in normal and malignant tissues and to optimize the clinical use of rhEPO in the supportive care of cancer patients.

Topics: Anemia; Animals; Antineoplastic Agents; Disease Progression; Erythropoietin; Humans; Neoplasms; Risk Factors

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

In this chapter we want to give an overview on various supportive measures, which help to prevent or to fight complications of multiple myeloma, improve patient wellbeing and increase safety of administration of specific anti-myeloma therapy.

Topics: Anemia; Blood Transfusion; Bone Diseases; Calcitonin; Clodronic Acid; Diphosphonates; Erythropoietin; Fractures, Bone; Hematinics; Humans; Hypercalcemia; Imidazoles; Multiple Myeloma; Osteoporosis; Pamidronate; Recombinant Proteins; Renal Insufficiency; Zoledronic Acid

Anemia in heart failure is both common and associated with worse symptoms and increased mortality. Several small randomized controlled trials (RCTs) have assessed erythropoiesis-stimulating agents (ESAs), but definitive evaluation and clinical guidance are required. We sought to systematically review the effects of ESAs in chronic heart failure.. An extensive search strategy identified 11 RCTs with 794 participants comparing any ESA with control over 2 to 12 months of follow-up. Published and additionally requested data were incorporated into a Cochrane systematic review (CD007613).. Nine studies were placebo controlled, and 5, double blinded. Erythropoiesis-stimulating agent treatment significantly improved exercise duration by 96.8 seconds (95% CI 5.2-188.4, P = .04) and 6-minute walk distance by 69.3 m (95% CI 17.0-121.7, P = .009) compared with control. Benefit was also noted for peak oxygen consumption (+2.29 mL/kg per minute, P = .007), New York Heart Association class (-0.73, P < .001), ejection fraction (+5.8%, P < .001), B-type natriuretic peptide (-226.99 pg/mL, P < .001), and quality-of-life indicators with a mean increase in hemoglobin level of 2 g/dL. There was a significantly lower rate of heart failure-related hospitalizations with ESA therapy (odds ratio 0.56, 95% CI 0.37-0.84, P = .005). No associated increase in adverse events or mortality (odds ratio 0.58, 95% CI 0.34-0.99, P = .047) was observed, although the number of events was limited.. Meta-analysis of small RCTs suggests that ESA treatment can improve exercise tolerance, reduce symptoms, and have benefits on clinical outcomes in anemic patients with heart failure. Confirmation requires larger, well-designed studies with careful attention to dose, attained hemoglobin level, and long-term outcomes.

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Randomized Controlled Trials as Topic; Treatment Outcome

Anemia is a common comorbidity in patients with acute and chronic heart failure (HF) with preserved and reduced systolic function. It is recognized as a new therapeutic goal in HF since the reduction in hemoglobin levels is considered a significant independent predictive factor of mortality and hospitalization. At present, it is difficult to determine the real magnitude of the problem in terms of actual incidence and prevalence as no consistent definition of anemia associated with HF does exist, and a variety of hemoglobin thresholds have been used in clinical trials and epidemiological studies. The etiology of anemia is multifactorial with the main causes including renal failure, gastrointestinal bleeding and nutritional deficiency. Nevertheless, such criteria are not present in some patients, who show a peculiar type of anemia that may be classified as anemia of chronic diseases, likely due to the chronic inflammatory process of HF. No guidelines for the treatment of anemia in HF patients are available. Most of the previous studies in the literature are limited by small sample sizes. The very few randomized multicenter studies that evaluated the effects of erythropoiesis-stimulating agents associated with intravenous iron therapy did not provide the expected results. Indeed, despite an increase in hemoglobin levels, they did not show any improvement of NYHA functional class, nor of left ventricular ejection fraction. In addition, reasonable hemoglobin levels as a goal of therapy have not been established yet, in particular in relation to the side effects and the cardiovascular risk observed after the administration of erythropoiesis-stimulating agents in oncologic patients. Further studies are warranted to define the magnitude of the problem and establish appropriate therapeutic strategies. It is likely that more reliable data will be derived from an ongoing randomized, double-blind, multicenter study, the RED-HF (Reduction Event with Darbepoetin alfa in Heart Failure), which aims at evaluating morbidity and mortality in a cohort of 2600 HF patients with anemia treated with darbepoetin alfa.

Topics: Anemia; Cardiovascular Agents; Cytokines; Darbepoetin alfa; Defibrillators, Implantable; Double-Blind Method; Erythropoiesis; Erythropoietin; Heart Failure; Hematinics; Hematocrit; Hemoglobins; Humans; Iron; Malnutrition; Models, Biological; Multicenter Studies as Topic; Practice Guidelines as Topic; Prognosis; Randomized Controlled Trials as Topic; Research Design; Stroke Volume

Anaemia of chronic disease is the second most common form of anaemia worldwide, and is seen in a variety of inflammatory, infective and malignant diseases. Functional iron deficiency is fundamental to the pathogenesis of the anaemia, and the polypeptide, hepcidin, plays a key role. Diagnosis may be difficult, but new automated red cell indices, algorithms for detection of functional iron deficiency, and assays for hepcidin levels are being developed. Management of the causative disease process will usually improve haemoglobin levels, but where this is not possible, erythropoietic stimulating agents are often used, although there are still concerns about potential adverse effects, especially thromboembolism. There is increasing evidence that supplemental iron given parenterally can safely overcome the functional iron deficiency. Inhibitors of hepcidin, and various inflammatory modulators show promise for the future.

Topics: Algorithms; Anemia; Antimicrobial Cationic Peptides; Chronic Disease; Diagnosis, Differential; Erythropoietin; Hepcidins; Humans; Iron

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

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

Topics: Anemia; Chronic Disease; Dietary Supplements; Erythropoietin; Iron; Iron, Dietary; Recombinant Proteins

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

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

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

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

Over the past few decades, understanding of the physiologic function of erythropoietin (EPO) has evolved significantly. EPO binds to erythropoietin receptors (EPOR), initiating signaling that stimulates growth, inhibits apoptosis, and induces the differentiation of erythroid progenitors to increase red blood cell mass. EPO has additionally been shown to exert tissue-protective effects on multiple tissues, suggesting a pleiotropic mechanism of action. Erythropoiesis-stimulating agents (ESA) are used clinically for treating cancer-related anemia [chemotherapy-induced anemia (CIA)]. Recent clinical trials have reported increased adverse events and/or reduced survival in ESA-treated cancer patients receiving chemotherapy, potentially related to EPO-induced cancer progression. Signaling pathways downstream of EPO/EPOR have been shown to influence numerous cellular functions in both normal and tumor cells, including proliferation, apoptosis, and drug resistance. Some studies have reported effects on proliferation, reduced chemotherapy efficacy, reduction of apoptosis, and resistance to selective therapies on cancer cell lines, whereas others have shown null effects. In addition, newer targeted cancer therapies that are directed toward specific signaling pathways may be antagonized by ESAs. This molecular interplay between anticancer agents and potential survival signals triggered by ESAs may have been underestimated and may contribute toward decreased survival seen in certain trials. As more targeted anticancer therapies become available, these types of interactions may mitigate therapeutic efficacy by allowing tumor cells to acquire drug resistance. Therefore, a more complete understanding of the complex pathways involved will allow for the rational use of ESAs for the safe treatment of CIA in oncology patients.

Topics: Anemia; Antineoplastic Agents; Disease Progression; Drug Interactions; Erythropoietin; Hematinics; Humans; Neoplasms; Signal Transduction

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

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

Patient blood management (PBM) is a patient-specific multidisciplinary, multimodal, evidence-based concept to appropriately conserve and manage a patient's own blood as a vital resource. PBM is based on 3 pillars: the first is the optimization of the patient's endogenous red cell mass, the second is the minimization of bleeding and blood loss and the third involves harnessing and optimizing the patient-specific physiological tolerance of anemia, including adopting more restrictive transfusion thresholds. PBM primarily identifies patients at risk of transfusion and provides a management plan aimed at reducing or eliminating the need for allogeneic transfusion, thus reducing the inherent risks, inventory pressures and the escalating costs associated with transfusion. PBM is applicable to surgical and medical patients. The application of PBM systematically reduces the impact of 3 major contributors to negative outcome: anemia, blood loss and transfusion.

Topics: Anemia; Austria; Benchmarking; Blood Transfusion; Erythrocyte Transfusion; Erythrocyte Volume; Erythropoietin; Hematologic Diseases; Humans; Intraoperative Care; Operative Blood Salvage; Patient Care Management; Perioperative Care; Plasma Substitutes; Platelet Transfusion; Postoperative Care; Postoperative Complications; Preoperative Care

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

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

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

Anemia is a common comorbidity in children with chronic kidney disease (CKD). This condition is associated with multiple adverse clinical consequences and its management is a core component of nephrology care. Increased morbidity and mortality, increased risk of cardiovascular disease and decreased quality of life have been associated with anemia of CKD in children. Although numerous complex factors interact in the development of this anemia, erythropoietin deficiency and iron dysregulation (including iron deficiency and iron-restricted erythropoiesis) are the primary causes. In addition to iron supplementation, erythropoietin-stimulating agents (ESAs) can effectively treat this anemia, but there are important differences in ESA dose requirements between children and adults. Also, hyporesponsiveness to ESA therapy is a common problem in children with CKD. Although escalating ESA doses to target increased hemoglobin values in adults has been associated with adverse outcomes, no studies have demonstrated this association in children. The question of appropriate target hemoglobin levels in children, and the approach by which to achieve these levels, remains under debate. Randomized, controlled studies are needed to evaluate whether normalization of hemoglobin concentrations is beneficial to children, and whether this practice is associated with increased risks.

Topics: Anemia; Child; Comorbidity; Erythropoietin; Humans; Renal Insufficiency, Chronic; Risk Factors

Myelodysplastic syndromes (MDS) are heterogeneous clonal diseases characterized by cytopenias resulting from ineffective hemopoiesis. Anemia affects the vast majority of patients with MDS and contributes substantially to their symptoms. For more than 20 years, recombinant human erythropoietin has been available for clinical use, and it has been employed in an attempt to relieve MDS-related anemia. Erythropoietin-alpha, erythropoietin-beta, and more recently darbepoetin have been found to increase hemoglobin levels and abolish transfusion dependence in 19%-68% of MDS cases. This wide range in clinical response depends on several biological and clinical variables that allow the selection of patients with the highest probability of successful treatment. These agents are a mainstay in MDS therapy, but many issues are still open in terms of the initiation of therapy, the optimal dosage of erythropoietic stimulating agents (ESAs), the most efficient type of ESA, and the duration and outcome of such treatments. In this review, the mechanisms of response and predictive factors as well as an analysis of the clinical activity of ESAs in MDS therapy are presented.

Topics: Anemia; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Myelodysplastic Syndromes; Recombinant Proteins

This review will explore the basic assumptions needed to perform predictive modeling of hemoglobin response to erythropoiesis stimulating agents (ESAs) and summarize the current literature in the area so that the practitioner can incorporate these tools as part of an improved anemia management process.. During the last year, several publications have demonstrated some advances in the field that may improve anemia management. The first of these was the publication of a randomized, controlled clinical trial of model predictive control in the dosing of erythropoietin. This work showed that hemoglobin variability can be decreased using predictive models of hemoglobin response. The second publication is potentially more interesting in the long run, as new markers of erythropoietin response were identified in a well-defined population of patients.. Predictive models of hemoglobin response improve anemia management by decreasing hemoglobin variability. This will result in more patients within the target range. Coupling these tools with new biomarkers of hemoglobin response has the potential to dramatically improve anemia management.

Topics: Anemia; Computer Simulation; Erythropoietin; Expert Systems; Hematinics; Hemoglobins; Humans; Models, Biological; Recombinant Proteins; Renal Dialysis

Heavy chain deposition disease (HCDD) is a comparatively recently described entity characterized by glomerular and tubular basement membrane deposition of monoclonal heavy chains without associated light chains. To our knowledge, review of the literature shows only 24 previously reported cases of HCDD with unequivocal evidence of monoclonal heavy chain deposition in the kidney using immunofluorescence microscopic and electron microscopic studies. The predominant heavy chain subtype was γ. There has been a single case of μ HCDD and 2 previously reported cases of α HCDD. In this report, we describe 3 additional cases of α HCDD, all with a crescentic pattern of injury and one of which was associated with cutis laxa. We compare their clinicopathologic features with all previously reported cases of HCDD.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cutis Laxa; Dexamethasone; Diabetic Nephropathies; Erythropoietin; Fatal Outcome; Female; Heavy Chain Disease; Hematuria; Humans; Hypertension, Renal; Immunoglobulin alpha-Chains; Immunoglobulin gamma-Chains; Immunoglobulin mu-Chains; Kidney Glomerulus; Male; Multiple Myeloma; Paraproteinemias; Proteinuria; Pyrazines; Thalidomide; Urticaria; Vasculitis, Leukocytoclastic, Cutaneous

Erythropoietin is a glycoprotein predominantly produced in the kidney. It is an essential regulator of erythropoiesis in the bone marrow. Although cancer-associated anemia is caused by multiple factors, recombinant erythropoietin (rhuEpo) was widely used to treat and prevent this condition. Several clinical studies showed that the use of rhuEpo results in an efficient reduction of red blood cell transfusions in cancer-associated anemia. However, over the past twenty years, Epo and its receptor EpoR were found to be expressed also outside the hematopoietic system and in malignant tumors. This led to a discussion concerning potential risks associated with the application of erythropoiesis-stimulating agents in oncology.

Topics: Anemia; Erythrocyte Transfusion; Erythropoietin; Humans; Neoplasms; Risk Factors

Anemia is common in persons with HIV infection and is associated with poor prognosis. There is a need to assess the effects of anemia treatments, and to determine whether these interventions are beneficial.. To determine the efficacy and safety of treatments for anemia in people with HIV infection and AIDS.. The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 10, 2010), MEDLINE (1980-November 25, 2010), EMBASE (1980-November 25, 2010), LlLACS (1982 to November 25, 2010), Africa Index Medicus (up to November 9, 2010), ISI Web of Knowledge (2005 to October 9, 2010), Scirus (October 9, 2010) reference lists of relevant articles. We asked the Cochrane HIV/AIDS and Pregnancy and Childbirth Groups to check their Specialised Registers. We also checked the reference lists of all trials identified by the above methods.. Randomized trials assessing the effects of treatments for anemia in people diagnosed with HIV infection. There were no age restrictions.. Two authors independently assessed relevant studies for inclusion. Data extraction and quality assessment of relevant studies was performed by two authors and checked by the other two authors.. Six trials with a high risk of bias, including 537 patients, met the inclusion criteria. These trials only covered recombinant Human erythropoietin alfa (rHuEPO). Two of them including adult and paediatric participants (84 participants and 4 events) comparing rHuEPO to placebo did not reduce the risk of mortality with a follow up to 12 weeks (pooled RR 0.56, 95% confidence interval (CI) 0.08 to 4.05, I(2) = 0%). Any trials that compared rHuEPO to placebo did not show any benefit on hematological values response, number of patients transfused, or number of packed red cell transfused. Two trial compared the effects of two rHuEPO dosing regimens on hemoglobin value and quality of life, but the effects are unclear. Three RCT reported high risk of attrition bias; therefore, were not included in a meta-analysis.. This updated Cochrane review provides evidence that rHuEPO compared with placebo does not reduce mortality, does not reduce transfusion requirements, did not increase hemoglobin levels, and did not improve quality of life in HIV-infected patients with anemia. The results are based on six RCTs with high risk of bias. Therefore prescription of this intervention for treating anemia in patients with AIDS is not justified, unless new evidence from a large high quality trial alters this conclusion.

Topics: Acquired Immunodeficiency Syndrome; Anemia; Erythropoietin; Hematinics; Humans; Randomized Controlled Trials as Topic; Recombinant Proteins

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

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

The myelodysplastic syndromes (MDS) are clonal bone marrow disorders that lead to underproduction of normal blood cells. The consequent cytopenias result in infections and bleeding complications. MDS transform to acute myeloid leukemia in one-third of patients. The number of diagnoses has exploded in the past decade as a result of increased recognition and understanding of the disease and the aging of the population. New therapies can extend life. MDS are now considered the most common form of leukemia, and in some cases deserve immediate intervention. This review describes common presentations of MDS, optimal diagnostic approaches, and therapies for lower-and higher-risk disease.

Topics: Age Distribution; Anemia; Anti-Bacterial Agents; Blood Cell Count; Chelation Therapy; Erythrocyte Transfusion; Erythropoietin; Hematinics; Humans; Myelodysplastic Syndromes; Recombinant Proteins

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

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

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

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

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

Chronic hepatitis C is one of the leading causes for chronic liver disease globally. The past two decades have seen many advances in hepatitis C treatment. Despite these advances, side effects of treatment are common. Haematological complications of treatment can result in treatment cessation and suboptimal results. Recent data have suggested a role for epoetin/granulocyte colony stimulating factor (G-CSF) in optimizing sustained virological response (SVR).. To investigate the nature, frequency and management of haematological side effects in the treatment of chronic hepatitis C infection.. The terms hepatitis C, hepatitis C virus (HCV), treatment, side effects, interferon, peginterferon, ribavirin, anaemia, haemoglobin, neutropenia, thrombocytopenia, haematological, growth factor, erythropoietin and G-CSF were searched on MEDLINE for the period 1991-2009. References from selected articles were also included.. Haematological side effects such as anaemia, neutropenia and thrombocytopenia are frequent in anti-HCV treatment. The off-label use of haematological growth factors is common and effective.. Erythropoietic agents are effective in treating anaemia, preventing ribavirin dose reduction, improving patients' quality of life, but the effect on SVR is not fully elucidated. G-CSF is effective in raising absolute neutrophil count; however, neutropenic HCV-infected patients on combination treatment may not experience increased bacterial infections. Eltrombopag, a new oral thrombopoietin mimetic, may allow combination treatment in patients with thrombocytopenia.

Topics: Anemia; Antiviral Agents; Dose-Response Relationship, Drug; Drug Therapy, Combination; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Neutropenia; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Thrombocytopenia; Viral Load

Anemia is the leading clinical manifestation in myelodysplastic syndromes (MDS), significantly altering quality of life. Darbepoetin alfa has recently been added to the armentarium of erythropoiesis stimulating agents (ESAs) for the treatment of anemia in MDS.. We review here the efficacy and safety data on the use of darbepoetin alfa in the management of anemia in MDS patients. Published reports covering the period from 2005 till today were reviewed, as well as updated guidelines on the use of ESAs.. Darbepoetin alfa administered, during correction phase, once a week or at longer intervals, yielded erythroid response rates comparing favourably with those obtained with recombinant human erythropoietin (rHuEPO) in lower-risk MDS. During maintenance phase, intervals between injections can be further increased in many responders. Quality of life was consistently improved in responders and the drug was overall well tolerated.. Those results, together with recent studies showing improved long-term outcomes in responders, support the use of darbepoetin, among other ESAs, for the treatment of anemia of lower-risk MDS, as recommended by international guidelines.

Topics: Anemia; Clinical Trials as Topic; Darbepoetin alfa; Erythropoietin; Hematinics; Humans; Myelodysplastic Syndromes

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

Posttransplantation anemia (PTA) is a prevalent sequela of solid organ transplantation and a potential independent risk factor for cardiovascular morbidity and mortality in kidney transplant recipients. There are multiple causes of PTA, some of which are associated with early phase anemia (<6 months), whereas others more often induce anemia in the late posttransplant phase (>6 months). Although impaired kidney function contributes to PTA, it is only one of many factors that result in anemia in transplant recipients. Other causes include iron deficiency, medications, infections, acute rejection, inflammation, and erythropoietin deficiency. Unlike in the predialysis chronic kidney disease population, the impact of anemia after kidney transplantation outcomes is unknown. This is in large part due to the absence of controlled trials that address whether correction of anemia improves allograft function or patient morbidity and mortality. Current guidelines recommend evaluation for hemoglobin level of less than 12 g/dL and treatment when the value falls less than 11 g/dL and a target of 11 to 12 g/dL. Additional treatments may entail removing the cause of the anemia, nutritional supplementation, and/or an erythrocyte stimulating agent.

Topics: Anemia; Cohort Studies; Erythropoietin; Heart Diseases; Hemoglobins; Humans; Incidence; Liver Transplantation; Lung Transplantation; Organ Transplantation; Prevalence; Quality of Life; Recombinant Proteins

ver the last half century, the use of erythropoietin (Epo) in the management of malignancies has been extensively studied. Originally viewed as the renal hormone responsible for red blood cell production, many recent in vivo and clinical approaches demonstrate that various tissues locally produce Epo in response to physical or metabolic stress. Thus, not only its circulating erythrocyte mass regulator activity but also the recently discovered nonhematological actions are being thoroughly investigated in order to fulfill the specific Epo delivery requirements for each therapeutic approach.

Topics: Anemia; Animals; Cell Line; Cells, Immobilized; Drug Compounding; Drug Delivery Systems; Erythropoiesis; Erythropoietin; Genetic Engineering; Humans; Implants, Experimental; Myoblasts; Polymers; Recombinant Proteins

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

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

The kidney is a highly sensitive oxygen sensor and plays a central role in mediating the hypoxic induction of red blood cell production. Efforts to understand the molecular basis of oxygen-regulated erythropoiesis have led to the identification of erythropoietin (EPO), which is essential for normal erythropoiesis and to the purification of hypoxia-inducible factor (HIF), the transcription factor that regulates EPO synthesis and mediates cellular adaptation to hypoxia. Recent insights into the molecular mechanisms that control and integrate cellular and systemic erythropoiesis-promoting hypoxia responses and their potential as a therapeutic target for the treatment of renal anemia are discussed in this review.

Topics: Anemia; Animals; Basic Helix-Loop-Helix Transcription Factors; Bone Marrow; Erythrocytes; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Hematinics; Homeostasis; Humans; Hypoxia; Iron; Kidney; Oxygen; Polycythemia; Procollagen-Proline Dioxygenase; Protein Processing, Post-Translational; Von Hippel-Lindau Tumor Suppressor Protein

Anaemia is a frequent complication of cancer. Recently, some concerns have appeared regarding the safety of erythropoiesis-stimulating agents (ESAs) for the treatment of anaemia in cancer patients. The current review will analyse the main arguments in favour of erythropoietin (EPO), as well as those against EPO in chemotherapy-induced anaemia and in cancer-related anaemia. The principal concerns are tumour progression, increased mortality and the risk of venous thromboembolic events (VTEs). Recent meta-analyses have come to divergent conclusions.. Several meta-analyses have reviewed the data regarding VTEs, EPO receptors on tumours and tumour progression as well as mortality.. As of now, ESAs should only be used within the indications as given in the various guidelines.

Topics: Anemia; Disease Progression; Erythropoietin; Hematinics; Humans; Hypertension; Neoplasms; Red-Cell Aplasia, Pure; Risk Assessment; Seizures

Erythropoiesis-stimulating agents (ESA) are used to treat renal anemia. The TREAT study (Trial to Reduce Cardiovascular Events with Aranesp Ther- apy) of diabetic patients with chronic kidney disease (CKD) found that the risk of stroke was significantly higher than in the control arm. This raises the question as to what causes this phenomenon. Platelets may play a crucial role in this context. Atherogenesis involves complex interactions between platelets and monocytes (platelet-monocyte crosstalk) and with endothelial cells. Platelets are activated in cases of diabetes mellitus, especially. During atherogenesis, partial functions of platelets other than those inhibited by aspirin, as a cyclooxygenase inhibitor, or by adenosine diphosphate receptor P2Y(12)antagonists, such as thienopyridines, are of relevance. During platelet-monocyte crosstalk, specifically, an important role is played by adhesion receptors such as selectins and integrins. In addition, ESA cause platelet activation by direct and indirect mechanisms. Antagonistic thereto is a renal bleeding tendency in cases of severe CKD, due to platelet dysfunction, which can be remedied with appropriate renal replacement therapy and administration of ESA in order to reach a hemoglobin (Hb) level of 10 g/dl. However, if the Hb level exceeds 10 g/dl, the even stronger platelet activation caused by ESA, combined with the activation caused by diabetes, leads to a prothrombotic state, which in patients with severe atherosclerosis can result in acute atherothrombotic complications, in the genesis of which platelets play a key role. This would be one hypothesis for explaining the increased incidence of strokes in the TREAT study.

Topics: Anemia; Atherosclerosis; Blood Platelets; Darbepoetin alfa; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Erythropoietin; Female; Hematinics; Hemoglobinometry; Humans; Integrins; Intracranial Embolism; Male; Monocytes; Platelet Activation; Randomized Controlled Trials as Topic; Receptor Cross-Talk; Renal Replacement Therapy; Selectins

After iron deficiency anemia the anemia of chronic disorder is the second most frequent anemia, and in hospitalized patients and/or patients suffering from chronic disease, especially infection, cancer and autoimmune disorders it is even the most frequent anemia. Morphologically it belongs to the normochromic, normocytic, hyporegeneratoric anemias. Pathogenetically it is induced by the upregulation of hepcidin, a recently detected acute phase protein with most important regulatory function in the iron-household. As a consequence of elevated hepcidin at the same time iron absorption in the bowel as well as iron release from macrophages are reduced, resulting in sequestration of iron in the RES and therefore functional iron deficiency. The other reason is a blunted release of erythropoetin (EPO) with at the same time reduced effectiveness due to down-regulation of EPO-receptors on erythroid cells. Treatment consists first of all in the therapy of the underlying disease and possibly in the combined application of EPO and iron.

Topics: Anemia; Chronic Disease; Dietary Supplements; Erythropoietin; Humans; Iron

Anemia in elderly patients should never be regarded as a normal physiological response to aging. The main categories of anemia in older patients are the nutritional anemia attributed to iron deficiency, including blood loss, folate and vitamin B12 deficiency, anemia of chronic disease in patients with cancer, infections and other chronic inflammation. A further category is the unexplained anemia due most probably to impaired corrective mechanisms to stress in older persons. Investigations such as a complete blood count, red cell indices and morphology, reticulocyte count, iron parameters, vitamin B12 and folate will detect the underlying disease in many cases, when anemia is classified according to red blood cell mean corpuscular volume. Microcytic anemia is typically for iron deficiency, but normocytic anemia can also be found in iron deficiency or anemia of chronic disease. Anemia due to vitamin B12 or folate deficiency is typically macrocytic. The treatment should aim to correct the underlying cause of disorder. Recombinant human erythropoietin is a standard treatment in anemia associated with chronic renal failure and tumor-associated anemia, but not in other forms of anemia. Regular blood transfusions may be required for elderly patients with chronic anemia.

Topics: Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Geriatric Assessment; Humans; Iron; Male

Blood transfusion is a not causal therapeutic option in symptomatic anemia. For long time, since the discovery of the blood circulation and the first experiments in transfusion over 300 years ago, blood transfusions were the only possibility to improve the tissue oxygenation. Pretransfusion testing of the blood components as well as of the donor and the recipient has made transfusion of allogeneic blood increasingly safe. Despite transfusion reactions still do occur, they have considerably diminished, inter alia by the introduction of hemovigilance systems and decreasing the hemoglobin value used as transfusion trigger, hence performing less unnecessary transfusions. In chronic anemia, usually accepted transfusion triggers today are 70 g/l hemoglobin in patients without comorbidities. The use of erythropoetin stimulating agents is widely used and should - after a careful examination of the anemia - be considered early in the treatment plan in patients with chronic anemic.

Topics: Anemia; Blood Transfusion; Chronic Disease; Erythropoietin; Humans; Transfusion Reaction

Erythropoiesis stimulating proteins are approved for chemotherapy-induced anemia. Treatment with ESPs results in an increase in hemoglobin in 60 - 70 % of patients and in a significant reduction in transfusion need. A marked increase in hemoglobin levels usually is associated with an improvement in quality of life. Relevant side effects include an increase in thromboembolic complications and, in case of use in unapproved indications, a minimally increased mortality, which is not seen when ESPs are used in the approved indications. Treatment with ESPs should be initiated at hemoglobin levels < 100 g/l and a target level of 120 g/l should not be exceeded.

Topics: Anemia; Antineoplastic Agents; Erythropoietin; Hematinics; Humans; Neoplasms; Proteins; Recombinant Proteins

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

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

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

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

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

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

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

Erythropoietin (EPO) is a hematopoietic hormone with extensive nonhematopoietic properties. The discovery of an EPO receptor outside the hematopoietic system has fuelled research into the beneficial effects of EPO for various conditions, predominantly in cardiovascular disease. Experimental evidence has revealed the cytoprotective properties of EPO, and it seems that the EPO-EPO receptor system provides a powerful backbone against acute myocardial ischemia, gaining from the different properties of EPO. There is an ongoing discussion about possible discrepancy between preclinical and clinical effects of EPO on the cardiovascular system. Large, randomized, placebo-controlled clinical trials are underway to give a final verdict on EPO treatment for acute coronary syndromes.

Topics: Acute Coronary Syndrome; Acute Disease; Anemia; Erythropoiesis; Erythropoietin; Humans; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion; Receptors, Erythropoietin; Syndrome

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

The synthesis of erythropoiesis-stimulating agents (ESAs), especially recombinant human erythropoietin, has provided a new therapeutic option for the treatment of patients with various forms of anemia, including that of chronic renal disease, malignancy, hematologic disorders, prematurity, and acquired immune deficiency syndrome. These agents are effective in improving the hematologic response and reducing the need for red blood cells transfusion, and they also appear to have a positive effect on some health-related quality-of-life indicators. The incidence of side effects and survival, however, remains highly uncertain, and several studies have recently highlighted the problem of an increased trend of tumor progression, mortality and thrombotic complications, especially venous thromboembolism, in patients undergoing therapy with ESAs. Specifically, the biological background underlying the prothrombotic effects of ESAs is multifaceted (polycythemia/hyperviscosity syndrome, hypertension, thrombocytosis, platelet hyperactivity, activation of blood coagulation) and context dependent, and it most likely requires the presence of additional prothrombotic factors. Nevertheless, this clinical and biological evidence supports the hypothesis that therapy with ESAs might not be ultimately beneficial or advantageous in patients with anemia of chronic disorders, and these drugs should not be routinely used as an alternative to blood transfusion unless future studies affirm safety and clinical benefits within these populations.

Topics: Anemia; Animals; Erythropoietin; Hematinics; Humans; Recombinant Proteins; Thrombosis

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

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

The erythropoietin is produced by the kidney and other organs. EPO does not only affect erythroid cells, but also other blood cell lines, such as myeloid cells, lymphocytes and megakaryocytes. This hormone can also enhance phagocytes function of the polymorph nuclear cells and reduces the activation of macrophages, thus modulating the inflammatory process. Hematopoietic and endothelial cells probably have the same cellular origin, and the discovery of erythropoietin receptors also on mesangial and myocardial cells and smooth muscle fibro-cells has prompted the study of the pleiotropic actions of this hormone. Through its receptors, spread out over the body, it carries out many actions which range from the erythrogenesis after hypoxic stimuli to the tissue protection of the heart and the brain after ischemia. Erythropoietin also acts in the endothelial proliferation of new vessels involving the tumor genesis, but it opens new frontiers to the employment of rHuEPO in the Regenerative Medicine.

Topics: Anemia; Animals; Brain; Cardiovascular Diseases; Endothelium, Vascular; Erythroid Cells; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Humans; Hypoxia; Ischemia; Kidney; Mice; Models, Biological; Myeloid Cells; Myocardium; Neovascularization, Pathologic; Neovascularization, Physiologic; Organ Specificity; Oxygen; Receptors, Erythropoietin

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

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

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

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

Anaemia is a relatively frequent co-morbidity of chronic heart as well as chronic renal failure. In both conditions, it represents a strong and independent predictor of increased morbidity and mortality. Aetiology of this anaemia is multi-factorial. A number of various factors play a role in its development, e.g. inadequate erythropoietin production in the kidneys, bone marrow inhibition, iron deficiency as well as haemodilution associated with fluid retention. Treatment strategies aim at two directions. One is the stimulation of erythropoiesis with recombinant human erythropoietin or its analogues such as darbepoetin alpha. The other involves iron substitution, administered preferably intravenously for improved efficacy and tolerability. Clinical studies evaluating treatment of anaemia in chronic heart failure with erythropoiesis-stimulating agents conducted so far were ofa small scale, were not controlled with placebo and usually assessed proxy parameters. Their results suggested that effective treatment of anaemia in patients with chronic heart failure improves exertion tolerance, clinical status (NYHA class) as well as the quality of life and reduces the need for blood transfusions. Recently completed TREAT study was the first large morbidity and mortality study evaluating treatment of anaemia with an erythropoietin analogue compared to placebo. On a sample of more than 4000 patients with diabetes mellitus, chronic renal failure and significant anaemia, this study has shown that effective treatment of anaemia with darbepoetin alpha did not affect at all the incidence of cardiovascular and renal events; on the other hand, it had lead to a nearly two-fold increase in the incidence of cerebrovascular events. Some doubts about the safety of treatment with erythropoiesis-stimulating agents have occurred in the past based on the studies of anaemia treatment in patients with cancer and renal diseases. An answer to the question whether the treatment of anaemia associated with chronic heart failure affects positively the patient prognosis will be provided following the completion of the currently running morbidity and mortality RED-HF study.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Iron

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

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

Inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), among others, play a major role in the pathophysiology of anemia in the cancer patient not only through complex mechanisms of the purely inflammatory situation but also through genetic regulatory aspects of erythropoiesis via GATA-1 and GATA-2, and other factors. In terms of therapy, iron is used more and more; the late side effects of transfusions are not really understood and the recent controversy regarding erythropoietin usage has resulted in regulatory authorities and scientific societies providing several recommendations and guidelines. These various aspects are addressed herein.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Erythropoietin; Humans; Neoplasms

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

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

To update American Society of Hematology/American Society of Clinical Oncology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer.. An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched.. The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews.. For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels ≥ 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations.

Topics: Adult; Anemia; Darbepoetin alfa; Disease Progression; Erythropoietin; Hematinics; Humans; Neoplasms; Recombinant Proteins

Topics: Anemia; Biomarkers; Erythropoietin; Heart Failure; Humans; Population Surveillance; Predictive Value of Tests; Survival Rate

To update American Society of Clinical Oncology/American Society of Hematology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer.. An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched.. The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews.. For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels ≥ 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations.

Topics: Adult; Anemia; Darbepoetin alfa; Disease Progression; Erythropoietin; Hematinics; Humans; Neoplasms; Recombinant Proteins

β-Thalassemia is a genetic disorder caused by mutations in the β-globin gene and characterized by chronic anemia caused by ineffective erythropoiesis, and accompanied by a variety of serious secondary complications such as extramedullary hematopoiesis, splenomegaly, and iron overload. In the past few years, numerous studies have shown that such secondary disease conditions have a genetic basis caused by the abnormal expression of genes with a role in controlling erythropoiesis and iron metabolism. In this article, the most recent discoveries related to the mechanism(s) responsible for anemia/ineffective erythropoiesis and iron overload are discussed in detail. Particular attention is paid to the pathway(s) controlling the expression of hepcidin, which is the main regulator of iron metabolism, and the Epo/EpoR/Jak2/Stat5 signaling pathway, which regulates erythropoiesis. Better understanding of how these pathways function and are altered in β-thalassemia has revealed several possibilities for development of new therapeutic approaches to treat of the complications of this disease.

Topics: Anemia; Animals; Antimicrobial Cationic Peptides; beta-Thalassemia; Erythropoiesis; Erythropoietin; Hepcidins; Humans; Iron; Iron Overload; Receptors, Erythropoietin

Anemia in cancer patients is common and often associated with decreased survival and quality-of-life scores. The introduction of erythropoiesis-stimulating agents (ESAs) for the treatment of anemia in patients with solid tumors and nonmyeloid malignancies in the 1990s has proved an important alternative to red blood cell transfusions. ESAs have been consistently shown to increase hemoglobin levels and reduce transfusion requirements in anemic cancer patients whilst also being associated with improvements in quality of life. Several recent studies, however, have raised concerns about the safety of ESAs with regards to an increased number of thrombo-embolic events, decreased on-study survival and possible effects of ESAs on tumor progression. This has led to a reappraisal of the role of ESAs in the treatment of anemic cancer patients. It remains generally accepted that, if used within current guidelines and labeling recommendations, ESAs can still be considered safe in patients receiving chemotherapy once individual risks are balanced against possible benefits.

Topics: Anemia; Disease Progression; Erythropoietin; Hematinics; Humans; Iron; Neoplasms; Prognosis; Quality of Life; Recombinant Proteins; Venous Thromboembolism

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

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

It has recently been recognized that many patients with congestive heart failure (CHF) are anemic. The anemia is very often associated with chronic kidney disease (CKD). The more severe the anemia the more severe the CHF, with higher mortality, morbidity, and hospitalization rate. The only way to prove that the anemia is itself a causative factor in the progression of both the CKD and the CHF is to correct it. In this paper we review the results of published papers and some preliminary reports about correction of this anemia in CHF. These studies frequently showed that erythropoietic stimulating agents (ESA) with oral or IV iron often resulted in improvement in left ventricular systolic and diastolic function, dilation, and hypertrophy, stabilization or improvement in renal function, reduced hospitalizations, diuretic dose, mitral regurgitation, pulmonary artery pressure, plasma volume, heart rate, serum brain natriuretic peptide levels, and the inflammatory markers C reactive protein and Interleukin 6, and an improvement in New York Heart Association class, exercise capacity, oxygen utilization during exercise, sleep apnea, caloric intake, depression, and quality of life. The activity of endothelial progenitor cells was also increased. Iron deficiency may also play an important role in the anemia, because significant improvement of cardiac, renal, and functional status in these anemic CKD-CHF has been seen after treatment with IV iron alone. Clearly more work is needed to clarify the relationship between anemia, CKD and CHF.

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Iron; Renal Insufficiency, Chronic

Therapy with erythropoiesis-stimulating agents (ESAs) is associated with well-documented benefits to anemic cancer patients undergoing chemotherapy, most importantly a reduction in the likelihood of needing red cell transfusions. One challenge in supportive cancer care is a relative resistance to ESAs, requiring high doses with a significant rate of nonresponse. Recent advances in our understanding of iron metabolism in patients with chronic illness and the results of clinical trials indicate that parenteral iron improves ESA response in this setting. Another issue is the safety of ESA treatment in cancer patients. There is an increased risk of venous thrombosis that must be considered in clinical decision making. There are also recent data raising concerns that ESAs may enhance tumor progression or decrease patient survival. Although the preponderance of the data suggests that ESAs do not alter survival when used to treat chemotherapy-induced anemia, large well-controlled trials addressing this issue are needed.

Topics: Anemia; Cell Hypoxia; Disease Progression; Drug Resistance; Erythropoietin; Hematinics; Humans; Neoplasm Metastasis; Neoplasms

Epoetin alpha (EPO) continues to be the initial treatment of choice for most anemic patients with myelodysplastic syndromes (MDS). Over the years, different therapeutic strategies have been adopted to optimize the clinical benefits of EPO in this setting.. In the current meta-analysis of published literature, erythroid response (ER) rates with EPO as a single agent versus its combination with granulocyte-colony-stimulating factor (G-CSF) or granulocyte-macrophage-colony-stimulating factor (GM-CSF) were compared.. The assessment indicated that the ER rates were comparable between the 2 EPO-based therapeutic strategies. Furthermore, EPO monotherapy at a higher dose of 60,000 to 80,000 U weekly produced significantly higher ER rates (64.5%) compared with the standard oncology dose of 30,000 to 40,000 U weekly either as a single agent (49%; P < .001) or in combination with G-CSF/GM-CSF (50.6% P = .007). In addition, when transfusion-dependent patients were assessed separately, both EPO monotherapy and its combination with G-CSF/GM-CSF produced comparable and appreciable levels of transfusion independence (28.8% and 24.8%, respectively).. In the current meta-analysis, higher doses of EPO demonstrated better ER rates compared with EPO at standard doses alone or in combination with G-CSF/GM-CSF. Furthermore, the authors concluded that prospective clinical studies are warranted to evaluate the use of higher doses of EPO in anemic patients with MDS.

Topics: Aged; Anemia; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Hematinics; Humans; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Recombinant Proteins

Patients with colorectal cancer are frequently anaemic and many receive allogeneic red blood cell transfusions peri and post-operatively. Transfusions are accompanied by complications and may increase the rate of recurrence in patients who have a colorectal resection. Recombinant erythropoietin was first used in dialysis patients and more recently in orthopedic surgery to facilitate autologous transfusions. Erythropoietin levels are thought to be lower in cancer patients and erythropoietin is widely used in chemotherapy to treat anaemia and improve quality of life. There may be adverse events associated with its use. Several studies have investigated erythropoietin in colorectal cancer surgery.. The primary objective of this systematic review was to evaluate the efficacy of erythropoietin pre and peri-operatively, in reducing allogeneic blood transfusions in patients undergoing colorectal cancer surgery. Secondary objectives were to determine whether pre and peri-operative erythropoietin improves hematologic parameters (hemoglobin, hematocrit and reticulocyte count), quality of life, recurrence rate, and survival, without increasing the occurrence of thrombotic events and the peri-operative mortality.. A literature search was performed using MEDLINE, EMBASE, abstracts from the annual meetings of the American Society of Clinical Oncology and the American Society of Colon and Rectal Surgeons until May 2008.. Randomized controlled trials of erythropoietin versus placebo or no treatment/standard of care were eligible for inclusion. The study must have reported one of the primary or secondary outcomes and included anaemic patients undergoing surgery for colorectal cancer.. The methodological quality of the trials was assessed using the information provided. Data were extracted and effect sizes were estimated and reported as relative risks(RR) and mean differences (MD) as appropriate.. Four eligible studies were identified of ten retrieved in full. There were no statistically significant differences in the proportion of patients transfused between the erythropoietin group and control group. One of the studies showed a small difference in the median number of units transfused per patient favouring treatment. Reporting of hematologic parameters was varied however, there is no evidence for clinically significant changes. There were no significant differences in post-operative mortality or thrombotic events between groups. No included study evaluated recurrences, survival, or quality of life. Studies were of fair methodologic quality and the overall sample size was small therefore results should be interpreted with caution.. There is no sufficient evidence to date to recommend pre and peri-operative erythropoietin use in colorectal cancer surgery.

Topics: Anemia; Blood Transfusion; Colorectal Neoplasms; Erythrocyte Transfusion; Erythropoietin; Humans; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Transplantation, Homologous

Since the late 1980s recombinant human erythropoietin (r-EPO) has been studied as an alternative to packed red blood cell (RBC) transfusion for the treatment of anemia of prematurity in very low birth weight infants. Initial trials and reports focused on r-EPO's ability to prevent or treat anemia of prematurity with the goal of eliminating RBC transfusion but achieved limited success. New concerns about the safety of r-EPO administration have emerged. Past cost-benefit analyses of r-EPO administration versus transfusion for the treatment of anemia of prematurity have been nearly balanced. Autologous transfusion, blood-sparing technologies, changes in RBC transfusion technique and safety, and further elucidation of the risk-benefit ratio of r-EPO therapy may change the cost-benefit analysis.

Topics: Anemia; Erythrocyte Transfusion; Erythropoietin; Hematinics; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Recombinant Proteins

Anaemia is common in patients with chronic heart failure (HF), and erythropoiesis stimulating proteins (ESPs) are frequently used for its treatment. However, recent studies in patients with malignancies and renal failure have raised concerns about the safety of these agents.. To determine whether treatment of anaemic patients with chronic HF with ESPs is associated with an effect on morbidity and mortality.. A systematic literature search in Medline, the Cochrane Controlled Trials Register Database and ClinicalTrials.gov through July 2008 was performed.. Randomised clinical trials comparing the effect of ESP treatment with placebo or usual care in anaemic patients with HF were included.. Seven randomised controlled trials were identified that enrolled 650 patients, of whom 363 were treated with ESPs and 287 with placebo. ESP treatment had a significantly lower risk of HF hospitalisation (risk ratio (RR) = 0.59; 95% CI 0.41 to 0.86; p = 0.006).There was no significant difference in the mortality risk between the two groups (RR = 0.69; 95% CI 0.39 to 1.23; p = 0.21). No significant differences were observed in the occurrence of hypertension or venous thrombosis.. In chronic HF, treatment with ESPs is not associated with a higher mortality rate or more adverse events, whereas a beneficial effect on HF hospitalisation is seen. These outcomes are in contrast with studies in cancer and kidney disease, and support a large phase III morbidity and mortality trial of anaemia correction in patients with chronic HF.

Topics: Anemia; Chronic Disease; Erythropoietin; Heart Failure; Hematinics; Humans; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors

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

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

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

The Standards, Options, and Recommendations (SOR) project undertaken by the French National Federation of Cancer Centers (FNCLCC) to develop and disseminate clinical practice guidelines in oncology has now been taken over by the French National Cancer Institute. In 2007, the SOR updated the information related to the use of erythropoiesis-stimulating agents (ESA) in anemic children with cancer. Updates were based on a review of the most reliable scientific data available, followed by critical appraisal by a multidisciplinary group of experts and validation by independent experts. The literature review identified four randomized trials likely to provide reliable new information on the use of ESA in children. This review confirmed four points: treatment increases hemoglobin levels and decreases the need for blood transfusions; no quality-of-life and no survival benefit has been demonstrated; treatment does not seem associated with significantly more side effects; impact on thromboembolic events and patient quality of life remains unclear. The main result of the study was the elaboration of a new standard of care unavailable at the time of the 2003 version. Systematic administration of ESA is not recommended for the prevention or treatment of anemia in pediatric cancer patients. However, treatment decision must be made on a case-by-case basis and, when treatment is considered, the intravenous route must be preferred. The full French document is available at www.sor-cancer.fr.

Topics: Anemia; Animals; Cell Proliferation; Child; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Injections, Intravenous; Neoplasms; Practice Guidelines as Topic; Quality of Life; Receptors, Erythropoietin; Recombinant Proteins; Survival Rate

Darbepoetin alfa is an erythropoiesis-stimulating agent (ESA), with a longer half-life than previous recombinant human erythropoietins. After its initial development for anaemia due to renal insufficiency, an extensive clinical trial program has defined its role in cancer patients.. Review of the initial registration studies, further development and recent progress, guidelines for use in clinical practice (EORTC, ASCO/ASH), and specific focus on recent safety concerns.. Darbepoetin alfa significantly decreases the number of red blood cell transfusions in patients with chemotherapy-induced anaemia, and has been shown to improve health-related quality of life in several studies. The prolonged half-life allows a prolonged dosing interval. Administration every three weeks, a suitable schedule to synchronise with day 1 of many chemotherapy regimens, is as efficient as the initially registered weekly administration. Recent data strongly suggest that the addition of intravenous iron improves haemoglobin response rates. The use of these agents in clinical practice has to be according to the guidelines. Recent safety data reported a negative effect on survival when ESAs were used to treat anaemia that was either not chemotherapy related, or when used to maintain high levels of haemoglobin and prevent anaemia. All of these studies were not in accordance with existing guidelines, while safety data from clinical trials using ESAs according to the guidelines remain reassuring.. Darbepoetin alfa has a well defined place in the treatment of chemotherapy-induced anaemia, and is safe when used in line with existing guidelines. Recent safety signals on cancer outcomes in studies not in accordance with these guidelines illustrate the need for further research into the complex interaction between anaemia and tumour hypoxia in cancer patients.

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Erythropoietin; Humans

There is a high prevalence of anaemia among patients admitted to the intensive care unit (ICU), and it may have a negative effect on patient's outcome. The most common treatment for anaemia in the ICU patient is allogeneic blood transfusion (ABT), yet it has been found to be a risk factor associated with an increased risk of morbidity and mortality in critical care patients. As a reduction of erythropoietin secretion and action is observed in most ICU patients, the administration of (rHuEPO) has emerged as a therapeutic option. Unfortunately, the results from different studies show that rHuEPO treatment results in a small reduction of ABT requirements when "restrictive" transfusion criteria are applied, which has only been supported by three of the studies. Yet this did not result in a decreased mortality rate, except for patients with a diagnosis on admission of trauma in two studies, even though one study reported a dose-dependent increase of thrombotic vascular events among patients without thromboprophylaxis. Altogether, clinical data suggest a role for rHuEPO in the treatment of anaemia in trauma patients, especially in those sustaining neurotrauma, whereas for non-trauma patients without an approved indication, rHuEPO administration is an expensive approach, does not seem to improve outcome, and might result in serious adverse effects. Consequently, more basic and clinical studies are required to ascertain which patients are more likely to benefit from these treatments, as well as to identify the optimal doses and administration schedules, and iron administration.

Topics: Anemia; Critical Illness; Erythropoietin; Humans; Recombinant Proteins

Anemia of chronic kidney disease due to deficiency of erythropoietin is common and has clinical consequences. Erythropoiesis stimulating agents including darbepoetin alfa (DA) are effective in correcting anemia. DA is generally well tolerated and has side effect profile similar to recombinant human erythropoietin. It has a long half-life permitting infrequent dosing. DA has been tested extensively in preclinical and clinical studies and significant experience has accumulated in clinical practice. Global safety profile of DA must consider recent data indicating worse survival, poor cardiovascular outcomes and thrombotic risks of targeting near normal hemoglobin levels and administering high doses of erythropoiesis stimulating agents. Strategies to achieve and maintain a reasonable, individualized target hemoglobin level with minimal variations in hemoglobin level are needed.

Topics: Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Hematinics; Hemoglobins; Humans; Renal Insufficiency, Chronic

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 is one of the world's most common preventable conditions, yet it is often overlooked, especially in people with diabetes mellitus. Diabetes-related chronic hyperglycemia can lead to a hypoxic environment in the renal interstitium, which results in impaired production of erythropoietin by the peritubular fibroblasts and subsequent anemia. Anemia in patients with diabetes mellitus might contribute to the pathogenesis and progression of cardiovascular disease and aggravate diabetic nephropathy and retinopathy. Anemia occurs earlier in patients with diabetic renal disease than in nondiabetic individuals with chronic kidney disease. Although erythropoietin has been used to treat renal anemia for nearly two decades, debate persists over the optimal target hemoglobin level. Most guidelines recommend that hemoglobin levels be maintained between 105g/l and 125g/l. The suggested role of anemia correction--to prevent the progression of left ventricular hypertrophy in patients with diabetes mellitus--is yet to be established. However, an emphasis on regular screening for anemia, alongside that for other diabetes-related complications, might help to delay the progression of vascular complications in these patients.

Topics: Anemia; Diabetes Mellitus; Diabetic Nephropathies; Erythropoietin; Hemoglobins; Humans; Models, Biological

Topics: Anemia; Comorbidity; Darbepoetin alfa; Erythropoietin; Ferric Compounds; Germany; Heart Failure; Hematinics; Humans; Injections, Intravenous; Prevalence; Prognosis

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

Although numerous clinical trials have demonstrated the efficacy and tolerability of erythropoiesis-stimulating agents (ESAs) in patients with chemotherapy-induced anemia (CIA), results of some recent trials and one meta-analysis have suggested that ESAs may negatively impact survival and/or disease control in patients with cancer.. To assess the benefits and risks of ESAs in CIA, we conducted a pooled analysis of individual patient-level data from all randomized, double-blind, placebo-controlled trials in 2,122 patients with CIA receiving darbepoetin alfa (DA; n = 1,200) or placebo (n = 912).. DA did not increase mortality (hazard ratio = 0.97; 95% CI, 0.85 to 1.1) and had no effect on progression-free survival (hazard ratio = 0.93; 95% CI, 0.84 to 1.04) and disease progression (hazard ratio = 0.92; 95% CI, 0.82 to 1.03), but, as expected, increased the risk for thromboembolic events (hazard ratio = 1.57; 95% CI, 1.10 to 2.26). Overall and progression-free survival were not affected by baseline hemoglobin and seemed better in patients who achieved hemoglobin more than 12 or more than 13 g/dL. Transfusions and rates of hemoglobin increase (> 1 g/dL in 14 days; > 2 g/dL in 28 days) owing to transfusions were associated with an increased risk for death and disease progression in both treatment groups; in the absence of transfusions, rates of hemoglobin increase did not appear to increase the risk for adverse outcomes. Compared with placebo, DA significantly reduced the risk of receiving one or more transfusion.. There seemed to be no association between DA and risk of death or disease progression in this meta-analysis of individual patient data from DA studies conducted in CIA, the approved indication for ESAs in oncology.

Topics: Anemia; Antineoplastic Agents; Blood Transfusion, Autologous; Clinical Trials as Topic; Darbepoetin alfa; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Female; Hemoglobins; Humans; Male; Randomized Controlled Trials as Topic; Treatment Outcome

Randomized clinical studies, carried out in patients with haematological malignancies and with solid tumours, have consistently demonstrated that treatment with recombinant human erythropoietin (Epo) increases haemoglobin levels, reduces blood transfusion requirements, and improves the quality of life. In addition, identification of erythropoietin receptor (EpoR) expression on many types of non-erythroid and cancer cells has spurred an interest in the extra-haematological activities of Epo itself and other erythropoiesis-stimulating agents (ESAs). Epo and its derivatives have emerged as major tissue-protective cytokines in ischaemic and degenerative damage of cardiovascular, neurological and renal diseases, while their angiogenetic and immunomodulatory properties indicate that their therapeutic potential may extend well beyond erythropoiesis alone. Both preclinical and clinical data, however, have suggested that they may contribute to tumour progression and prejudice survival when administered to anaemic cancer patients, though the results are equivocal and the assumed mechanisms by which tumour growth could be promoted are not fully understood. While these findings offer new perspectives, they nonetheless demand caution in the employment of ESAs. Further, well-designed experimental and clinical studies are warranted.

Topics: Anemia; Antineoplastic Agents; Blood Physiological Phenomena; Erythropoietin; Hematinics; Humans; Neoplasms; Receptors, Erythropoietin; Recombinant Proteins

Besides stimulating erythropoiesis, erythropoietin (EPO) exerts powerful proangiogenic and antiapoptotic effects. These erythropoiesis-independent effects are potentially useful as a supplement for the treatment of chronic heart failure (CHF). EPO may improve microvascular capacity of ischemic myocardial tissue and could thereby (partially) restore myocardial function. In addition, EPO could protect cardiomyocytes from hypoxic damage and prevent them from apoptosis. However, the clinical value of these erythropoiesis-independent effects for the treatment of CHF remains to be elucidated. Small-sized trials evaluating the effects of EPO treatment on surrogate endpoints in patients with CHF showed positive effects in general; however, their mutual results are not always unambiguous. Moreover, increasing hematocrit levels with EPO has been associated with increased blood viscosity and an inherent risk of thromboembolic events. A currently running multicenter phase III trial is designed to provide clarity concerning the effects of EPO on outcome and safety in patients with CHF. Focusing primarily on outcome, however, does not provide insight into the mode of action and isolated benefits of the erythropoiesis-independent effects of EPO. Further exploration of these effects is a key issue to gain knowledge of the full potential of EPO for the treatment of CHF.

Topics: Anemia; Animals; Apoptosis; Chronic Disease; Erythropoietin; Heart Failure; Humans; Myocardial Reperfusion

Erythropoiesis-stimulating agents reduce anaemia in patients with cancer and could improve their quality of life, but these drugs might increase mortality. We therefore did a meta-analysis of randomised controlled trials in which these drugs plus red blood cell transfusions were compared with transfusion alone for prophylaxis or treatment of anaemia in patients with cancer.. Data for patients treated with epoetin alfa, epoetin beta, or darbepoetin alfa were obtained and analysed by independent statisticians using fixed-effects and random-effects meta-analysis. Analyses were by intention to treat. Primary endpoints were mortality during the active study period and overall survival during the longest available follow-up, irrespective of anticancer treatment, and in patients given chemotherapy. Tests for interactions were used to identify differences in effects of erythropoiesis-stimulating agents on mortality across prespecified subgroups.. Data from a total of 13 933 patients with cancer in 53 trials were analysed. 1530 patients died during the active study period and 4993 overall. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio [cHR] 1.17, 95% CI 1.06-1.30) and worsened overall survival (1.06, 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 for mortality during the active study period, and I(2) 7.1%, p=0.33 for overall survival). 10 441 patients on chemotherapy were enrolled in 38 trials. The cHR for mortality during the active study period was 1.10 (0.98-1.24), and 1.04 (0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients given different anticancer treatments (p for interaction=0.42).. Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival. The increased risk of death associated with treatment with these drugs should be balanced against their benefits.. German Federal Ministry of Education and Research, Medical Faculty of University of Cologne, and Oncosuisse (Switzerland).

Topics: Adolescent; Adult; Aged; Anemia; Antineoplastic Agents; Effect Modifier, Epidemiologic; Erythrocyte Transfusion; Erythropoietin; Female; Hematinics; Humans; Linear Models; Male; Middle Aged; Neoplasms; Proportional Hazards Models; Randomized Controlled Trials as Topic; Recombinant Proteins; Research Design; Survival Rate; Treatment Outcome; Young Adult

Though elderly patients represent a majority of cancer patients, their treatment of is still inadequate, mainly due to the lack of data deriving from randomized clinical trials. Factors limiting the use of standard chemotherapy regimens in elderly cancer patients are the fear of toxicity and unexpected side effects. The assessment of comorbidity and the multidimensional geriatric assessment are of major importance in the decision plan. All supportive measures must be adopted in order to successfully treat vulnerable and unfit elderly patients with cancer, and in particular, the use of growth factors when chemotherapy is given with curative intent; rule out anemia and possible causes of anemia, and correct them whenever possible; choose cytotoxics according to expected adverse events and possible interference with concomitant medications. Particular attention must be paid to treatment of pain in the elderly with cancer. Caregivers must be involved in the treatment plan, and phone contacts with the patient and caregivers are needed to verify physical conditions and compliance to prescriptions.

Topics: Aged; Aging; Anemia; Antineoplastic Agents; Caregivers; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Neoplasms; Pain, Intractable

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

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

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

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

The treatment of cancer-induced anemia with erythropoietin-stimulating agents (ESAs) is reviewed.. Before the introduction of ESAs, the only treatment option for cancer-related anemia was red blood cell (RBC) transfusion. The use of ESAs in multiple disease states has been well established and is now considered first-line treatment for many forms of anemia. Chang et al. evaluated the effect of epoetin alfa (40,000 units administered subcutaneously every week) and standard-of-care therapy on quality of life (QOL), transfusion requirements, and hemoglobin levels in 354 patients with breast cancer who had a baseline hemoglobin concentration of <15 g/dL. The authors concluded that early initiation of treatment with epoetin alfa in patients with breast cancer is effective in maintaining hemoglobin levels, reducing transfusions, and improving QOL. Leyland-Jones et al. conducted a study evaluating the effects of early intervention with epoetin alfa (40,000 units administered subcutaneously every week) on survival and QOL of mainly nonanemic patients with metastatic breast cancer. In contrast to Chang et al., this study was discontinued because of lower overall survival rates within the epoetin alfa group. In 2008, the Food and Drug Administration issued a black-box warning for both epoetin alfa and darbepoetin alfa. The warning acknowledges that ESAs have shortened overall survival and time to disease progression in patients with advanced breast cancer who are given these agents to achieve a target hemoglobin concentration of > or =12 g/dL.. When used in patients with cancer-induced anemia, ESAs should only be given at the lowest dose possible to prevent RBC transfusions. During treatment, hemoglobin levels should be monitored closely and ESA doses need to be adjusted accordingly.

Topics: Anemia; Blood Transfusion; Breast Neoplasms; Darbepoetin alfa; Drug Labeling; Drug Monitoring; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Rate

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

Tumour hypoxia increases tumour invasiveness and has a negative impact on response to therapy. Hypoxic tumours are also associated with severely anaemic individuals. It has therefore been hypothesised that correcting anaemia, by increasing haemoglobin levels using erythropoietin, improves tumour oxygenation and consequently the patient's prognosis.. To assess whether combined treatment with radiotherapy and erythropoietin (RT plus EPO) is better than standard radiotherapy (RT alone) for the treatment of head and neck cancer patients.. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; mRCT and additional sources for published and unpublished trials. The date of the most recent search was 24 February 2009.. Two independent authors assessed identified studies according to the eligibility criteria: RCTs which delivered radiotherapy combined with or without erythropoietin, in patients of any age with head and neck cancer of any stage or type. In addition, trials administering concomitant iron therapy among one or both arms were also eligible.. For statistical analysis of survival data, we computed a weighted estimate of the typical treatment effect across studies. We used Chi(2) heterogeneity tests to test for statistical heterogeneity among trials and performed the statistical analyses using Review Manager 5.0.. Five RCTs with a total of 1397 patients were included. Pooled data yielded a significantly worse overall survival (OS) for RT plus EPO as compared to RT alone (Peto odds ratio 0.73; 95% confidence interval (CI) 0.58 to 0.91; P = 0.005, five trials). For local regional tumour control (LRTC) analyses resulted in a small but non-significant difference between the RT alone group and the RT plus EPO group (RR 0.92; 95% CI 0.81 to 1.03; P = 0.15, four trials). In addition, the local regional progression free survival (LRPFS) measured in four studies was significantly different between groups (Peto odds ratio 0.63; 95% CI 0.49 to 0.80; P = 0.0002, four trials), in favour of the RT alone group. Two studies used supplemental iron in the RT plus EPO group and not in the RT alone group. When excluding these studies from the analyses, the statistically (non-) significant differences in OS, LRTC and LRPFS are maintained.. There are strong suggestions that RT plus EPO has a negative influence on outcome as opposed to RT alone. However, the target haemoglobin concentration, which was higher than recommended in four of the five included RCTs, may have had a significant role. Nevertheless, based on these findings EPO should not be administered as an addition to RT outside the experimental setting for patients with head and neck cancer.

Topics: Anemia; Cell Hypoxia; Chemotherapy, Adjuvant; Darbepoetin alfa; Erythropoietin; Head and Neck Neoplasms; Humans; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Analysis

Erythropoiesis-stimulating agents (ESAs) reduce anemia in cancer patients and may improve quality of life, but there are concerns that ESAs might increase mortality.. Our objectives were to examine the effect of ESAs and identify factors that modify the effects of ESAs on overall survival, progression free survival, thromboembolic and cardiovascular events as well as need for transfusions and other important safety and efficacy outcomes in cancer patients.. We searched the Cochrane Library, Medline, Embase and conference proceedings for eligible trials. Manufacturers of ESAs were contacted to identify additional trials.. We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusions (as necessary) versus red blood cell transfusions (as necessary) alone, to prevent or treat anemia in adult or pediatric cancer patients with or without concurrent antineoplastic therapy.. We performed a meta-analysis of randomized controlled trials comparing epoetin alpha, epoetin beta or darbepoetin alpha plus red blood cell transfusions versus transfusion alone, for prophylaxis or therapy of anemia while or after receiving anti-cancer treatment. Patient-level data were obtained and analyzed by independent statisticians at two academic departments, using fixed-effects and random-effects meta-analysis. Analyses were according to the intention-to-treat principle. Primary endpoints were on study mortality and overall survival during the longest available follow-up, regardless of anticancer treatment, and in patients receiving chemotherapy. Tests for interactions were used to identify differences in effects of ESAs on mortality across pre-specified subgroups. The present review reports only the results for the primary endpoint.. A total of 13933 cancer patients from 53 trials were analyzed, 1530 patients died on-study and 4993 overall. ESAs increased on study mortality (combined hazard ratio [cHR] 1.17; 95% CI 1.06-1.30) and worsened overall survival (cHR 1.06; 95% CI 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 and I(2) 7.1%, p=0.33, respectively). Thirty-eight trials enrolled 10441 patients receiving chemotherapy. The cHR for on study mortality was 1.10 (95% CI 0.98-1.24) and 1.04; 95% CI 0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients receiving different cancer treatments (P for interaction=0.42).. ESA treatment in cancer patients increased on study mortality and worsened overall survival. For patients undergoing chemotherapy the increase was less pronounced, but an adverse effect could not be excluded.

Topics: Adult; Anemia; Child; Darbepoetin alfa; Disease-Free Survival; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Hematinics; Humans; Male; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins

The glycoprotein hormone erythropoietin is an essential viability and frowth factor for the erythrocytic progenitors. EPO signaling involves tyrosine phosphorylation of the homodimeric EPO receptor and subsequent activation on intracellular proteins, kinases and transcription factors. Treatment with recombinant human EPO(rHu EPO) is efficient and safe in improving the management of the anemia associated with chronic kidney disease, and allowing avoidance of transfusions with blood products. however, the unanticipated increase in mortality found in recent randomized studies is prompting a reassessment of this view. The present review will show what is known about the physiology of this plasma factor that, it is now clear, is more than just an erythrocyte production factor, and its pleitropic effects influencing the incidence of malignancy, thrombosis, hypertension and retinopathy.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Hypertension

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

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

Divalent metal transporter 1 (DMT1) is the protein that allows elemental iron entry into the duodenal cell. It is expressed ubiquitously and it also allows the iron exit from the endosomes. This protein plays a central role in iron metabolism and it is strictly regulated. Several animal models elucidate its role in physiology. Recently three patients affected with DMT1 deficiency have been described. This recessively inherited condition appears at birth with severe microcytic anemia. Serum markers could be particularly useful to establish a correct diagnosis: high serum iron, normal total iron-binding capacity (TIBC), increased saturation of transferrin (Tf), slightly elevated ferritin, and increased soluble transferrin receptor (sTfR). Increased free erythrocyte protoporphyrins (FEPs) could address the diagnosis to iron-deficient anemia. All patients appeared to respond to erythropoietin (Epo) administration. Because mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) did not change during Epo treatment, it was concluded that Epo did not improve iron utilization of the erythroblasts but likely reduced the degree or intensity of apoptosis, affecting erythropoiesis. Moreover liver iron overload was present and documented in all of the affected patients. In this review we analyze the role of DMT1 in iron metabolism and the major causes of reduction and their consequences in animal models as well in humans, and we attempt to define the correct treatment for human mutants.

Topics: Anemia; Animals; Biomarkers; Cation Transport Proteins; Disease Models, Animal; Erythropoiesis; Erythropoietin; Genotype; Hematinics; Humans; Iron; Iron Overload; Iron-Binding Proteins; Mutation; Phenotype; Treatment Outcome; Up-Regulation

Too often anemia is considered a rare or unimportant manifestation in inflammatory bowel disease (IBD). However, over the last 10 years a number of studies have been conducted and the most relevant conclusions obtained are: (1) anemia is quite common in IBD; (2) although in many cases anemia parallels the clinical activity of the disease, many patients in remission have anemia, and iron, vitamin B12 and/or folic acid deficiency; (3) anemia, and also iron deficiency without anemia, have important consequences in the clinical status and quality of life of the patient; (4) oral iron can lead to gastrointestinal intolerance and failure of treatment; (5) intravenous iron is an effective and safe way to treat iron deficiency; (6) erythropoietin is needed in a significant number of cases to achieve normal hemoglobin levels. Thus, the clinician caring for IBD patients should have a comprehensive knowledge of anemia, and apply recently published guidelines in clinical practice.

Topics: Anemia; Anemia, Iron-Deficiency; Dietary Supplements; Erythropoietin; Humans; Inflammatory Bowel Diseases; Iron; Iron Deficiencies; Prevalence; Quality of Life; Treatment Outcome

Anemia is the most common complication of inflammatory bowel disease (IBD). Control and inadequate treatment leads to a worse quality of life and increased morbidity and hospitalization. Blood loss, and to a lesser extent, malabsorption of iron are the main causes of iron deficiency in IBD. There is also a variable component of anemia related to chronic inflammation. The anemia of chronic renal failure has been treated for many years with recombinant human erythropoietin (rHuEPO), which significantly improves quality of life and survival. Subsequently, rHuEPO has been used progressively in other conditions that occur with anemia of chronic processes such as cancer, rheumatoid arthritis or IBD, and anemia associated with the treatment of hepatitis C virus. Erythropoietic agents complete the range of available therapeutic options for treatment of anemia associated with IBD, which begins by treating the basis of the inflammatory disease, along with intravenous iron therapy as first choice. In cases of resistance to treatment with iron, combined therapy with erythropoietic agents aims to achieve near-normal levels of hemoglobin/hematocrit (11-12 g/dL). New formulations of intravenous iron (iron carboxymaltose) and the new generation of erythropoietic agents (darbepoetin and continuous erythropoietin receptor activator) will allow better dosing with the same efficacy and safety.

Topics: Anemia; Erythropoiesis; Erythropoietin; Hematinics; Hepatitis C; Humans; Inflammatory Bowel Diseases; Ribavirin

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

Epoetin-beta is used to treat patients with cancer undergoing chemotherapy to alleviate the symptoms of anaemia, reduce the risk of blood transfusions and improve quality of life (QoL).. This meta-analysis of all 12 randomised, controlled studies of epoetin-beta evaluated the impact of therapy at different Hb-initiation levels and to different target Hb levels on overall survival, tumour progression and thromboembolic events (TEE). An analysis of risk factors pre-disposing patients to TEEs under epoetin-beta therapy was also performed. A total of 2297 patients are included in the analysis.. Analyses based on various Hb-initiation levels indicate no detrimental impact on survival (HR 0.99; 95% CI 0.70, 1.40) and a favourable impact on disease progression (HR 0.73; 95% CI 0.57, 0.94) when epoetin-beta was used within its licensed indication (Hb initiation < or = 10 g dl(-1)) or the EORTC recommended level of 11 g dl(-1). An increased risk of TEEs is seen for all Hb-initiation level strata and a detrimental impact on survival is seen when initiating epoetin-beta therapy at Hb levels >11 g dl(-1). We observe no association between high target Hb levels (> or = 13 g dl(-1)) and an increased risk of mortality, disease progression or TEEs with epoetin-beta compared with control.. The results of this analysis indicate that epoetin-beta therapy has no detrimental impact on survival or tumour progression when initiated at Hb levels up to 11 g dl(-1). Furthermore, there is no evidence to suggest that high Hb values achieved during epoetin-beta therapy are associated with an increased mortality, disease progression or TEE rate.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents; Disease Progression; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors; Thromboembolism

Anemia of cancer and chronic inflammatory diseases is a frequent complication affecting quality of life. For cancer patients it represents a particularly bad prognostic. Low level of erythropoietin is considered as one of the causes of anemia in these pathologies. The deficiency in erythropoietin production results from pro-inflammatory cytokines effect. However, few data is available concerning molecular mechanisms involved in cytokine-mediated anemia. Some recent publications have demonstrated the direct effect of pro-inflammatory cytokines on cell differentiation towards erythroid pathway, without erythropoietin defect. This suggested that pro-inflammatory cytokine-mediated signaling pathways affect erythropoietin activity. They could interfere with erythropoietin-mediated signaling pathways, inducing early apoptosis and perturbing the expression and regulation of specific transcription factors involved in the control of erythroid differentiation. In this review we summarize the effect of tumor necrosis factor (TNF)alpha, TNF-related apoptosis-inducing ligand (TRAIL), and interferon (IFN)-gamma on erythropoiesis with a particular interest for molecular feature.

Topics: Anemia; Apoptosis; Cytokines; Erythropoiesis; Erythropoietin; Humans; In Vitro Techniques; Inflammation; Inflammation Mediators; Interferon-gamma; Models, Biological; Neoplasms; Oxidative Stress; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha

Since the isolation and purification of erythropoietin (EPO) in 1977, the essential role of EPO for mature red blood cell production has been well established. The cloning of the EPO gene and production of recombinant human EPO led to the widespread use of EPO in treating patients with anaemia. In addition to stimulating erythropoiesis, EPO has several extrahaematopoietic functions including neuro-, reno- and caridioprotection. EPO receptor (EPOR) expression is also found in endothelial, brain, cardiovascular and other tissues, although at levels considerably lower than that of erythroid progenitor cells. This review discusses the survival and proliferative activity of EPO that extends beyond erythroid progenitor cells. Loss of EpoR expression in mouse models provides evidence for the role of endogenous EPO signalling in nonhaematopoietic tissue during development or for tissue maintenance and/or repair. Determining the extent and distribution of receptor expression provides insights into the potential protective activity of EPO in brain, heart and other nonhaematopoietic tissues. The administration of recombinant EPO reduced brain injury associated with stroke, blunt trauma, and prevented ischaemic injury in the spinal cord. Studies suggest that EPO also protects heart tissues by enhancing angiogenesis, attenuating myocardial ischaemic/reperfusion injury, and attenuating the effects of cytotoxic drugs. EPO protects against ischaemic/reperfusion injury by inhibition of apoptosis and hypoxia, limiting infarct size and preserving myocardium.

Topics: Anemia; Animals; Erythropoietin; Humans; Receptors, Erythropoietin; Recombinant Proteins

Anemia is an important and frequent secondary effect of the treatment with pegylated interferon and ribavirin in patients with chronic viral C hepatitis. Ribavirin produces more often hemolytic anemia, while pegylated interferon may determine medullary suppression. The level of hemoglobin beneath 10 g/dL is considered by most authors as being the reference level for anemia secondary to the antiviral treatment. Beneath this hemoglobin value it is recommended to reduce or to stop the treatment with ribavirin, to administer recombinant human erythropoietin or blood transfusion, based on the severity of the anemia. The growth rate of the serum erythropoietin in the first few weeks of treatment is correlated with the necessity of decreasing the doses or even to stop the treatment with ribavirin. The SVR (sustained viral response) rate of the patients is reduced when the ribavirin doses are reduced due to anemia.

Topics: Anemia; Antiviral Agents; Erythropoietin; Hepatitis C, Chronic; Humans; Interferon-alpha; Recombinant Proteins; Ribavirin

Epoetin beta effectively increases hemoglobin levels, reduces the need for transfusions and improves the quality of life in patients with symptomatic chemotherapy-induced anemia with a range of solid tumors and lymphoid malignancies. Recent evidence-based guidelines recommend the once weekly administration of epoetin beta. This once-weekly regimen is generally well tolerated, and studies to date have reported that epoetin beta has a neutral effect on survival of patients with cancer. The once-weekly administration regimen is convenient for the physician and patient alike. Methods to further optimize this treatment are discussed.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Erythropoietin; Evidence-Based Medicine; Hematinics; Hemoglobins; Humans; Neoplasms; Practice Guidelines as Topic; Quality of Life; Recombinant Proteins; Survival Rate

Epoetin-beta is used to treat patients with metastatic cancer undergoing chemotherapy to alleviate the symptoms of anaemia, reduce the risk of blood transfusions and improve quality of life. This meta-analysis of 12 randomised, controlled studies evaluated the impact of epoetin-beta on overall survival, tumour progression and thromboembolic events (TEEs). A total of 2297 patients were included in the analysis (epoetin-beta, n=1244; control, n=1053; 65% solid and 35% nonmyeloid haematological malignancies). A prespecified subgroup analysis assessed the effects in patients with a baseline Hb

Topics: Adult; Aged; Aged, 80 and over; Anemia; Disease Progression; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Analysis; Thromboembolism

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

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

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

Anaemia is common in patients with heart failure and is associated with poorer prognosis. The aetiology of anaemia in heart failure is diverse and includes renal failure, iron and vitamin deficiency, the use of medication, and insensitivity of the bone marrow to erythropoietin. Recently, small-scale clinical trials investigating the effect of erythropoietin on anaemia showed an improvement in the surrogate cardiovascular endpoints exercise tolerance, haemodynamics and number of hospitalisations. Erythropoietin also has non-haematopoietic (pleiotropic) effects, such as inhibition of apoptosis and neovascularisation. In preclinical studies, erythropoietin had a beneficial effect on heart function following acute myocardial infarction and in heart failure. Currently, these pleiotropic effects are being studied in patients with acute myocardial infarction.

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Heart Failure; Humans; Myocardial Infarction; Myocardial Revascularization; Prognosis

Erythropoietin (EPO) has firstly known to regulate cell proliferation and differentiation along the erythroid lineage. Recent studies have shown that EPO, a pleiotropic cytokine, is proangiogenic and exerts broad tissue-protective effects in diverse nonhematopoietic organs. A series of studies have documented the expression of EPO and EPO receptor (EPO-R) in various cancer cells. The presence of an autocrine-paracrine EPO/EPO-R system may associate with the potential for stimulation of tumor neoangiogenesis and tumor proliferation, inhibition of apoptosis, or modulation of sensitivity to chemoradiotherapy. The complex mechanism needs further research. Recombinant human erythropoietin (rh-EPO) has been widely used in clinic to treat malignancy-associated anemia. Clinical trials have documented the efficacy of rh-EPO in increasing hemoglobin levels, reducing red blood cell (RBC) transfusion requirements and improving quality of life in cancer patients. However, three randomized trials reported negative outcomes with rh-EPO, as patients in the rh-EPO arm fared worse than their placebo-treated counterparts with progression-free survival. This review described EPO and EPO-R biology, focusing on the expression, pleiotropic function and mechanism on nonhematopoietic tissues especially on cancer cells.

Topics: Anemia; Erythropoietin; Humans; Neoplasms; Receptors, Erythropoietin; Recombinant Proteins

The introduction of recombinant human erythropoietin (rHuEpo) nearly 20 years ago has revolutionised the management of patients with CKD, providing the opportunity for safe long-term anaemia correction without the attendant risks identified with blood products. Based on our expanding knowledge in this area, there are many exciting and innovative new approaches to anaemia correction that stand on, or are close to, the threshold of yielding products ready for clinical use. Recently, an Epo-related molecule called continuous Epo receptor activator has been licensed in Europe, and other molecules are in various processes of development, including Epo mimetic peptide. The search goes on for orally active antianaemic therapies, and several strategies are being investigated. Furthermore, it is now clear that in addition to the anaemia-correction properties of erythropoiesis-stimulating agents, there is the potential for cytoprotection by prevention of cellular apoptosis. This effect could be used in the prevention of ischaemia-reperfusion injury as well as other conditions associated with acute kidney injury and other disease processes. The aim of this article is to discuss these possible future strategies, focusing in particular on those with a reasonable likelihood of a pharmaceutical product that is likely to be used clinically.

Topics: Anemia; Erythropoiesis; Erythropoietin; Forecasting; Hematinics; Humans; Recombinant Proteins

Erythopoietin (EPO) treatment of anemia during cancer has dramatically improved the tolerance of chemotherapy and quality of life of patients at all stages of the disease. Several surveys have demonstrated a high prevalence and a high incidence of anemia in lung cancer patients. The guidelines updates concerning EPO treatment for these patients are described. They take into account the debate concerning the potential harm of these molecules on the neoplastic disease and the possible role of EPO receptors expressed by several tumors, including non small cell lung cancer.

Topics: Anemia; Antineoplastic Agents; Disease Progression; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Humans; Lung Neoplasms; Practice Guidelines as Topic; Quality of Life; Recombinant Proteins; Risk Factors

Patients who have cancer, particularly those undergoing chemotherapy, frequently become anemic. Therapy with erythropoiesis-stimulating agents (ESAs) is associated with an increase in hemoglobin levels, a reduction in transfusion requirements, and, according to many clinical trialists and experienced clinicians, an improvement in functional status, productivity, and quality of life. Several randomized trials of ESAs in patients who have cancer have recently reported inferior outcomes in tumor progression or survival, raising appropriate concerns about the safety of ESAs in oncology. However, 3 important caveats to these reports exist. First, these clinical trials did not reflect the common use of ESAs in oncology practice (i.e., to treat, rather than prevent, anemia in patients undergoing chemotherapy). Second, the trials were seriously flawed and did not meet reasonable standards for cancer progression or survival trials. Third, during the same period, randomized trials were presented or published that showed no negative impact on tumor progression or survival; these trials have approximately the same shortcomings as trials that suggest a safety issue exists. The lack of definitive answers about the safety of ESAs for treating chemotherapy-related anemia has placed physicians, regulators, and most importantly patients in a difficult position that can only be addressed with additional data. This article reviews relevant preclinical and clinical available data to help improve understanding and guide decision making.

Topics: Anemia; Antineoplastic Agents; Erythropoietin; Hematinics; Humans; Neoplasms; Recombinant Proteins

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

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

The effectiveness of erythropoiesis-stimulating agents (ESAs) for the treatment of anemia in patients with non-myeloid hematological malignancies needs to be assessed as the response to their administration is not uniform and their cost is high. We conducted a systematic review (SR) of the literature to identify reports of the effect of ESAs on survival, quality of life (QOL), transfusion requirements, and anemia. The entries to MEDLINE, EMBASE, and the Cochrane Library databases, and abstracts published in the proceedings of the annual meetings of the American Society of Clinical Oncology and the American Society of Hematology were searched. Seventeen reports and five abstracts of randomized trials fulfilled prospective criteria for inclusion. Five trials reported on survival; three failed to detect differences between groups and two demonstrated inferior survival in patients allocated to an ESA. Seven trials and three abstracts reported on QOL with four articles and three abstracts describing improvements in patients allocated to erythropoietin. However, important methodologic limitations were identified in these reports. Seven randomized controlled trials reported a reduction in the proportion of patients transfused. The absolute risk reduction in transfusions ranged from 15% to 24%. This is the only SR that assesses the use of erythropoiesis-stimulating agents specifically in patients with hematological malignancies. We conclude that available data evaluating ESAs in patients with hematologic malignancies demonstrate that these agents reduce transfusion requirements. Limitations of these data preclude conclusions that these agents improve QOL. More data are required to confirm the inferior survival associated with ESAs.

Topics: Anemia; Erythropoietin; Hematinics; Humans; Lymphoma; Multiple Myeloma; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Analysis

Anemia is the most frequent hematologic abnormality among cancer patients. Its pathophysiology comprises reduction in erythrocyte half-life, poor iron reutilization by the bone marrow, and inadequate response to erythropoietin (EPO), with reduced endogenous EPO (eEPO) levels. Current treatment implies the use of erythropoiesis- stimulating agents (ESA), to which 35-48% of patients show primary resistance. The search for predictors of response to ESA treatment has been inconclusive. Iron or vitamin deficiency, the recent need for transfusion, or a lack of hemoglobin increase within the first 2-4 weeks usually predict resistance to ESA. High serum eEPO levels at treatment initiation (>100-150 mU/ml) may also predict resistance, especially in hematologic malignancies, but the results in solid tumors are not consistent. Although patients with cancer-related anemia show higher eEPO levels than patients without anemia, there is extreme variability among individuals. Future studies are needed to clarify eEPO usefulness in predicting response to ESA treatment.

Topics: Anemia; Antineoplastic Agents; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematinics; Humans; Neoplasms; Predictive Value of Tests; Recombinant Proteins

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

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

Erythropoiesis-stimulating agents (ESA) improve the hemoglobin level of roughly half the patients receiving chemotherapy for solid tumors or for blood diseases. These figures vary highly between studies. On average, 6 of these patients must be treated with ESA to prevent a transfusion for one patient. The impact of ESA prescription on quality of life is difficult to assess in the studies available today. The medicoeconomic analyses are on the whole unfavorable to the prescription of ESA for chemotherapy-induced anemia. This analysis might change if there were a way to select the patients highly likely to respond to ESA. Concern also exists about the potential negative impact of ESA prescription on patient survival when the objective of the prescription is to normalize hemoglobin. International guidelines must be followed to ensure that under treatment hemoglobin is always less than 12 g/dL.

Topics: Anemia; Erythropoietin; Hematologic Neoplasms; Humans; Neural Tube Defects; Practice Guidelines as Topic

Cancer-related fatigue is an important clinical problem. It is common, distressing, and often difficult to treat. There is a role for drug treatment of cancer-related fatigue, but no consensus has been reached on which drugs are useful. This systematic review and meta-analysis aims to review the available evidence and make recommendations for practice and research.. We searched the Cochrane register of controlled trials (through the second quarter 2007), Medline (January 1, 1966, through August 1, 2007), and EMBASE (January 1, 1980, through August 1, 2007) by use of a predetermined list of search terms. Cochrane Collaboration meta-analysis review methodology was used for this study. The change in fatigue score on the instrument used in each study and other outcomes of interest (adverse events and withdrawal rates) were compared between treatment and control arms by use of the standardized mean difference (SMD) with 95% confidence intervals (CIs). All statistical tests were two-sided.. We identified 27 eligible trials of drug treatments for cancer-related fatigue (with a total of 6746 participants). The overall effect size for all drug classes was small. A meta-analysis of two studies (n = 264 patients) indicated that methylphenidate (a psychostimulant) was superior to placebo (standardized mean difference [SMD] in change in fatigue score = -0.30, 95% confidence interval [CI] = -0.54 to -0.05; P = .02) for treating cancer-related fatigue. A meta-analysis of 10 studies (n = 2226 patients) evaluating erythropoietin in anemic cancer patients who were undergoing chemotherapy indicated that erythropoietin was superior to placebo (SMD = -0.30, 95% CI = -0.46 to -0.29; P = .008). Among anemic patients (four studies with n = 964 patients), improvement in fatigue was associated with darbepoetin treatment compared with placebo treatment (SMD = -0.13, 95% CI = -0.27 to 0.00; P = .05). Progestational steroids and paroxetine were no better than placebo in the treatment of cancer-related fatigue.. There is some evidence that treatment of cancer-related fatigue with methylphenidate appears to be effective. More robust evidence indicates that treatment with hematopoietic agents appears to relieve cancer-related fatigue caused by chemotherapy-induced anemia. Further confirmatory trials are required for both observations.

Topics: Anemia; Antidepressive Agents, Second-Generation; Antineoplastic Agents; Central Nervous System Stimulants; Darbepoetin alfa; Dopamine Uptake Inhibitors; Erythropoietin; Fatigue; Hematinics; Humans; Methylphenidate; Neoplasms; Odds Ratio; Paroxetine; Progestins; Randomized Controlled Trials as Topic; Treatment Outcome

Topics: Anemia; Chronic Disease; Erythropoietin; Humans; Mortality; Oxygen Consumption; Prevalence; Prognosis; Randomized Controlled Trials as Topic; Severity of Illness Index

Many patients with Congestive Heart Failure (CHF) are anaemic. This anaemia is associated with more severe CHF and a higher incidence of mortality, hospitalisation and morbidity. The only way to prove that the anaemia is causing this worsening of CHF is to correct it. We review here some of the published papers about correction of anaemia. Many studies show a positive effect of Erythropoietin (EPO) or its' derivatives when administered in combination with oral or IV iron, with improvements in left and right ventricular systolic and diastolic function, dilation and hypertrophy and renal function. In addition, a reduction in hospitalisations, diuretic dose, pulmonary artery pressure, plasma volume, heart rate, serum Brain Natriuretic Peptide levels, the inflammatory marker Interleukin 6, soluble Fas ligand--a mediator of apoptosis, and improvements in New York Heart Association class, exercise capacity, oxygen utilization, caloric intake, Quality of Life and the activity of Endothelial Progenitor Cells, have been observed. Iron deficiency may also play an important role in this anaemia, since improvements in CHF have also been reported following treatment with IV iron alone. However, until the ongoing large placebo-controlled studies of the EPO derivative darbepoetin or IV iron are completed, we will not know whether these treatments really influence CHF outcome.

Topics: Anemia; Clinical Trials as Topic; Erythropoietin; Heart Failure; Humans; Iron; Practice Guidelines as Topic

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

Anemia with consequent tissue hypoxia is common problem in cancer patients. Developed via various patophysiological mechanisms, it has deleterious effect on quality of life and survival of patients with cancer. Recognition of symptoms and timely initiation of treatment improve patients' quality of life, as well as efficacy of oncological treatment. Red blood cells transfusions are well known and efficient way of anemia correction. They are "golden standard" in treatment of cancer-related anemia today, and are unavoidable in almost all patients with hemoglobin concentration below 80 g/L. Newest therapy guidelines in developed countries, supported by recent literature, encourage use of recombinant human erythropoietin (rHu-EPO), although detailed meta-analyses and prospective randomized clinical trials have shown that rHu-EPO decreases the need for transfusions in only 9-45% patients with cancer, only if they have mild anemia, rHu-EPO increases incidence of thromboembolic events, and suspicion arises that it supports tumor cells growth and multiplication. Therefore, it is necessary to define subgroups of patients which are best candidates for rHu-EPO therapy, to accomplish lower intensity of transfusion therapy.

Topics: Anemia; Animals; Blood Transfusion; Epoetin Alfa; Erythropoietin; Humans; Neoplasms; Quality of Life; Recombinant Proteins

The recognition of the high prevalence and the independent prognostic role of anemia in heart failure (HF) has contributed to intensification of the search for an effective treatment. A central role of erythropoietin in cardiorenal anemia syndrome has been proposed. Several clinical trials have established the safety and efficacy of erythropoiesis-stimulating agents in correcting anemia in patients with HF. The recognition of the pleiotropic effect of erythropoietin has expanded targets of therapy. The ongoing outcomes trial with darbepoetin alfa will determine the role of this novel therapy in the treatment of HF.

Topics: Anemia; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoiesis; Erythropoietin; Female; Heart Failure, Systolic; Hematinics; Hemoglobins; Humans; Iron Compounds; Male; Prognosis; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Assessment; Severity of Illness Index; Treatment Outcome

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

Topics: Anemia; Critical Illness; Epoetin Alfa; Erythropoietin; Humans; Recombinant Proteins; Treatment Outcome

Among the elderly, anemia occurs with increasing frequency with each advancing decade. Unlike when anemia occurs in younger adults, the cause of anemia in the elderly is oftentimes not readily apparent or attributable to a single cause. However, this commonly observed form of anemia in the elderly (termed unexplained anemia [UA]) can generally be dissected to its root causes, which include renal insufficiency, inflammation, testosterone deficiency, and stem cell proliferative decline. Myelodysplasia (MDS) occurs commonly in this age group but can and should, for both diagnostic and therapeutic considerations, be distinguished from UA.

Topics: Adult; Aged; Aging; Androgens; Anemia; Cellular Senescence; Cytokines; Erythropoietin; Hematopoietic Stem Cells; Humans; Inflammation; Recombinant Proteins; Renal Insufficiency

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

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

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

Erythropoiesis-stimulating agents reduce the transfusion requirements of anemic cancer patients receiving chemotherapy. Risks associated with the use of erythropoiesis-stimulating agents in cancer patients have more recently been identified.. Several recently published phase III trials and a meta-analysis have shown an increased risk of venous thromboembolism and a decreased survival in anemic cancer patients treated with erythropoiesis-stimulating agents.. To minimize risks associated with erythropoiesis-stimulating agent use in cancer patients, the most recent American Society of Clinical Oncology/American Society of Hematology clinical practice guidelines and Food and Drug Administration recommendations should be followed.

Topics: Anemia; Antineoplastic Agents; Blood Transfusion; Clinical Trials as Topic; Erythropoietin; Humans; Iron; Neoplasms; Quality of Life; Risk; Signal Transduction; Treatment Outcome; United States; United States Food and Drug Administration; Venous Thromboembolism

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

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

Clinical development of erythropoiesis-stimulating agents (ESAs) revolutionized the management of anemia. The major clinical benefits of ESAs are effective treatment of anemia and avoidance of blood transfusion risks. Erythropoietin (EPO) interacts directly with the EPO receptor on the red blood cell (RBC) surface, triggering activation of several signal transduction pathways, resulting in the proliferation and terminal differentiation of erythroid precursor cells and providing protection from RBC precursor apoptosis. The magnitude of increase in RBC concentration in response to administration of recombinant human EPO products (rhEPO) is primarily controlled by the length of time EPO concentrations are maintained, not by the EPO concentration level. Subcutaneous (SC) EPO administration results in slower absorption than intravenous (IV) administration, leading to lower peak plasma levels and an apparent extended terminal half-life. However, SC administration requires additional needle-sticks and is associated with an increased risk of immunogenicity compared with IV administration. Multiple pathways may play a role in EPO clearance from the body. Epoetin alfa was the first rhEPO produced and approved for pharmaceutical use, followed by several related products and by newer ESAs with the same mechanism but more prolonged action. Darbepoetin alfa is a hyperglycosylated EPO analog with an extended terminal half-life and a greater relative potency compared with rhEPO at extended dosing intervals. PEGylation of EPO (addition of polyethylene glycol) has been used to further extend the terminal half-life. Also, new strategies are under investigation for stimulating erythropoiesis through activation of the EPO receptor.

Topics: Anemia; Animals; Apoptosis; Blood Transfusion; Cell Proliferation; Darbepoetin alfa; Erythrocytes; Erythroid Precursor Cells; Erythropoietin; Half-Life; Hematinics; Humans; Infusions, Intravenous; Injections, Subcutaneous; Receptors, Erythropoietin; Signal Transduction

In addition to more restrictive "transfusion triggers", presently available allogeneic blood conservation strategies in surgery include preoperative increase in red blood cells (RBC) mass, techniques or pharmaceutical agents that reduce blood loss, and perioperative blood salvage. Because of very important risk reduction in allogeneic blood, benefit/risk of preautologous blood donation (PAD) is quite questionable at this moment. Indeed, at this moment in France, we focus to avoid any transfusion (allogeneic and autologous blood). Therefore the most important techniques used are pharmacological: erythropoietin before surgery with a number of injections related to baseline Hb, and tranexamic acid during and after surgery. Cell saving is used only if bleeding is enough important like arthroplasty revisions. All blood conservation techniques carry their own efficiency limits, constraints and risks that, in addition to institutional considerations and individual patient characteristics are determinant to settle a blood conservation strategy. The choice of a technique should take into account (a) the delay before surgery, (b) the anticipated blood loss for the procedure that varies among institutions, (c) the tolerable blood loss without transfusion for the patient, and (d) the efficacy of the blood conservation technique in the given setting. Nevertheless, at this moment in France, it is quite important to notice that the risk of delay or lack of transfusion induces much more deaths that the transfusion itself during or after anesthesia [Anesthesiology 105, 1087-97].

Topics: Anemia; Aprotinin; Blood Loss, Surgical; Blood Transfusion; Blood Transfusion, Autologous; Drug Administration Schedule; Erythropoietin; Ferric Compounds; Ferric Oxide, Saccharated; Ferritins; Glucaric Acid; Hematinics; Hemodilution; Humans; Intraoperative Complications; Orthopedic Procedures; Postoperative Hemorrhage; Preoperative Care; Recombinant Proteins; Sucrose; Time Factors; Tranexamic Acid; Transfusion Reaction

Anaemia is the most common haematological abnormality in cancer patients, and unfortunately, it is often under-recognised and undertreated. The aetiopathology of anaemia in cancer patients is complex and is usually multifactorial. There is enough evidence suggesting that tumour hypoxia in anaemic patients has a negative impact on the treatment outcomes in cancer patients. The use of recombinant human erythropoietin is becoming a new standard of care in cancer patients. Various well-controlled studies have shown that the use of erythropoietin (EPO) increases the haemoglobin level, thereby decreasing the need for frequent transfusions and improving the tumour responses, cancer-free survival and quality-of-life parameters in cancer patients. However, a few recent clinical trials failed to replicate the survival benefit. Hence, a free unrestricted use of EPO is to be avoided. The past belief that anaemia does not matter in cancer patients is now considered invalid and is being seriously challenged. This article aims to present some recent findings on the impact of anaemia on outcomes, with discussion on the possible causes and effects. The benefits of the use of EPO analogues in cancer-related anaemia are also presented.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Disease-Free Survival; Erythropoietin; Hemoglobins; Humans; Hypoxia; Neoplasms; Quality of Life; Recombinant Proteins; Treatment Outcome

Topics: Anemia; Cardiovascular Diseases; Erythropoietin; Evidence-Based Medicine; Hemoglobins; Humans; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Treatment Outcome

Topics: Anemia; Cardiovascular Diseases; Communicable Diseases; Erythropoietin; Evidence-Based Medicine; Hematocrit; Hemoglobinometry; Hemoglobins; Hospitalization; Humans; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Renal Insufficiency; Risk Factors; Treatment Outcome

Topics: Anemia; Darbepoetin alfa; Erythropoiesis; Erythropoietin; Extracellular Signal-Regulated MAP Kinases; GATA2 Transcription Factor; Hematinics; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Oxygen; Phosphorylation; Phosphotransferases; Polyethylene Glycols; Receptors, Erythropoietin; Recombinant Proteins

Erythropoietin (EPO), a glycoprotein, plays an important role in erythropoiesis and neuroprotection. EPO therapies for anemia or neurodegenerative diseases require frequent injections or high-dose systemic administration which may cause unwanted side effects. Various strategies for EPO delivery have been investigated for increasing EPO bioavailability and decreasing side effects, including nano/micro particles, PEGylation of EPO and transport-mediated delivery systems. Nano/micro particles provide EPO with long-term effect and protect EPO against proteolytic cleavage. PEGylated EPO prolong circulating time and reduce injection frequency of anemia treatment. A transport-mediated delivery system enables protein to cross biological barriers. Presently, there is no report about an effective delivery system of EPO for neuroprotection. This review focuses on EPO delivery systems for erythropoiesis or neuroprotection with prolonged duration and enhanced bioavailability.

Topics: Anemia; Animals; Delayed-Action Preparations; Drug Compounding; Drug Delivery Systems; Erythropoiesis; Erythropoietin; Hematinics; Humans; Neurodegenerative Diseases; Neuroprotective Agents; Recombinant Proteins

Erythropoietin is a hormone produced by the kidney, which regulates proliferation, differentiation and maturation of red cells. Recombinant human EPO (rH-EPO) is well known to correct anaemia in patients with chronic renal failure in terminal stage. However, recent studies showed the existence of several not haematopoietic effects of erythropoietin. EPO receptors have been found to be expressed in several tissues, included the cardiovascular system. An increase in cardiac systolic function has been observed in patients with chronic heart failure treated with EPO. Other beneficial effects appear to be related to the pro-angiogenic properties on endothelial cells and could be useful for treatment of ischemic heart disease. These findings suggest that EPO could provide potential therapeutic benefits in the management of cardiovascular diseases beyond anaemia correction. This review focuses its attention on the pleiotropic effects of EPO and its future promising applications in cardiovascular pathology.

Topics: Anemia; Apoptosis; Cardiovascular Diseases; Endothelium, Vascular; Erythropoietin; Heart Failure; Humans; Myocardial Ischemia; Receptors, Erythropoietin; Recombinant Proteins

Topics: Anemia; Erythropoietin; Global Health; Heart Failure; Hematinics; Humans; Prevalence; Prognosis; Recombinant Proteins

Anemia is a common feature of chronic kidney disease, but the management of anemia in children is complex. Erythropoietin and supplemental iron are used to maintain hemoglobin levels. The National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) clinical practice guidelines for the management of anemia specifically in children were recently published. Pediatric nephrologists are encouraged to use current clinical practice guidelines and best evidence in conjunction with their clinical experience to optimally manage patients with anemia.

Topics: Adolescent; Anemia; Child; Child, Preschool; Dietary Supplements; Erythropoietin; Female; Hemoglobins; Humans; Infant; Iron Compounds; Male; Practice Guidelines as Topic; Recombinant Proteins; Renal Insufficiency, Chronic

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

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

To update the American Society of Clinical Oncology/American Society of Hematology (ASCO/ASH) recommendations for the use of epoetin. The guideline was expanded to address use of darbepoetin and thromboembolic risk associated with these agents.. An Update Committee ("Committee") reviewed and analyzed data published since 2002 through July 2007. MEDLINE and the Cochrane Collaboration Library databases were searched.. For patients with chemotherapy-associated anemia, the Committee continues to recommend initiating an erythropoiesis-stimulating agent (ESA) as hemoglobin (Hb) approaches, or falls below, 10 g/dL, to increase Hb and decrease transfusions. ESA treatment continues to be recommended for patients with low-risk myelodysplasia for similar reasons. There is no evidence showing increased survival as a result of ESA treatment. Conclusive evidence is lacking that, absent clinical circumstances necessitating earlier treatment, initiating ESAs at Hb levels greater than 10 g/dL either spares more patients from transfusion or substantially improves their quality of life. Starting doses and dose modifications based on response or lack thereof should follow the package insert. Continuing ESAs beyond 6 to 8 weeks in the absence of response, assuming appropriate dose increase has been attempted in nonresponders as per US Food and Drug Administration-approved label, does not seem to be beneficial, and ESA therapy should be discontinued. The Committee recommends monitoring iron stores and supplementing iron intake for ESA-treated patients. ESAs should be used cautiously with chemotherapy, or in clinical states, associated with elevated risk for thromo-embolic complications. The Committee also cautions against ESA use for patients with cancer who are not receiving chemotherapy, since recent trials report increased thromboembolic risks and decreased survival under these circumstances.

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Hematology; Humans; Medical Oncology; Neoplasms; Recombinant Proteins; Societies, Medical

The purpose of this paper is to provide an overview of the current therapeutic options afforded to anemic chronic kidney disease (CKD) patients and the costs of these interventions.. Literature search of articles within Ovid MEDLINE between 1996 and 2007 that pertained to the treatment of anemia in chronic kidney disease patients.. Early detection and treatment of anemia associated with CKD has proven to provide positive cognitive and physical effects. Treatment options that increase iron storage and availability within the body and production of erythropoietin can assist in anemic CKD patients in achieving recommended levels of hemoglobin. Acknowledgement of the potential side effects associated with the medications selected to treat anemia can help in avoiding additional injury to the patient and thus reduce healthcare expenditure. A limitation of this review is that the search was performed within a single database.. Health care providers can play an active role in detecting anemia early and optimizing available treatment options. Future research on the effects of erythropoiesis-stimulating agents (ESA) on patients before they need dialysis, and a cost analysis between epoetin and darbepoetin alpha, would be beneficial.

Topics: Anemia; Darbepoetin alfa; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Health Care Costs; Hematinics; Humans; Iron; Practice Guidelines as Topic; Recombinant Proteins; Renal Insufficiency, Chronic

Topics: Anemia; Biological Products; Epoetin Alfa; Erythropoietin; European Union; Hematinics; Humans; Recombinant Proteins; Therapeutic Equivalency

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

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

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

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

The mortality rate in diabetics with chronic kidney disease (CKD) is seven times higher than end-stage renal disease mainly because of cardiac causes. Anaemia may have a relevant role in the pathogenesis of cardiovascular (CV) disease in CKD. Anaemia occurs at an earlier stage of CKD in diabetic individuals than in those with other causes of CKD. Observational findings support the unfavourable influence of anaemia on mortality in CKD patients, and the combination of anaemia and CKD in diabetics identifies a group with a particularly high mortality risk. While the effect of erythropoietin on these patients' quality of life is known, its impact on mortality and CV risk is uncertain. The recent Anaemia Correction in Diabetes (ACORD) trial in diabetic CKD patients, which targeted haemoglobin levels of 13-15 mg/dl, disclosed no statistically significant favourable or adverse effects on mortality or morbidity over the 2-year follow-up, while other studies endeavouring to nearly normalize haemoglobin have reportedly proved risky. Even if anaemia is causally involved, the pathogenesis of CV disease in diabetics with CKD is so complex that addressing just one factor (anaemia) may not suffice to prevent CV risk, and normalizing haemoglobin levels may even be harmful.

Topics: Anemia; Cardiovascular Diseases; Diabetic Nephropathies; Erythropoietin; Humans; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Risk

Anemia is common in patients who have both heart failure and chronic kidney disease, and there is an association between anemia and progression of both diseases. The main causes of anemia are deficient production of erythropoietin (EPO), iron deficiency, and chronic disease with endogenous EPO resistance. EPO has been successfully used for over a decade to treat anemia in patients with chronic kidney disease. Less obvious are the safety and efficacy of EPO treatment in patients with both heart failure and renal disease. Up to 10% of patients receiving EPO are hyporesponsive to therapy and require large doses of the agent. Several mechanisms could explain resistance to endogenous and exogenous EPO. Proinflammatory cytokines antagonize the action of EPO by exerting an inhibitory effect on erythroid progenitor cells and by disrupting iron metabolism (a process in which hepcidin has a central role). EPO resistance might also be caused by inflammation, which has a negative effect on EPO receptors. Furthermore, neocytolysis could have a role. As resistance to exogenous EPO is associated with an increased risk of death, it is important to understand how cardiorenal failure affects EPO production and function.

Topics: Anemia; Drug Resistance; Erythropoietin; Heart Failure; Humans; Renal Insufficiency

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

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

Supportive care constitutes the basis of the management of patients with myelodysplastic syndromes (MDS). Appropriate treatment of cytopenia, as well as of other related complications, not only improves quality of life but also may positively affect the overall survival of patients. Anemia is the most common cytopenia in MDS, and the requirement for regular transfusions is a major clinical problem for patients with low-risk MDS. An important therapeutic goal in this patient group is to maintain acceptable hemoglobin levels without transfusions. Today, this goal can be achieved by treatment with erythropoietin (Epo) +/- granulocyte colony-stimulating factor (G-CSF), or by more targeted treatment such as antithymocyte globulin or lenalidomide in around 50% of patients. For the remaining patients, and for those who lose their therapeutic response, chronic transfusion therapy, with or without the addition of chelating agents, is the only option and it is important that this treatment is scheduled to meet the needs of the individual patient. Severe thrombocytopenia has recently been reported to respond to thrombopoietic agents, such as AMG 531.

Topics: Anemia; Colony-Stimulating Factors; Erythrocyte Transfusion; Erythropoietin; Hematopoiesis; Humans; Myelodysplastic Syndromes; Neutropenia; Prognosis; Recombinant Proteins; Thrombocytopenia

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

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

Erythropoiesis-stimulating agents (ESAs) are genetically engineered forms of erythropoietin that are used in the treatment of anaemia. Their successful use in the treatment of anaemia associated with renal disease, cancer and other diseases, as well as the development of multiple agents, has increased the visibility of these agents in the clinical and health economics literature. The circumstances under which the use of ESAs is cost effective, or indeed, whether it is cost effective, is of central concern for clinicians and payers who must make informed decisions regarding the management of these costly resources. Much of the recent literature on ESAs in the treatment of anaemia associated with chronic kidney disease and cancer, the two major therapeutic areas for ESA treatment, has focused on comparisons between individual ESAs, particularly epoetin alfa and darbepoetin alfa. While there have been some studies of cost effectiveness, many studies in these treatment areas have employed a cost-minimization approach and have relied on published prices rather than actual market prices. In general, this review of the literature suggests a cost advantage for epoetin alfa relative to darbepoetin alfa in the treatment of anaemia in renal and oncology indications. For other indications in which the literature is less developed, such as anaemia induced by antiviral therapy and blood management in surgery, small prospective studies or decision-analytic models comparing ESA therapy and standard care have been most common. Few conclusions can be drawn about the overall and relative costs or cost effectiveness of ESAs in these treatment areas. With the recent concerns about the safety of ESAs, especially when used outside the approved product labelling, future evaluations of epoetin alfa and darbepoetin alfa should factor their safety profiles into estimates of cost effectiveness. Moreover, additional studies are needed to evaluate whether the treatment of anaemia with ESAs is cost effective compared with no treatment or minimal blood transfusions, and whether the cost effectiveness of ESAs would be improved if ESA doses and durations were reduced. With the introduction of new longer-acting ESAs, such as the continuous erythropoietin receptor activator, the relative cost effectiveness among the different ESAs will continue to be an important question for public and private payers, policy makers and clinicians who must consider the emergence of new data and changing dos

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Humans; Recombinant Proteins

Anemia is increasingly recognized as a common, important and treatable condition in patients with congestive heart failure. Despite increasing knowledge of anemia, as well as its co-association with chronic renal disease, advanced New York Heart Association class and worse prognosis, there are very few evidence-based recommendations for treatment. The use of supplemental iron, especially intravenous forms, for the treatment of iron-deficiency anemia in heart failure patients is associated with improved symptoms, cardiac size and function, and possibly improved outcomes. However, many patients with heart failure suffer from anemia due to other causes, including renal failure (so-called cardiorenal syndrome), erythropoietin resistance, possible ACE inhibitor use and extracellular fluid expansion. The association between anemia and adequate iron stores has led to interest in the use of erythrocyte-stimulating agents, such as erythropoietin and darbepoetin. While early data are promising, recent evidence in non-heart failure trials has led to caution in their use and given way to anticipation of results of ongoing definitive randomized trials of this therapy, such as the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) and Reduction of Events with Darbepoetin-alpha in Heart Failure (RED-HF) studies.

Topics: Anemia; Cardiology; Darbepoetin alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Ventricular Dysfunction, Left

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

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

Anemia is common in patients with chronic heart failure, and is related to increased morbidity and mortality. The etiology of anemia in heart failure is complex and still not fully resolved. The review will describe current advances in the understanding of the pathophysiology of anemia and the potential therapeutic effects of recombinant human erythropoietin.. Recent attempts to resolve the preponderant etiology of anemia in chronic heart failure have further defined its multifactorial nature. Impaired renal perfusion and function resulting in blunted erythropoietin production as well as impaired erythropoiesis in the bone marrow account for a vulnerable erythropoietic system. Moreover, fluid retention causes hemodilutional anemia. Correction of anemia with recombinant human erythropoietin seems feasible and is currently being evaluated in a phase 3 clinical trial. In addition, recombinant human erythropoietin improves cardiac function in chronic heart failure through the recruitment of endothelial progenitor cells and exerts cytoprotective effects during acute myocardial infarction. Although recombinant human erythropoietin shows great promise, we should not neglect other treatable causes of anemia.. Although the etiology of anemia in chronic heart failure is clearly multifactorial, correction of anemia with recombinant human erythropoietin seems promising. In addition to correction of anemia, recombinant human erythropoietin might exert important protective and regenerative effects on the myocardium.

Topics: Anemia; Chronic Disease; Erythropoietin; Heart Failure; Humans; Recombinant Proteins

Anemia in children with cancer is not an uncommon complication and is usually multifactorial in etiology. In numerous trials in adult cancer patients, treatment with recombinant erythropoietin has been shown to increase hemoglobin levels, reduce red blood cell transfusion requirements, and improve quality of life. Much less has been published of its use in the prevention or treatment of cancer-associated anemia (CAA) in children, in whom chemotherapy is usually more intensive and likely to result in greater myelosuppression. This review critically evaluates the published evidence of its use in childhood cancer especially; its safety and efficacy in the prevention and treatment of CAA and some indications for its use in childhood cancer are suggested.

Topics: Age Factors; Anemia; Child; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Neoplasms; Recombinant Proteins

The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin are licensed to treat chemotherapy-associated anemia in patients with nonmyeloid malignancies. Although systematic overviews of trials have identified venous thromboembolism (VTE) risks, none have identified mortality risks with ESAs.. To evaluate VTE and mortality rates associated with ESA administration for the treatment of anemia among patients with cancer.. A published overview from the Cochrane Collaboration (search dates: January 1, 1985-April 1, 2005) and MEDLINE and EMBASE databases (key words: clinical trial, erythropoietin, darbepoetin, and oncology), the public Web site of the US Food and Drug Administration and ESA manufacturers, and safety advisories (search dates: April 1, 2005-January 17, 2008).. Phase 3 trials comparing ESAs with placebo or standard of care for the treatment of anemia among patients with cancer.. Mortality rates, VTE rates, and 95% confidence intervals (CIs) were extracted by 3 reviewers from 51 clinical trials with 13 611 patients that included survival information and 38 clinical trials with 8172 patients that included information on VTE.. Patients with cancer who received ESAs had increased VTE risks (334 VTE events among 4610 patients treated with ESA vs 173 VTE events among 3562 control patients; 7.5% vs 4.9%; relative risk, 1.57; 95% CI, 1.31-1.87) and increased mortality risks (hazard ratio, 1.10; 95% CI, 1.01-1.20).. Erythropoiesis-stimulating agent administration to patients with cancer is associated with increased risks of VTE and mortality. Our findings, in conjunction with basic science studies on erythropoietin and erythropoietin receptors in solid cancers, raise concern about the safety of ESA administration to patients with cancer.

Topics: Anemia; Clinical Trials, Phase III as Topic; Darbepoetin alfa; Erythropoietin; Hematinics; Humans; Neoplasms; Recombinant Proteins; Risk; Survival Rate; Venous Thromboembolism

Evidence regarding the cost-effective use of and benefits associated with epoetin alfa in treating anemia of critically ill patients is assessed.. Anemia of critical illness is a leading cause of inadequate oxygen delivery that affects almost all patients in the intensive care unit setting after day 3. Red blood cell transfusions are commonly used to correct anemia of critical illness, but they are also associated with risks including hemolytic reactions and viral transmission. The latest evidence suggests that when a strict transfusion protocol is implemented, epoetin alfa does not decrease the transfusion requirements of critically ill patients. In the absence of a strict transfusion protocol, an average of 5.1 doses of epoetin, at a cost of $2154, is required to avoid one transfusion. Evidence is accumulating that epoetin may reduce mortality rates in trauma patients. However, important questions remain regarding the magnitude and mechanism of the potential benefit and if the benefit outweighs the risk of thromboembolism. Therefore, the reduction in transfusion-related adverse events is the only clinical outcome benefit that is well-supported by current evidence. However, the known risk of transfusion-related adverse events is low; approximately 29,000 patients would need to be treated to avoid a serious transfusion-related event. Treating these patients would cost over $25 million, and it would take over 100 years to prevent one serious event in a unit admitting 20 epoetin-eligible patients per month.. Published data suggest a prohibitive cost associated with epoetin alfa use in critically ill patients given that the only well-supported clinical benefit of this treatment is the avoidance of transfusion-related adverse events. Continued research is necessary to clarify if there is a net clinical benefit of epoetin use (especially in trauma patients) and to develop optimal blood management strategies.

Topics: Anemia; Cost-Benefit Analysis; Critical Care; Critical Illness; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Hematinics; Humans; Intensive Care Units; Oxygen; Randomized Controlled Trials as Topic; Recombinant Proteins; Thromboembolism

Topics: Anemia; Cell Differentiation; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Transcription, Genetic

Anemia of chronic disease (ACD) is a mild to moderate anemia seen with many infections and inflammatory disorders. These patients have low serum iron, but high serum ferritin levels. As for the pathogenesis of ACD, previous studies have reported several abnormalities, such as insufficient EPO production, impaired growth response of erythroid progenitors to EPO, and shortened survival of erythrocytes, due to the inflammatory cytokines. However, recent analyses have clearly shown that hepcidin, of which expression is induced by inflammatory cytokines such as IL-1beta and IL-6, suppresses the expression of the iron transporter, ferroportin-1, thereby inhibiting the absorption of iron from the duodenum, the release of iron from the reticulo-endothelial system. So, the abnormal expression of hepcidin alone may be able to explain the unique iron metabolism in ACD.

Topics: Anemia; Antimicrobial Cationic Peptides; Cation Transport Proteins; Chronic Disease; Cytokines; Duodenum; Erythroid Precursor Cells; Erythropoietin; Ferritins; Hepcidins; Humans; Infections; Inflammation; Inflammation Mediators; Intestinal Absorption; Iron; Iron Deficiencies

For cancer treatment-related anemia, it is recommended to use erythropoietin or darbepoetin alpha by the National Comprehensive Cancer Network (NCCN). The guideline proposed the risk assessment for anemia, as well. The introduction of erythropoietin or darbepoetin alpha for anemia in treated cancer patients is based on the improvement of quality of life. For patients with myelodysplastic syndrome (MDS), those with 5q- anomaly is recommended to use lenalidomide and low-risk MDS patients without 5q- and serum erythropoietin of less than 500 mU/ml are recommended to treat with erythropoietin or darbepoetin alpha. These new agents are currently under clinical trials in Japan.

Topics: Anemia; Benzoates; Clinical Trials as Topic; Darbepoetin alfa; Deferasirox; Erythropoietin; Hematinics; Humans; Iron Chelating Agents; Iron Overload; Lenalidomide; Myelodysplastic Syndromes; Neoplasms; Thalidomide; Triazoles

Anemia is common in patients with cancer. The incidence and severity of anemia depend on the type and extent of the malignancy. Anemia may be the result of the malignancy itself, cancer treatment, blood losses, hemolysis or inflammatory cytokines associated with chronic disease. Anemia can have a profound impact on physical and psychosocial function and quality of life. However, in Japan, only iron supplementation and blood transfusion were available for the treatment of anemia with cancer. On the other hand, in Europe and America, erythropoietic agents such as erythropoietin and novel erythropoiesis stimulating protein (NESP) have been clinically used for anemia in patients with cancer.

Topics: Anemia; Antineoplastic Agents; Erythropoietin; Hematinics; Hemolysis; Hemorrhage; Humans; Iron Metabolism Disorders; Neoplasms; Prognosis; Recombinant Proteins

Several studies with erythropoiesis-stimulating agents (ESAs) have raised a number of safety issues. Therefore, a discussion of available data in light of the current EORTC guidelines 2006 on the use of ESAs in anemic patients is warranted.. Literature is reviewed with respect to experimental and clinical data on the effect of ESA therapy on tumor growth both in the preclinical setting and on patient survival.. Studies showing an adverse effect of ESA therapy on patient survival generally exhibit considerable methodological deficiencies. Moreover, they investigated treatment situations for which ESAs are not approved and/or did not involve recommended baseline ("intervention") or target hemoglobin levels.. When used as indicated, ESAs are valuable and safe drugs for the treatment of anemia and do not negatively affect patient survival. In particular, the data situation confirms the importance and correctness of the EORTC guidelines 2006 and their recently updated version. It is therefore recommended that these guidelines continue to be strictly followed in the treatment of chemotherapy-induced anemia.

Topics: Adult; Anemia; Animals; Antineoplastic Agents; Blood Transfusion; Clinical Trials as Topic; Clinical Trials, Phase II as Topic; Disease Models, Animal; Disease Progression; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Meta-Analysis as Topic; Mice; Neoplasms; Neoplasms, Experimental; Oxygen; Practice Guidelines as Topic; Prospective Studies; Randomized Controlled Trials as Topic; Rats; Receptors, Erythropoietin; Recombinant Proteins; Risk Factors; Safety; Tumor Cells, Cultured

To discuss the clinical issues we addressed in the development of our institutional guidelines regarding the assessment of iron stores for cancer- and treatment-related anemia and the administration of parenteral iron with erythropoiesis-stimulating agents (ESAs).. Studies published from January 1995 to August 2007 were identified by computer searches of Medline and hand searching of bibliographies of the articles identified via the computer searches. The current clinical practice guidelines were identified by computer searches of the web sites for national professional organizations that represent health care professionals who treat patients with cancer.. of data analysis. Hematopoietic responses demonstrate that epoetin alfa and darbepoetin alfa provide similar outcomes for patients with chemotherapy-induced anemia (CIA); however, up to 50% of patients receiving these agents fail to adequately respond. Functional iron deficiency defined as a state of iron-restricted erythropoiesis is likely the primary contributor to the lack of response. Hematopoietic responses following ESA therapy with parenteral iron are substantially higher compared to response with no or oral iron.. Iron stores should be assessed in all patients with cancer- or treatment-related anemia and parenteral iron should be administered to patients receiving ESA therapy to improve hematopoietic response. A unique algorithm that summarizes our institutional guidelines to assess iron stores and administer parenteral iron with ESA therapy in patients with CIA is included.

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Drug Therapy, Combination; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematinics; Humans; Injections, Intravenous; Iron Compounds; Practice Guidelines as Topic; Recombinant Proteins

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

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

The present meta-analysis was undertaken to (1) assess erythroid response rates in myelodysplastic syndromes (MDS) patients treated with epoetin alfa as a monotherapy, (2) gain further insights into predictors of response rates, and (3) compare the erythroid response rates observed with epoetin alfa and darbepoetin alfa. A systematic review of studies from 1990 to 2006 in MDS patients treated with epoetin alfa or darbepoetin alfa was performed and yielded 30 studies evaluating a total of 1,314 patients (epoetin alfa: 22 studies, 925 patients; darbepoetin alfa: eight studies, 389 patients). Pooled estimates of erythroid response rates, stratified by the International Working Group criteria (IWGc) and treatment group, were calculated using random-effects meta-analysis methods. Univariate meta-regression analyses were further conducted to identify study characteristics associated with erythroid response rate. The pooled estimate of erythroid response rate was significantly higher for epoetin alfa IWGc studies (57.6%) as compared to non-IWGc studies (31.6%; p < 0.001). Study factors predictive of higher response rate in the epoetin alfa IWGc studies included higher proportion of patients with RA/RARS (p < 0.001), lower mean baseline serum erythropoietin level (p = 0.007), and fixed dosing regimen (p < 0.001). There was no significant difference in the pooled erythroid response rates between the two agents (epoetin alfa: 57.6% vs. darbepoetin alfa: 59.4%; p = 0.828). The current study reported significantly higher erythroid response rates predominantly in the more recent studies that primarily utilized IWGc to define response. With the use of standardized patient selection and response evaluation methods, epoetin alfa and darbepoetin alfa yielded comparable erythroid response rates in MDS patients.

Topics: Aged; Anemia; Anemia, Refractory; Anemia, Sideroblastic; Blood Transfusion; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Evaluation; Epoetin Alfa; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Male; Myelodysplastic Syndromes; Recombinant Proteins; Treatment Outcome

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

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

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

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

An association between anaemia, poor functional status and, compared to non-anaemic patients, worse clinical status and a higher risk of hospitalisation and death has been consistently reported in chronic heart failure (CHF), although cause an effect has not been proven. While it is attractive to think that correction of a co-morbidity that exacerbates already diminished delivery of oxygen to the tissues in heart failure is likely to beneficial, the possible haemodynamic effects of increasing haemoglobin, for example vasoconstriction, might not be. Consequently, the balance of benefit and risk of anaemia correction in CHF is uncertain, may vary according to the severity of anaemia (and other factors) and needs to be properly evaluated. To date, most studies of anaemia correction in CHF have used erythropoiesis stimulating agents (ESAs). The trials with erythropoietin have been of small size, uncontrolled or unblended/single blind, raising concerns again about interpretation of subjective outcomes. In addition, the analyses of these trials have been suboptimal. Two double-blind, placebo-controlled, darbepoetin studies have been published in full. Neither showed an improvement in functional capacity or consistent effect on patient reported symptoms/quality of life. Darbepoetin is, however, currently being tested in a large-scale, phase III morbidity and mortality trial, the Reduction of Events with Darbepoetin alfa in Heart Failure (RED-HF) which should contribute important information of the safety and efficacy of ESAs in this syndrome. Other approaches, notably parenteral iron supplementation, are also being evaluated and other agents for anaemia correction are under development.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Heart Failure; Hematinics; Humans; Iron; Iron Deficiencies

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

Recombinant human erythropoietin (rHuEPO) has become the standard therapy for treatment of the anaemia of chronic kidney disease (CKD) during the past two decades. In addition, rHuEPO can be indicated for the treatment of cancer patients on chemotherapy and surgical patients to avoid allogeneic red blood cell transfusion. This review first describes recent attempts in developing rHuEPO congeners (mutated and pegylated rHuEPOs) and mimetics with prolonged half-lives and improved application requirements. Secondly, the pathophysiological background of the regulatory guideline, that blood haemoglobin levels in anaemic CKD or cancer patients on chemotherapy should not be raised above the target value of 120 g/l, is discussed. Finally, potential novel indications are considered for the use of rHuEPO and its analogues as pleiotropic cytoprotectant agents for cardio-, nephro-, hepato- and neuroprotection.

Topics: Anemia; Erythropoiesis; Erythropoietin; Hematinics; Hematocrit; Hemoglobins; Humans; 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

Certain studies in which erythropoiesis-stimulating agents (ESAs) have been given not with the aim of correcting anemia but to achieve higher target levels of hemoglobin have shown significantly poorer survival among treated patients. However, studies in which ESAs were administered with the aim of reducing the need for RBC transfusions in patients with chemotherapy-associated anemia demonstrate that the use of these agents is not associated with any adverse effect on survival when compared with placebo controls. We can therefore be reassured that using ESAs within the labeled indications will not adversely affect patient outcome.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Drug Approval; Erythropoietin; Hematinics; Hemoglobins; Humans; Meta-Analysis as Topic; Neoplasms; Recombinant Proteins

Venous thromboembolic events (VTEs) are frequent in cancer patients because of the effects of malignant disease, its treatment, and comorbidities. The higher risk for VTEs associated with the use of erythropoiesis-stimulating agents (ESAs) appears to be a class effect but may be particularly pronounced when these agents are used in patients who are not anemic at baseline and/or to achieve hemoglobin targets higher than those recommended in current labeling. Particular attention should be taken to assess the balance of risks and benefits in patients with a history of thromboembolism. If the goal of treatment of patients with chemotherapy-associated anemia is aimed to raise the hemoglobin level to 12 g/dl, and is confined to that, ESA-induced VTEs should rarely be a problem.

Topics: Anemia; Antineoplastic Agents; Drug Labeling; Erythropoietin; Hematinics; Hemoglobins; Humans; Neoplasms; Recombinant Proteins; Thromboembolism

Tumor hypoxia, mostly resulting from poor perfusion and anemia, is one of the key factors in inducing the development of cell clones with an aggressive and treatment-resistant phenotype that leads to rapid progression and poor prognosis. Studies in patients with solid tumors suggest that there is a range of hemoglobin (Hb) concentrations that is optimum for tumor oxygenation. When used to achieve an Hb level within this range, erythropoiesis-stimulating agents (ESAs) can be expected to increase tumor oxygenation, and this may favorably influence sensitivity to treatment as well as quality of life. There is no robust evidence that ESAs, when used as indicated, have a negative effect on survival in patients with solid tumors. When used outside the indications recommended, the rise in Hb level that results may reduce tumor blood flow and tissue oxygenation because of a raised viscosity within the abnormal tumor microvasculature. In the current situation, it remains important to use ESAs within the approved indications and according to treatment guidelines such as those developed by the European Organization for Research and Treatment of Cancer.

Topics: Anemia; Cell Differentiation; Cell Hypoxia; Cell Proliferation; Cell Transformation, Neoplastic; Erythropoietin; Hematinics; Hemoglobins; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Neoplasms; Oxygen; Recombinant Proteins

Erythropoiesis-stimulating agents are indicated for the treatment of chemotherapy induced-anemia in cancer patients. Controlled clinical studies have shown that epoetin alfa consistently and significantly increases levels of hemoglobin (Hb), decreases the need for RBC transfusion, and improves the quality of life that is of such importance in cancer patients with a limited life expectancy. The rise achieved in Hb level correlates with an improvement in quality of life. Studies have also demonstrated that earlier initiation of epoetin therapy (i.e., starting treatment at an Hb level of 10-11 g/dl rather than waiting for Hb to fall to <10 g/dl) is associated with a faster achievement of an optimal Hb level, a lower transfusion requirement, and a maintained quality of life.

Topics: Anemia; Antineoplastic Agents; Erythrocyte Transfusion; Erythropoietin; Hematinics; Hemoglobins; Humans; Neoplasms; Recombinant Proteins

Since 1988, millions of patients have received epoetin products intravenously (IV) and subcutaneously. In 1998, epoetin-associated pure red cell aplasia (PRCA) was first reported and causation was attributed to formulations without human serum albumin (HSA), subcutaneous administration, and uncoated rubber stoppers.. Data on erythropoietin (EPO)-associated PRCA were obtained from the Food and Drug Administration (FDA), regulatory authorities in other countries, and the manufacturers of epoetin alfa, epoetin beta, and darbepoetin. The data included information on numbers of PRCA cases and estimated exposure-adjusted incidence rates by EPO product, anemia etiology, administration route, country of PRCA identification, and date reported.. In 1999, academicians in Paris identified 12 EPO-treated patients with antibody-mediated PRCA; 11 of these patients were on hemodialysis and had received subcutaneous Eprex (Johnson & Johnson). In 2002, authorities in Europe, Australia, Singapore, and Canada mandated Eprex by IV route to hemodialysis patients, and the relevant manufacturers added Teflon coating to prefilled syringes of Eprex; PRCA cases subsequently decreased by 90 percent. By 2003, 180 Eprex-associated PRCA cases were identified in Europe, Canada, Australia, and Asia, despite improvements in handling. Since 2002, FDA safety databases include information on 59 new cases of antibody-associated PRCA, primarily associated with subcutaneous epoetin alfa and darbepoetin that does not contain HSA.. Independent actions by regulatory authorities, manufacturers, and academic researchers identified significant numbers of PRCA cases between 1998 and 2003 and characterized the probable etiology. Today, antibody-mediated PRCA is an infrequent class toxicity occurring among some hemodialysis patients on EPOs.

Topics: Anemia; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoietin; Hematinics; Humans; 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

Beginning 1998, a working group of specialists convened by the guidelines department (Standards, Options and Recommendations: SOR) of the National French Federation of Comprehensive Cancer Centres (FNCLCC) published then regularly updated Recommendations relative to the use of ESA in anaemic patients with cancer. This article presents a short version of the Recommendations updated in 2007.. This updating process is based on the methodology developed and used in the "Standards, Options: Recommendations" programme. The methodological approach combines systematic review with the judgement of a multidisciplinary group of experts. A Recommendation is a proposal of one or several clinical attitudes intended to improve cancer patient care. There are two levels of gradation for the Recommendations: Standards and Options. Their setting takes into account the organisational context of care, the particular situation of the patient and the expression of his preferences. Before publication, the RPC-SOR are re-examined by independent reviewers selected according to the same principles as the group of expert writers.. New data are sufficiently important to update the latest Recommendations validated in 2003. Thus, five clinical questions were updated. The resulting modifications were either major (new Options or new Standards) or minor (increased level of evidence). It should be noted that for the clinical question--use of ESA in radiotherapy--new data are not sufficient to generate modifications in the initial Recommendations which remain valid.. Because of the important new data published on the subject between 2003 and 2007, it appears relevant to re-examine these Recommendations according to a systematic monitoring process which should be renewed in 2 years.

Topics: Adult; Anemia; Child; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; France; Hematinics; Humans; Iron Compounds; Neoplasms; Recombinant Proteins

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

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

Myelofibrosis with myeloid metaplasia (MMM) is currently classified as a classic (ie, BCR-ABL-negative) myeloproliferative disorder characterized by anemia, multiorgan extramedullary hematopoiesis, constitutional symptoms, and premature death from either leukemic transformation or other disease complications. Stem cell transplantation can be curative, but many patients either are not appropriate candidates or do not choose to accept the significant risks associated with transplantation. Current pharmacologic therapy has been beneficial mainly in terms of palliating disease-associated cytopenias, constitutional symptoms, splenomegaly, and other organ damage from excess myeloproliferation. Novel treatment strategies are under investigation, including targeted inhibition of JAK2(V617F), the activating tyrosine kinase point mutation present in about half of patients with MMM. In this article, we review both the old and new pharmacologic options for MMM.

Topics: Aged; Alkylating Agents; Anemia; Antimetabolites, Antineoplastic; Blood Coagulation Disorders; Disease Progression; Drug Delivery Systems; Drugs, Investigational; Erythropoietin; Hematopoiesis, Extramedullary; Humans; Immunologic Factors; Janus Kinase 2; Leukemia, Myeloid, Acute; Middle Aged; Mutation, Missense; Palliative Care; Point Mutation; Primary Myelofibrosis; Protein Kinase Inhibitors; Signal Transduction; Thrombocytopenia

Congestive heart failure (CHF) is a common clinical problem, especially affecting the elderly. Current strategies of neurohormonal blockade with medications like angiotensin converting enzyme inhibitors have improved morbidity and mortality, but further improvement in outcomes requires new strategies. Both anemia and chronic renal disease commonly accompany congestive heart failure; their close relationship, in which one disease exacerbates the other, has been termed the cardio-renal-anemia syndrome. Correction of anemia in CHF patients using recombinant erythropoietin is feasible; small studies suggest that anemic congestive heart failure patients may have improved morbidity with this therapy. Recent animal and human studies of erythropoietin have shown that its benefit may be derived from both hematological and newly discovered non-hematological properties. Anemia might soon be considered a modifiable risk factor for optimal CHF management.

Topics: Anemia; Erythropoietin; Heart Failure; Humans

Myelodysplastic syndromes (MDS) are a group of complex diseases of the myeloid stem cell that result in chronic cytopenias. In some instances, these disorders may progress to acute myeloid leukemia. Patients with MDS frequently experience chronic, symptomatic anemia, and many become dependent on chronic transfusions of packed red blood cells. However, long-term transfusion dependence has clinical and economic consequences, including a potentially negative impact on patients' quality of life (QOL). Recently, studies have investigated various strategies to reduce or eliminate transfusion needs in MDS patients. Supportive measures with hematopoietic growth factors such as erythropoietin are often less effective in MDS-associated anemia than in anemia from other causes, but some patients may benefit from this approach. Treatment with other agents, such as antithymocyte globulin, azacitidine, decitabine, thalidomide, and lenalidomide, has resulted in transfusion independence in some subsets of MDS patients. Nurses who care for patients with MDS should be aware of the impact of transfusion dependence on the patient's QOL, as well as the benefits and risks of the various other treatment options available to these patients. Such knowledge will enable the nurse to provide accurate, relevant information, so that patients can make informed choices regarding treatment options for MDS.

Topics: Anemia; Antilymphocyte Serum; Antimetabolites, Antineoplastic; Azacitidine; Decitabine; Drug Costs; Erythrocyte Transfusion; Erythropoietin; Health Services Needs and Demand; Humans; Immunosuppressive Agents; Informed Consent; Myelodysplastic Syndromes; Nurse's Role; Oncology Nursing; Patient Education as Topic; Patient Selection; Quality of Life; Thalidomide; Treatment Outcome

In vitro and animal model studies have shown erythropoietin receptor (Epo-R) mRNA and/or protein may be present in a range of human tumours and cancer cell lines, and erythropoiesis-stimulating agents (ESAs) have been reported to have tumour cell growth-modulating effects. Following a review of the literature, we conclude that considerations must be made when interpreting data from the preclinical studies. First, supraphysiological doses of ESAs were usually used. Second, there are no well validated, commercially available antibodies for identifying the presence and functionality of Epo-R at the protein level, either intracellularly or on the cell surface. Data from previous studies that used antibodies only for Epo-R detection must therefore be interpreted with caution. Together with diverging results in the literature, these methodological limitations indicate that findings from preclinical studies must not be over-translated in terms of their clinical relevance to patients with cancer.

Topics: Anemia; Cell Hypoxia; Disease Progression; Drug Evaluation; Erythropoiesis; Erythropoietin; Humans; Neoplasms; Neovascularization, Pathologic; Receptors, Erythropoietin

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

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

Anaemia is frequently diagnosed in patients with cancer, and may have a detrimental effect on quality of life (QoL). We previously conducted a systematic literature review (1996-2003) to produce evidence-based guidelines on the use of erythropoietic proteins in anaemic patients with cancer.[Bokemeyer C, Aapro MS, Courdi A, et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 2004;40:2201-2216.] We report here an update to these guidelines, including literature published through to November 2005. The results of this updated systematic literature review have enabled us to refine our guidelines based on the full body of data currently available. Level I evidence exists for a positive impact of erythropoietic proteins on haemoglobin (Hb) levels when administered to patients with chemotherapy-induced anaemia or anaemia of chronic disease, when used to prevent cancer anaemia, and in patients undergoing cancer surgery. The addition of further Level I studies confirms our recommendation that in cancer patients receiving chemotherapy and/or radiotherapy, treatment with erythropoietic proteins should be initiated at a Hb level of 9-11 g/dL based on anaemia-related symptoms rather than a fixed Hb concentration. Early intervention with erythropoietic proteins may be considered in asymptomatic anaemic patients with Hb levels 11.9 g/dL provided that individual factors like intensity and expected duration of chemotherapy are considered. Patients whose Hb level is below 9 g/dL should primarily be evaluated for need of transfusions potentially followed by the application of erythropoietic proteins. We do not recommend the prophylactic use of erythropoietic proteins to prevent anaemia in patients undergoing chemotherapy or radiotherapy who have normal Hb levels at the start of treatment, as the literature has not shown a benefit with this approach. The addition of further supporting studies confirms our recommendation that the target Hb concentration following treatment with erythropoietic proteins should be 12-13 g/dL. Once this level is achieved, maintenance doses should be titrated individually. There is Level I evidence that dosing of erythropoietic proteins less frequently than three times per week is efficacious when used to treat chemotherapy-induced anaemia or prevent cancer anaemia, with studies supporting the use of epoetin alfa and epoetin beta weekly and darbepoetin alfa given every week or every 3 weeks.

Topics: Anemia; Antineoplastic Agents; Bone Marrow Transplantation; Chronic Disease; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Hypertension; Iron; Neoplasms; Practice Guidelines as Topic; Radiotherapy; Thromboembolism

Anemia has an incidence both on the quality of life and the evolution of cancer. Anemia may result in cancer from either a bone marrow infiltration of cancer cells or a cytotoxic effect of chemotherapy and/or radiotherapy, or both. EPO is a glycoprotein which stimulates erythrocyte formation by bone marrow progenitory cells. Recombinant EPO has considerably improved treatment of anemic patients, by increasing hemoglobin serum levels and reducing the need for blood transfusion. The quality of life of cancer patients is thus improved and several studies highlight the beneficial role of EPO on the clinical outcome. A preclinical background and some clinical data suggest however a detrimental role of EPO in cancer by a possible stimulation of tumor growth. There is a need of more clinical trials in order to assess the effects of EPO on tumors and their treatment.

Topics: Anemia; Animals; Antineoplastic Agents; Clinical Trials as Topic; Erythropoietin; Hemoglobins; Humans; Neoplasms; Quality of Life; Radiotherapy; Risk Factors

The elements and limitations of pharmacoeconomic models, types of analytic methods used in pharmacoeconomic evaluations, outcomes used in studies of anemia treatments, and comparative efficacy and cost-effectiveness of the two available erythropoietic therapies in the treatment of anemia in cancer and critical care patients are discussed.. Clinical, humanistic, and economic outcomes should be taken into consideration in pharmacoeconomic models. The validity of such models may be compromised by a lack of outcome data, unreasonable assumptions, the heterogeneity of the patient population, patient selection bias in comparative studies, and inconsistent use of instruments to measure outcomes. The degree of anemia in patients with cancer correlates with health-related quality of life (QOL). Erythropoietic therapy increases hemoglobin concentrations and QOL, reduces the need for blood transfusions, and is cost-effective for treating anemia in cancer and critical care patients. Epoetin alfa may provide a more rapid hemoglobin response and improvement in QOL at a lower cost than darbepoetin alfa. Front loading with weekly doses of either erythropoietic agent followed by a three-week-long dosing interval for maintenance treatment may be used to quickly correct anemia, improve convenience, and reduce costs.. Erythropoietic therapy for the treatment of anemia in cancer and critical care patients is cost-effective.

Topics: Anemia; Cost-Benefit Analysis; Critical Care; Critical Illness; Darbepoetin alfa; Economics, Pharmaceutical; Epoetin Alfa; Erythropoietin; Humans; Neoplasms; Quality of Life; Recombinant Proteins

The incidence, etiology, impact, and considerations in developing guidelines for treating anemia in patients with cancer are described.. Anemia is common in patients with cancer. The incidence and severity of anemia depend on the type and extent of the malignancy; the type, schedule, and intensity of cancer therapy; and patient age, gender, and comorbid conditions. Anemia may be the result of the malignancy itself, cancer treatment, blood losses, nutritional deficiencies, hemolysis, endocrine disorders, or inflammatory cytokines associated with chronic disease. Anemia can have a profound impact on physical and psychosocial function and quality of life. Guidelines and protocols for treating anemia should be evidence-based and take into consideration patient age, the type and extent of malignancy, comorbid conditions, and the etiology and impact of anemia. Patient-specific issues that guidelines should address include strategies for identifying patients with anemia, treating anemia, evaluating the response to treatment, and modifying treatment based on response. Erythropoietic agents are preferred over blood transfusions for patients whose anemia is chronic, although transfusions are indicated for acute, severe blood losses. Iron supplementation often is required in patients receiving erythropoietic therapy or with iron deficiency due to hemorrhage.. The use of evidence-based guidelines and protocols that take into consideration the heterogeneity of patients with cancer can optimize anemia treatment.

Topics: Anemia; Blood Transfusion; Clinical Protocols; Comorbidity; Endocrine System Diseases; Erythropoietin; Humans; Incidence; Neoplasms; Practice Guidelines as Topic

Anemia is a common clinical disease in persons with HIV infection and is associated with poor prognosis. There is a need to assess the effects of anemia treatments, and to determine whether these interventions are beneficial.. To determine the efficacy and safety of treatments for anemia in people with HIV infection and AIDS.. The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 3, 2005), MEDLINE (1980-July 2005), EMBASE (1980-July 2005), LlLACS (1982 to July 2005), reference lists of relevant articles and contact with authors. See Cochrane HIV/AIDS Group search strategy.. Randomized trials assessing the effects of treatments for anemia in people diagnosed with HIV infection. There were no age restrictions.. Both authors independently assessed relevant studies for inclusion. Data extraction and quality assessment of relevant studies was performed by one author and checked by the other author.. We included four trials, but focused on the results based on three trials with acceptable attrition rate. None of the trials reported data on death. The two trials that compared recombinant human erythropoietin (rHuEPO) to placebo did not show any benefit on hematological values response, number of patients transfused, or number of packed red cell transfused. One trial compared the effects of two rHuEPO dosing regimens on hemoglobin value and quality of life, but the effects are unclear.. There is a lack of reliable evidence on interventions for treating anemia in patients with HIV infection. This Cochrane review has found some evidence that rHuEPO reduces transfusion requirements, increases hemoglobin levels, and improves quality of life in HIV-infected patients with anemia. However, this is based on evidence from randomized trials with weak or poor methodological quality. There is a need for randomized trials of high methodological quality to evaluate the effect of interventions on anemia in persons infected with human immunodeficiency virus.

Topics: Acquired Immunodeficiency Syndrome; Anemia; Erythropoietin; Humans; Randomized Controlled Trials as Topic; Recombinant Proteins

In the light of the enthusiasm regarding the use of recombinant human erythropoietin (Epo) and its analogues for treatment of the anaemias of chronic renal failure and malignancies it is worth remembering that today's success has been based on a century of laborious research. The concept of the humoral regulation of haematopoiesis was first formulated in 1906. The term 'erythropoietin' for the erythropoiesis-stimulating hormone was introduced in 1948. Native human Epo was isolated in 1977 and its gene cloned in 1985. During the last 15 yr, major progress has been made in identifying the molecules controlling Epo gene expression, primarily the hypoxia-inducible transcription factors (HIF) that are regulated by specific O2 and oxoglutarate requiring Fe2+-containing dioxygenases. With respect to the action of Epo, its dimeric receptor (Epo-R) has been characterised and shown to signal through protein kinases, anti-apoptotic proteins and transcription factors. The demonstration of Epo-R in non-haematopoietic tissues indicates that Epo is a pleiotropic viability and growth factor. The neuroprotective and cardioprotective potentials of Epo are reviewed with a focus on clinical research. In addition, studies utilising the Epo derivatives with prolonged half-life, peptidic and non-peptidic Epo mimetics, orally active drugs stimulating endogenous Epo production and Epo gene transfer are reviewed.

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; History, 16th Century; History, 19th Century; History, 20th Century; History, 21st Century; Hormones; Humans; Hypoxia; Oxygen

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

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

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

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

Patients with cancer-related anaemia generally have a poor prognosis. Evidence suggests that an effective erythropoietic protein (epoetin)-mediated haemoglobin (Hb) response provides marked improvement in quality of life (QoL). An early Hb response to erythropoietic protein therapy in these patients would appear ideal but few studies have compared the speed of response to different erythropoietic proteins, or the potential benefits associated with an early Hb response.. The pharmacokinetic/pharmacodynamic profiles of commercially available erythropoietic proteins are reviewed along with available clinical data to examine Hb response and associated clinical outcomes for each of these agents. Randomised, head-to-head trials comparing epoetin alfa and darbepoetin alfa suggest that patients administered with epoetin alfa achieve a satisfactory Hb response significantly earlier than those given darbepoetin alfa, and with consistently lower monthly transfusion rates. Non-comparative studies support this, suggesting also that epoetin beta may provide a relatively faster Hb response in a greater number of patients than either epoetin alfa or darbepoetin alfa, irrespective of malignancy or chemotherapy type. Moreover, studies suggest consistently that a 'front-loading' dosing regimen with epoetin alfa does not convey improved speed of Hb response over epoetin beta administered according to current clinical practice guidelines.. Given the poor prognosis of anaemic patients with cancer, the use of an agent which provides clinical benefits quickly but with minimal thromboembolic risk, should be considered an essential component of anaemia management in these patients. However, more head-to-head studies are required to confirm the relative efficacy of currently available erythropoietic proteins.

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Hemoglobins; Humans; Neoplasms; Quality-Adjusted Life Years; Recombinant Proteins; Retrospective Studies; Thromboembolism; Treatment Outcome

Patients with lymphoid malignancies frequently require repetitive and intensive anticancer treatments to induce and maintain disease remission. Anaemia (haemoglobin [Hb] <12 g/dL) is a common and debilitating problem associated with both the malignancy itself and its treatment burden. Anaemia negatively impacts on all aspects of patient quality of life (QOL) and treatment outcomes and survival, particularly in this disease setting. Widely acknowledged goals of anaemia treatment include Hb correction to approximately 12 g/dL, reduction in transfusion requirements and optimisation of patient QOL. Since the introduction of recombinant human erythropoietic therapy, transfusion (once the only anaemia treatment option available) is now primarily reserved for non-responders or those with severe or life-threatening anaemia. Data from randomised, double-blind, placebo-controlled studies, and large, non-randomised, open-label, community-based studies, along with almost 15 years of practical experience, support the assertion that epoetin alfa administered at a dosage of 150-300 U/kg three times weekly or 40,000-60,000U once weekly, both of which are US FDA-approved dose administration schedules, can effectively and safely achieve anaemia treatment goals for the majority of patients with lymphoid malignancies. Data and practical experience collected over the last 5 years on another erythropoietic agent with a slightly longer half-life but lower binding affinity, darbepoetin alfa, show that this agent when administered according to the FDA-approved dose administration schedules (2.25-4.5 microg/kg once weekly or 500microg once every 3 weeks) or according to a commonly-administered dose in clinical practice (3.0-5.0 microg/kg once every 2 weeks) can also effectively and safely correct anaemia, reduce transfusion requirements and improve QOL in many patients with lymphoid malignancies. One comparative head-to-head trial suggested that epoetin alfa might be superior to darbepoetin alfa in anaemic cancer patients receiving chemotherapy with respect to timing and magnitude of Hb correction, although further study is necessary, especially concerning optimal dose administration. Alternative dose administration schedules, such as epoetin alfa 80,000U every 2 weeks from initiation or 80,000U every 3 weeks following initiation with once weekly administration and darbepoetin alfa 4.5 microg/kg every 3 weeks following initiation with once weekly administration, are being actively

Topics: Anemia; Antineoplastic Agents; Blood Transfusion; Combined Modality Therapy; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Iron; Lymphoma; Practice Guidelines as Topic; Quality of Life; Recombinant Proteins; Trace Elements

Healthcare organizations must evaluate the cost effectiveness of the alternative therapies that are available to treat anemia and improve quality of life (QoL) of patients with cancer, that is, erythropoietic protein therapy and blood transfusion.. Pharmacoeconomic studies that evaluated the cost of not treating anemia or treating with transfusion or erythropoietic protein therapy were reviewed and compared. Studies of individual erythropoietic proteins (epoetin alfa, epoetin beta or darbepoetin alfa) were also assessed. As no prospective trials have compared the erythropoietic proteins, retrospective studies and the results of separate trials were analyzed. The database searched for this review was PubMed (open date to August 2006). Recent conference abstracts were also searched (2003-July 2006).. There is a high cost associated with anemia in cancer patients. Treatment of anemia is likely to lead to increased hemoglobin (Hb) levels and improved QoL as principal outcomes. Therefore, in assessing erythropoietic protein versus transfusion, it is more appropriate to use Hb or QoL as endpoint rather than quality adjusted life year. Studies with the former approach showed that erythropoietic protein therapy is more cost effective than transfusion. Also, its cost effectiveness should be improved with the use of evidence-based guidelines for patient selection and more tailored utilization. Increasing evidence suggests there might be differences among the erythropoietic proteins in terms of response rate, speed of response, and need for dose escalation.. Significant costs are incurred when anemia in cancer is not treated. Erythropoietic protein therapy is more cost effective than blood transfusion for the treatment of cancer-related anemia. Transfusion should be reserved for patients with poor responses to erythropoietic protein or for the emergency setting, when rapid improvement in Hb is required.

Topics: Absenteeism; Anemia; Blood Transfusion; Budgets; Cost-Benefit Analysis; Darbepoetin alfa; Drug Costs; Epoetin Alfa; Erythropoietin; Health Care Costs; Hemoglobins; Humans; Iron; Neoplasms; Quality of Life; Quality-Adjusted Life Years; Recombinant Proteins; Treatment Outcome

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

To review the hematologic adverse effects of hepatitis C virus (HCV) therapy and adjuvant treatment with epoetin alfa and granulocyte colony-stimulating factor (ie, filgrastim).. Medical literature indexed in MEDLINE (1966-January 2007) and EMBASE (1980-January 2007) was searched, and published conference abstracts were reviewed.. Peer-reviewed articles and relevant conference abstracts regarding the use of epoetin alfa and granulocyte colony-stimulating factor were reviewed.. Ribavirin induces a dose-dependent hemolytic anemia. Studies using epoetin alfa 40 000 units subcutaneously once weekly have demonstrated efficacy in maintaining hemoglobin, ribavirin dose, and quality of life scores, but clear benefit shown with sustained virologic response (SVR) is lacking. The hemoglobin threshold for initiation of epoetin alfa used in studies may not adequately reflect values used in clinical practice. Treatment-related neutropenia is caused primarily by interferon or peginterferon. Few studies have investigated the impact of granulocyte or granulocyte-macrophage colony-stimulating factor derivatives on neutropenia. Results of dose maintenance evaluation vary, and studies reporting data on SVR showed no effect from growth factor therapy. The frequency of bacterial infections was not reported.. The role and benefit of hematopoietic growth factors in HCV therapy have not been conclusively determined to date. However, the possibility of a benefit to individual patients seen on an outpatient basis remains, and an individualized treatment approach is recommended.

Topics: Anemia; Chemotherapy, Adjuvant; Epoetin Alfa; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematinics; Hepatitis C; Humans; Interferons; MEDLINE; Neutropenia; Recombinant Proteins; Ribavirin

Anemia raises special concerns in older cancer patients. This review addresses the prevalence, causes, and mechanisms of anemia in older individuals, the complications of anemia in this population (including its impact on cancer treatment), and the appropriate management of anemia in the elderly.

Topics: Aged; Aging; Anemia; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Neoplasms

Anemia is common in patients with cancer or myelodysplastic syndrome. Erythropoietic therapy offers an effective way to manage anemia by increasing hemoglobin levels, decreasing transfusion requirements, and alleviating symptoms. We reviewed data showing the feasibility and effectiveness of treatment with the erythropoiesis-stimulating protein darbepoetin alfa at extended dosing intervals to treat anemia in patients with cancer receiving multicycle chemotherapy. We also explored the darbepoetin alfa's potential for treating anemia in patients with myelodysplastic syndrome. Data from clinical studies and drug therapy evaluations confirm that darbepoetin alfa administered weekly, every 2 weeks, and every 3 weeks corrects and maintains hemoglobin levels in patients with chemotherapy-induced anemia. In addition, the data demonstrate that both weight-based and fixed dosing with darbepoetin alfa are effective, and that early intervention to treat anemia has clinical benefits. Darbepoetin alfa also is an effective treatment for anemia in patients with cancer not receiving chemotherapy, at extended dosing intervals of at least 3 weeks. Extended dosing for anemia treatment can provide benefits for patients, caregivers, and clinicians because it reduces the number of clinic visits needed and permits synchronizing anemia treatment with chemotherapy cycles. Data from recent studies suggest that darbepoetin alfa is effective for treating anemia in patients with myelodysplastic syndrome; this potential use is being investigated further in ongoing studies. Thus, darbepoetin alfa is an attractive therapy option for patients with chemotherapy or cancer-induced anemia. It allows increased flexibility and simplified dosing and may offer some benefit in the treatment of anemia in patients with myelodysplastic syndrome.

Topics: Anemia; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Humans; Myelodysplastic Syndromes; Neoplasms; Recombinant Proteins

Topics: Anemia; Animals; Cardiotonic Agents; Clinical Trials as Topic; Dogs; Drug Administration Schedule; Erythropoietin; Heart Failure; Humans; Mice; Myocardial Infarction; Myocardial Ischemia; Rats; Recombinant Proteins; Signal Transduction

Erythropoietin has been successfully used in Europe since 1997 in the treatment of anemia induced by chemotherapy of solid tumors. There is only limited experience with regard to its use when treating dermatologic tumors such as metastatic melanoma. We review here current guidelines on the use of erythropoietin in cancer patients and report on our own melanoma patients treated with erythropoietin for chemotherapy-induced anemia.

Topics: Anemia; Antineoplastic Agents; Dermatology; Erythropoietin; Humans; Medical Oncology; Practice Guidelines as Topic; Practice Patterns, Physicians'; Skin Neoplasms

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

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

Anemia is a common side effect that begins soon after the initiation of peginterferon/ribavirin in the treatment of hepatitis C virus (HCV) infection. It can cause symptoms that negatively impact quality of life (QOL) and is the most common reason for reducing the dose and temporarily or permanently discontinuing ribavirin. Such dose modifications have been shown to reduce the efficacy of treatment. Administering erythropoietin can improve anemia caused by peginterferon and ribavirin therapy and is more effective than dose reduction at improving QOL during treatment. However, erythropoietin, which is not approved by the U.S. Food and Drug Administration (FDA) for use in patients with HCV infection, adds another parenteral drug to the patient's treatment regimen, and is associated with additional costs, inconvenience, and potential side effects. A new ribavirin analog, viramidine, is expected to be associated with a lower incidence of anemia and, if proven effective, may eventually be substituted for ribavirin in combination with peginterferon to treat chronic hepatitis C. In the meantime, physicians must make the best possible use of the available options for managing anemia, especially in select patient groups who are most at risk for anemia and its complications.

Topics: Anemia; Antiviral Agents; Drug Therapy, Combination; Erythropoietin; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Quality of Life; Recombinant Proteins; Ribavirin

To assess the effectiveness and cost-effectiveness of epoetin alpha, epoetin beta and darbepoetin alpha (referred to collectively in this report as epo) in anaemia associated with cancer, especially that attributable to cancer treatment.. Electronic databases were searched from 2000 (1996 in the case of darbepoetin alpha) to September 2004.. Using a recently published Cochrane review as the starting point, a systematic review of recent randomised controlled trials (RCTs) comparing epo with best standard was conducted. Inclusion, quality assessment and data abstraction were undertaken in duplicate. Where possible, meta-analysis was employed. The economic assessment consisted of a systematic review of past economic evaluations, an assessment of economic models submitted by the manufacturers of the three epo agents and development of a new individual sampling model (the Birmingham epo model).. In total 46 RCTs were included within this systematic review, 27 of which had been included in the Cochrane systematic review. All 46 trials compared epo plus supportive care for anaemia (including transfusions), with supportive care for anaemia (including transfusions), alone. Haematological response (defined as an improvement by 2 g/dl(-1)) had a relative risk of 3.4 [95% confidence interval (CI) 3.0 to 3.8, 22 RCTs] with a response rate for epo of 53%. The trial duration was most commonly 16-20 weeks. There was little statistical heterogeneity in the estimate of haematological response, and there were no important differences between the subgroups examined. Haemoglobin (Hb) change showed a weighted mean difference of 1.63 g/dl(-1) (95% CI 1.46 to 1.80) in favour of epo. Treatment with erythropoietin in patients with cancer-induced anaemia reduces the number of patients who receive a red blood cell transfusion (RBCT) by an estimated 18%. Health-related quality of life (HRQoL) data were analysed using vote counting and qualitative assessment and a positive effect was observed in favour of an improved HRQoL for patients on epo. Published information on side-effects was of poor quality. New trials provided further evidence of side-effects with epo, particularly thrombic events, but it is still unclear whether these could be accounted for by chance alone. The results of the previous Cochrane review had suggested a survival advantage for epo (HR 0.84, 95% CI 0.69 to 1.02), based on 19 RCTs. The update, based on 28 RCTs, suggests no difference (HR 1.03, 95% CI 0.88 to 1.21). Subgroup analysis suggested some explanations for this heterogeneity, but it is difficult to draw firm conclusions without access to the substantial amounts of missing or unpublished data, or more detailed results from some of the trials with heterogeneous patient populations. The conclusions are, however, broadly in line with those of a Food and Drug Administration (FDA) safety briefing, which recommended that patients with a haemoglobin above 12 g/dl(-1) should not be treated; the target rate of rise in Hb should not be too great, and further carefully conducted trials are required to determine which subgroups of patients may be harmed by the use of these products, in particular through the stimulation of tumour activity. Five published economic evaluations identified from the literature had inconsistent results, with estimates ranging from a cost per quality-adjusted life-year (QALY) u. Epo is effective in improving haematological response and reducing RBCT requirements, and appears to have a positive effect on HRQoL. The incidence of side-effects and effects on survival remains highly uncertain. However, if there is no impact on survival, it seems highly unlikely that epo would be considered a cost-effective use of healthcare resources. The main target for further research should be improving estimates of impact on survival, initially through more detailed secondary research, such as the individual patient data meta-analysis started by the Cochrane group. Further trials may be required, and have been recommended by the FDA, although many trials are in progress, completed but unreported or awaiting mature follow-up. The Birmingham epo model developed as part of this project contains new features that improve its flexibility in exploring different scenarios; further refinement and validation would therefore be of assistance. Finally, further research to resolve uncertainty about other parameters, particularly quality of life, adverse events, and the rate of normalisation, would also be beneficial.

Topics: Anemia; Antineoplastic Agents; Cost-Benefit Analysis; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Neoplasms; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Analysis; Treatment Outcome

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

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

Two independent reviewers used the methodological criteria published by the ISPOR Task Force on Retrospective Data to assess the quality of four posters presenting the results of retrospective database studies on the use of erythropoiesis-stimulating agents (epoetin alfa, epoetin beta, or darbepoetin alfa) for treating patients with cancer. A third reviewer consolidated the results. Overall, from the information reported in the four posters, their methodological quality ranged from poor to very poor; only a few of the criteria were satisfactorily addressed. The quality of the data sources and the research design received very poor scores. Key elements such as selection bias were not considered. These findings caution against the use of posters without appropriate assessment of their methodological quality. The ISPOR guidelines for the evaluation of retrospective analyses are a useful tool for assessing the quality of scientific posters.

Topics: Anemia; Antineoplastic Agents; Benchmarking; Darbepoetin alfa; Data Interpretation, Statistical; Epoetin Alfa; Erythropoietin; Guidelines as Topic; Hematinics; Humans; Neoplasms; Recombinant Proteins; Research Design; Technology Assessment, Biomedical

Erythropoietin emerged as the biggest drug in oncology despite never having demonstrated a survival benefit in patients with cancer. Two phase III clinical trials reported more than 3 years ago that erythropoietin adversely affected cancer survival rates, due mainly to tumor progression. Despite changes to the product label for erythropoietins in 2004, clinical practice remained unchanged until recent weeks when, following reports of three new phase III studies and a phase II trial, a "black box warning" for erythropoietin products was issued by the Food and Drug Administration (FDA). Whether erythropoietin products can be considered safe when used for FDA-approved indications is currently at issue; however, addressing this question will be difficult until the mechanisms of erythropoietin-stimulated tumor progression are understood. A thorough evaluation of materials from clinical trials already completed may shed new light on how erythropoietin promotes cancer progression. Until these issues are resolved, oncologists should inform their patients of erythropoietin's potential adverse impact on cancer progression and survival. Disclosure of potential conflicts of interest is found at the end of this article.

Topics: Anemia; Clinical Trials, Phase III as Topic; Contraindications; Disease Progression; Erythropoietin; Health Planning Guidelines; Humans; Neoplasms

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

Major transfusion-free orthopaedic surgery can be performed successfully. This requires advanced planning, good routines and close collaborative team efforts. Since most blood saving techniques reduce blood usage by just 1-2 units, a series of integrated preoperative, intraoperative and postoperative blood saving approaches is required. These include preoperative autologous donation, erythropoietic support, acute normovolemic hemodilution, intraoperative autotransfusion, individualized assessment of anemia tolerance, meticulous surgical techniques and the use of pharmacologic agents for limiting blood loss. For various reasons, we do not recommend the transfusion of wound drainage. This article describes the various methods for bloodless medical care.

Topics: Adult; Anemia; Blood Coagulation Tests; Blood Loss, Surgical; Blood Transfusion, Autologous; Child; Clinical Trials as Topic; Contraindications; Cost-Benefit Analysis; Drainage; Erythropoiesis; Erythropoietin; Hematocrit; Hemodilution; Hemoglobinometry; Humans; Intraoperative Care; Jehovah's Witnesses; Meta-Analysis as Topic; Orthopedic Procedures; Preoperative Care; Risk Factors; Time Factors; Wounds and Injuries

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

The distinct molecular structure of darbepoetin alfa, in both its amino acid sequence and its carbohydrate content, results in a biologic profile with lower binding affinity, longer circulating half-life, and higher in vivo potency compared with the epoetins. The mechanisms responsible for these differences in biological effects have not been fully explained. Pharmacokinetic investigations of darbepoetin alfa using prolonged blood sampling times established that the mean terminal half-life after subcutaneous (SC) administration is 70 to 105 hours. Pharmacodynamic studies were conducted to assess the suitability of darbepoetin alfa for use in weekly or less frequent (once every other week or once a month) dosing regimens to maintain haemoglobin levels in patients with anaemia of renal disease. Regardless of dialysis status, route of administration, or prior treatment with an erythropoiesis-stimulating agent, darbepoetin alfa administered at extended intervals was able to raise or maintain hemoglobin levels to target. More rigorous studies will be needed to confirm these findings.

Topics: Anemia; Animals; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous

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

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

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

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

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

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

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

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

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

Anemia is commonly observed in patients with heart failure, and portends worsening functional capacity and poorer long-term prognosis. Nevertheless, uncertainty remains regarding the underlying pathophysiology and natural history of anemia in the setting of chronic heart failure. The optimal therapeutic targets and treatment options for this "anemia of heart failure" are also uncertain. Careful evaluation of potential underlying reversible causes, particularly renal insufficiency and iron or nutritional deficiencies, may lead to potential treatment options. Recent concerns have focused on the appropriate hemoglobin target and the efficacies of erythropoiesis-stimulating agents (ESAs), such as erythropoietin and darbepoetin alfa, in reducing long-term clinical events. Much work is needed to clarify the safety and efficacy of this drug class. Nevertheless, early unblinded studies and phase II results using ESAs in patients with heart failure have found overall significant improvements in exercise capacity and quality of life, and it is hoped that ongoing pivotal outcome trials and investigations into iron supplementation will clarify their appropriate use.

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Heart Failure; Hemoglobins; Humans; Prognosis

Anemia is a decrease in circulating red blood cells that contributes to a complex group of symptoms. Anemia may be present in more than half of all patients with cancer but often is assessed, documented, prevented, and treated inadequately. Individuals with cancer are living longer, and the number of cancer treatment options provided at various points in the cancer continuum is growing; however, many treatments contribute to anemia. Because anemia can develop from multiple causes, treatment must be tailored to the underlying etiology. Cancer-related anemia can significantly affect therapeutic outcomes and patients' quality of life. Therapeutic interventions may include blood transfusions, administration of recombinant human erythropoietin, and interventions to support patient symptoms, most significantly, fatigue. Oncology nurses play a central role in risk assessment, symptom management, treatment planning, and evaluation and therefore must understand the etiology and physiology of cancer-related anemic states as well as evidence-based interventions to ensure optimal outcomes.

Topics: Algorithms; Anemia; Blood Transfusion; Causality; Cost of Illness; Decision Trees; Diagnosis, Differential; Erythropoietin; Evidence-Based Medicine; Fatigue; Hematinics; Hematocrit; Hemoglobins; Humans; Neoplasms; Nurse's Role; Nursing Assessment; Oncology Nursing; Patient Care Planning; Patient Education as Topic; Quality of Life; Risk Assessment

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

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

The clinical availability of recombinant hematopoietic growth factors was initially thought to be breakthrough in the treatment of bone marrow failure syndromes. However, in most disorders of hematopoeisis, the clinical use was rather disappointing. Only in congenital neutropenias (CNs) has the long-term administration of granulocyte colony-stimulating factor (G-CSF) led to a maintained increase in absolute neutrophil count (ANC) and a reduction of severe bacterial infections. In other disorders of hematopoiesis, the use of lineage-specific growth factors is either not possible due to mutations in the growth factor receptor or leads to a transient benefit only. Initial clinical trials with multilineage hematopoietic growth factors, such as stem cell factor (SCF; c-kit ligand) were discontinued due to adverse events. It is well known that bone marrow failure syndromes are pre-leukemic disorders. So far, there is no evidence for induction of leukemia by hematopoietic growth factors. However, it has been shown in patients with CN and Fanconi anemia that hematopoietic growth factors might induce preferential outgrowth of already transformed cells. Thus, it is strongly recommended to monitor patients for clonal aberrations prior to and during long-term treatment with hematopoietic growth factors.

Topics: Anemia; Anemia, Diamond-Blackfan; Anemia, Dyserythropoietic, Congenital; Erythropoietin; Fanconi Anemia; Granulocyte Colony-Stimulating Factor; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Humans; Neutropenia; Stem Cell Factor; Thrombocytopenia

Anemia is frequently diagnosed in patients with cancer and its treatment is an important clinical problem. The deficiency in red blood cells (RBCs) can be a debilitating problem, and anemia correlates with poor performance status, deteriorates quality of life, and may negatively influence the prognosis of cancer patients. The development of recombinant human erythropoietins (rhEPO) provides a therapeutic option in patients with mild to moderate anemia. However, clinical experience demonstrates that more than half of anemic cancer patients are not treated. There is clear evidence that rhEPO reliably increases haemoglobin (Hb) levels in patients suffering from cancer-related or treatment-associated anemia. The dosing and management of these patients should strictly follow evidence-based guidelines of the clinical societies, as well as the manufacturer's recommendations. Furthermore, treatment of patients beyond the correction of anemia must be regarded as potentially harmful and should only be conducted in an experimental clinical setting. In this review, recently published recommendations and standards for the use of rhEPO will be discussed.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Erythrocyte Transfusion; Erythropoiesis; Erythropoietin; Hemoglobins; Humans; Neoplasms; Practice Guidelines as Topic; Recombinant Proteins; Survival Analysis

The well-established physiological function of erythropoietin (EPO) is the induction of erythropoiesis. A growing body of evidence indicates that EPO has tissue-protective effects and prevents tissue damage during ischemia and inflammation. Tissue protection after ischemia and injury has been found in the brain, heart, and kidney. It has been speculated that EPO has anti-apoptotic effects in cardiovascular cells. These novel effects of EPO seem to be independent of its erythropoietic activity. Unclear is the role of the known EPO receptor or whether other signaling pathways are involved; a novel EPO receptor might be involved in tissue protection by this hormone. This review article summarizes present knowledge of cardiovascular and renal protective effects of EPO and discusses possible underlying mechanisms.

Topics: Acute Kidney Injury; Anemia; Animals; Cardiovascular Diseases; Erythropoiesis; Erythropoietin; Humans; Recombinant Proteins; Vascular Diseases

Erythropoietin (Epo) stimulates red blood cell production by docking with its cognate receptor on the erythroid progenitor cell and triggering an array of signaling pathways that inhibit apoptosis and promote cell proliferation and differentiation. In its pharmaceutical forms, epoetin and darbepoetin, Epo is widely used to treat various anemias, including those associated with cancer. The Epo receptor is also expressed by nonhematopoietic cells, including cancer cells, and Epo exhibits a "tissue-protective" effect on nonhematopoietic tissues, possibly mediated through a novel heteroreceptor, blocking apoptosis induced by a variety of insults. The unexpected results of several clinical studies in which Epo was used to treat cancer patients have now raised the question of a potential direct growth-promoting action of Epo on cancer cells.

Topics: Anemia; Apoptosis; Cell Differentiation; Cell Division; Clinical Trials as Topic; Cytokine Receptor Common beta Subunit; Disease Progression; Erythropoiesis; Erythropoietin; Humans; Janus Kinase 2; MAP Kinase Signaling System; Neoplastic Stem Cells; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction; STAT5 Transcription Factor; Structure-Activity Relationship; Treatment Outcome

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

Inherent risks and increasing costs of allogeneic transfusions underline the socioeconomic relevance of safe and effective alternatives to banked blood. The safety limits of a restrictive transfusion policy are given by a patient's individual tolerance of acute normovolaemic anaemia. latrogenic attempts to increase tolerance of anaemia are helpful in avoiding premature blood transfusions while at the same time maintaining adequate tissue oxygenation. Autologous transfusion techniques include preoperative autologous blood donation (PAD), acute normovolaemic haemodilution (ANH), and intraoperative cell salvage (ICS). The efficacy of PAD and ANH can be augmented by supplemental iron and/or erythropoietin. PAD is only cost-effective when based on a meticulous donation/transfusion plan calculated for the individual patient, and still carries the risk of mistransfusion (clerical error). In contrast, ANH has almost no risks and is more cost-effective. A significant reduction in allogeneic blood transfusions can also be achieved by ICS. Currently, some controversy regarding contraindications of ICS needs to be resolved. Artificial oxygen carriers based on perfluorocarbon (PFC) or haemoglobin (haemoglobin-based oxygen carriers, HBOCs) are attractive alternatives to allogeneic red blood cells. Nevertheless, to date no artificial oxygen carrier is available for routine clinical use, and further studies are needed to show the safety and efficacy of these substances.

Topics: Anemia; Blood Donors; Blood Substitutes; Blood Transfusion; Consumer Product Safety; Erythropoietin; Hematocrit; Hemodilution; Hemoglobins; Humans; Intraoperative Period; Oxygen; Preoperative Care; Recombinant Proteins

An increasing understanding of the process of erythropoiesis raises some interesting questions about the pathophysiology, diagnosis and treatment of anemia and erythrocytosis. The mechanisms underlying the development of many of the erythrocytoses, previously characterised as idiopathic, have been elucidated leading to an increased understanding of oxygen homeostasis. Characterisation of anemia and erythrocytosis in relation to serum erythropoietin levels can be a useful addition to clinical diagnostic criteria and provide a rationale for treatment with erythropoiesis stimulating agents (ESAs). Recombinant human erythropoietin as well as other ESAs are now widely used to treat anemias associated with a range of conditions, including chronic kidney disease, chronic inflammatory disorders and cancer. There is also heightened awareness of the potential abuse of ESAs to boost athletic performance in competitive sport. The discovery of erythropoietin receptors outside of the erythropoietic compartment may herald future applications for ESAs in the management of neurological and cardiac diseases. The current controversy concerning optimal hemoglobin levels in chronic kidney disease patients treated with ESAs and the potential negative clinical outcomes of ESA treatment in cancer reinforces the need for cautious evaluation of the pleiotropic effects of ESAs in non-erythroid tissues.

Topics: Anemia; Erythropoietin; Humans; Polycythemia

Erythropoietin (EPO) has been used clinically both as an erythropoietic stimulating agent in the treatment of anemia and as a tissue-protective agent in diverse clinical settings including stroke, multiple sclerosis, acute myocardial infarction and others. However, use of EPO or EPO-analogues leads to simultaneous targeting of both the erythropoietic and tissue-protective properties of EPO, and this strategy has been associated with several problems. Specifically, the benefit of correction of cancer-related anemia can be offset by the tissue-protective effects of EPO, which may lead to stimulation of cancer cell proliferation. Conversely, the benefit of tissue-protection in patients with stroke or myocardial infarction can be offset by adverse effects associated with the erythropoietic effects of EPO such as elevation of red blood cell mass, hypertension and prothrombotic phenomena. The finding that the erythropoietic and tissue-protective properties of EPO are conferred via two distinct receptor systems raises the interesting possibility of discovering novel drugs that selectively stimulate either the erythropoietic or the tissue-protective activities of EPO. This article reviews the current status of the clinical use of EPO and EPO-analogues in the treatment of cancer-related anemia and for tissue protection, outlines the distinct molecular biology of the tissue-protective and erythropoietic effects of EPO and discusses strategies of selective targeting of these activities with the goal of exploiting the full therapeutic potential of EPO.

Topics: Anemia; Animals; Erythropoiesis; Erythropoietin; Hematinics; Humans; Neoplasms; Receptors, Erythropoietin; Recombinant Proteins

The practice of blood conservation is aimed at improving patient outcomes by avoiding allogeneic transfusions via a coordinated multidisciplinary, multipronged approach. The numerous blood conservation techniques and transfusion alternatives now available are described.. Ongoing concerns exist regarding the availability of the nation's and the world's blood supply. In addition, the number of measures required to ensure blood safety has led to increases in the price of blood and blood products over the past 10-15 years. Moreover, blood transfusion carries inherent risks even under the most favorable circumstances. Investigations have established that injudicious transfusion is associated with development of ventilator-associated pneumonia, nosocomial infection, and organ dysfunction. Because most single blood-conservation techniques reduce blood usage by a mere 1-2 units, a series of integrated conservation approaches are required. These include preoperative autologous donation, use of erythropoietic agents, blood conservation techniques such as acute normovolemic hemodilution, individualized assessment of anemia tolerance, implementation of conservative transfusion thresholds, meticulous surgical techniques, and judicious use of phlebotomy and pharmacologic agents for limiting blood loss. Erythropoietic agents such as epoetin alfa have been used successfully to increase hemoglobin and decrease transfusion requirements, and are appropriate when used in advance of elective surgical procedures. Acquisition costs of erythropoietic stimulating agents versus costs of blood justify economic evaluation by hospitals to make the most cost-effective choice under current economic constraints.. Initiating a blood management program requires planning and support from those who are concerned about blood usage reduction and outcomes improvement. Launching a vigorous and ongoing educational program to raise awareness about the risks and hazards associated with blood transfusion is an important step in helping to reshape the medical staffs' attitudes about transfusion and the most cost-effective way to achieve clinical goals.

Topics: Anemia; Blood Banks; Blood Donors; Blood Loss, Surgical; Blood Transfusion, Autologous; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Hemodilution; Hospital Costs; Humans; Insurance, Health, Reimbursement; Medicare; Recombinant Proteins

Anemia is common among patients with coronary artery disease (CAD) and portends a higher risk of short- and long-term mortality, major adverse cardiac events, and bleeding complications. Blood transfusion has long been the cornerstone of therapy for anemia; however, its benefit in patients with CAD is controversial and the appropriate threshold for transfusion has been widely debated. In this review, we summarize the studies evaluating the impact of anemia in patients with CAD undergoing percutaneous coronary intervention and address several issues regarding the use of transfusion in anemic patients. In addition, we discuss alternative options for the management of anemia, such as the use of erythropoietin, aqueous oxygen, and hemoglobin-based oxygen carriers.

Topics: Anemia; Angioplasty, Balloon, Coronary; Blood Substitutes; Blood Transfusion; Coronary Disease; Erythropoietin; Fibrinolytic Agents; Fluorocarbons; Hematinics; Hemoglobins; Hemorrhage; Humans; Oxygen; Recombinant Proteins; Risk Factors

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

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

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

Standing orders serve an important role in various healthcare settings by empowering nurses to implement certain procedures and activities on behalf of physicians, enabling more immediate interventions, and ultimately improving patient care. Standing orders are based on established clinical practice guidelines and are well suited for supportive interventions. Several evidence-based clinical practice guidelines are available for the treatment of anemia in patients with cancer. The guidelines can serve as a basis for the development of standing orders for the management of treatment-related anemia in patients with cancer, which will enable the delivery of consistently high-quality care to patients. A major advantage to the implementation of standing orders is that patients with suboptimal hemoglobin levels can be treated by oncology nurses in a timely manner and receive high-quality care that is consistent with available clinical evidence.

Topics: Algorithms; Anemia; Clinical Protocols; Decision Trees; Drug Monitoring; Epoetin Alfa; Erythropoietin; Evidence-Based Medicine; Ferritins; Hematinics; Hemoglobins; Humans; Iron; Iron-Binding Proteins; Mass Screening; Neoplasms; Nurse's Role; Nursing Assessment; Oncology Nursing; Patient Care Team; Practice Guidelines as Topic; Professional Autonomy; Quality Assurance, Health Care; Recombinant Proteins; Safety Management; Transferrin

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

Anemia and the need for red blood cell transfusions are common among patients admitted to intensive care units. Erythropoietin has been used to decrease the need for transfusions; however, its ability to improve clinical outcomes is unknown. We evaluated the effect of erythropoietin-receptor agonists on clinically important outcomes, including mortality, length of stay in hospital or intensive care unit, ventilator use, transfusion requirements and major adverse events.. To identify relevant studies, we searched electronic databases covering 1950 to 2007 (MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and the Scopus database). We also searched conference proceedings and grey literature sources. We selected all randomized controlled trials involving critically ill patients that compared an erythropoietin-receptor agonist with a placebo or no intervention. No language restrictions were considered. Data were extracted using a standardized extraction template. We used a fixed effects model to calculate all summary measures of treatment effects.. Of 673 identified records, 9 studies that investigated erythropoietin alpha met the eligibility criteria and were included in our analysis. Erythropoietin, compared with placebo or no intervention, had no statistically significant effect on overall mortality (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.71-1.05, I2 = 0%). The treatment and control groups did not differ in the length of stay in hospital or intensive care unit, or in the duration of mechanical ventilation, in the 3 studies that reported these outcomes. Erythropoietin, compared with placebo, significantly reduced the odds of a patient receiving at least 1 transfusion (OR 0.73, 95% CI 0.64-0.84, I2 = 54.7%). The mean number of units of blood transfused per patient was decreased by 0.41 units in the erythropoietin group (95% CI 0.10-0.74, I2 = 79.2%). Most of the included studies were performed before the widespread adoption of a restrictive transfusion strategy. Only 1 study provided detailed reports of adverse events, and none of the studies systematically evaluated all patients for venous thromboembolism.. At this time, we do not recommend the routine use of erythropoietin-receptor agonists in critically ill patients. The reduction in red blood cell transfusions per patient was very small, and there is insufficient evidence to determine whether this intervention results in clinically important benefits with acceptable risks.

Topics: Anemia; Critical Illness; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Hematinics; Humans; Randomized Controlled Trials as Topic; Receptors, Erythropoietin; Recombinant Proteins

Anemia is a frequent complication in patients with inflammatory bowel disease (IBD), and is associated with decreased quality of life and increased rate of hospitalization. The primary therapeutic targets of IBD-associated anemia are iron deficiency and anemia of chronic disease. An important prognostic parameter of the success or failure of therapy is the outcome of the underlying disease. Iron deficiency should be appropriately managed with iron supplementation. However, the use of oral iron therapy is limited by several problems, the most important being gastrointestinal side effects leading occasionally to disease relapse and poor iron absorption. Intravenous iron preparations are more reliable, with iron sucrose demonstrating the best efficacy and tolerability. Treatment with erythropoietin or darbepoetin has been proven to be effective in patients with anemia, who fail to respond to intravenous iron. Patients with ongoing inflammation have anemia of chronic disease and may require combination therapy comprising of intravenous iron sucrose and erythropoietin. After initiating treatment, careful monitoring of hemoglobin levels and iron parameters is needed in order to avoid recurrence of anemia. In conclusion, anemia in the setting of IBD should be aggressively diagnosed, investigated, and treated. Future studies should define the optimal dose and schedule of intravenous iron supplementation and appropriate erythropoietin therapy in these patients.

Topics: Anemia; Erythropoiesis; Erythropoietin; Humans; Inflammatory Bowel Diseases; Iron

Oxygen plays a direct role in cell death after exposure to ionizing radiations and tumour hypoxia, favoured by anaemia, is a factor of poor treatment response. Tumour phenotype is directly influenced by tissue oxygenation, inducing tumour cells adaptation to the environment and potential resistance to treatment. The correction of tumour hypoxia can increase treatment response. It is however difficult to directly correlate pO2 and vascularisation. Vessels from angiogenesis get endothelial cells but have lost the functions of normal vessels (receptors, muscles...). The role of angiogenesis has been demonstrated on initial tumour growth and on metastatic potential and regulation. Many pre clinical studies have demonstrated the benefit of combining anti angiogenic compounds and cytotoxic agents (chemotherapy drugs and ionizing radiations). Clinical studies are on going and new evaluation models of treatment response will be necessary.

Topics: Anemia; Angiogenesis Inhibitors; Animals; Cell Hypoxia; Combined Modality Therapy; Endothelium, Vascular; Erythropoietin; Humans; Neoplasms; Neovascularization, Pathologic; Oxygen; Oxygen Consumption; Partial Pressure; Radiation Tolerance; Recombinant Proteins

Due to concerns related to treatment with erythropoietin (EPO) and possible negative effects on tumour control, a workshop was organised by the Medical Products Agency of Sweden with the aim to revise national treatment guidelines if needed. In patients with solid tumours, conflicting results have been reported with respect to tumour control and survival. Until further notice it is therefore recommended that EPO should be used restrictively in the treatment of patients with cancer and that the anticipated improvement in quality of life should be evaluated against potential risks.

Topics: Anemia; Contraindications; Erythropoietin; Female; Hematinics; Humans; Male; Neoplasms; Practice Guidelines as Topic; Receptors, Erythropoietin; Survival Analysis; Sweden; Treatment Failure

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

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

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

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

Topics: Administration, Oral; Anemia; Ascorbic Acid; Erythropoietin; Humans; Injections, Intravenous; Recombinant Proteins; Renal Dialysis

To review evidence on the use of erythropoietic stimulating agents (erythropoietin or darbepoetin) in children with cancer.. A systematic review of the published literature was performed using MEDLINE (1966-July 2007) and references from a Cochrane systematic review (focusing mainly on adults) published in 2006.. The review identified 12 studies, comprising five randomized trials, six case control studies and one open-label, dose-escalation study. All the studies that used adequate doses of recombinant human erythropoietin (rhEPO) (usually 150 IU/kg three times per week) demonstrated benefits for rhEPO except for one study in which rhEPO was added to G-CSF in children with high-risk neuroblastoma. Despite the heterogeneity of the populations studied, in terms of age, tumour type and chemotherapy regimen, rhEPO use was associated with consistent benefits in terms of reduced transfusion requirements and improved haematological parameters. Only one case of darbepoietin use was reported.. While more studies are required, it appears that rhEPO is safe in this vulnerable patient group and can benefit children with cancer by preventing or ameliorating anaemia.

Topics: Anemia; Child; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Neuroblastoma; Recombinant Proteins

At present, anaemia in the patients with cancer remains a problem of the first magnitude and of increasing interest due to the high incidence, the major knowledge of its physiopathology, the negative impact on the quality of life of the patient, the influence on the evolution of the disease and its treatments and, finally to the progressive development of new alternatives of treatment, especially the erythropoietic agents. For all this, it becomes necessary to consider the treatment of the anemia of the patients with cancer as a basic part of their support treatment. The erythropoietic agents have demonstrated in the last years that constitute a therapeutic alternative to obtain an increase of the levels of hemoglobin in the patients with anticancer treatments, considering specially that the correction of the anemia not only represents the improvement of an analytical value but also has a significant impact on the quality of life of the patients and diminishes the transfusion requirements. Erythropoietic proteins available for the treatment of the anemia of the patients with cancer are Epoetin-alpha, Epoetin-beta and Darbepoetin-alpha. The existence of different drugs, different doses and intervals of administration, clinical different situations and heterogeneous studies, made necessary the development of documents of consensus and guides of clinical recommendations which provide information on the scientific evidence that supports the use of these agents in medical care. This paper summarizes the main recommendations from panels of experts and scientific societies published so far.

Topics: Anemia; Antineoplastic Agents; Erythropoietin; Hematinics; Humans; Neoplasms; Practice Guidelines as Topic; Societies, Scientific

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

Topics: Anemia; Antineoplastic Agents; Erythropoietin; Humans

Anemia is a common condition among medical and surgical patients admitted to the intensive care unit (ICU) and generally has a multifactorial origin. In order to avoid the deleterious effects of anemia, 40% of ICU patients receive allogenic blood transfusion (ABT). This figure increases up to 70% if the ICU stay is longer than 7 days. However, ABT is associated with a dose-dependent increase in morbidity and mortality. In contrast, the administration of exogenous erythropoietin plus iron supplements, especially iv iron, improves anemia and reduces ABT requirements, although it does not reduce mortality. To ascertain whether treatment of anemia in the critically ill with exogenous erythropoietin and iron might improve outcomes and to optimize drug administration schedules and dosage, further studies with sufficient statistical power and adequate follow-up are warranted.

Topics: Anemia; Blood Transfusion; Critical Illness; Erythropoiesis; Erythropoietin; Humans; Injections, Intravenous; Iron; Prevalence; Recombinant Proteins

Recent randomized, controlled trials indicate that there is a strong trend for increased risk for death or adverse composite outcomes with erythropoiesis-stimulating agent treatment in kidney disease to hemoglobin targets higher than those currently recommended. The failure of these trials to find a benefit of higher hemoglobin is in stark contrast to findings from large, observational, population-based studies that continue to demonstrate the association of low hemoglobin with adverse outcomes. The mechanisms for the adverse effect of higher hemoglobin targets that are seen in the randomized, controlled trials are poorly understood. This review explores hypotheses involving (1) the effect of achieved hemoglobin itself, (2) the role of erythropoiesis-stimulating agent treatment, (3) the use of iron supplementation, (4) increased blood pressure, and (5) erythropoiesis-stimulating agent hyporesponsiveness. Because the causal pathway has yet to be determined, further research is strongly encouraged. Clinical practice, however, should avoid erythropoiesis-stimulating agent treatment to higher hemoglobin targets, particularly in those with significant cardiovascular morbidity and those who require disproportionately high dosages of erythropoietin-stimulating agents to achieve recommended hemoglobin levels.

Topics: Anemia; Blood Platelets; Erythropoietin; Hemoglobins; Humans; Hypertension; Iron; Renal Dialysis

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

Advanced age alone should never be the reason for refusing elderly people an effective oncological therapy which could improve their quality of life and possibly also meaningfully extend their survival. However, age-related physiological organ changes and potential cognitive, emotional and social problems must be precisely analyzed before beginning a therapy. Only then can a decision be made for a specific tumour therapy or perhaps symptom management with supportive measures. Treatability is evaluated using test instruments that have been developed for geriatric assessment.

Topics: Age Factors; Aged; Aged, 80 and over; Anemia; Antineoplastic Agents; Erythropoietin; Geriatric Assessment; Humans; Life Expectancy; Middle Aged; Neoplasms; Palliative Care; Patient Selection; Prognosis; Quality of Life; Risk Factors

Anemia is a frequent problem in cancer patients, especially in those treated with chemotherapy, and has an important negative impact on quality of life. Red blood cell transfusions provide clear but rather temporary comfort. The development of erythropoietic stimulating agents (ESAs) led to a more durable anemia treatment. Darbepoetin alpha is a unique ESA with a long plasma half life, thereby suitable for administration with different dosing intervals. Apart from administration every week, darbepoetin alpha also proved to be efficient in reducing red blood cell transfusion rates and in improving health-related quality of life when administered at a dose of 500 microg once every 3 weeks. This is a convenient therapy schedule because it can be synchronized with the chemotherapy cycle in many patients. Recently, concerns have been raised about the long-term safety of ESAs, more specifically about their effect on survival. Available data must be interpreted with caution, but at present there is no clear evidence to support a negative effect on outcome with darbepoetin alpha therapy when used according to the guidelines for treatment of chemotherapy-induced anemia. Further studies focusing on survival as the primary end point are ongoing.

Topics: Anemia; Antineoplastic Agents; Blood Transfusion; Clinical Trials as Topic; Combined Modality Therapy; Darbepoetin alfa; Drug Administration Schedule; Drug Approval; Erythropoietin; Humans; Injections, Intravenous; Injections, Subcutaneous; Iron-Dextran Complex; Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Thromboembolism

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

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

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

Anaemia has a high incidence in cancer patients, especially when it is a consequence of myelosuppressive treatments. The incidence and prevalence of this condition is influenced by the type and extension of the tumour, type and intensity of the myelosuppressive treatment that patients receive, and previous surgery or intercurrent infections. Clinical manifestations of anaemia, overlapped by tumour symptomatology, depend on haemoglobin (Hb) levels; these manifestations cause impairment of the functional capacity, as well as a negative impact on the quality of life (QOL) of cancer patients as a consequence. Erythropoietin treatment for anaemia has been established as optimal for correcting Hb levels. Its impact on patients' QOL has been evaluated in numerous randomised prospective studies by the use of diverse types of erythropoietin and administration modes. The three types of erythropoietin, alpha, beta and darbepoetin alpha, have shown a clear efficacy in all haematological parameters. This positive effect is related with significant improvements in the QOL of patients, especially those patients undergoing myelosuppressive treatments, and with regard to specific scales of fatigue and anaemia.

Topics: Anemia; Antineoplastic Agents; Erythropoietin; Female; Humans; Male; Neoplasms; Quality of Life; Recombinant Proteins

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

Anaemia is a frequent complication in cancer patients and may be multifactorial in origin. Treatment with recombinant human erythropoietin (rHuEPO) is an alternative to red blood cell transfusion. The evidence from clinical trials has established that patients with chemotherapy-induced anaemia with a haemoglobin concentration below 10 g/dl benefit from epoetin therapy. The native glycoprotein hormone consists of 165 amino acids with three N-glycosylation and one O-glycosylation sites. Epoetin and darbepoetin bind to the EPO receptor to induce intracellular signalling by the same intracellular molecules as native EPO. There are some differences in the glycosylation pattern which lead to variations in the pharmacokinetics and pharmacodynamics profiles. Pharmacokinetic and therapeutic studies have examined the use of rHuEPO administered intravenously and subcutaneously and there is accumulating evidence that the latter route has several advantages in cancer patients. After subcutaneous administration, the bioavailability of epoetin is about 20-30% and has a plasma half-life of >24 h. Darbepoetin has a longer half-life after subcutaneous administration of 48 h. The general recommendations are based on evidence from trials in which epoetin was administered 150 U/kg thrice weekly. The recommended initial dose for darbepoetin alpha is 2.25 mug/kg per week. The most serious adverse effects are hypertension, bleeding and increased risk of thrombotic complications. Caution is advised when used in patients who are at high risk for thromboembolic events. In the management of anaemic cancer patients, physicians should closely follow the National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH) guidelines.

Topics: Anemia; Antineoplastic Agents; Erythropoietin; Humans; Neoplasms; Recombinant Proteins

The safety and efficacy of extended-dosage-interval regimens of erythropoiesis-stimulating agents (ESAs) for managing chemotherapy-induced anemia (CIA) are reviewed.. Anemia is a frequent complication of chemotherapy. The ESAs epoetin alfa and darbepoetin alfa have been shown to safely and effectively manage CIA; comparable outcomes have been demonstrated between epoetin alfa 40,000 units once weekly and darbepoetin alfa 200 microg every two weeks. These commonly prescribed regimens necessitate extra clinic visits by cancer patients receiving cyclic chemotherapy. ESA administration can now often be synchronized with a three-week chemotherapy cycle because of the recent approval of darbepoetin alfa 500 microg every three weeks for CIA. However, in the Phase III trial providing the basis for this new dosage recommendation, more than 70% of patients required a 40% reduction in the dosage, resulting in an average dose of 375 microg every three weeks. The extended-dosage-interval regimens have not been associated with an increase in cardiovascular or thrombotic adverse events. Extended-dosage-interval regimens of epoetin alfa are under investigation and may provide additional alternatives. Synchronizing ESA therapy with scheduled chemotherapy visits would help minimize disruptions for patients and caregivers and improve the use of health care resources.. Administration of darbepoetin alfa every three weeks offers the convenience of synchronization of treatment with 21-day-cycle chemotherapy in many patients with CIA. Extended-dosage-interval regimens for epoetin alfa are being investigated and show promise.

Topics: Anemia; Antineoplastic Agents; Drug Administration Schedule; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematinics; Humans; Recombinant Proteins

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

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Neoplasms; Recombinant Proteins

Topics: Anemia; Animals; Disease Models, Animal; Erythropoiesis; Erythropoietin; Female; Heart Failure; Humans; Male; Multicenter Studies as Topic; Myocardial Ischemia; Neovascularization, Physiologic; Oxygen Consumption; Prognosis; Randomized Controlled Trials as Topic; Rats; Recombinant Proteins; Risk Assessment; Stroke Volume; Survival Analysis; Treatment Outcome

Recombinant human erythropoietins (rhEPO) reliably increase hemoglobin levels in cancer patients experiencing chemotherapy-associated anemia. However, in patients with "anemia of cancer" not being treated with chemotherapy, rhEPO appears less effective. Recently, two studies have been broadly discussed which have raised concern on the concomitant use of erythropoietin and chemo- or radiation therapy in cancer patients. In addition, use of rhEPO is generally not considered cost-effective. Thus, the application of rhEPO should be limited to indications with proven clinical benefit. This review will provide an overview of the state of the art use of rhEPO in anemic patients and will discuss future developments.

Topics: Anemia; Bone Marrow Transplantation; Clinical Trials as Topic; Cost-Benefit Analysis; Erythropoietin; Female; Humans; Male; Myelodysplastic Syndromes; Neoplasms; Recombinant Proteins

Anaemia is a common occurrence in patients with cancer, resulting in symptoms such as fatigue that have a profound impact on quality of life. Anaemia is also associated with poor treatment outcome and overall survival. Epoetin beta, a recombinant human erythropoietin that has the same structure and function as the endogenous hormone, is an effective and safe treatment of cancer-related anaemia. Various studies in patients with solid tumours have shown that this agent effectively increases haemoglobin levels and reduces the need for emergency blood transfusions regardless of the type of concomitantly administered chemotherapy. Epoetin beta also improves the quality of life of anaemic patients with cancer, decreasing fatigue and improving the ability to perform usual daily activities. In addition, epoetin beta prevents severe anaemia and reduces transfusion requirements in patients with a high-risk of developing anaemia during chemotherapy, such as those receiving platinum-based regimens. A meta-analysis of epoetin beta trials showed that epoetin beta has no negative impact on survival or thrombosis-related survival and may reduce the risk of tumour progression in patients with solid or lymphoid malignancies. Another study has shown epoetin beta to be equally effective when administered once weekly or three times weekly. Therefore, epoetin beta offers an effective, safe and convenient therapy for the management of anaemia in patients with cancer.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Erythropoietin; Humans; Neoplasms; Recombinant Proteins

Anaemia and associated fatigue are common problems in patients with cancer, and fatigue is considered by patients with cancer to be their most limiting symptom. The introduction of erythropoiesis-stimulating proteins (ESPs) has greatly improved the management of anaemia; however, many European patients with cancer-related anaemia are untreated because of a lack of awareness among healthcare professionals of the benefits of anaemia treatment to patients, or because of regional differences in treatment practices. Recently, the European Organisation for Research and Treatment of Cancer (EORTC) developed the first European evidence-based guidelines for the use of ESPs in cancer-related anaemia in order to facilitate and standardize the assessment and management of the condition. These guidelines, and the implications for oncology nurses in implementing them in practice, are discussed.

Topics: Algorithms; Anemia; Decision Trees; Diagnosis, Differential; Documentation; Drug Administration Schedule; Drug Monitoring; Erythropoietin; Evidence-Based Medicine; Fatigue; Hemoglobins; Humans; Neoplasms; Nurse's Role; Nursing Assessment; Oncology Nursing; Patient Education as Topic; Patient Selection; Practice Guidelines as Topic

In recent years there has been an increasing debate regarding the benefits of initiating erythropoietic treatment in patients with cancer when anemia is still relatively mild. To address this, a systematic review of studies was conducted that answered the following question: Is there a clinical benefit associated with early erythropoietic intervention (hemoglobin > or = 10 g/dL) for chemotherapy-induced anemia?. A systematic review of published literature and meeting abstracts was undertaken to identify relevant studies. Data were extracted from studies meeting prespecified eligibility criteria. For outcome measures not associated with significant heterogeneity, summary measures of relative risk associated with early erythropoietic intervention were estimated using the method of Mantel and Haenszel.. Eleven studies were eligible and were included in the review. Erythropoietic treatment effectively decreased transfusion incidence and the proportion of patients with hemoglobin < 10 g/dL compared with no treatment, with relative risk reductions of 0.50 (95% confidence interval [CI], 0.43, 0.59; 7 studies, P < 0.0001) and 0.40 (95% CI, 0.19, 0.83; 4 studies, P = 0.147), respectively. The findings from both prospective studies and planned subset analyses in which early and late intervention were compared also indicated a reduction in the relative risk of both transfusions and hemoglobin < 10 g/dL after early intervention (0.55 [95% CI, 0.42, 0.73; 5 studies, P < 0.0001] and 0.44 [95% CI, 0.33, 0.57; 2 studies, P < 0.0001], respectively).. Collectively, these findings suggest that optimal clinical benefit from erythropoietic treatment of chemotherapy-induced anemia may be achieved through early intervention.

Topics: Anemia; Antineoplastic Agents; Erythrocyte Transfusion; Erythropoietin; Hemoglobins; Humans; Neoplasms; Quality of Life; Randomized Controlled Trials as Topic

To review and compare the data concerning the clinical activity of epoetin alfa versus darbepoetin alfa when administered to patients with cancer who are experiencing treatment-related anemia.. English-language publications from the MEDLINE database (1990-June 2005), published articles, and meeting abstracts were reviewed.. Relevant data were extracted from published reports and abstracts on studies of humans with cancer who developed treatment-related anemia and were treated with epoetin alfa or darbepoetin alfa.. Epoetin alfa and darbepoetin alfa are similar agents with identical indications for treatment of anemia in patients with cancer. Clinical trials have demonstrated that both agents can significantly improve hemoglobin levels, reduce transfusion requirements, and improve quality of life. Epoetin alfa is approved for administration at a dose of 150 units/kg subcutaneously 3 times per week, and darbepoetin alfa is approved for administration at a dose of 2.25 units/kg once a week. Clinical studies have demonstrated that epoetin alfa may be administered at 40,000 units once a week and that darbepoetin alfa may be administered at 200 microg every 2 weeks without loss of efficacy. Cost analysis, based on the average wholesale price of each drug alone administered for 12 weeks at Food and Drug Administration-approved doses, revealed that epoetin alfa is less expensive than darbepoetin alfa. When they are administered in the extended schedules, the cost of darbepoetin alfa is slightly less than that of epoetin alfa. However, the total expense associated with the extended schedule of either agent is further reduced by a reduction in other costs associated with drug administration.. Epoetin alfa and darbepoetin alfa have identical indications for treatment of anemia in patients receiving cancer chemotherapy. Clinical trials have demonstrated similar activities with both agents. Darbepoetin alfa, with a longer half-life, can be administered less frequently, saving costs as well as reducing patient office visits.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Neoplasms; Recombinant Proteins

Carnitine is a metabolic cofactor which is essential for normal fatty acid metabolism. Patients with chronic kidney disease on dialysis have been shown both to suffer from disordered fatty acid metabolism and to have a significant deficiency in plasma and tissue carnitine. Aberrant fatty acid metabolism has been associated with a number of cellular abnormalities such as increased mitochondrial permeability (a promoter of apoptosis), insulin resistance, and enhanced generation of free radicals. These cellular abnormalities have, in turn, been correlated with pathological clinical conditions common in dialysis patients including cardiomyopathy with attendant hypotension and resistance to the therapeutic effect of recombinant human erythropoietin (EPO). In 1999, the Food and Drug Administration approved levocarnitine injection for the prevention and treatment of carnitine deficiency in patients on dialysis based on documentation of free plasma carnitine levels in dialysis patients similar to other serious carnitine deficiency states for which treatment was required. Data analysis performed by expert panels convened by both the American Association of Kidney Patients and, subsequently, the National Kidney Foundation recommended a trial of levocarnitine therapy for specific subsets of dialysis patients including those with EPO resistance, dialysis-related hypotension, cardiomyopathy and muscle weakness. In 2003, the Centers for Medicare and Medicaid services convened a Medical Advisory Committee which established reimbursement on a national level for carnitine-deficient dialysis patients who had either dialysis-related hypotension or EPO resistance. Recently, a correlation between reductions in hospitalization rates of dialysis patients receiving levocarnitine therapy has been demonstrated in a large retrospective study. Despite data-based recommendations and national reimbursement, only a small minority of dialysis patients have been prescribed a therapeutic trial of levocarnitine. Whereas the reasons for the reluctance of nephrologists to prescribe this therapeutic trial are unclear, possible explanations include a lack of appreciation of the pivotal role played by carnitine in cellular metabolism and the strength of evidence for a substantial deficiency of carnitine in dialysis patients, an underestimation of the prognostic import of EPO resistance and dialysis-related hypotension, inadequate dissemination of the clinical trial data supporting the use of le

Topics: Acetylcarnitine; Anemia; Cardiomyopathies; Drug Resistance; Erythropoietin; Humans; Hypotension; Recombinant Proteins; Renal Dialysis; Vitamin B Complex

The database for carnitine supplements in dialysis includes no large-scale randomized trials and no registered trials. Medical practitioners prefer to make treatment decisions based on the outcome of randomized clinical trials, with appropriate controls. Furthermore, registered trials provide a further level of integrity, since trial registration avoids publication bias by ensuring that all outcomes are reported, including trials that are not completed. Positive effects reported from carnitine administration in dialysis patients include decreased erythropoietin dose, increased hematocrit, less intradialytic hypotension, and less fatigue. The evidence for carnitine effectiveness is limited to trials that are mostly open-label and that include no more than a total of 1,000 patients. An analysis of recent carnitine administrations to patients in a large dialysis practice database indicates no overall change in hemoglobin or erythropoietin dose following 6 months of carnitine administration. As outcomes of controlled trials with appropriate power to examine for the benefits of carnitine are not yet available, the dialysis practitioner cannot justify the administration of carnitine.

Topics: Anemia; Carnitine; Drug Resistance; Erythropoietin; Fatigue; Hypotension; Randomized Controlled Trials as Topic; Recombinant Proteins; Renal Dialysis; Treatment Outcome; Vitamin B Complex

Critically ill patients receive an extraordinarily large number of blood transfusions. Between 40% and 50% of all patients admitted to intensive care units (ICUs) receive at least one allogeneic red blood cell (RBC) unit and average close to 5 U of RBCs during their ICU admission. RBC transfusion is not risk-free, and there is little evidence that "routine" transfusion of stored allogeneic RBCs is beneficial to critically ill patients. It is clear that most critically ill patients can tolerate hemoglobin levels as low as 7 g/dL, and therefore, a more conservative approach to RBC transfusion is warranted. Anemia of critical illness is a distinct clinical entity characterized by blunted erythropoietin (EPO) production and abnormalities in iron metabolism identical to what is commonly referred to as anemia of chronic disease. As such, the bone marrow in many of these patients responds to the administration of exogenous EPO, in spite of their underlying critical illness. The efficacy of perioperative recombinant human erythropoietin (rHuEPO) has been demonstrated in a variety of elective surgical settings. Similarly, in critically ill patients, rHuEPO therapy will also stimulate erythropoiesis. In randomized placebo-controlled trials, therapy with rHuEPO resulted in a significant reduction in allogeneic RBC transfusions. Strategies to increase the production of RBCs are complementary to other approaches to reduce blood loss in the ICU and decrease the transfusion threshold in the management of all critically ill patients.

Topics: Anemia; Blood Loss, Surgical; Chronic Disease; Critical Illness; Elective Surgical Procedures; Erythrocyte Transfusion; Erythropoietin; Humans; Iron; Recombinant Proteins

Many controversial questions regarding the practice of neonatal red blood cell (RBC) transfusions exist, so that practices and policies vary widely. This article will critically assess information pertaining to two of these controversies, namely, the transfusion of RBCs stored for up to 42 days after collection vs the transfusion of fresh RBCs stored 7 days or less after donation and the use of recombinant human erythropoietin (rHuEPO) in attempts to either diminish the severity of or to treat the anemia of prematurity. Based on both theoretical considerations and several published clinical trials, RBCs from one donor stored up to 42 days in extended storage preservative solutions can safely provide all RBCs needed by most infants for small-volume transfusions. Based on a large number of clinical trials and a meta-analysis of these trials, it is impossible to provide firm guidelines for the use of rHuEPO in the treatment of the anemia of prematurity. Clearly, rHuEPO has efficacy in stimulating erythropoiesis in preterm infants, but success in the elimination or marked reduction in the need for RBC transfusions has not been definitively demonstrated.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Animals; Blood Preservation; Child; Child, Preschool; Clinical Trials as Topic; Erythrocyte Transfusion; Erythropoietin; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Male; Middle Aged; Pregnancy; Premature Birth; Recombinant Proteins

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

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

The introduction of recombinant human erythropoietin to the management of anemia in cancer patients has resulted in significant reductions in allogeneic blood transfusions, while at the same time contributing to improvements in quality of life. A recent meta-analysis of five randomized, placebo-controlled trials with patient-level data revealed that, while epoetin alfa was very effective in reducing transfusions compared with placebo, patients who were pretransfused were twice as likely to subsequently be transfused during epoetin alfa treatment.. To further assess the validity of this rather provocative concept, another integrated analysis was conducted with patient-level data from three Canadian trials, with a combined total of 665 patients receiving epoetin alfa treatments for their cancer- and chemotherapy-induced anemia.. Once again, pretransfusion was the most significant baseline predictor of transfusion, with patients that were pretransfused having a significantly greater likelihood of being transfused than their transfusion-naive counterparts. Furthermore, and corroborating previous findings, baseline hemoglobin (Hb) level was again found to be a significant predictor of transfusion, with patients who were treated at a baseline Hb level < 10 g/dl having a higher chance of being transfused than patients in whom epoetin alfa was initiated at baseline Hb levels of 10-11 g/dl. In addition, when the total units transfused in patients receiving epoetin alfa at different baseline Hb levels were analyzed, >85% of the units of blood transfused were received by patients with baseline Hb levels < 10 g/dl.. These data strongly suggest that early treatment with epoetin alfa could significantly optimize clinical benefit in reducing the use of transfusion in cancer patients receiving chemotherapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Canada; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Linear Models; Male; Middle Aged; Multivariate Analysis; Neoplasms; Recombinant Proteins; Risk; Risk Factors; Time Factors

Anemia, a potentially correctable cardiovascular risk factor, continues to be a major problem in kidney-transplant patients. Erythropoietin levels increase rapidly after successful kidney transplantation, and by 3 months, most patients achieve hemoglobin levels greater than 12 g/dL. Anemia may be caused by problems commonly seen in the general population such as iron deficiency or gastrointestinal blood loss, by immunosuppressive medications, or by more rare abnormalities such as hemolytic uremic syndrome or parvovirus B19-induced aplastic anemia. Iron deficiency is common at the time of transplantation and beyond and frequently contributes to anemia. Markers of iron deficiency (ferritin or transferrin saturation) are frequently inconclusive because of the presence of inflammation and infection. Immunosuppressive medications, such as azathioprine and mycophenolate mofetil (MMF), are a common cause of mild bone-marrow suppression and, thus, anemia. Sirolimus can cause more severe bone-marrow suppression, although this effect can lessen over time. The transplant patient with chronic kidney disease (CKD) frequently develops anemia, yet agents such as epoetin-alpha and darbepoetin are greatly underutilized. Evaluation of anemia should be undertaken when hemoglobin fails to normalize by 3 months after transplantation. Later after transplantation, especially in the setting of chronic allograft dysfunction, evaluation should take place when the hemoglobin falls to less than 11 g/dL in premenopausal females or to less than 12 g/dL in males and postmenopausal females.

Topics: Anemia; Erythropoietin; Humans; Kidney Transplantation; Prevalence; Risk Factors

The refusal of Jehovah's Witnesses to agree to blood or blood product transfusion based on religious beliefs is one of the most challenging conflictive issues health care givers have to face today. Such conflict is a by product of the ideological and religious diversity in society today. The perioperative care of such patients constitutes a genuine challenge for anesthesiologists and surgeons from technical, scientific, ethical, and legal perspectives. We review the reasons why Jehovah's Witnesses refuse transfusion and discuss the ethical, legal, and anesthetic aspects of their care. The literature up to August 2005 was reviewed by MEDLINE search. The following search terms were used: Jehovah's Witnesses, anesthesia (and anaesthesia), legislation and jurisprudence, ethics, blood transfusion, alternatives, anemia (and anaemia), erythropoietin, trigger, and critical care. To further cover ethical and legal aspects, we reviewed current laws in Spain and similar practice settings.

Topics: Anemia; Anesthesia; Attitude of Health Personnel; Blood Component Transfusion; Blood Preservation; Blood Substitutes; Blood Transfusion; Blood Transfusion, Autologous; Critical Care; Culture; Erythropoietin; European Union; Forms and Records Control; Human Rights; Informed Consent; Intraoperative Care; Jehovah's Witnesses; Medical Records; Physicians; Postoperative Care; Preoperative Care; Spain; Treatment Refusal

Topics: Anemia; Erythrocyte Transfusion; Erythropoietin; Evidence-Based Medicine; Humans; Meta-Analysis as Topic; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins

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

For cancer patients, anemia can be a debilitating problem that negatively influences their overall quality of life and worsens their prognosis. The condition is caused either by the cancer itself or by cytotoxic treatment. Anemia is the primary indication for transfusion of red blood cells, but the development of recombinant human erythropoietins (epoetins) provides an alternative to red blood cell transfusions. Treatment with epoetins has been shown to reduce transfusion rates and increase hemoglobin response. There is some evidence that epoetins improve quality of life. It remains unclear, however, whether erythropoietin affects tumor growth and survival, and this area requires further investigation. Data from clinical trials suggest that erythropoietin increases the risk of thromboembolic complications. In the management of anemic patients, physicians should follow closely the dosing recommendations in products' package inserts or the ASCO/American Society of Hematology guidelines. Treatment of patients beyond the correction of anemia, however, has to be regarded as experimental and is potentially harmful, so should only be conducted in clinical trials.

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Humans; Neoplasms; Practice Guidelines as Topic; Quality of Life; Recombinant Proteins; Survival Analysis

Topics: Anemia; Erythropoietin; Humans; Receptors, Erythropoietin; Recombinant Proteins; Renal Insufficiency

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

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

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

Recombinant human erythropoietin (rHuEpo) has become the most widely used cytokine in the world. Following the success of its use in patients with end-stage renal disease, the usefulness of rHuEpo to ameliorate other anemias was assessed, including pediatric patients and newborn infants. The treatment or prevention of anemia of prematurity with rHuEpo resulted in a significant reduction in the number of transfusions and donor exposure. A clear definition of which premature babies must receive therapy needs yet to be established. Other indications in neonatal period include hyporegenerative and hemolytic anemias. With the exception of chronic renal failure, in older children the efficacy of rHuEpo has not been evaluated as in adults. While an impressive amount of studies were carried out during the last years in adult patients with cancer-related or HIV-infection-related anemias, allowing to establish clear conclusions on its efficacy, only a few trials with small number of patients have been reported in children. Up to date, results in pediatric patients suggest that rHuEpo therapy is as useful as in adult patients, but prospective, randomized trials including large number of patients are essential to achieve definitive conclusions. Results of studies designed to evaluate the efficacy of rHuEpo for sustaining an adequate dose of ribavirin in patients receiving treatment for hepatitis C are encouraging. The potential for use of the non-hematopoietic effects of rHuEpo in newborn infants is a novel and exciting issue. The role of rHuEpo as a tissue protective factor for central nervous system and intestinal mucosa is under exhaustive investigation.

Topics: Adult; Anemia; Anemia, Neonatal; Child; Child, Preschool; Erythropoietin; Hepatitis C; HIV Infections; Humans; Infant; Infant, Newborn; Infant, Postmature; Neoplasms; Recombinant Proteins; Renal Dialysis; Renal Insufficiency

Topics: Anemia; Blood Transfusion; Erythropoietin; Female; History, 20th Century; Humans; Male; Neoplasms; Recombinant Proteins

Pegylated interferon and ribavirin combination therapy represent the standard-of-care treatment for chronic hepatitis C, that allows to cure more than half of the patients. However, the success of this bitherapy is in balance with numerous side effects, especially hematologic and psychiatric. This review is focused on complementary treatments (erythropoietin, G-CSF, vitamin E, glutathion, ursodeoxycholic acid and antidepressants) likely to bring a benefit in maintaining adequate interferon and ribavirin dosages and in improving quality of life. This analysis has been performed by using the Medline(R) data base and with data from laboratories which commercialized these molecules. Erythropoietin, G-CSF and antidepressants are the best tools to optimize the bitherapy in its dose and its duration while privileging the quality of life of HCV-infected patients.

Topics: Anemia; Antidepressive Agents; Antioxidants; Antiviral Agents; Erythropoietin; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Neutropenia; Polyethylene Glycols; Recombinant Proteins; Ribavirin; Thrombocytopenia

Anaemia is a common finding in patients with diabetes, particularly in those with overt nephropathy or renal impairment. In tertiary clinics, at least one outpatient in five with diabetes has anaemia, for whom it constitutes a significant additional burden.. Anaemia is associated with an increased risk of diabetic complications including nephropathy, retinopathy and macrovascular disease. Anaemia may also be significant in determining the outcome of heart failure and hypoxia-induced organ damage in diabetes. While several factors contribute to the increased prevalence of anaemia in diabetes, the failure of the kidney to increase erythropoietin in response to falling haemoglobin appears to be the dominant factor. Although there is a clear rationale for correcting anaemia in people with diabetes, it remains to be established whether this will lead to improved outcomes. Moreover, the balance of risks, costs, and benefits remains to be established in patients with diabetes. The Trial to Reduce Cardiovascular Events with Aranesp (darbepoetin alpha) Therapy (TREAT) is a randomised controlled trial designed to determine the impact of anaemia correction on mortality and non-fatal cardiovascular events in patients with type 2 diabetes and stage 3-4 nephropathy.. It is anticipated that TREAT will help to define the optimal approach to the management of anaemia in diabetes.

Topics: Anemia; Diabetes Complications; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Erythropoietin; Humans

To present information regarding the use of recombinant human erythropoietin (rHuEPO) to treat anemia in intensive care unit (ICU) patients. Anemia is common in critically ill patients. Approximately 95% of patients have subnormal hemoglobin (Hb) values by day 3 of their ICU stay. ICU-associated anemia often requires replacement of red blood cells (RBCs) via transfusion. Recent surveys of ICU practice document that approximately 50% of ICU patients receive RBC transfusions. ICU-associated anemia is largely the result of the cumulative effects of blood loss and decreased RBC production. Blood loss in critically ill patients may be overt, occult, or due to phlebotomy. Decreased RBC production is the other major factor influencing the development of anemia. Decreased RBC production is due to the combined effects of abnormal iron metabolism, inappropriately low erythropoietin production, diminished response to erythropoietin, and direct suppression of RBC production. Inflammatory mediators play a pivotal role in the pathogenesis of decreased RBC production. Clinical trials have shown that, compared with nontreated subjects, rHuEPO-treated ICU patients will have increased serum erythropoietin concentrations, increased reticulocyte counts, and increased hemoglobin and hematocrit values and require fewer RBC transfusions. These clinical trials have not detected significant differences in outcomes in association with rHuEPO, however.. rHuEPO can be used to increase hemoglobin and hematocrit values and decrease the number of RBC transfusions in ICU patients. Further investigation is necessary to identify the appropriate target population of ICU patients for treatment, to clarify the appropriate dosing schedule, and to ascertain whether such therapy has a positive impact on outcomes.

Topics: Anemia; Blood Component Transfusion; Critical Illness; Erythropoietin; Humans; Intensive Care Units; Randomized Controlled Trials as Topic; Recombinant Proteins

Allogeneic red blood cell (RBC) transfusions are associated with multiple disadvantages, such as limited availability, high costs, multiple risks and side effects. In addition, large outcome studies comparing liberal (hemoglobin transfusion trigger range 9-10 g/dL) and restrictive (hemoglobin transfusion trigger range 7-9 g/dL) transfusion regimens still need to be performed for surgical patients. Different transfusion alternatives are known for the pre-, intra- and postoperative period. Autologous blood donation and erythropoietin are efficacious in the preoperative period. Intraoperatively, acute normovolemic hemodilution (ANH), cell salvage, antifibrinolytics, specific anesthetic and surgical techniques, coagulation monitoring, acceptance of minimal hemoglobin values and hopefully soon artificial oxygen carriers can reduce allogeneic RBC transfusions. In the postoperative period cell salvage, antifibrinolytics, and accepting minimal hemoglobin values represent alternatives to RBC transfusions. When treating a bleeding patient, the initial administration of crystalloids and colloids to restore and maintain normovolemia is important. RBC transfusions are recommended under the following circumstances: for hemoglobin levels <6 g/dL and for physiologic signs of inadequate oxygenation such as hemodynamic instability, oxygen extraction rate >50% and myocardial ischemia, detectable by new ST-segment depressions >0.1 mV, new ST-segment elevations >0.2 mV or new wall motion abnormalities by transesophageal echocardiography. The aim of this article is to review the efficacy, risk and side effects of RBC transfusions, to discuss transfusion alternatives and to summarize current indications for RBC transfusions. This information will help the physician to judiciously use RBC transfusions when they are indeed indicated.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anemia; Blood Loss, Surgical; Blood Transfusion; Blood Transfusion, Autologous; Cardiovascular Diseases; Child; Critical Care; Erythropoietin; Hemoglobins; Hemorheology; Humans; Immune System; Infant, Newborn; Oxygen; Oxyhemoglobins; Postoperative Period; Risk; Sepsis; Transfusion Reaction

As with other groups of chronic kidney disease patients, the treatment of anaemia is of paramount importance in the general management of patients receiving regular peritoneal dialysis. The availability of agents able to stimulate erythropoiesis has transformed the management of anaemia in CKD, but questions are still raised as to the optimum means of using these drugs. Iron management is also pivotal to the satisfactory correction of anaemia, and again there is much discussion as to whether oral or intravenous iron is the preferred mode of administration in peritoneal dialysis patients. On the basis of the published evidence to date, PD patients should maintain a haemoglobin above 11 g/dL in line with the US and the European Anaemia guidelines, and intravenous iron should be used to correct any iron deficiency. Oral iron may be effective in a minority of patients. This article aims to explore some of these issues in greater detail so that patients on peritoneal dialysis can derive the greatest benefits from correction of anaemia and maintenance of an adequate haemoglobin.

Topics: Anemia; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hemoglobins; Humans; Iron; Peritoneal Dialysis; Peritonitis; Recombinant Proteins

Darbepoetin alfa (Aranesp) is an analogue of recombinant human erythropoietin (rHuEPO) produced using recombinant DNA technology. The high number of sialic acid moieties in darbepoetin alfa results in a prolonged half-life and enhanced in vivo biological activity compared with rHuEPO (as demonstrated in animal studies) and permits a reduction in the frequency of administration. Subcutaneous darbepoetin alfa 2.25 microg/kg once weekly or 500 microg once every 3 weeks (with a provision for dose adjustments) is an effective and well tolerated erythropoietic agent in anaemic patients with cancer receiving chemotherapy. In randomised, controlled clinical trials, the drug increased haemoglobin levels and reduced the need for blood transfusions in patients with various types of nonmyeloid malignancies and also ameliorated anaemia-related fatigue, thereby improving their health-related quality of life (HR-QOL) scores. The once-every-3-weeks dosage regimen provides further convenience by offering the possibility of synchronising its administration with most chemotherapy regimens. Direct comparisons between approved dosages of darbepoetin alfa and other erythropoietic agents have not been conducted. Such comparisons would be very helpful in formulating definitive conclusions about their relative efficacy and cost effectiveness. Darbepoetin alfa provides an effective and well tolerated treatment option for the treatment of anaemia in patients with cancer receiving chemotherapy.

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Erythropoietin; Humans; Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Treatment Outcome

Febrile neutropenia and anemia are two major complications of chemotherapy. Human recombinant cytokines as G-CSF and erythropoietin allow efficient fight against these secondary effects but require iterative injections due to a short half life. The glycosylation of natural cytokines results in enhanced stability of these molecules of new generation and makes it possible to space the injections which become concomitant of chemotherapies. With regard to the erythropoietin, the prolonged half-life form shows a similar effectiveness with the natural molecule. For the G-CSF, the glycosylated form could still show itself more effective for the prevention of febrile neutropenias. Finally, these new molecules allow an improvement of the quality of life while ensuring an optimal dose-intensity of the treatment.

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Delayed-Action Preparations; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Neutropenia; Polyethylene Glycols; Recombinant Proteins

The Standards, Options and Recommendations on the use of erythropoietin in cancer patients are recalled. The recent literature is analysed and allows some further comments to the SOR. Medico-economic aspects, new schedules of administration, extra-hematologic virtues of erythropoietin and its impact on cancer outcomes are debated.

Topics: Adult; Anemia; Brain; Child; Cognition Disorders; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Heart; Hematinics; Humans; Medical Oncology; Practice Guidelines as Topic; Recombinant Proteins

Hypoxia is now recognized as a major explanation of tumor radioresistance and is an important prognostic factor in head and neck and cervical cancers. Anemia, which had also a negative impact on cancer prognosis, increase tumor hypoxia. But we do not know actually if anemia has a direct role in tumor resistance or if it only reflect aggressiveness of the disease. Some trials have demonstrated that erythropoietin could increase the hemoglobin level during radiation courses. The only published randomised trial, performed in head and neck cancers, did not find any benefit for erythropoietin ; moreover, a deleterious effect was demonstrated. Possible explanations for this paradoxal result were discussed, particularly biological hypothesis and statistical bias.

Topics: Anemia; Blood Transfusion; Cell Hypoxia; Erythropoietin; Hematinics; Humans; Neoplasms; Otorhinolaryngologic Neoplasms; Radiation Tolerance; Randomized Controlled Trials as Topic; Recombinant Proteins

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

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

Topics: Anemia; Antineoplastic Agents; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Humans; Neoplasms

Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoietin (Epo), darbepoetin (Darbepo) and red blood cell transfusions.. The aim of this systematic review was to assess the effects of Epo or Darbepo to either prevent or treat anaemia in cancer patients.. We searched the Central Register of Controlled Trials, MEDLINE and EMBASE and other data bases. Searches were done for the periods 01/1985 to 12/2001 for the first review and 1/2002 to 04/2005 for the update. We also contacted experts in the field and pharmaceutical companies.. Randomised controlled trials on managing anaemia in cancer patients that compared the use of Epo/Darbepo (plus transfusion if needed) with observation until red blood cell transfusion was required.. Several reviewers independently assessed trial quality and extracted data.. This update of the systematic review included a total of 57 trials with 9,353 patients. Of these, 27 trials with 3,287 adults were also included in the first Cochrane Review. Thirty trials with 6,066 patients were added during the update process. Use of Epo/Darbepo significantly reduced the relative risk of red blood cell transfusions (RR 0.64; 95% CI 0.60 to 0.68, 42 trials, n = 6,510). On average participants in the Epo/Darbepo group received one unit of blood less than the control group (WMD -1.05; 95% CI -1.32 to -0.78, 14 trials, n = 2,353). For participants with baseline haemoglobin below 12 g/dL haematological response was observed more often in participants receiving Epo/Darbepo (RR 3.43; 95% CI 3.07 to 3.84, 22 trials, n = 4,307). There was suggestive evidence that Epo/Darbepo may improve Quality of Life (QoL). The relative risk for thrombo embolic complications was increased in patients receiving Epo/Darbepo compared to controls (RR 1.67, 95% CI 1.35 to 2.06; 35 trials, n = 6,769). Uncertainties remain whether and how Epo/Darbepo effects tumour response (fixed effect RR 1.12; 95% CI 1.01 to 1.23, 13 trials, n = 2,833; random effects: RR 1.09; 95% CI 0.94 to 1.26) or overall survival (unadjusted and adjusted data: HR 1.08; 95% CI 0.99 to 1.18; 42 trials, n = 8,167).. There is consistent evidence that administration of Epo/Darbepo reduces the relative risk for blood transfusions and the number of units transfused in cancer patients. For patients with baseline haemoglobin below 12 g/dL (mild anaemia) there is strong evidence that Epo/Darbepo improves haematological response. There is suggestive evidence that Epo/Darbepo may improve QoL. However, there is strong evidence that Epo/Darbepo increases the relative risk for thrombo embolic complications. Whether and how Epo/Darbepo effects tumour response and overall survival remains uncertain.

Topics: Anemia; Darbepoetin alfa; Erythrocyte Transfusion; Erythropoietin; Humans; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins

Erythropoiesis-stimulating proteins (ESPs) are indicated for the treatment of chemotherapy-induced anemia (CIA). Evidence-based guidelines and systematic reviews of the management of CIA do not yet include all currently approved ESPs or all of the clinically relevant benefits and risks of ESPs.. The aims of this work were to provide up-to-date assessments of the clinical efficacy and effectiveness (ie, transfusions and quality-of-life [QoL] benefits) and safety (ie, risk of venous thromboembolism [VTE] and all-cause or treatment-associated death) of epoetin-alfa, epoetin-beta, and darbepoetin-alfa for the treatment of CIA in cancer patients with hemoglobin<11 g/dL. We also considered the impact of differences in study design, patients, and treatments on the results.. A systematic review of the literature was performed to identify and analyze English-language studies (controlled trials and prospective uncontrolled studies with >or=300 patients) published between 1980 and July 2005. The databases searched were MEDLINE and the Cochrane Library. Relevant abstracts from the last 2 annual meetings of the American Society of Clinical Oncology, American Society of Hematology, and European Society for Medical Oncology were also included. Studies were selected, using predefined eligibility criteria. Two reviewers had to agree on all included and excluded studies, and on all data extracted from each accepted study before they were entered into a relational database. Meta-analyses were performed to quantify benefit and risk outcomes.. In total, 40 studies including 21,378 patients were eligible for analysis. Each ESP was found to have efficacy relative to standard care or placebo. The odds ratio (OR) for transfusions in studies of epoetin versus controls was 0.44 (95% CI, 0.35-0.55) and of darbepoetin versus controls was 0.41 (95% CI, 0.31-0.55). Patients receiving ESPs experienced a significant improvement in QoL; the mean difference in Functional Assessment of Cancer Therapy-Fatigue score for ESPs versus controls was 0.23 (95% CI, 0.10-0.36; P=0.001). The frequency of VTE and death was not significantly different between ESPs and control (VTE OR, 1.41 [95% CI, 0.81-2.47]; all-cause mortality OR, 1.00 [95% CI, 0.69-1.44]).. This analysis of key clinical benefits and risks of epoetin and darbepoetin in the treatment of CIA found no clinically relevant differences between these drugs.

Topics: Adult; Anemia; Antineoplastic Agents; Blood Transfusion; Child; Clinical Trials as Topic; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Quality of Life; Recombinant Proteins; Thromboembolism; Venous Thrombosis

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

Cardiovascular disease (CVD) is the major cause of morbidity and mortality in people with diabetes and in those with chronic kidney disease (CKD). Diabetes, occurring in epidemic proportions in the United States and worldwide, is also the leading cause of CKD and kidney failure. Identification of modifiable risk factors for CVD in patients with diabetes and CKD is thus of paramount importance. Anemia is increasingly recognized as a potential CVD risk factor in patients with diabetic nephropathy, in whom it is generally more severe and occurs at an earlier stage of CKD. In this review, we discuss the epidemiologic evidence, pathophysiologic mechanisms, and the current research findings, highlighting the role of anemia as a potential modifiable risk factor for CVD in patients with diabetic nephropathy, a particularly vulnerable population for CVD.

Topics: Anemia; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Diabetic Nephropathies; Erythropoietin; Humans; Risk Factors

Anemia is common in patients with hematologic malignancies, and it has negative effects on their quality of life. The current clinical practice guidelines recommend erythropoietic therapy in patients with cancer- or chemotherapy-related anemia, but anemia is often undertreated in patients with hematologic malignancies. Several randomized controlled trials have shown that treatment with erythropoiesis-stimulating proteins such as epoetin alfa (Procrit), epoetin beta, and darbepoetin alfa (Aranesp) increases hemoglobin levels, reduces the need for red blood cell transfusions, and improves quality of life in patients with hematologic malignancies and anemia receiving chemotherapy. Furthermore, preliminary data from a recent open-label study suggest that early treatment of mild anemia in patients with hematologic malignancies treated with chemotherapy produces marked improvements in quality of life and productivity. Increasing patients' hemoglobin levels may also improve their cognitive function. These findings support the use of erythropoietic therapy to manage anemia in patients with hematologic malignancies who are treated with chemotherapy.

Topics: Anemia; Darbepoetin alfa; Epoetin Alfa; Erythropoiesis; Erythropoietin; Hematologic Neoplasms; Humans; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins

Anemia is common in patients treated with chemotherapy for both solid and hematologic malignancies, contributing to fatigue and diminished quality of life and exposing them to the inherent risks of red blood cell transfusions. Erythropoiesis-stimulating proteins have been shown to increase hemoglobin levels, reduce the need for transfusions, and improve quality of life. The current practice guidelines recommend treating moderate to severe chemotherapy-induced anemia with erythropoiesis-stimulating proteins, but the risk of transfusions may be less with earlier intervention at higher hemoglobin levels. A review of the literature suggests that treating mild chemotherapy-induced anemia with erythropoiesis-stimulating proteins reduces the risks of transfusions and the development of more-severe anemia. Weighing the clinical evidence together with other clinical and economic considerations should provide greater insight into the benefits of treating mild anemia in patients treated with chemotherapy.

Topics: Anemia; Drug-Related Side Effects and Adverse Reactions; Epoetin Alfa; Erythropoiesis; Erythropoietin; Humans; Neoplasms; Recombinant Proteins; Time Factors

Chemotherapy-induced anemia is common in patients who have cancer. Erythropoiesis-stimulating proteins such as epoetin alfa (Procrit) and darbepoetin alfa (Aranesp) have been shown to improve hematologic and clinical outcomes in these patients. Darbepoetin alfa has a longer serum half-life than epoetin alfa, making less frequent administration possible and offering the possibility of synchronizing the administration of erythropoietic therapy and chemotherapy. Several clinical trials have evaluated the utility of darbepoetin alfa given every 3 weeks (q3wk) in patients with chemotherapy-induced anemia. An exploratory study showed that darbepoetin alfa q3wk stabilized hemoglobin levels and reduced transfusion requirements. It was also shown that giving darbepoetin alfa q3wk at the same time as the chemotherapy produced hematopoietic benefits similar to those observed when it is given later in the chemotherapy cycle. The q3wk dosing schedule was effective in patients with mild and moderate anemia, and treatment goals were achieved in most of them. The equivalence of q3wk and qwk darbepoetin alfa has also been established. Synchronous administration of darbepoetin alfa with chemotherapy is a convenient option for patients with chemotherapy-induced anemia, with clinical trials showing it to be an effective treatment strategy.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Darbepoetin alfa; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Hematinics; Humans; Neoplasms

Anemia is common in many patients with cancer treated with chemotherapy. One option for managing chemotherapy-induced anemia (CIA) is erythropoiesis-stimulating proteins (ESPs), which are indicated for the treatment of CIA in patients with most types of cancer. They have been shown to be safe and effective in numerous well-documented studies, and their side effects are well known. The rate of thrombotic events with the long-acting ESP darbepoetin alfa (Aranesp) has been consistent in studies conducted before and after its approval. The association of thrombotic events with high hemoglobin levels or rapid increases in its levels in patients with cancer remains controversial. Adjusting the dose of the ESP to maintain and monitor a target hemoglobin level of 11 to 12 g/dL is certainly prudent and may help prevent or minimize these events. Chemotherapy-induced anemia has been associated with shorter survival in patients with cancer, and the relation is likely multifactorial. Data on the treatment of CIA with ESPs have not shown a consistent effect on survival. Two studies in patients with hemoglobin levels above the target level showed that survival was shorter in the patients treated with ESPs. A review of data from other trials found no effect of ESPs on survival, and other trials suggested a positive effect. This article reviews data on survival in patients treated with ESPs and discusses five large randomized controlled trials of darbepoetin alfa that are addressing this issue.

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Erythropoiesis; Erythropoietin; Hematinics; Humans; Neoplasms; Randomized Controlled Trials as Topic; Survival Rate

Topics: Anemia; Antiemetics; Antineoplastic Agents; Erythropoietin; Evidence-Based Medicine; Humans; Incidence; Nausea; Neoplasms; Nurse's Role; Oncology Nursing; Practice Guidelines as Topic; Quality of Life; Radiotherapy; Risk Factors; Stomatitis; Survivors; Vomiting

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

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

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

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

Anemia is a common finding in diabetes, particularly in patients with albuminuria or renal impairment. We recently showed that at least 1 in 5 outpatients with type 1 or type 2 diabetes in tertiary clinics have anemia, in whom it constitutes a significant additional burden. Anemia is associated strongly with an increased risk of diabetic complications including nephropathy, retinopathy, and heart failure. Although a number of factors contribute to an increased prevalence of anemia in diabetes, an uncoupling of hemoglobin concentration and renal erythropoietin synthesis associated with tubular dysfunction appears to be the dominant factor. In our patients with diabetes and anemia, more than three quarters had functional erythropoietin deficiency. This association was most pronounced in patients with renal impairment, in whom nearly half of all patients had anemia. However, 70% of anemic patients without renal impairment also had inappropriately low erythropoietin levels. Consequently, the likelihood of functional erythropoietin deficiency, as a cause of anemia in patients with diabetes, is not dependent on the severity of renal impairment. Although there is a clear rationale for correction of anemia in diabetes, it remains to be established whether this will lead to improved outcomes. Some small studies suggest improvement in cardiac outcomes and hospitalization. It is anticipated that large ongoing studies will help define the optimal approach to the management of anemia in diabetes.

Topics: Anemia; Diabetes Complications; Diabetic Angiopathies; Diabetic Nephropathies; Erythropoietin; Heart Diseases; Humans

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

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

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

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

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

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

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

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

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

As with many other therapeutic areas in modern-day medicine, scientific advances in drug development (using such techniques as recombinant DNA technology, site-directed mutagenesis, pegylation of molecules, peptide library screening, and gene transfer) have resulted in the development of potential new agents and strategies for stimulating erythropoiesis. These advances are of possible benefit in treating anaemia due to various causes, including chronic renal failure. Several new treatments will soon become clinically available, while others are at present at an early stage of development but are nevertheless of scientific interest. We review these new therapeutic strategies, and discuss at what stage some of the newer products are in relation to their clinical development programme.

Topics: Anemia; Animals; Darbepoetin alfa; Epoetin Alfa; Erythropoiesis; Erythropoietin; Humans; 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

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

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

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

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

Erythropoietin (EPO), already known as the stimulating hormone for erythropoiesis, has shown different and interesting pleiotropic actions. It does not only affect erythroid cells, but also myeloid cells, lymphocytes and megakaryocytes. This hormone can also enhance phagocytic function of the polymorphonuclear cells and reduce the activation of macrophages, thus modulating the inflammatory process.Moreover, hematopoietic and endothelial cells probably have the same cellular origin, and the discovery of erythropoietin receptors (EPO-R) also on mesangial and myocardial cells, smooth muscle fibrocells and neurons has prompted the study of the non-erythropoietic functions of this hormone.The interaction between EPO and VEGF may be of particular importance in neovascularization and wound healing. Different studies have demonstrated that EPO has an important direct hemodynamic and vasoactive action, which does not depend exclusively on any increase in hematocrit and viscosity. Moreover EPO showed protective effects on myocardial cells against apoptosis induced by ischemia/repefusion injury, but it could negatively affect pulmonary hypertension in patient with chronic cor pulmonale.This review aims to stress the importance of the increasing interest in EPO applications and the necessity of further studies to gain a deeper knowledge of this hormone and its pleiotropic and complex actions.

Topics: Anemia; Angiogenesis Modulating Agents; Clinical Trials as Topic; Erythropoietin; Humans; Hypoxia; Shock; Vascular Endothelial Growth Factor A

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

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

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

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

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

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

To assess the early effect of epoetin beta on survival and tumour progression in anaemic patients with cancer, data were pooled from nine randomised clinical trials comparing epoetin beta with placebo or standard care. Studies were not primarily designed to assess these end points. Follow-up was for treatment duration plus 4 weeks following therapy completion. All adverse events (AEs) were retrospectively reviewed blinded, for progression. Thromboembolic events were also assessed. Data analysis involved standard statistical tests. Overall, 1413 patients were included (epoetin beta, n = 800; control, n = 613; 56% haematological, and 44% solid). Median initial epoetin beta dose was 30,000 IU/week. Overall survival during months 0-6 was similar with epoetin beta and control (0.31 vs 0.32 deaths/patient-year). No increased mortality risk was seen with epoetin beta (relative risk (RR) 0.97, 95% CI: 0.69, 1.36; P = 0.87). There was a significantly reduced risk of rapidly progressive disease for epoetin beta (RR 0.78, 95% CI: 0.62, 0.99; P = 0.042). Epoetin beta was associated with a slightly higher frequency of thromboembolic events vs control (5.9% vs 4.2% of patients) but thromboembolic-related mortality was identical in both groups (1.1%). Epoetin beta provided a slight beneficial effect on tumour progression and did not impact on early survival or thromboembolic-related mortality.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Disease Progression; Erythropoietin; Female; Humans; Male; Middle Aged; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Rate

Anemia has recently been recognized as a frequent complication of diabetic nephropathy, appearing earlier than in nondiabetic renal disease and amplifying the risks of cardiovascular and microvascular complications. A major cause is an inappropriate erythropoietin response to anemia, often accompanied by iron deficiency and therapy with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

Topics: Anemia; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Disease Progression; Erythropoietin; Heart Diseases; Humans

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

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

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

Ribavirin (RBV) is an antiviral nucleoside analogue commonly used in combination with interferon for the treatment of chronic hepatitis C. Severe anemia develops in about 10% of treated patients, and requires close monitoring of hemoglobin and often RBV dose reduction, which may compromise sustained virologic response. Anemia is likely related to extensive RBV accumulation in erythrocytes subsequent to active unidirectional transmembraneous transport. RBV exerts its toxicity through an inhibition of intracellular energy metabolism and oxidative membrane damage, leading to an accelerated extravascular hemolysis by the reticulo-endothelial system. Concentration-dependent toxicity and improvement of anemia upon dose-reduction point towards the importance of pharmacokinetic factors for RBV-induced anemia. On the other hand, pronounced variability in the correlation between RBV concentration and Hb reduction limits the prediction of anemia based on plasma or erythrocyte concentrations in individual patients and points towards additional factors determining individual susceptibility to RBV-induced anemia. Recent studies suggest that erythrocyte oxidative defense mechanisms may play an important role in RBV-induced anemia. Clinical risk factors for severe RBV-induced anemia include impaired renal function, high age, high dose per body weight and female gender. Determination of RBV concentrations has little value in the management of anemia. The only proven effective prevention of RBV-induced anemia is the concomitant administration of erythropoietin. Future research on RBV pharmacokinetics and pharmacodynamics, as well as erythrocyte antioxidant defense mechanisms may improve safety and efficacy of RBV therapy and guide the development of new treatments for RBV-induced anemia and alternative antiviral agents.

Topics: Anemia; Antiviral Agents; Erythropoietin; Humans; Oxidants; Ribavirin; Risk Factors

The morbidity, mortality and economic burden of chronic kidney disease (CKD) and associated anaemia are substantial. With the increasing numbers of patients who are likely to be affected in the future, approaches are required to improve anaemia management without increasing the burden on health-care professionals. A multidisciplinary approach to treatment, where early initiation of erythropoiesis-stimulating agents (ESA) is encouraged, may improve patient outcomes. Recent studies also suggest that the early use of iron therapy in patients with CKD not on dialysis may be associated with beneficial effects on haemoglobin levels. Another strategy to reduce the burden on health-care providers is to simplify anaemia management by extending the administration interval of ESA. Indeed, recent studies have explored the efficacy of extending the administration interval of ESA in clinical practice in CKD patients on dialysis and not on dialysis. The ability to maintain haemoglobin levels within guideline ranges at extended administration intervals may improve patient care and reduce the workload of health-care providers.

Topics: Anemia; Erythropoietin; Humans; Iron; Nephrology; Recombinant Proteins; Renal Insufficiency, Chronic

Lenalidomide, an IMiD drug (a novel type of immunomodulating drug) was recently approved by the US Food and Drug Administration for the treatment of transfusion-dependent anemia in patients with myelodysplastic syndromes (MDS) and interstitial deletions of chromosome 5q [del(5q)]. This review examines the clinical experience from the MDS-001 and MDS-003 clinical trials that led to this approval, the results of biological correlates supporting the targets of drug action, and the results from a non-del(5q) multicenter study (MDS-002). Lenalidomide treatment resulted in both erythroid and cytogenetic responses in the majority of patients with del(5q), accompanied by reductions in inflammatory cytokine generation and marrow microvessel density and improvement in primitive hematopoietic progenitor recovery. Central pathology review showed that resolution of cytologic dysplasia was common in patients with del(5q) but was infrequent in erythroid-responding patients without the chromosome 5 deletion. These findings indicate that lenalidomide promotes erythropoiesis in lower-risk MDS, with two apparently distinct mechanisms of action: suppression of the ineffective del(5q) clone and promotion of effective erythropoiesis in non-del(5q) MDS progenitors. These studies identified lenalidomide as a highly active erythropoietic- and cytogenetic-remitting agent in lower-risk MDS patients who otherwise would not be expected to benefit from recombinant erythropoietin therapy. The most common adverse reactions include dose-dependent neutropenia and thrombocytopenia that are more pronounced in patients with del(5q) in whom early suppression of the clone is expected.

Topics: Anemia; Antineoplastic Agents; Chromosome Deletion; Chromosomes, Human, Pair 5; Drug Delivery Systems; Erythropoiesis; Erythropoietin; Humans; Immunosuppressive Agents; Lenalidomide; Myelodysplastic Syndromes; Randomized Controlled Trials as Topic; Recombinant Proteins; Thalidomide; Treatment Outcome

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

The general concept of blood saving covers a number of technical and pharmacological actions which all aim to maintain the erythrocyte mass of the patient, and of which blood transfusion is only one. Severe anemia (Hb <60-80 g/l) increases postoperative mortality and morbidity. However, its correction by blood transfusion tends to worsen the prognosis. It is therefore imperative to conserve the patient's blood by any means possible. Detecting anemia is of primary importance. Whenever possible, its cause should be identified and treated. Depending on the detected anemia, as well as the blood loss expected during surgery, the patient should receive EPO (anemia with foreseeable moderate blood loss), or autologous pre-donation associated with EPO (anemia with foreseeable large blood loss).

Topics: Anemia; Blood Loss, Surgical; Blood Transfusion, Autologous; Erythropoietin; Hematocrit; Hemoglobins; Humans; Perioperative Care

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

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

EPO is known as an inducer of maturation and proliferation of erythrocytes. Moreover, it favours angiogenesis. In several studies it was encountered that EPO is a trophic agent that mediates survival and inhibits apoptosis of hypoxia affected cells, particularly those which build masses of irregularly vascularized cancers. The main task concerning EPO for oncologists is the choice to give or not to give recombinant EPO to anemia endangered cancer patients. EPO can do the quality of life better and cause recovery from anemia post chemotherapy and radiation of cancer patients. Nevertheless, EPO therapy shortens survival of patients in some cancers, in which antiapoptotic effect of EPO predominates directly in malignant cells. Thus, separately in every type of cancer, therapeutic use of recombinant EPO calls for prior investigations, if EPO signaling causes proliferation of cancer cells by direct stimulation of EPOR positive malignant cells. Unless the proliferative effect of EPO on cancer cells is excluded, its use in the therapy of anemia in cancer patients is not quite safe.

Topics: Anemia; Erythropoietin; Humans; Neoplasms; Recombinant Proteins

Anemia is highly prevalent in patients with lung cancer, often occurring at baseline and frequently exacerbated as a result of treatment with platinum-based chemotherapy. Anemia has been shown to have a negative effect on quality of life in patients with lung cancer, and additional data indicate that decreases in hemoglobin in these patients are associated with impaired survival. Multiple clinical studies have demonstrated that treatment of anemia with erythropoietic agents in patients with lung cancer results in a significant increase in hemoglobin, decrease in transfusions, and improvement in quality of life. Ongoing research is evaluating whether erythropoietic therapy can reduce cognitive impairment associated with lung cancer, cytotoxic therapy, and anemia. Despite the known adverse effects of anemia and the established benefits of erythropoietic therapy in anemic patients with lung cancer, more than half of these patients do not receive any anemia treatment. The purpose of this review is to report results of the European Cancer Anaemia Survey that describe the prevalence of anemia in patients with lung cancer, to review the major studies evaluating the clinical outcomes of erythropoietic therapy in patients with lung cancer, to discuss the recent safety concerns regarding the use of erythropoietic agents in patients with cancer treated to high hemoglobin levels, and to describe various novel therapeutic applications of erythropoietic agents in lung cancer.

Topics: Anemia; Antineoplastic Agents; Cognition Disorders; Erythropoietin; Humans; Lung Neoplasms; Quality of Life; Survival Rate

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

The PO2 at this site where erythropoietin release is regulated should vary only when the hemoglobin concentration changes in capillary blood. The kidney cortex is an ideal location for this O2 sensor for four reasons. First, it extracts a small proportion of the oxygen that is delivered in each liter of blood; this makes the PO2 signal easier to recognize. Second, there is a constant ratio of the work performed (consumption of O2) to the renal blood flow rate (delivery of O2). Third, the high renal blood flow rate improves diffusion of O2 from capillaries to this O2 receptor. Fourth, a high renal cortical PCO2 prevents an additional shift of the O2:hemoglobin dissociation curve by other factors from being a confounding variable. This suggests that the GFR and the renal blood flow rate should be examined in patients with unexplained anemia or erythrocytosis.

Topics: Anemia; Carbon Dioxide; Diffusion; Erythropoietin; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney Cortex; Microcirculation; Oxygen; Oxygen Consumption; Partial Pressure; Polycythemia; Renal Circulation

Locoregional recurrence remains a major obstacle to achieving a cure of locally advanced head and neck cancers, despite multimodality therapy. Multiple studies report that a low hemoglobin (Hgb) before or during radiation therapy is an important risk factor for poor locoregional disease control and survival. Anemia is common in the head and neck cancer population and is suspected to contribute to intratumoral hypoxia with resultant radioresistance. Although having a low Hgb level has been shown to be detrimental, it is unclear as to exactly what the threshold should be for low Hgb (studies in this area have used thresholds ranging from 9-14.5 g/dL). Quality-of-life studies suggest that correction of moderately severe anemia may result in significant gains. Optimal Hgb levels for improving outcomes may vary across and within tumor types, and this is an area that requires further evaluation. However, the correction of anemia may be a worthwhile strategy for radiation oncologists to improve local control and survival. This article reviews the impact of anemia on outcomes after radiotherapy of head and neck cancers.

Topics: Anemia; Cell Hypoxia; Erythropoietin; Head and Neck Neoplasms; Humans; Neoplasm Recurrence, Local; Nitroimidazoles; Prognosis; Quality of Life; Risk Factors; Survival Analysis

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

Anaemia is considered a common problem in many cancers secondary to the disease itself or related to chemo- and/or radiotherapy. Several clinical trials have advocated the prognostic value of anaemia and hypoxia in the outcome of many cancers. Erythropoietin is recognised as an effective treatment for anaemia, which also improves the quality of life in patients with malignant disease. External radiotherapy plays an important role in the treatment of loco-regional cancer but its efficacy can be compromised by many factors. Tumor hypoxia is considered by many authors as an important factor contributing to radioresistance. We report in this article the radiobiological rationale in favour of combining radiotherapy and erythropoietin, and review relevant clinical papers published in this field.

Topics: Anemia; Clinical Trials as Topic; Combined Modality Therapy; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Neoplasms; Recombinant Proteins; Treatment Outcome

Preoperative autologous blood donation (PABD) with no risk of blood-borne infection transmission has been considered the supreme blood transfusion therapy, and it has been reported to decrease incidence of postoperative deep-vein thrombosis. However, the need for PABD has decreased in the USA, because 1) risk of blood-borne infection transmission through allogeneic blood transfusion (ABT) has decreased after introduction of nucleic acid amplification test (NAT), and 2) blood collection-induced anemia has been found in many cases due to inapplicability of erythropoietin (rEPO). ABT risks are decreasing in Japan as in the USA, however, ABT has several issues proper to Japan, such as, outpacing of blood demand over supply in the near future and increase of HIV positive donors. Also, as rEPO can be used in Japan, PABD-induced anemia risks are low. Accordingly, necessity of PABD should increase in Japan. However, as those who usually perform PABD in Japan are surgeons, big issues arise such as bacterial contamination during blood collection and ABO incompatibility during transfusion. Underutilization of PABD in gastrointestinal cancer surgery should also be addressed. Appropriate technique and methodology must be established to increase the safety of PABD and to spread PABD in cancer surgery.

Topics: Anemia; Blood Donors; Blood Group Incompatibility; Blood Transfusion, Autologous; Cost-Benefit Analysis; Erythropoietin; HIV Infections; Humans; Japan; Medical Errors; Postoperative Complications; Preoperative Care; Recombinant Proteins; Safety; Venous Thrombosis

Anemia is a common complication in patients with chronic kidney diseases (CKD), including transplanted patients. Recent studies have found a prevalence of anemia of about 30%, whereas less than 10% of these patients received recombinant human erythropoietin. Factors explaining this high incidence of anemia in renal transplant recipients include delayed and impaired graft function and use of drugs inhibiting the action of angiotensin II and preventing rejection. Like in CKD patients, chronic anemia may impact on the cardiovascular system and finally on the high mortality of these patients. Recent data suggest also that anemia may be a factor of progression of renal dysfunction in kidney transplant recipients. A French randomized multicenter study was designed to answer this question.

Topics: Anemia; Erythropoietin; Humans; Kidney Transplantation; Prevalence; Recombinant Proteins

The use of recombinant human erythropoietin (r-HuEPO) in cancer patients improves hemoglobin levels and quality of life. This fact, already well known, made oncologists expect a positive outcome in radio and chemotherapy results, as well as in survival. However, new clinical trials show a preliminary evidence of impaired, instead of improved, survival when these agents are prescribed. Erythropoietin (EPO) is becoming a more complex hormone than it was expected. Its non-erythropoietic effects include, among others, angiogenesis and proliferation of certain types of cancer cells. In this work, we review erythropoietin as a natural hormone, as well as the different types of r-HuEPO, focusing on the confusing situation with regard to their use in oncology. We conclude that extreme care must be taken when EPO is prescribed to cancer patients, and we suggest to limit its use to symptomatic anemia, just to achieve moderate hemoglobin levels.

Topics: Anemia; Erythropoietin; Hemoglobins; Humans; Neoplasms; Recombinant Proteins

Recently there has been considerable interest in the associations between blood hemoglobin (Hb) level, renal function, and cardiovascular disease. Anemia is a common feature of end-stage renal disease, but it also accompanies lesser degrees of chronic kidney disease (CKD). The degree of anemia roughly approximates the severity of CKD. Anemia seen in diabetes has been linked to diabetic nephropathy; however, diabetes itself affects the hematologic system in several ways. Anemia is associated with left ventricular hypertrophy, cardiovascular morbidity, progressive loss of kidney function, and poor quality of life. Anemia seems to act as a mortality multiplier; that is, at every decrease in Hb below 12 g/dL, mortality increases in patients with CKD, cardiovascular disease, and those with both. Unlike blood transfusion, treatment of anemia with exogenous erythropoietin in patients with cardiorenal disease has shown promise in reducing morbidity and in improving survival and quality of life. Increasing the Hb level from less than 10 g/dL to 12 g/dL has resulted in favorable changes in left ventricular remodeling, improved ejection fraction, improved functional classification, and higher levels of peak oxygen consumption with exercise testing. Clinical trials are underway to test the role of erythropoietin in patients with CKD and in patients with heart failure.

Topics: Anemia; Cardiovascular Diseases; Chronic Disease; Comorbidity; Diabetes Complications; Erythropoietin; Humans; Prevalence; Prognosis; Renal Insufficiency; Risk Factors

Anaemia, often associated with chemotherapy, is a common and debilitating disorder in cancer patients. Recombinant human erythropoietin (epoetin alfa) was introduced in the 1990s for the treatment of chemotherapy-related anaemia. Data from randomised, double-blind, placebo-controlled studies and large, non-randomised, community-based studies have demonstrated that either of the FDA-approved dosing schedules of epoetin alfa 150 - 300 U/kg three times weekly or 40,000-60,000 U/week s.c., significantly increases haemoglobin levels, reduces transfusion requirements, and improves quality of life in anaemic cancer patients undergoing chemotherapy or chemoradiation therapy. Guidelines for the effective and safe use of epoetin alfa have been published by major oncology/haematology organisations and are reviewed in this article. Areas of recent and ongoing investigation with epoetin alfa are also covered in this review.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Epoetin Alfa; Erythropoietin; Humans; Neoplasms; Practice Guidelines as Topic; Recombinant Proteins

Topics: Anemia; Animals; Blood Transfusion; Chronic Disease; Erythroid Precursor Cells; Erythropoietin; Homeostasis; Humans; Iron

Classic iron deficiency (ID) does not represent a challenge for the laboratory and physicians. The anemia that accompanies infection, inflammation, and cancer, commonly termed anemia of chronic disease (ACD), features apparently normal or increased iron stores. However, 20% of these patients have iron-restricted erythropoiesis (functional ID), an imbalance between the iron requirements of the erythroid marrow and the actual iron supply. Functional ID leads to a reduction in red cell hemoglobiniza-tion, causing hypochromic microcytic anemia. The diagnosis of functional ID in real time is based on measuring the hemoglobin content of reticulocytes. An examination of the biochemical markers of iron metabolism demonstrates weaknesses in the diagnosis of functional ID. We developed a diagnostic plot for the assessment of iron status in ACD and the detection of advancing ID in patients with ID, ACD, and the combined state of functional ID and ACD. The plot indicates the correlation between a marker of the iron supply for erythropoiesis (ie, the ratio of the soluble transferrin receptor value to the logarithm of the ferritin value) and the reticulocyte hemoglobin content and functions as a marker of iron demand. The diagnostic plot shows good selectivity for assessing the iron status of disease-specific anemias such as classic ID, end-stage renal failure, cancer-related anemia, and the anemia of infection and inflammation. The therapeutic implications of the diagnostic plot are to differentiate patients who should be administered oral iron supplements, recombinant human erythropoietin (r-HuEPO), or a combination of r-HuEPO and iron. The response of erythropoiesis to r-HuEPO depends on the iron supply and the proliferation of erythropoiesis. The lack of an increase or a decrease in reticulocyte hemoglobin levels indicates a nonresponder to r-HuEPO or functional ID.

Topics: Anemia; Chronic Disease; Erythropoiesis; Erythropoietin; Homeostasis; Humans; Iron

The importance of recombinant human erythropoietin (epoetin) therapy has been clearly demonstrated in patients with anemia due to chronic kidney disease. The use of biopharmaceuticals to replace endogenous proteins, which may be inadequately low, carries the risk of stimulating the immune system to develop autoantibodies. Although these proteins are designed to closely mimic the endogenous proteins, they may have potential immunogenic properties. Erythropoietin produced by recombinant DNA technology is the most successful and efficacious agent for treating anemia. It was initially used in treating anemia in chronic kidney disease patients. Pure red cell aplasia (PRCA) ensuing from production of neutralizing anti-erythropoietin antibodies occurred very rarely with epoetin treatment. This agent was initially administered intravenously, but the mode of administration was progressively altered to subcutaneous without apparent increase in immune reaction. However, between 1998 and 2001, a sharp increase in the number of PRCA cases was seen. PRCA had been a very rare complication until this time. All of these patients had high affinity neutralizing anti-erythropoietin antibodies. This observation was made primarily in cases where one brand of epoetin, Eprex, was administered subcutaneously to patients with chronic kidney disease treated outside the United States, although a small number of cases among chronic kidney disease patients treated solely with epoetin beta were also identified. The marked increase in the number of Eprex cases was attributed to a change in the stabilizers, storage, and route of administration of Eprex to patients with chronic kidney disease. Since then changes have been made to the route of administration, storage, and handling of Eprex, and more recently to the rubber stoppers used in the prefilled syringes. Eprex was administered intravenously to chronic kidney disease patients and, with improved storage and handling, there was a subsequent dramatic reduction in the number of cases. More recently, the rubber stoppers have been replaced by Teflon-coated ones to prevent interactions with stabilizers and release of chemicals that have adjuvant properties. However, this concern is still relevant in the new generation of epoetin agents and generic formulations of epoetins. Epoetin treatment for anemia requires regular follow-up of hemoglobin levels but also of reticulocyte counts in chronic kidney disease patients.

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

Anemia is a common complication of cancer or anticancer therapy, with a significant negative impact on the functional status of patients and their quality of life (QOL). Recombinant human erythropoietin (EPO) was developed in the 1980's and was initially developed for the treatment of anemia associated with chronic renal failure. Subsequently, randomized, placebo-controlled clinical trials in the oncology setting were performed in the early 1990's. These studies demonstrated in cancer patients that EPO could increase the levels of hemoglobin (Hb), decrease the need for red blood cell transfusions, and also suggested that these outcomes were associated with improved QOL metrics as reported by the patients themselves. Based on the results of these studies, EPO was granted regulatory approval to be used for the treatment of anemia in patients with non-myeloid malignancies where anemia was due to the effect of concomitantly administered chemotherapy. To further expand the findings of the registration studies, and to develop more complete QOL data, three similarly designed open-label community-based studies were performed, enrolling a total of approximately 7000 patients. These studies consistently demonstrated in the supportive care of cancer patients receiving chemotherapy that the use of EPO could induce increases in the levels of Hb and that these correlated with patient-reported improvements in QOL metrics. The correlation between an improvement in Hb and QOL has also been confirmed in a larger randomized, placebo-controlled trial. Careful analyses of data from this study also helped support earlier findings that EPO could be effective for patients with varying degrees of anemia, and that increasing and maintaining Hb levels close to the physiologically normal levels resulted in the optimal improvements in QOL. While further investigations of EPO as a mechanism to improve the antineoplastic efficacy of chemoradiotherapy have not yet been positive, the overall experience with this agent remains very favorable after extensive studies and long-term clinical use in oncology.

Topics: Anemia; Erythropoietin; Hemoglobins; Humans; Neoplasms; Placebos; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Treatment Outcome

Anemia occurring in patients with renal failure on dialysis has been shown to both increase transfusion requirements and decrease functional status and quality of life. As a result, treatment of these patients with an erythropoietic agent such as epoetin alfa or darbepoetin alfa has become established as an essential part of optimal patient care. Anemia resulting from cancer or chemotherapy is a common problem in oncology, and has been shown similarly to increase transfusion risk and decrease patient reported outcomes. For reasons that are not clear, but may include either frequently encountered slow response or nonresponse and higher doses and hence higher costs, treatment of anemia in oncology has not become a standard treatment for all patients. Erythropoietic agents (epoetin alfa and darbepoetin alfa) have been used to improve anemia-related fatigue and quality of life in cancer patients. Epoetin is administered 1 to 3 times per week whereas darbepoetin, with up to a 3-fold greater half-life, is given once every 1 or 2 weeks. Recent data demonstrate that darbepoetin can be administered as infrequently as every 3 weeks with comparable erythropoietic efficacy. Several studies have been carried out to determine the optimum schedule of dosing to obtain maximum patient benefit. Following treatment with darbepoetin, antibodies to darbepoetin were not detected, no unusual adverse event was seen with darbepoetin, and the mean increase in hemoglobin remained unchanged when the dosing interval was increased from 1 to 2 weeks. The safety and efficacy of darbepoetin was also determined in patients with solid tumors receiving chemotherapy; the lowest clinically effective dose was determined to be 3.0 and 5.0 microg/kg every 2 weeks with a 66 and 84% response, respectively. No additional benefit was seen with higher doses. A multicenter study evaluated the safety and efficacy of darbepoetin administered either weekly, every 3 weeks, or every 4 weeks in anemic patients with cancer who were not receiving chemotherapy or radiotherapy. The results indicated that with weekly dosing, 70% of patients showed an increase in hemoglobin. The dose of 4.5 microg/kg/week resulted in 100% hematopoietic response. In a randomized, active control, pilot trial, front-loading darbepoetin followed by lower doses or less frequent doses also appears to be efficacious and may decrease the time to response. At the present time, darbepoetin improves anemia, reduces requirements for transfus

Topics: Anemia; Clinical Trials, Phase III as Topic; Darbepoetin alfa; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Hemoglobins; Humans; Neoplasms; Quality of Life; Recombinant Proteins; Treatment Outcome

Anemia is a common problem in the management of elderly patients. Anemia in the elderly is linked to an increase in morbidity and mortality, and serves as an independent variable associated with poor outcomes. In the elderly population, anemia is a risk factor for cardiovascular health and early death, contributes to fatigue, and negatively impacts on cognitive function, physical function, and the quality of life and serves as a marker of increased vulnerability. A greater understanding of pathophysiology of anemia in the setting of chronic disease has provided insights into the rationale for the potential clinical application of erythropoietic agents in the treatment of anemia. The impact of erythropoietic therapy, as it relates to specific afflictions affecting the older age patient, including diminished exercise tolerance, frailty, loss of functional capacity, immobility, depression, increased care needs and cardiovascular fitness, remains to be determined and is worthy of further investigation.

Topics: Age Factors; Anemia; Chronic Disease; Erythropoietin; Hemoglobins; Humans

The only combined effort between the American Society of Hematology (ASH) and the American Society of Clinical Oncology (ASCO) in practice guideline development was in studying the use of erythropoietin in chemotherapy-related anemia and in myelodysplasia. This process began with an application to the Agency for Health Care Policy and Research (AHCPR, now called the Agency for Healthcare Research and Quality, or AHRQ) jointly from ASH and ASCO. As part of a competitive review process, the topic was selected by the Agency for funding. Subsequently, as part of the Agency's Evidence-based Practice program, funding to conduct the review was awarded to the Evidence-based Practice Center of the Blue Cross/Blue Shield Technology Evaluation Center, which performed an extensive literature review using principals of evidence-based medicine and with input from representatives of ASH and ASCO. That evidence-based review was then shared with an ASH and ASCO guidelines committee funded by both organizations and made up of members from both organizations. The guideline was developed over a period of 21/2 years, culminating in simultaneous publication in both Blood and The Journal of Clinical Oncology in October 2002. This field is in flux and much of the guideline discussed potential future directions for research. Projected research topics include whether a hemoglobin level of 11g/dl as a clinical trigger point has clinical benefit; whether increasing hemoglobin levels greater than 12g/dL has clinical benefit; what role iron supplementation plays in erythropoietin treated patients; weekly versus more frequent dosing; and cost benefit analyses. Quality of life considerations are important, but the practice guideline committee felt that there was not enough data in this area to view it with the same importance as avoidance of transfusion or rises in hemoglobin value as therapeutic goals for patients being treated with erythropoietin.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Hematology; Humans; Neoplasms; Societies, Medical; United States

Epoetin (EPO; erythropoietin) treatment offers an attractive but costly alternative to red blood cell transfusion for managing anemia associated with cancer therapy. The goal of this paper is to review the findings of the 2001 Blue Cross/Blue Shield Association Technology Evaluation Center overview on EPO use in oncology, which served the foundation for the 2002 ASH/ASCO clinical guideline on this subject. The BC/BS review had two major aims: (1) to quantify the effects of EPO on the likelihood of transfusion and on quality of life in patients with cancer treatment-related anemia, and (2) to evaluate whether outcomes are superior when EPO treatment is initiated at higher hemoglobin thresholds. Two independent reviewers followed a prospective protocol for identifying relevant studies published between 1985 and 1998. Outcomes data were combined with the use of a random-effects meta-analysis model. Double-blind, randomized controlled trials that minimized patient exclusions were defined as higher quality for sensitivity analysis; randomized, but unblinded trials and trials with excessive exclusions were included in the meta-analysis, but were defined as lower quality. Twenty-two trials (n=1927) met inclusion criteria, and 12 (n=1390) could be combined for estimation of odds of transfusion. EPO decreased the percentage of patients transfused by 9-45% in adults with mean baseline hemoglobin concentrations of 10g/dL or less (7 trials; n=1080), by 7-47% in those with hemoglobin concentrations greater than 10g/dL, but less than 12g/dL (7 trials; n=431), and by 7-39% in those with hemoglobin concentrations of 12g/dL or higher (5 trials; n=308). In a sensitivity analysis, the combined odds ratio for transfusion in EPO-treated patients as compared with controls was 0.45 (95% confidence interval [CI]=0.33-0.62) in higher quality studies and 0.14 (95% CI=0.06-0.31) in lower quality studies. The number of treated patients needed to prevent one transfusion is 4.4 for all studies, 5.2 for higher quality studies, and 2.6 for lower quality studies. Only studies with mean baseline hemoglobin concentrations of 10g/dL or less reported statistically significant effects of EPO treatment on quality of life; quality-of-life data were insufficient for meta-analysis. No studies addressed the effects of EPO on anemia-related symptoms. The review concluded that EPO reduced the odds of transfusion for cancer patients undergoing therapy. Evidence was insufficient to determine whether i

Topics: Anemia; Blue Cross Blue Shield Insurance Plans; Erythropoietin; Hemoglobins; Humans; Meta-Analysis as Topic; Neoplasms; Outcome Assessment, Health Care; Prospective Studies; Quality of Life

Health care decision-making is affected by the values of patients and providers, available resources, and information substantiating effectiveness (or efficacy) of a particular therapy. A number of factors contribute to our growing need for evidence-based decision-making. Our aging population generally requires greater medical attention in a system with limited resources devoted to health care. Technologic advances have produced an ever-expanding range of expensive treatment options. Patients, and their providers, expect early access to these emerging therapies. Patients also expect care of universally high quality, even as respected authorities suggest there exists a substantial gap between these expectations and the care actually delivered. Evidence based decision-making offers the opportunity to use medical evidence to reduce uncertainty regarding research information and improve the value of health care delivered. Evidence based medicine (EBM) is the 'conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients.' It combines clinical judgment and experience, best available scientific evidence, and patient preferences to improve medical decision-making. Though often incorrectly maligned as cookbook medicine that dismisses any research findings that do not derive from randomized clinical trials, it provides clinicians, health care systems, payers and policymakers with tools to appropriately evaluate the research evidence that substantiates various therapies and integrate that evidence with clinical expertise and patient's values in medical decision-making. The erythropoietic stimulants epoetin and darbepoetin have shown efficacy in improving anemia of chronic renal failure and following chemotherapy for many patients. In some studies these agents have also improved health-related quality of life. Unfortunately, only 60-80% of patients treated with erythropoietic stimulants respond, and like many emerging therapies, they are quite expensive. Likewise, there is substantial variation in their usage, suggesting both inappropriate use and non-usage. Reimbursement coverage decisions for erythropoietic stimulants have been hampered by the lack of high-quality evidence in certain applications. Physicians are increasingly turning to evidence-based medicine resources (guidelines, systematic reviews) to inform their decisions regarding application of new therapies. Evidence-based medicine offers healt

Topics: Anemia; Antineoplastic Agents; Chronic Disease; Erythropoiesis; Erythropoietin; Evidence-Based Medicine; Humans; Neoplasms; Quality of Life

Cancer and cancer therapy-associated anemia may have an impact on tumor response and overall survival. Additionally, anemia represents an important economic factor. Therefore, therapeutic alternatives such as erythropoietin (EPO) and red blood cell transfusions have to be evaluated systematically. The effectiveness of recombinant human EPO to prevent or alleviate anemia in patients with malignant disease was determined. Randomized controlled trials comparing prophylaxis or treatment of anemia with EPO plus red blood cell transfusion (RBCT) or RBCT only in patients with malignant disease undergoing antineoplastic therapy were included. The endpoints needed for RBCT were hematological response (hemoglobin increase of 2g/dL or hematocrit increase of 6%), tumor response, and overall survival. Medical databases (Cochrane Library, MEDLINE, EMBASE) and conference proceedings were searched (1985-2001). Full-text and abstract publications were included as well as unpublished data. Data extraction and quality assessment were done in duplicate. All authors were contacted to obtain missing data. Out of 33 eligible studies, 27 trials with 3,287 randomized patients were included.

Topics: Anemia; Databases, Factual; Decision Trees; Erythrocyte Transfusion; Erythropoietin; Europe; Humans; Meta-Analysis as Topic; Multicenter Studies as Topic; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins; United States

Clinical research evidence on outcomes of using epoetin (EPO) to treat or prevent anemia in oncology has recently been systematically synthesized to provide a scientific foundation for developing and implementing clinical practice guidelines. Two groups have distinguished themselves by their meticulous research methods, the Blue Cross and Blue Shield Association Technology Evaluation Center (BCBSA TEC) and the Cochrane Review Group (CRG), and have summarized existing research evidence on the role of EPO in anemia associated with cancer treatment. An ASH/ASCO (American Society of Hematology/American Society of Clinical Oncology) panel has used the BCBSA TEC review to develop practice guidelines on the use of EPO in patients with cancer. The ASH/ASCO guideline panel identified eight important clinical circumstances for which use of EPO in oncology might be considered and used the BCBSA TEC evidence review to formulate evidence-based guidelines that support use of EPO. Both BCBSA TEC and CRG found solid evidence exists to show that EPO improves hemoglobin levels and reduce the risk for transfusion. The ASH/ASCO panel concluded that best empirical evidence exists to support the use of EPO to correct anemia due to chemotherapy if Hgb

Topics: Anemia; Blue Cross Blue Shield Insurance Plans; Erythropoietin; Hematology; Humans; Medical Oncology; Meta-Analysis as Topic; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins; Research Design; Societies, Medical; United States

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

Pure red cell aplasia (PRCA) is a relatively rare condition defined as severe anemia secondary to the virtual absence of red cell precursors in the bone marrow. The incidence of PRCA was associated with subcutaneous administration of epoetin alfa (human recombinant erythropoietin [rHuEPO]). PRCA occurs from the generation of antibodies against rHuEPO, which neutralize not only the recombinant protein, but also native erythropoietin, resulting in the absence of red cell precursors in the bone marrow. Drug-induced PRCA has very similar characteristics to idiopathic PRCA, making the patients transfusion-dependent. Prior to 1998 only four cases had been associated with administration of rHuEPO; however, post-1998 a sharp increase in incidence was reported outside the United States. A change in formulation in 1998 was thought to be the reason for the induction of PRCA. A number of possible mechanisms have been proposed. The modification in the drug formulation probably played a major role. A sharp decrease of PRCA cases has been reported after 2002 related to the change in the mode of administration from subcutaneous to intravenous. In addition to the modification to the route of administration, revised storage and handling protocols have contributed to the reduced incidence of PRCA in the last 3 years. Nevertheless, the usefulness of this drug to the chronic renal patients who suffer from anemia far outweighs the disadvantages. Maintaining target hemoglobin levels, monitoring the response to erythropoietin, and adjuvant therapy to rHuEPO are all critical issues in the clinical management of renal and cancer patients with anemia.

Topics: Anemia; Antibodies; Drug Administration Routes; Erythropoietin; Humans; Recombinant Proteins; Red-Cell Aplasia, Pure

Chemotherapy-induced anaemia, with its important consequences on quality of life and social function of cancer patients, can be improved with erythropoietic therapy. Darbepoetin alfa is the first of a novel generation of erythropoietic proteins with a unique molecular structure and a circulating half-life that is threefold longer than that of the previous recombinant human erythropoietin. The efficacy and safety of weekly administration have been confirmed in different Phase II and III randomised trials. In order to optimise the efficacy profile of darbepoetin alfa, extended dosing intervals and front-loading regimens are evaluated, as well the optimal haemoglobin level to initiate therapy. Across all trials, darbepoetin alfa was shown to be a well-tolerated and safe therapy. The possible favourable effect on the outcome of cancer patients needs to be further elucidated.

Topics: Anemia; Antineoplastic Agents; Clinical Trials, Phase III as Topic; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Hemoglobins; Humans; Neoplasms; Recombinant Proteins

Anemia associated with cancer and cancer therapy is an important clinical and economic factor in the treatment of malignant diseases.. We conducted a systematic literature review to assess the efficacy of erythropoietin to prevent or treat anemia in cancer patients with regard to red blood cell transfusions, hematologic response, adverse events, and overall survival. We searched the Cochrane Library, Medline, EMBASE, and other databases for relevant articles published from January 1985 to December 2001. We included all randomized controlled trials that compared the use of recombinant human erythropoietin (plus transfusion, if needed) with no erythropoietin treatment (plus transfusion, if needed). Relative risks (RRs) and 95% confidence intervals (CIs) were calculated under a fixed-effects model. Clinical and statistical heterogeneity were examined with sensitivity analyses and meta-regression. Statistical tests for effect estimates were two-sided.. We identified 27 trials involving 3287 adult patients. Patients treated with erythropoietin had a lower relative risk of having a blood transfusion than untreated patients (RR = 0.67, 95% CI = 0.62 to 0.73). Erythropoietin-treated patients with baseline hemoglobin levels lower than 10 g/dL were more likely to have a hematologic response than untreated patients (RR = 3.60, 95% CI = 3.07 to 4.23). The relative risk for thromboembolic complications after erythropoietin treatment was not statistically significantly increased (RR = 1.58, 95% CI = 0.94 to 2.66) compared with that of untreated patients. There is suggestive but inconclusive evidence that erythropoietin may improve overall survival (adjusted data: hazard ratio [HR] = 0.81, 95% CI = 0.67 to 0.99; unadjusted data: HR = 0.84, 95% CI = 0.69 to 1.02).. Erythropoietin treatment may reduce the risk for blood transfusions and improve hematologic response in cancer patients. However, our favorable survival outcome is in contrast to two large (N = 351 and 939) recently published randomized controlled trials in which erythropoietin-treated patients had statistically significantly worse survival than untreated patients. Possible reasons for the disparity with our results include differences in study population and design, higher target hemoglobin levels and higher risk of thromboembolic complications, and concerns that erythropoietin may stimulate tumor growth.

Topics: Anemia; Blood Transfusion; Erythropoietin; Hematinics; Humans; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Assessment; Survival Analysis; Treatment Outcome

During the treatments of carcinomas of the cervix, anemia is relatively frequent and its origin is complex combining often hemorrhage, iron deprivation, inflammatory reactions and infection. The frequency of the primary anemia (hemoglobin level<12 g/dl) is correlated with clinical stage and varies from one publication to another, mainly from 25% for stage I, to 33% for stage II and can approach 40% for stage III. Anemia is correlated with patient survival and it appears to be one of the most powerful prognostic factor after clinical stage and tumor size. Anemia is a bad prognostic factor related to stage and tumor size but it has not been proven to be an independent factor. Anemia increases hypoxia of cervix carcinomas, which is an independent prognostic factor for patients N0. Moreover, we know that the oxygenation of these tumors is correlated with hemoglobin levels. The normalization of Hb levels by transfusion could certainly modify the prognosis of patients anemic before treatment, or of those becoming anemic during radiotherapy treatment. For smokers, anemia is certainly more important that we can appreciate from the Hb levels only, by the presence of carboxyhemoglobin. Concomitant chemotherapies with cisplatin compounds are actually standards and they can largely increase the risk of inducing anemia, therefore more than 50% of patients will experiment it during their different treatments. Transfusion is recommended by the SOR (Standards Options and Recommendations of the Fédération nationale des centres de lutte contre le cancer) under 10 g/dl. The use of erythropoietin is a therapeutic option for Hb levels between 10 and 12 g/dl and strongly recommended after a Hb normalization by blood transfusion. For 70% of patients who respond to erythropoietin, a better control of the Hb level is obtained. The impact of this anemia on quality of life and treatments compliance justifies the use of erythropoietin, especially in cancers for which treatments induce a deep fatigue and a very bad tolerance, which could be a limiting factor.

Topics: Anemia; Antineoplastic Agents; Blood Transfusion; Carboxyhemoglobin; Cell Hypoxia; Cisplatin; Combined Modality Therapy; Erythropoietin; Female; Hemoglobins; Humans; Incidence; Prognosis; Quality of Life; Radiotherapy; Radiotherapy Dosage; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Factors; Smoking; Uterine Cervical Neoplasms

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

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

Topics: Anemia; Animals; Cytokines; Erythropoietin; Genetic Therapy; Granulocyte Colony-Stimulating Factor; Humans; Neoplasms; Neutropenia; Receptors, Cytokine; Recombinant Proteins; Signal Transduction

In gynaecology, anaemia treatment is indicated in extremely different situations. In cancer patients, treatment with epoetin can relieve fatigue and improve quality of life. In these patients, epoetin treatment can also have a positive influence on survival through increasing the efficacy of radiotherapy and chemotherapy. Recent data are presented. In gynaecological surgery, the use of epoetin--based on results in oncology and orthopaedic surgery--makes a constructive contribution to the improvement of quality of life and during patient recovery through rapid normalisation of perioperative anaemia, thus reducing the risk of a transfusion with donated blood. Encouraging data from recent publications concerning the prevention of PRCA under epoetin treatment are presented.

Topics: Adult; Anemia; Blood Transfusion; Epoetin Alfa; Erythropoietin; Fatigue; Female; Hematinics; Humans; Pregnancy; Pregnancy Complications; Quality of Life; Recombinant Proteins; Risk Factors

Anaemia is frequently associated with lymphoma. Many causes are implicated and can sometimes be associated to each other so that the level of haemoglobin is often very low. In follicular lymphoma, the level of haemoglobin remains an independent predictive prognostic factor. Likewise, anaemia seems correlated to survival for both Hodgkin's and non-Hodgkin's lymphomas. However, therapeutic strategies to control anaemia remain somewhat unsatisfactory. Thus, recombinant erythropoietin might be an effective drug to increase the haemoglobin rate, limit the transfusional risk and improve patients' quality of life.

Topics: Anemia; Blood Transfusion; Erythropoietin; Fatigue; Hemoglobin A; Humans; Lymphoma; Prognosis; Quality of Life; Recombinant Proteins

Anemia and fatigue are frequent in lung cancer patients. Anemia is due to cancer and platinum-based chemotherapy. Anemia leads to a wide range of symptoms and affects health-related quality of life. Anemia also worsens outcome of therapy and prognosis. Efficient treatment exist: blood transfusion and recombinant erythropoietin. Early treatment of anemia is recommended as soon as diagnosis is made. But few patients receive optimal treatment. Its cost and unsolved question regarding therapeutic strategies may explain this phenomenon. This debate should not preclude correct treatment prescription. Clinical trials have to be preformed to clarify unsolved questions. As EPO administration can affect survival, this point should be of particular interest in future trials.

Topics: Anemia; Antineoplastic Agents; Blood Transfusion; Erythropoietin; Fatigue; Hemoglobin A; Humans; Lung Neoplasms; Prognosis; Recombinant Proteins

Anemia is very common in head and neck cancer patients, and seems to be correlated with intratumoral hypoxia. Anemia is one of the main prognostic factors of locoregional recurrence and, in some studies, of poor survival. Blood transfusions and human recombinant erythropoietin (rHuEPO) are the two main methods used in clinical practice to correct hemoglobin level during curative treatment. Blood transfusions were rarely evaluated, and did not influence locoregional control of patients treated with radiotherapy with or without chemotherapy. Retrospective studies evaluating combined treatment of rHuEPO and radiotherapy reported positive impact on locoregional recurrence and actuarial survival. Since the end of 2003, this approach is a matter for debate after the negative results of a prospective randomized study on progression-free survival concerning head and neck cancer patients treated with definitive or postoperative external radiotherapy with or without rHuEPO. Although many biases were reported against this publication, several questions are to be answered in the near future. Among them, erythropoietin receptor expression and activation on tumour cell seem to be the more appropriate explanation of these negative results. In October 2004, preliminary results of the RTOG 99-03 study have been presented at the Astro annual meeting in Atlanta. This prospective randomized trial was designed to determine if concurrent rHuEPO administration (40,000 units) with radiotherapy (with or without chemotherapy) could improve locoregional control in non-operative head and neck cancers. In the rHuEPO arm, haemoglobin level was significantly increased compared with control arm. However, the addition of concurrent rHuEPO to definitive radiotherapy did not improve locoregional control or survival for mildly/moderately anemic patients with head and neck squamous cell carcinoma. Future clinical trials using biological markers are thus imperative to target which patients could benefit from these molecules.

Topics: Anemia; Blood Transfusion; Cell Hypoxia; Erythropoietin; Head and Neck Neoplasms; Hemoglobin A; Humans; Prognosis; Quality of Life; Recombinant Proteins

Recombinant human erythropoietin (epoetin) has become the most widely used cytokine in the world. Following the success of its use in patients with end-stage renal disease, the usefulness of epoetin in other anaemias was assessed, including paediatric patients, mainly newborns. The treatment or prevention of anaemia of prematurity with epoetin resulted in a significant reduction in the number of transfusions and donor exposure. A clear definition of which premature babies must receive therapy is yet to be established. Other indications in neonatal period include hyporegenerative and haemolytic anaemias. The potential for use of the nonhaematopoietic effects of epoetin in newborn infants is a novel and exciting issue. The role of epoetin as a tissue-protective factor for the CNS and intestinal mucosa is under exhaustive investigation. With the exception of chronic renal failure, in older children the efficacy of epoetin has not been evaluated as in adults. Although an impressive amount of studies were carried out during recent years in adult patients with cancer-related or HIV-infection-related anaemias, thus allowing clear conclusions to be established on its efficacy, only a few trials with a small number of patients have been reported in children. Up-to-date, results in paediatric patients suggest that epoetin therapy is as useful as in adult patients, but prospective, randomised trials including large number of patients are essential to achieve definitive conclusions.

Topics: Anemia; Child; Erythropoietin; Humans; Infant, Newborn; Recombinant Proteins

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

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

Anaemia effects up to 90% of cancer patients, with more than 60% requiring blood transfusion during or after treatment. With the advent of recombinant human erythropoietins (rHuEPO), an alternative to red blood cell transfusion has become available. So far, three drugs have been approved for the treatment of anaemia in patients with malignancies (epoetin alfa, epoetin beta and darbepoetin alfa). New concepts for the use of erythropoietin in cancer patients include 3- and 4-weekly dosing, as well as loading-dose concepts. Important factors helping to judge the impact of erythropoietin in cancer treatment include pharmacoeconomics and better predictive factors. Lately, the influence of erythropoietin therapy on survival in cancer patients has been discussed very intensively, because conflicting data have emerged. Studies aimed at correcting anaemia in cancer patients had indicated a possible survival advantage of those patients receiving erythropoietin. In contrast, two recent trials aimed at correction of haemoglobin levels beyond anaemia reported a poorer survival of patients receiving erythropoietin. This might grossly be attributed to a higher risk of thrombosis in these patients. The largest systematic review on the use of erythropoietin in cancer patients undergoing treatment indicates a suggestive but not significant survival advantage of erythropoietin-treated patients. In addition, very recent results of a Food and Drug Administration meeting on safety and survival of patients treated with erythropoietin are presented.

Topics: Anemia; Economics, Pharmaceutical; Erythropoietin; Humans; Neoplasms; Prognosis; Recombinant Proteins; Risk Factors; Survival; Thrombosis

Topics: Anemia; Erythrocyte Transfusion; Erythropoietin; Humans; Neoplasms; Practice Guidelines as Topic; Prognosis

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

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

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

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

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

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

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

Therapeutic proteins have revolutionized the treatment of many diseases but low activity or rapid clearance limits their utility. New approaches have been taken to design drugs with enhanced in vivo activity and half-life to reduce injection frequency, increase convenience, and improve patient compliance. One recently used approach is glycoengineering, changing protein-associated carbohydrate to alter pharmacokinetic properties of proteins. This technology has been applied to erythropoietin and resulted in the discovery of darbepoetin alfa (DA), a hyperglycosylated analogue of erythropoietin that contains two additional N-linked carbohydrates, a threefold increase in serum half-life and increased in vivo activity compared to recombinant human erythropoietin (rHuEPO). The increased serum half-life allows for less frequent dosing to maintain target hemoglobin levels in anemic patients. Carbohydrates on DA and other molecules can also increase molecular stability, solubility, increase in vivo biological activity, and reduce immunogenicity. These properties are discussed.

Topics: Anemia; Animals; Antibody Formation; Darbepoetin alfa; Erythropoietin; Glycoproteins; Glycosylation; Humans; Leptin; Protein Engineering; Recombinant Proteins

Cancer has a negative systemic impact on its host in addition to its local or metastatic effects, and no cancer complication is more ubiquitous than anaemia, a condition for which there is now a specific remedy, the recombinant growth factor erythropoietin. This is not a trivial therapeutic consideration, because cancer-associated anaemia has an adverse influence on survival regardless of tumour type. However, the pharmacological correction of anaemia with recombinant erythropoietin could promote tumour growth, whereas the use of tumour-necrosis factor-alpha (TNFalpha) and TNF-related apoptosis-inducing ligand as antitumour agents could exacerbate anaemia, thereby perpetuating tissue hypoxia and tumour progression.

Topics: Anemia; Carcinogens; Cell Death; Erythropoiesis; Erythropoietin; Humans; Hypoxia; Neoplasms; Recombinant Proteins; Signal Transduction

Treatment with epoetin alfa has repeatedly been shown to improve the quality of life (QoL) of cancer patients with anaemia. We used meta-analytical techniques to synthesise data from all available (published and unpublished) studies of epoetin alfa in cancer patients receiving chemotherapy that used validated QoL instruments. Results from 23 studies were synthesised. These employed the CLAS, FACT, SF-36 and ECOG (WHO) QoL scales. The meta-analysis indicated that treatment with epoetin alfa was associated with a clear and statistically significant improvement in QoL as measured by all subscales of CLAS, all subscales of FACT, and 5 subscales of SF-36. In contrast, control groups experienced no significant change, or, in some cases, a deterioration in QoL. Improvement was related to treatment duration. The generic ECOG (WHO) performance scale indicated that, even though epoetin alfa treatment is associated with clear benefits in terms of QoL, this population of patients receiving chemotherapy for cancer experience a gradual decrease in functional status over time.

Topics: Anemia; Antineoplastic Agents; Epoetin Alfa; Erythropoietin; Female; Humans; Male; Neoplasms; Quality of Life; Recombinant Proteins

Patents of innovator biopharmaceutical products, such as epoetin, are expiring, and biosimilar versions of these products may soon enter European and American markets. Copies of these products, termed biosimilars or follow-on biologics, are not truly equivalent and cannot gain market approval through the procedure typically applied to generic drugs. We evaluated literature reports of both analytic and clinical studies conducted with biosimilar epoetin products currently marketed outside the United States and Europe in light of recently implemented European Medicines Evaluation Agency guidelines. The analytic studies reported that products differed widely in composition, did not always meet self-declared specifications, and exhibited batch-to-batch variation. Although several clinical studies demonstrated correction of anemia with biosimilar epoetins by using an open-label or placebo-controlled study design, only 4 of 22 studies were competitor controlled. Most of the studies were small (median 41 patients, range 18-1079 patients) and of short duration (median 12 wks, range 6 wks-1 yr). Clinical experience with epoetin shows that the dosage required to achieve similar hemoglobin levels varies among patients, making it impossible to demonstrate bioequivalence without a comparator. The analytic reports did not demonstrate comparability of biosimilar epoetin products with innovator epoetin alfa, and the clinical studies were not rigorous enough to show equivalent safety and efficacy of a biopharmaceutical product. The variation between products illustrates the challenge in replicating and consistently producing biopharmaceutical proteins. Immunogenic reactions with epoetin indicate that large, long-term studies are needed to adequately monitor safety.

Topics: Anemia; Animals; Biological Products; Clinical Trials as Topic; Drug and Narcotic Control; Erythropoietin; Europe; Humans; Patents as Topic; Practice Guidelines as Topic; Recombinant Proteins; Therapeutic Equivalency; United States

While advances in treatment strategies and pharmacotherapy have produced a dramatic reduction in the mortality of patients with heart failure during the past 15 years, there is still a major challenge to improve patient well being, reduce hospitalizations and reduce mortality further. The prevalence of heart failure is not decreasing, and heart failure is currently a cause for hospitalization in >25% of admissions to internal medicine and cardiology departments. It has recently become apparent that anaemia is present in 20-30% of patients with heart failure, and the severity of anaemia has important implications regarding outcome and prognosis. Anaemia may be due to a number of causes, including iron and vitamin deficiency, insidious blood loss, haemodilution, renal impairment and bone marrow depression with resistance to erythropoietin. In the presence of a damaged heart and often coronary artery disease, anaemia may worsen contractile ability and systolic function, while the necessary volume load and ventricular hypertrophy which accompany anaemia contribute to diastolic dysfunction. Preliminary data show that appropriate treatment of anaemia, based on correction of the underlying cause, with, in most patients, the addition of exogenous erythropoietin and iron therapy, improves ventricular function and clinical status. Treatment of anaemia has opened a new frontier in the management of heart failure. We await the results of ongoing clinical trials for more detailed information regarding appropriate haemoglobin targets, choice of medication and dosing and the degree of improvement that may be expected when the issue of anaemia is properly addressed.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Erythropoietin; Heart Failure; Humans; Iron; Middle Aged; Prevalence; Ventricular Dysfunction, Left

Heart failure (HF) is a common disease associated with poor prognosis. Anaemia is commonly associated with HF due to bone marrow depression, reduced availability of iron and haemodilution, and is sometimes aggravated by too frequent blood testing. Low haemoglobin is very detrimental to the haemodynamic state of the patient with decreased cardiac output as it further diminishes the oxygen supply to the tissues. When anaemia is associated with HF. and renal failure, the patient enters a vicious cycle called cardio renal anaemia syndrome. The prognosis of patients with HF is worse as the haemoglobin is lower and even mild anaemia is associated with <1 year survival. Aggressive correction of the anaemia by subcutaneous injections of erythropoeitin and intravenous iron has been shown to improve the functional capacity and quality of life of patients with cardio renal anaemia syndrome and to reduce the need for hospitalization. However, intravenous iron can be detrimental because of increased formation of free radicals, oxidative stress and risk of infection. The level of haemoglobin needed to be achieved is not clear, but it seems indicated to maintain it above 12 g%.

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Iron; Prognosis; Renal Insufficiency

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

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

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

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

We have uncovered a physiologic process which negatively regulates the red cell mass by selectively hemolyzing young circulating red blood cells. This allows fine control of the number of circulating red blood cells under steady-state conditions and relatively rapid adaptation to new environments. Neocytolysis is initiated by a fall in erythropoietin levels, so this hormone remains the major regulator of red cell mass both with anemia and with red cell excess. Physiologic situations in which there is increased neocytolysis include the emergence of newborns from the hypoxic uterine environment and the descent of polycythemic high-altitude dwellers to sea level. The process first became apparent while investigating the mechanism of the anemia that invariably occurs after spaceflight. Astronauts experience acute central plethora on entering microgravity resulting in erythropoietin suppression and neocytolysis, but the reduced blood volume and red cell mass become suddenly maladaptive on re-entry to earth's gravity. The pathologic erythropoietin deficiency of renal disease precipitates neocytolysis, which explains the prolongation of red cell survival consistently resulting from erythropoietin therapy and points to optimally efficient erythropoietin dosing schedules. Implications should extend to a number of other physiologic and pathologic situations including polycythemias, hemolytic anemias, 'blood-doping' by elite athletes, and oxygen therapy. It is likely that erythropoietin influences endothelial cells which in turn signal reticuloendothelial phagocytes to destroy or permit the survival of young red cells marked by surface molecules. Ongoing studies to identify the molecular targets and cytokine intermediaries should facilitate detection, dissection and eventual therapeutic manipulation of the process.

Topics: Altitude; Anemia; Erythrocytes; Erythropoietin; Hemolysis; Humans

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

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

The management of cancer-related anemia with erythropoietic agents presents many unresolved issues. We reviewed the literature relating to epoetin alfa (Eprex)/Epypo); Ortho Biotech/Janssen-Cilag, High Wycombe, United Kingdom, http://www.orthobiotech.co.uk; Procrit); Ortho Biotech Products, L.P., Bridgewater, NJ, http://www.orthobiotech.com), epoetin beta (NeoRecormon); Hoffman-La Roche, Basel, Switzerland, http://www.roche.com), and darbepoetin alfa (Aranesp); Amgen Inc., Thousand Oaks, CA, http://www.amgen.com) highlighting the results of published clinical trials, safety, and cost-effectiveness. Studies were identified through MEDLINE and the bibliographies of relevant articles. Epoetin alfa, epoetin beta, and darbepoetin alfa have differing pharmacokinetic and pharmacodynamic profiles. They are all effective at reducing transfusion requirements and improving health-related quality-of-life parameters, irrespective of tumor response. A direct comparison between epoetin alfa and darbe poetin alfa is based on limited evidence, which does not allow definitive conclusions about relative efficacy and cost-effectiveness. No predictive factors for response to erythropoietic agents have been validated in prospective trials. The most consistent adverse events are thrombotic and may occur irrespective of an increase in hemoglobin. Recent research indicates that the erythropoietin receptor is expressed in several cancer cell lines, raising the concern of possible stimulation of tumor cell growth by these drugs. Studies on the cost-effectiveness of erythropoietins, particularly compared with transfusion therapy, have been challenging to conduct and analyze and have generated ambiguous results. The use of erythropoietins needs to be optimized in terms of cost-effectiveness, and issues surrounding safety need to be clarified. A stronger methodology for clinical studies and the design of new, randomized, clinical trials is a major priority.

Topics: Anemia; Clinical Trials as Topic; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Humans; Neoplasms; Recombinant Proteins

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

Eighty percent of children with cancer suffer from anemia at the time of diagnosis. The physiopathology of anemia is complex. Although anemia can be life threatening, its consequences on the physical, psychological and social state of the child are often minimized. Blood transfusion is the main treatment of anemia: its efficacy is immediate but shortlasting, and it involves infectious and hemolytic risks. The human recombinant erythropoietin has been used for more than 25-years, and is often prescribed to adults with cancer and anemia. The human recombinant erythropoietin rHuEPO is nowadays used when blood transfusion is contra-indicated because of religious or cultural considerations, although several promising studies have been conducted about rHuEPO and children with cancer since 1996: it might be soon the preferential alternative treatment to anemia in children with cancer.

Topics: Adolescent; Anemia; Blood Transfusion; Child; Child, Preschool; Erythropoietin; Female; Humans; Infant; Leukemia; Lymphoma; Male; Neoplasms; Neuroblastoma; Recombinant Proteins

To review the impact of anemia/tumor hypoxemia on the quality of life and survival in cancer patients, and to assess the problems associated with the correction of this difficulty.. MEDLINE searches were performed to find relevant literature regarding anemia and/or tumor hypoxia in cancer patients. Articles were evaluated in order to assess the epidemiology, adverse patient effects, anemia correction guidelines, and mechanisms of hypoxia-induced cancer cell growth and/or therapeutic resistance. Past and current clinical studies of radiosensitization via tumor oxygenation/hypoxic cell sensitization were reviewed. All clinical studies using multi-variate analysis were analyzed to show whether or not anemia and/or tumor hypoxemia affected tumor control and patient survival. Articles dealing with the correction of anemia via transfusion and/or erythropoietin were reviewed in order to show the impact of the rectification on the quality of life and survival of cancer patients.. Approximately 40-64% of patients presenting for cancer therapy are anemic. The rate of anemia rises with the use of chemotherapy, radiotherapy, and hormonal therapy for prostate cancer. Anemia is associated with reductions both in quality of life and survival. Tumor hypoxemia has been hypothesized to lead to tumor growth and resistance to therapy because it leads to angiogenesis, genetic mutations, resistance to apoptosis, and a resistance to free radicals from chemotherapy and radiotherapy. Nineteen clinical studies of anemia and eight clinical studies of tumor hypoxemia were found that used multi-variate analysis to determine the effect of these conditions on the local control and/or survival of cancer patients. Despite differing definitions of anemia and hypoxemia, all studies have shown a correlation between low hemoglobin levels and/or higher amounts of tumor hypoxia with poorer prognosis. Radiosensitization through improvements in tumor oxygenation/hypoxic cell sensitization has met with limited success via the use of hyperbaric oxygen, electron-affinic radiosensitizers, and mitomycin. Improvements in tumor oxygenation via the use of carbogen and nicotinamide, RSR13, and tirapazamine have shown promising clinical results and are all currently being tested in Phase III trials. The National Comprehensive Cancer Network (NCCN) guidelines recommend transfusion or erythropoietin for symptomatic patients with a hemoglobin of 10-11 g/dl and state that erythropoietin should strongly be considered if hemoglobin falls to less than 10 g/dl. These recommendations were based on studies that revealed an improvement in the quality of life of cancer patients, but not patient survival with anemia correction. Phase III studies evaluating the correction of anemia via erythropoietin have shown mixed results with some studies reporting a decrease in patient survival despite an improvement in hemoglobin levels. Diverse functions of erythropoietin are reviewed, including its potential to inhibit apoptosis via the JAK2/STAT5/BCL-X pathway. Correction of anemia by the use of blood transfusions has also shown a decrement in patient survival, possibly through inflammatory and/or immunosuppressive pathways.. Anemia is a prevalent condition associated with cancer and its therapies. Proper Phase III trials are necessary to find the best way to correct anemia for specific patients. Future studies of erythropoietin must evaluate the possible anti-apoptotic effects by directly assessing the tumor for erythropoietin receptors or the presence of the JAK2/STAT5/BCL-X pathway. Due to the ability of transfusions to cause immunosuppression, most probably through inflammatory pathways, it may be best to study the effects of transfusion with the prolonged use of anti-inflammatory medications.

Topics: Anemia; Blood Transfusion; Erythropoietin; Humans; Hyperbaric Oxygenation; Hypoxia; Neoplasms; Practice Guidelines as Topic; Quality of Life; Radiation Tolerance; Radiation-Sensitizing Agents; Recombinant Proteins

Topics: Anemia; Biomarkers; Diagnostic Techniques, Endocrine; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Humans; Myelodysplastic Syndromes; Nephrotic Syndrome; Polycythemia; Radioimmunoassay; Reference Values; Specimen Handling

The role of erythropoietin in the development of anemia in patients with oncohematological diseases has been discussed. Efficacy of use of erythropoietin in patients with oncohematological diseases was analyzed. Features of use, contraindication and adverse reactions have been discussed. Erythropoietins-beta have proved to be more effective than erythropoietins-alpha.

Topics: Anemia; Erythropoietin; Hematologic Neoplasms; Humans; Recombinant Proteins

Newborn infants in intensive care units, especially those born premature, are at particular risk for blood transfusion adverse effects. Aside improvements in the preparation of specific blood products for the neonatal period, such as multiple packed cells preparations from a single donor for multiple transfusions in premature infants, progress has involved prophylaxis of anemia of prematurity as well. Recombinant human erythropoietin has proven to be beneficial with high range evidence. Also, alternative methods have been proposed to compensate for the delay in the effect of rHuEPO, such as delayed clamping of umbilical cord at birth, or autologous placental blood transfusion. However, a better understanding of the indications of blood transfusion and the provision of practice guidelines may justify a re-evaluation of prophylactic strategies for anemia of prematurity.

Topics: Anemia; Antigens, Human Platelet; Blood Component Transfusion; Combined Modality Therapy; Erythrocyte Transfusion; Erythropoietin; Exchange Transfusion, Whole Blood; Granulocytes; Humans; Immunity, Maternally-Acquired; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature; Infant, Premature, Diseases; Intensive Care, Neonatal; Leukocyte Transfusion; Plasma; Platelet Transfusion; Practice Guidelines as Topic; Recombinant Proteins; Thrombocytopenia

Hypoxia and/or anaemia have an adverse prognostic impact in locally-advanced cancers of uterine cervix. Moreover, these parameters are independent of other well-known prognostic factors. However, the mechanisms by which treatment efficacy and survival are compromised by anaemia are not fully understood. Although it is clear that erythropoietin can reduce the need for transfusions for cancer patients with anaemia, there is no proof that the use of erythropoietin is in any way superior to transfusions with respect to the impact on clinical outcome, especially for patients receiving radiation therapy. Whether haemoglobin levels at the start of therapy, during therapy, or at the end of therapy are of prognostic value for better disease-free and overall survival, are matters for further studies as is the question of the best option for increasing the level of the patient's haemoglobin.

Topics: Anemia; Erythropoietin; Female; Humans; Hypoxia; Uterine Neoplasms

Anemia in children with chronic kidney disease (CKD) is common secondary to inadequate erythropoietin production, iron deficiency, blood loss, inflammation, secondary hyperparathyroidism, uremic toxins, and nutritional deficiencies. Anemia has a variety of deleterious consequences, including associations with increased mortality and left ventricular hypertrophy. Recombinant human erythropoietin is effective in treating anemia in children with CKD, and recent studies show that darbepoetin alpha is an attractive alternative because it requires less frequent injections. Iron deficiency is a major cause of anemia that is resistant to erythropoietin or darbepoetin alpha. Although oral iron is effective in some patients, many children, especially those receiving hemodialysis, require intravenous iron to replenish their iron stores. Both acute dosing and chronic dosing of intravenous iron are effective in pediatric patients.

Topics: Anemia; Child, Preschool; Erythropoietin; Hematinics; Humans; Iron; Renal Insufficiency, Chronic

Anaemia, a common problem in patients with cancer, usually leads to severe fatigue, which can dramatically impair patients' quality of life (QOL). Nurses are in the ideal position to assess and monitor cancer patients at risk of anaemia and recommend appropriate supportive care measures to alleviate anaemia-related symptoms. Erythropoiesis-stimulating proteins (ESPs) can increase haemoglobin levels, reduce the need for red blood cell transfusions, and improve QOL in patients with cancer and anaemia. Evidence-based guidelines published by national and international organisations make specific recommendations for the appropriate use of ESPs. Nurses are key members of the multidisciplinary teams that develop practice-specific protocols, which are based on the national guidelines. The practice guidelines should describe protocols to identify patients at risk for anaemia and interventions to correct anaemia, with specific details on the choice of ESP and when such interventions should be initiated and halted. In addition, nurses should also recommend strategies to reduce patient burden, such as patient self-administration with prefilled pens or synchronisation of visits for ESPs with chemotherapy visits, which is made possible with the once-every-3-weeks extended dosing with darbepoetin alfa. The implementation of such practice guidelines should improve the quality of care provided to patients.

Topics: Algorithms; Anemia; Erythropoietin; Hematinics; Humans; Neoplasms; Practice Guidelines as Topic; Recombinant Proteins; Risk Assessment

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

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

Consensus guidelines are in place for treating chronic hepatitis C virus infection. This article highlights some of the hematologic complications of hepatitis C therapy. Management options are presented.

Topics: Anemia; Antiviral Agents; Bone Marrow; Epoetin Alfa; Erythropoietin; Hematologic Diseases; Hepatitis C, Chronic; Humans; Interferon Type I; Neutropenia; Recombinant Proteins; Ribavirin; Thrombocytopenia

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

Anaemia is a common complication of cancer and its treatment. It is also associated with substantial impairment of patient quality of life (QOL). Erythropoietic agents are primary treatment options for cancer-related anaemia (CRA). This review summarises evidence supporting clinical use of the approved erythropoietic agents (epoetin alfa, epoetin beta, darbepoetin alfa). A MEDLINE((R)) search from January 2000 to September 2004 using the search terms "epoetin alfa," "epoetin beta," "darbepoetin alfa," "erythropoietin," and "anaemia" was conducted to identify studies evaluating erythropoietic agents in the treatment of CRA. Recent presentations at professional meetings were also included. Erythropoietic agents increase haemoglobin levels, decrease transfusion requirements, and improve QOL in patients with CRA. However, variations in study design, patient populations, dose titration schedules, and outcome measures among available studies make data comparisons between clinical trials difficult. Head-to-head trials are comparing erythropoietic agents in a randomised setting; other trials are evaluating optimal dosage schedules. Clinically relevant differences among approved erythropoietic agents have not been determined in direct comparative trials; however, epoetin alfa appears to be at least as effective as darbepoetin alfa in treatment of CRA.

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Drug Evaluation; Epoetin Alfa; Erythropoietin; Humans; Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Treatment Outcome

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

Anaemia is the most common haematological abnormality encountered by cancer patients. A large European survey of cancer patients (n = 15,367) reported that 67% had anaemia at some point during the survey, and that over 60% of these patients did not receive any treatment for their anaemia. Two other surveys (the FATIGUE surveys) showed that over 75% of cancer patients experienced fatigue at least monthly, with over 30% reporting this symptom on a daily basis. Significantly, patients regarded fatigue as having a greater negative impact on their daily lives than many other cancer- or treatment-related complications, with important emotional and mental consequences including lack of self-motivation, sadness, frustration, and mental exhaustion. Indeed, fatigue was considered so debilitating, 12% of patients felt their quality of life (QoL) was so reduced that they did not wish to continue living. Anaemia is also recognised as an independent predictor of poor prognosis in cancer patients. A systematic review evaluating survival showed a 65% overall increase in the risk of mortality in cancer patients with anaemia. Increasing physicians' awareness of the importance of effectively treating anaemia in cancer patients therefore has the potential to improve prognosis as well as QoL.

Topics: Activities of Daily Living; Anemia; Anemia, Hypochromic; Cost of Illness; Erythropoietin; Fatigue; Humans; Neoplasms; Predictive Value of Tests; Prognosis; Quality of Life; Recombinant Proteins; Risk Assessment; Risk Factors; Survival Analysis; Time Factors; Treatment Outcome

Topics: Age Factors; Aged; Anemia; Erythropoietin; Hemoglobins; Humans; Kidney; Prevalence; Survival Rate; United States

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

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

Heart failure affects 5 million persons in the United States, with 400,000 new cases occurring every year. Paradoxically, although advances in coronary angioplasty and effective drugs have increased survival post infarction, the myocardial damage and subsequent neurohormonal activation-induced remodeling causes significant morbidity years later in the form of heart failure. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) together with beta blockers modify the neurohormonal activation associated with heart failure and are key treatments for improving cardiac function and survival. Anemia is a significant risk factor predicting morbidity and mortality in heart failure. This article describes the various etiologies of anemia in heart failure. Of particular importance is the fact that recent stem cell studies have shown that the drugs acting on the renin-angiotensin system inhibit erythropoiesis in vivo and may cause anemia in patients with both normal renal function and end-stage renal disease (ESRD). The role of angiotensin-II as an erythropoietic growth factor and ACE in facilitating erythropoiesis is described in this article. Anemia has been shown to be a modifiable risk factor and its treatment correlates with improvement in clinical outcomes. Thus, anemia, its etiology (especially the contribution of ACEIs and ARBs), physiologic and prognostic impact, and treatment in the setting of heart failure are critical areas for investigation.

Topics: Anemia; Animals; Clinical Trials as Topic; Cytokines; Erythropoietin; Heart Failure; Humans; Renin-Angiotensin System; Risk Factors

Anaemia is common in patients with congestive heart failure (CHF). Its prevalence increases with disease severity as a consequence of renal insufficiency, cytokine production, blood loss, iron deficiency, malnutrition and/or plasma volume overload. Anaemia can contribute to worsening of CHF. There is a nonlinear relationship (U-shaped curve) between haemoglobin and survival. Prevalence of anaemia among elderly people with acute myocardial infarction is high and is associated with more frequent in-hospital events, including death. Anaemia is also associated with higher in-hospital mortality rate after coronary bypass surgery and with all-cause and cardiac mortality after percutaneous coronary interventions. Patients with anaemia and cardiovascular disease have a higher mortality rate after cardiac/noncardiac surgery as compared to those with anaemia but without cardiovascular disease or those with cardiovascular disease but without anaemia. However, not all authors confirmed these findings. Therefore, multicentre trials to clarify this issue are urgently needed. Pleiotropic effects of recombinant human erythropoietin include reduction of myocardial and cerebral infarct size without an increase in haematocrit, neovascularization as well as mobilization of endothelial progenitor cells.

Topics: Aged; Anemia; Coronary Circulation; Erythropoietin; Heart; Heart Failure; Humans; Myocardial Infarction; Myocardial Revascularization; Recombinant Proteins

This review focuses on the pathophysiology, incidence and treatment of anaemia in cancer patients. Causative factors such as different chemotherapy regimens and patient risk factors for the development of anaemia are discussed in order to identify the patient group that is most likely to receive red blood cell transfusions and would thus have the largest benefit from treatment with erythropoietic proteins. The data available with recombinant human erythropoietin alfa, recombinant human erythropoietin beta and darbepoetin alfa are described in more detail and the significant benefit of treating cancer anaemia by these molecules is outlined. Finally, differences in treatment approaches between these erythropoietic proteins are discussed in order to guide treatment decisions specific for the individual patients' situation.

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Drug Administration Schedule; Erythropoiesis; Erythropoietin; Hematinics; Humans; Neoplasms; Recombinant Proteins; Treatment Outcome

The anaemia associated with chronic renal failure is multi-factorial. Although a relative erythropoietin deficiency is a major factor, it has also been recognized in recent times that uraemia is a chronic inflammatory state, and thus patients with renal failure also develop anaemia due to mechanisms associated with chronic inflammation. Thus, patients with chronic renal failure have activation of various immune cells, both monocytes and T-cells. These mononuclear cells have also been shown to release pro-inflammatory cytokines such as IL-1, IL-6, TNF-alfa and interferon gamma. These cytokines, particularly TNF-alfa and interferon gamma, are known to cause significant suppression of erythropoiesis. The exact molecular mechanism for this effect is not yet clear, but interferon gamma is an important stimulator of apoptosis in various cell types, including erythroid progenitor cells. This effect may be potentiated by other cytokines such as TNF-alfa, and this might then antagonise the anti-apoptotic action of erythropoietin on erythroid progenitors cells, thus reducing responsiveness to exogenous erythropoietic therapy. Chronic renal failure is also associated with increased hepcidin production which may also exacerbate the anaemia by inducing a functional iron deficiency in such patients.

Topics: Anemia; Chronic Disease; Cytokines; Erythropoiesis; Erythropoietin; Humans; Inflammation; Renal Insufficiency

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

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

Anaemia is common in severe cardiac failure due to systolic dysfunction. The mechanisms are varied. Anaemia is a negative prognostic factor. Treatment with erythropoietin seems to improve the quality of life, functional status, effort tolerance and systolic function of these patients. Large scale clinical trials are on-going.

Topics: Anemia; Erythropoietin; Heart Diseases; Heart Failure; Humans; Recombinant Proteins

Since the very early manned missions in space, a state of anemia associated with reduced erythropoietin levels and reduced plasma volume was disclosed. The reduction in red blood cell mass is driven by a process of selective hemolysis, which has been named neocytolysis. This phenomenon also occurs in people living at a high altitude who descend rapidly to sea level. The origin of the signal leading to destruction of newly produced red blood cells probably is located in central circulation, but the operating mechanism is unknown. The importance of plasma cell volume reduction in the genesis of a lower red cell mass also is supported by the inverse correlation seen at moderate altitude. People arriving at moderate altitude have increased erythropoietin concentration that decreases after a few days and is in inverse correlation with central venous pressure. Studies under simulated microgravity conditions in human beings (bed rest, head-down tilt at -6 degrees , water immersion) and in rats provide further insight in unraveling the mechanism of astronauts' anemia, a problem difficult to study in space because of the limited availability of spaceflights.

Topics: Anemia; Animals; Case-Control Studies; Cell Physiological Phenomena; Erythrocyte Aging; Erythropoiesis; Erythropoietin; Female; Head-Down Tilt; Humans; Incidence; Male; Models, Animal; Rats; Research; Risk Assessment; Sensitivity and Specificity; Space Flight; Weightlessness

Anemia occurs in virtually all critically ill patients receiving long-term mechanical ventilation and has been associated with increased mortality and poor outcomes. Allogeneic RBC transfusions are routinely administered to critically ill anemic patients, especially during lengthy stays in ICUs or in long-term acute care facilities. Although RBC transfusions are a physiologically rational approach to raising hemoglobin levels, they may increase the risk of complications and have been associated with higher mortality in critically ill patients. Treatment with epoetin alfa, an erythropoiesis-stimulating agent, as a means of reducing transfusion requirements has been studied in the critically ill and in patients receiving long-term mechanical ventilation. Promising results have been reported, including a potential survival benefit, although larger and more definitive studies are needed in order to establish whether raising hemoglobin levels affects clinical outcomes in patients receiving mechanical ventilation.

Topics: Anemia; Blood Banks; Comorbidity; Critical Illness; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Hematinics; Hemoglobins; Humans; Recombinant Proteins; Respiration, Artificial; Respiratory Insufficiency; Time Factors; Ventilator Weaning

Healthy individuals are able to tolerate profound, short-term decreases in hemoglobin levels and oxygen saturation without serious consequences, but critically ill patients in respiratory failure lack the necessary reserve capacity to preserve tissue oxygenation. The development of progressive anemia in ICU patients has led to much interest and debate about transfusion practices, yet optimal hemoglobin levels and how they should be achieved remain unclear. Animal and human studies regarding critical oxygen delivery provide the rationale for optimizing hemoglobin levels and supporting cardiovascular function during respiratory failure. Theoretically, the oxygen-carrying benefit of RBCs should hasten recovery from respiratory failure, and transfusions would therefore be expected to shorten the duration of mechanical ventilation. However, evidence to the contrary has been reported. Controversies related to transfusions and their inability to improve outcomes suggest that further research regarding transfusion alternatives is needed, especially in anemic patients with respiratory failure.

Topics: Anemia; Animals; Cell Hypoxia; Comorbidity; Critical Illness; Erythrocyte Transfusion; Erythropoietin; Humans; Oxygen; Oxygen Consumption; Respiration, Artificial; Respiratory Insufficiency; Risk Factors

The rising incidence of type 2 diabetes mellitus and of its complications will make it the most important health care challenge in the first quarter of the 21st Century. Diabetic nephropathy left unchecked will overwhelm the renal resources. Simple methods (proper diet and exercise, prevention of obesity) are successful in preventing type 2 diabetes in the great majority of the persons at risk. In patients with established type 2 diabetes, nephropathy can be prevented or greatly delayed by strict metabolic control, strict control of blood pressure using angiotensin-converting enzyme inhibitors and angiotensin receptor blockers as the first line of drugs, tight control of serum lipids using statins as indicated, low protein diet, avoidance of smoking and other nephrotoxic influences, prevention of abnormalities in calcium/phosphorus metabolism, and prevention of renal anemia by the early use of erythropoietin. Current research offers the promise of definitive prevention of both type 2 diabetes and diabetic nephropathy.

Topics: Albuminuria; Anemia; Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Erythropoietin; Glomerular Filtration Rate; Humans; Hypertension; Mitochondria

Many patients with chronic heart failure also have anemia, an association that has been increasingly recognized in recent years. Whether treating anemia will improve outcomes in patients with heart failure has yet to be determined, however. The decision to use an agent to treat anemia in heart failure should be made on a case-by-case basis.

Topics: Anemia; Erythropoietin; Heart Failure; Humans; Recombinant Proteins; Survival Rate; Treatment Outcome

Cancer patients are frequently anemic. Treatment of anemic patients with erythropoiesis-stimulating proteins (ESPs) such as epoetin and darbepoetin is associated with benefits that include a reduced transfusion risk and improved quality of life. The recent reports of two randomized trials in which ESP treatment was associated with a decreased survival raised valid concerns regarding the safety of these agents in oncology practice. Reports of erythropoietin receptors on non-hematologic human tumor cells have increased the level of concern and provided a relatively simple model for the effects of ESPs on tumor progression and resistance to treatment. This article reviews available data, which lead to a number of conclusions: 1) the two trials suggesting a negative impact on survival have serious methodologic issues that may compromise interpretation; 2) when used to treat rather than prevent anemia in cancer patients, ESPs show no significant negative impact on survival outcomes; 3) with the exception of erythroleukemia cell lines, the presence of functional erythropoietin receptors on human tumor cells has not been conclusively shown; and 4) a sound theoretical basis exists, supported by preclinical evidence, that any effect of ESP therapy on tumor outcomes may depend on baseline hemoglobin levels, with different effects when anemic and non-anemic individuals are treated. For the present, it is prudent to withhold ESP therapy unless hemoglobin concentrations fall below 12 g/dL and to titrate treatment to maintain a target of 12 g/dL, with adjustments in therapy to insure that levels do not exceed 13 g/dL.

Topics: Anemia; Animals; Erythropoietin; Hematinics; Humans; Neoplasms; Recombinant Proteins; Survival Analysis; Treatment Outcome

Perioperative anemia is common and is associated with increased need for blood transfusion in the perioperative period. Perioperative anemia has also been linked to increased morbidity and mortality in surgical patients. Anemia may impede a patient's ability to recover fully and participate in postoperative rehabilitation. Pre-operative treatment of anemia is associated with a reduction in the need for blood transfusion in the perioperative period. Additional advances in surgical technology that reduce blood loss intraoperatively are associated with a reduction in postoperative anemia and should be used whenever possible. All strategies to prevent anemia in the perioperative period should be considered in an effort to minimize exposure of surgical patients to blood transfusion.

Topics: Anemia; Blood Transfusion; Combined Modality Therapy; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Male; Perioperative Care; Postoperative Care; Postoperative Complications; Preoperative Care; Primary Prevention; Recombinant Proteins; Risk Assessment; Severity of Illness Index; Surgical Procedures, Operative

Anemia in cancer patients undergoing treatment is common and can cause debilitating symptoms such as fatigue and reduced exercise tolerance. The introduction of recombinant human erythropoietin represents a potential improvement in the treatment of this condition. Clinical studies in patients with solid tumors and nonmyeloid hematologic malignancies have convincingly shown an improvement in mean hemoglobin concentration, a reduction in transfusion requirement along with an improvement in quality of life scores, although an effect on survival is less clear. In myeloid disorders such as myelodysplasia, response to single-agent recombinant human erythropoietin is disappointing but significant synergism with granulocyte colony stimulating factor has been demonstrated and different dosing regimens may also improve response. Unfortunately, a significant proportion of patients remain refractory to treatment. Efforts have been made to identify treatable causes of erythropoietin refractoriness, such as functional iron deficiency, and concomitant intravenous iron supplementation does appear to improve response rates. The search for pretreatment factors that predict response has been largely disappointing, although a promising model for myelodysplasia has been developed that awaits large-scale evaluation. Recombinant human erythropoietin is well tolerated, although there were concerns in the late 1990s due to a rising incidence of pure red cell aplasia in chronic renal failure patients treated with subcutaneous Eprex (Ortho Biologics) in Europe. Since potentially contributory manufacturing processes have been identified and corrected, the incidence of this complication has been falling.

Topics: Anemia; Clinical Trials as Topic; Epoetin Alfa; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematologic Neoplasms; Hemoglobins; Humans; Neoplasms; Prognosis; Quality of Life; Recombinant Proteins

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

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

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

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

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

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

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

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

Recombinant erythropoietin (EPO) is used to correct for anaemia caused by chronic renal failure or cancer therapy. Improvement of the quality of life of anaemic patients treated with EPO was recently demonstrated and preliminary clinical results suggest an improvement of cognitive functions in patients receiving EPO. High expression of EPO and its receptor in the brain during embryonic development has led to the investigation of not only the neurotrophic role of EPO but also its neuroprotective properties. The neuroprotective effects of EPO have various complementary actions including antagonism of the effects of glutamate, increased expression of antioxidant enzymes, changes in production of neurotransmitters and induction of neuroglobin. Convincing experimental results suggest a blood-brain transport of EPO whereas clinical pharmacokinetic data do not as yet support this. The neuroprotective effects of EPO and its therapeutic promise need to be underlined.

Topics: Anemia; Animals; Cognition; Erythropoietin; Humans; Neuroprotective Agents; Prognosis; Quality of Life; Recombinant Proteins

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

Diabetes as the dominant cause of ESRD is also the major cause of renal anaemia. However, most patients with diabetic kidney disease will succumb to co-morbid vascular disease or heart failure before developing severe renal impairment. In these patients, anaemia is also common finding, with a 2-3 times greater prevalence and earlier onset than in patients with renal impairment from other causes. We have recently shown that at least one in five outpatients with type 1 or type 2 diabetes in tertiary referral clinics have anaemia, in whom it constitutes a significant additional burden. Impaired renal erythropoietin release in response to declining haemoglobin levels appears to be the major contributor to anaemia in diabetes. This may be due to the predominance of damage to cells and vascular architecture of the renal tubulointerstitium associated with diabetic nephropathy that may be apparent, like albuminuria, before demonstrable changes in renal function. In addition, systemic inflammation, autonomic neuropathy and reduce red cell survival may also compound anaemia in diabetes. While anaemia may be considered a marker of diabetic kidney disease, reduced haemoglobin levels, even within the normal range, identify diabetic patients with an increased risk of hospitalisation and mortality. Anaemia may also be significant in determining the outcome of heart failure and hypoxia-induced organ damage in patients with diabetes. Upcoming studies will determine whether correction of anaemia in diabetes will lead to improved outcomes in these patients.

Topics: Anemia; Blood Pressure; Diabetes Complications; Diabetic Angiopathies; Diabetic Neuropathies; Diabetic Retinopathy; Erythrocytes; Erythropoietin; Glomerular Filtration Rate; Hematopoiesis; Humans; Infections; Kidney; Microcirculation; Prevalence; Wound Healing

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Humans; Neoplasms; Practice Guidelines as Topic; Recombinant Proteins

Anemia is a common occurrence in the primary care setting, and primary care physicians are often the first to detect its causes. Defined by the World Health Organization as serum hemoglobin (Hb) levels less than 13 g/dL in men and less than 12 g/dL in women, anemia affects persons of all ages and is especially prevalent in older adults. Older patients also appear to experience more profound consequences of anemia, such as an increased risk of morbidity, functional decline, and mortality. Nonetheless, the significance of anemia in the older patient population remains underappreciated, and the condition often goes undiagnosed and untreated. In this article, Dr Eisenstaedt reviews current evidence on the prevalence, causes, consequences, and management of the types of anemia most commonly encountered by the primary care physician and presents a detailed evaluation of the clinical considerations unique to anemia in older adults.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Nutrition Surveys; Prevalence; Primary Health Care; Sex Factors; Survival Analysis; United States; Young Adult

Topics: Anemia; Embryo, Mammalian; Endothelial Cells; Erythrocytes; Erythropoietin; Growth Substances; Humans; Neovascularization, Physiologic

Several factors are involved in conditioning renal anemia, and a critical role is attributed to parathyroid hormone (PTH) oversecretion, which has some direct effects on endogenous erythropoietin (EPO) synthesis, bone marrow erythroid progenitors, and red cell survival. Indirect effects are mainly based on the induction of bone marrow fibrosis. Indirect evidence of the role of PTH is based on the observation that parathyroidectomy, when performed in uremic patients, is often followed by restoration of the hematocrit. The interpretations of such positive results are based on the observation of the restored bone marrow space after operation and also in a rise of immunoreactive EPO serum concentrations observed in the first weeks after gland removal. Another field of clinical interest is the possible beneficial effects of vitamin D therapy in controlling PTH secretion, which in turn determines an improvement of anemia of uremic subjects. Several uncontrolled studies confirmed this possibility, indicating that patients who respond to calcitriol or its analogs also show an increase of their hemoglobin levels. Thus, a combined therapeutic approach to PTH oversecretion and anemia is possible by intravenous calcitriol or parathyroidectomy pointing to the possible reversibility of bone marrow fibrosis, which is a common feature of secondary hyperparathyroidism. The increased sensitivity to EPO therapy can also induce a successful reduction of its dosage, thus allowing an interesting reduction of costs.

Topics: Anemia; Bone Marrow; Erythropoiesis; Erythropoietin; Fibrosis; Humans; Hyperparathyroidism; Parathyroid Hormone; Parathyroidectomy; Uremia; Vitamin D

Recombinant erythropoietin (rEpo) has been administered to women with postpartum anemia in an attempt to accelerate their increase in hemoglobin concentration and reduce postpartum transfusions. However, it is not clear whether such an approach can be supported by evidence and should be generally recommended.. Medical and scientific literature from January 1990 to December 2002 was searched and studies that reported the administration of rEpo to women with postpartum anemia were evaluated.. Eight evaluated studies reported an aggregate of 480 women; 300 rEpo recipients and 180 controls. Significant diversity in design was observed in rEpo dose, route of rEpo administration, iron supplementation, and baseline hemoglobin. No significant safety concerns were reported. In all five studies where it was reported, 4 to 7 days after beginning treatment, greater increases in hemoglobin concentration were observed among the rEpo recipients than among the controls. However, heterogeneity of results (Q-test statistic, p<0.01) indicated that it was not appropriate to apply summary statistics. The effect of rEpo on postpartum transfusion rate was not measurable by summary statistics because of the limited number of transfusions given (no transfusions among the 300 rEpo recipients vs two transfusions among the 180 controls).. Administration of rEpo to women with postpartum anemia appears to be safe, and is associated with a trend toward a faster increase in hemoglobin concentration. However, its efficacy in terms of diminishing postpartum transfusions is unproven.

Topics: Adult; Anemia; Case-Control Studies; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Injections, Subcutaneous; Perinatology; Postpartum Period; Randomized Controlled Trials as Topic; Recombinant Proteins; Reference Values; Treatment Outcome

Erythrocyte transfusions to neonates can be categorized as "early" if given during the first 3 weeks of life and "late" if given thereafter. We used a meta-analysis to determine whether recombinant erythropoietin (rEpo) administration to very-low-birth-weight (VLBW, <1500 g) neonates, beginning in the first week of life, reduces either "early" or "late" transfusions.. Studies that used a randomized, placebo-controlled, double-masked design were deemed acceptable. We identified 12 acceptable, relevant, clinical trials. Additional data not provided in the publications were obtained from two of the authors.. The acceptable studies involved an aggregate of 561 rEpo and 529 placebo recipients. If rEpo was begun in the first week of life, the summary odds ratio (OR) for receiving any transfusion ("early" or "late") was 0.52, 95% confidence interval (CI): 0.34 to 0.79 (p=0.001). The OR for receiving an "early" transfusion was 0.54 (95% CI: 0.25 to 1.15; p=0.055), and the OR for receiving a "late" transfusion was 0.56 (95% CI: 0.37 to 0.83; p=0.036). Heterogeneity among studies was too great to estimate the effect of rEpo on the number of transfusions received or the volume of blood transfused (p<0.001 for the Q-test statistic). Subgroup analysis suggested that when rEpo is begun in the first week of life, neonates 1000 to 1500 g and >29 weeks are more likely to completely avoid transfusion than are extremely low-birth-weight (ELBW, <1000 g) neonates. No dose-response relationship was apparent between rEpo dose or iron dose and transfusion. No difference was apparent depending on whether the rEpo was given subcutaneously vs intravenously.. If rEpo is begun in the first week of life, a moderate reduction can be expected (p=0.001) in the proportion of VLBW neonates transfused. Reduction is less significant in "early" transfusion (p=0.055) than in "late" transfusion (p=0.036). Such treatment is not likely to eliminate transfusions among ELBW neonates completely.

Topics: Anemia; Blood Transfusion; Confidence Intervals; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Female; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Male; Odds Ratio; Probability; Prognosis; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Assessment; Severity of Illness Index; Survival Rate; Time Factors; Treatment Outcome

Since its initial indication as hormone-replacement therapy in the anemia of chronic kidney disease, epoetin alfa has become a mainstay of therapy for chemotherapy-related anemia. Clinical studies have shown that epoetin alfa administered once weekly or three times weekly improves hemoglobin levels, decreases transfusion requirements, and improves quality of life independent of tumor response to chemotherapy. Ongoing research is now evaluating ways to improve the response rate to epoetin alfa, the potential benefits of alternative dosing regimens and early treatment intervention, and nonanemia-related indications (e.g., cognitive impairment, asthenia). In addition, scientists are exploring the role of epoetin alfa in preventing apoptosis and ischemic brain injury, as well as its activity in other nonerythroid tissues. Thus, the role of epoetin alfa is likely to expand in the cancer setting in the coming years.

Topics: Anemia; Antineoplastic Agents; Epoetin Alfa; Erythropoietin; Humans; Neoplasms; Recombinant Proteins; Survival Analysis

Anemia is the most common hematological abnormality in cancer patients, unfortunately, it is often under-recognized and under-treated. The pathogenesis of cancer anemia is complex and most of the time multifactorial; involving factors related to the tumor itself or its therapy. While anemia can present in a wide range of symptoms, involving almost every organ, it is believed that it contributes much to cancer-related fatigue, one of the most common symptoms in cancer patients. In addition, there is increasing evidence to suggest that anemia is an independent factor adversely affecting tumor response and patient survival. While blood transfusion was the only option to treat cancer-related anemia, the use of recombinant human erythropoietin (rHuEPO) is becoming the new standard of care, more so with the recent studies demonstrating the feasibility of a single weekly injection. Things are even getting better with the recent approval of a new form of rHuEPO; Darbepoetin, an analogue with a 3-fold longer half-life. In addition to its effect in raising hemoglobin, several well-controlled studies demonstrated decrease in transfusion requirements and better quality of life assessed objectively using standard assessments scales.

Topics: Anemia; Blood Transfusion; Combined Modality Therapy; Comorbidity; Developing Countries; Erythropoietin; Female; Humans; Male; Neoplasms; Prognosis; Recombinant Proteins; Risk Assessment; Saudi Arabia; Severity of Illness Index; Survival Rate; Treatment Outcome

Topics: Anemia; Animals; Antimicrobial Cationic Peptides; Erythropoietin; Hepcidins; Humans; Mice; Mononuclear Phagocyte System; Nephritis

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

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

Epoetin beta (NeoRecormon) is a recombinant form of erythropoietin. It increases reticulocyte counts, haemoglobin (Hb) levels and haematocrit. Epoetin beta administered subcutaneously once weekly corrected anaemia and had equivalent efficacy to that of epoetin beta administered three times weekly in patients with haematological malignancies. Subcutaneous epoetin beta reduced transfusion requirements and increased Hb levels versus no treatment in patients with solid tumours and chemotherapy-induced anaemia in nonblind, randomised trials. Anaemia and quality of life were also improved, and blood transfusion requirements were reduced to a significantly greater extent than placebo or no treatment (with supportive blood transfusion) in patients with haematological malignancies. Most patients were receiving chemotherapy. Subcutaneous epoetin beta was well tolerated by patients with cancer; adverse events with the drug occurred with a similar incidence to those with placebo or no treatment (with supportive blood transfusion). Hypertension was relatively uncommon with epoetin beta in clinical trials. Patients with haematological malignancies and a baseline platelet count > or =100 x 10(9)/L, Hb levels of > or =9 g/dL or lower erythropoietin levels have demonstrated better responses to epoetin beta than other patients in clinical trials. However, neither baseline erythropoietin level nor the observed to predicted ratio of erythropoietin levels correlated with the response to epoetin beta in patients with solid tumours and chemotherapy-induced anaemia. A decrease of <1 g/dL or an increase in Hb with epoetin beta during the first chemotherapy cycle indicated a low transfusion need in subsequent cycles in patients with ovarian carcinoma. In general, the efficacy of epoetin beta is not limited by tumour type. Response to the drug occurred irrespective of the nature (platinum- or nonplatinum-based) or presence of chemotherapy treatment in randomised trials.. Epoetin beta has shown efficacy in the management of cancer-related anaemia in patients with haematological malignancies and of chemotherapy-induced anaemia in patients with solid tumours. Once-weekly administration provides added convenience for patients and may be cost saving, although additional research into the potential pharmacoeconomic benefits of this regimen are required. The drug is well tolerated in patients with cancer and is associated with little injection-site pain when administered subcutaneously. Epoetin beta is an important option in the prevention of chemotherapy-induced anaemia, and a valid and valuable alternative to blood transfusion therapy for the treatment of cancer-related or chemotherapy-induced anaemia.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Erythropoietin; Half-Life; Humans; Injections, Subcutaneous; Neoplasms; Quality of Life; Recombinant Proteins

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

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

Death from malaria occurs from the complications of the infection: cerebral manifestations leading to coma and a severe and refractory anemia leading to hypoxia and cardiac decompensation. Several mechanisms have been identified to play a role in the pathogenesis of malarial anemia, such as erythrocyte lysis and phagocytosis, and sequestration of parasitized red blood cells, but recent data indicate that these mechanisms (singly or in combination) do not adequately explain the severity of this anemia. By contrast, hematologic studies have shown that bone marrow suppression and ineffective erythropoiesis contribute importantly to the severe anemia of malaria infection. The host mechanisms responsible for suppression of erythropoiesis may involve an excessive or sustained innate immune response or a pathologic skewing of the T-cell differentiation response with the attendant production of certain proinflammatory cytokines. Experimental data also indicate that severe malarial anemia is associated with the immunologic expression of a circulating inhibitor of erythropoiesis that functionally antagonizes the action of erythropoietin. We review the clinical and experimental basis for these concepts and discuss ongoing experimental and genetic studies aimed at unraveling the molecular basis of this malaria-induced bone marrow suppression.

Topics: Adult; Anemia; Animals; Aotus trivirgatus; Bone Marrow; Child; Child, Preschool; Cytokines; Erythropoiesis; Erythropoietin; Genetic Predisposition to Disease; Heart Failure; Humans; Hypoxia; Infant; Inflammation Mediators; Malaria; Malaria Vaccines; T-Lymphocyte Subsets

To discuss the controversies regarding the use of epoetin alfa (EPO) for reducing red blood cell (RBC) transfusions in critically ill patients with anemia.. A MEDLINE search (1966-July 2003) was conducted using the search terms anemia; critical illness; erythropoietin; epoetin alfa; and erythropoietin, recombinant. References of selected articles were reviewed for studies that may have been missed by the computerized search.. Studies pertaining to the use of EPO for anemia of critical illness with an emphasis on data obtained from controlled trials.. Anemia is a common complication in patients admitted to the intensive care unit (ICU). Two prospective, randomized studies have demonstrated decreased transfusion requirements associated with EPO administration in medical/surgical patients who were in the ICU for at least 3 days and had hematocrit concentrations <38%. No differences were found in length of stay or mortality. A multicenter trial found that a restrictive strategy of RBC transfusion (hemoglobin goal 7-9 g/dL) was associated with in-hospital mortality lower than that with a more liberal approach, which calls into question the 38% hematocrit goal in the EPO trials. Furthermore, preliminary results from an economic analysis of EPO use in the ICU setting have demonstrated that EPO is not cost-effective.. Given the controversies surrounding EPO administration in critically ill patients, institutions are encouraged to develop EPO guidelines to help ensure the most appropriate use of this expensive product. Additional studies regarding patients most likely to benefit from EPO therapy, the most effective dosing regimen, and use of adjunctive therapies are needed.

Topics: Anemia; Blood Transfusion; Critical Illness; Dose-Response Relationship, Drug; Drug Administration Schedule; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Injections, Intravenous; Injections, Subcutaneous; Randomized Controlled Trials as Topic; Recombinant Proteins

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

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

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

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

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

Anemia can be the cause of heart failure, but also its consequence. The pathogenesis of anemia in chronic heart failure (CHF) has yet to be fully elucidated, but is likely to be complex. Epidemiologic studies suggest that kidney dysfunction (by reducing the erythropoietic response to anemia), inflammation (by inducing erythropoietin resistance), decreased body mass index, old age, female gender, and poor clinical status may be important factors in the development of anemia in CHF. Intestinal malabsorption, chronic aspirin use, and proteinuria predisposes to iron deficiency. Proinflammatory cytokines are likely to play a significant role in anemia in CHF by generating the "anemia of chronic illness" that is a hallmark of inflammatory conditions. Few studies have investigated the mechanisms of anemia in CHF. There is a need for such studies.

Topics: Anemia; Chronic Disease; Erythropoietin; Female; Heart Failure; Humans; Male; Risk Factors

Anemia occurs frequently in chronic heart failure (CHF) patients and is associated with increased morbidity and mortality risk. Clinical trials with recombinant human erythropoietin in patients with chronic kidney disease and concomitant structural heart disease have demonstrated beneficial effects on ventricular remodeling but variable effects on clinical outcome. Preliminary clinical trials in patients with CHF demonstrate that erythropoietin therapy is well-tolerated and associated with short-term clinical benefits. The optimum target hemoglobin, erythropoietin dosing regimen, and role of iron supplementation in patients with CHF are not known. Darbepoetin alfa is a glycosylated derivative of erythropoietin with a prolonged half-life that may allow less frequent dosing in CHF populations. Additional studies are needed to determine the safety and efficacy of long-term erythropoietic therapy in CHF patients.

Topics: Anemia; Chronic Disease; Darbepoetin alfa; Erythropoietin; Heart Failure; Humans; Morbidity; Randomized Controlled Trials as Topic; Renal Insufficiency; Treatment Outcome

Myelodysplastic Syndrome (MDS) comprises a heterogeneous group of clonal hemopathies derived from an abnormality affecting a multipotent hematopoietic stem cell and characterized by maturation defects resulting in ineffective hematopoiesis. It most frequently occurs in elderly patients. Despite trials testing numerous agents in patients with MDS, no single drug has yet emerged as the accepted standard of treatment. Most MDS patients, due to their age and co morbidity, are not eligible for allogeneic hematopoietic stem cell transplantation; the only established curative regimen. The effect of available lineage-specific growth factors is limited to improvement of single lineages and has not resulting in the survival benefit. Treatment with low dose Ara-C is disappointing in regard to response rate or duration. No benefit has been demonstrated in differentiation inducers such as retinoids and Vitamin D3 as single agents. We report a case of a patient with transfusion dependent MDS who was not a candidate for allogeneic stem cell transplantation or cytotoxic chemotherapy, who also failed to response to erythropoietin support but had a favorable response to 5-azacitidine. His blood transfusion requirement reduced significantly, and was correlated with the remarkable improvement of the pancytopenia, particularly anemia and thrombocytopenia after receiving the investigational therapy with 5-azacitidine. In summary, 5-azacitidine appears to be a promising alternative therapy for patient with refractory anemia secondary to MDS.

Topics: Aged; Anemia; Antimetabolites, Antineoplastic; Azacitidine; Blood Transfusion; Erythropoietin; Hematopoietic Cell Growth Factors; Humans; Male; Myelodysplastic Syndromes; Thrombocytopenia

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

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

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

Neutropenia and anemia are important complications of cancer chemotherapy and can be prevented and treated with granulocyte colony-stimulating factor and erythropoietin.

Topics: Anemia; Antineoplastic Agents; Erythropoietin; Female; Filgrastim; Genital Neoplasms, Female; Granulocyte Colony-Stimulating Factor; Humans; Neutropenia; Quality of Life; Recombinant Proteins

Anaemia is common in people with cancer, and may reduce their quality of life and life expectancy. Blood transfusion can increase haemoglobin levels but is usually reserved for those with moderate anaemia (haemoglobin level below 10 g/dL). A potential alternative is treatment with one of the human recombinant forms of erythropoietin, epoetin alfa (Eprex--Janssen-Cilag) or epoetin beta (NeoRecormon--Roche), or their hyperglycosylated derivative [symbol: see text] darbepoetin alfa (Aranesp--Amgen). These products have improved the management of patients with chronic renal failure who are anaemic. Here we assess the place of the epoetins and darbepoetin alfa in managing anaemia in patients with cancer.

Topics: Anemia; Darbepoetin alfa; Drug Costs; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Neoplasms; Quality of Life; Recombinant Proteins; Survival Analysis; Treatment Outcome

Anemia is common in patients with cancer. This systematic literature review of reports published in 1966 through February 2003 identified the prevalence of anemia in specific cancers and assessed the impact of anemia on survival and quality of life (QOL). Studies about chemotherapy-induced anemia were excluded. Anemia prevalence varied widely; most studies found that between 30% and 90% of patients with cancer had anemia. Prevalence was affected strongly by the definition of anemia: 7% of patients with Hodgkin disease had anemia when the condition was defined as a hemoglobin level <90.0 g/L; as many as 86% of patients had anemia when it was defined as a hemoglobin value <110.0 g/L. Prevalence varied by cancer type and disease stage: 40% of patients with early-stage colon tumors and nearly 80% of patients with advanced disease had anemia. Patients with anemia had poorer survival and local tumor control than did their nonanemic counterparts in 15 of 18 studies. In 8 of 12 studies, patients without anemia (most treated with epoetin) needed fewer transfusions. QOL was positively correlated with hemoglobin levels in 15 of 16 studies. There was no significant difference in treatment toxicity between patients with and without anemia. Tumor hypoxia, which has been associated with resistance to radiation therapy and chemotherapy, may stimulate angiogenesis, leading to poor local control of tumors and increased morbidity and mortality. Treatment of anemia may have a significant impact on patient survival and QOL. However, a standard definition of anemia is needed, as is research about the effect of anemia on cancer progression.

Topics: Activities of Daily Living; Anemia; Blood Transfusion; Comorbidity; Disease Progression; Erythropoietin; Health Status; Hemoglobins; Humans; Incidence; Neoplasm Staging; Neoplasms; Outcome Assessment, Health Care; Patient Satisfaction; Prevalence; Prognosis; Quality of Life; Severity of Illness Index; Survival Analysis

In patients with human immunodeficiency virus (HIV), anemia is a commonly encountered hematologic abnormality that has a significant impact on clinical outcomes and quality of life (QOL). This review describes the prevalence of anemia in several populations of patients with HIV and the effects of anemia on survival, morbidity, disease progression, transfusion requirements, and QOL. The prevalence of anemia in HIV disease varies considerably, ranging from 1.3% to 95%: it depends on several factors, including the stage of HIV disease, sex, age, pregnancy status, and injection-drug use as well as the definition of anemia used. In general, as HIV disease progresses, the prevalence and severity of anemia increase. Anemia is also more prevalent in HIV-positive women, children, and injection-drug users than in HIV-negative women, children, and injection-drug users. Anemia has been shown to be a statistically significant predictor of progression to the acquired immunodeficiency syndrome and is independently associated with an increased risk of death in patients with HIV. Treatment of anemia with epoetin-alpha has resulted in significantly fewer patients requiring transfusion as well as decreases in the mean number of units of blood transfused. Resolution of HIV-related anemia has been shown to improve QOL, physical functioning, energy, and fatigue in individuals with HIV. More recently, the use of highly active antiretroviral therapy has also been associated with a significant increase in hemoglobin concentrations and a decrease in the prevalence of anemia.

Topics: Activities of Daily Living; Adult; Anemia; Anti-HIV Agents; Blood Transfusion; CD4 Lymphocyte Count; Child; Comorbidity; Disease Progression; Epoetin Alfa; Erythropoietin; Fatigue; Female; Hematinics; HIV Infections; Humans; Infant; Male; Outcome Assessment, Health Care; Pregnancy; Prevalence; Quality of Life; Recombinant Proteins; Severity of Illness Index; Substance Abuse, Intravenous; Survival Analysis

The prevalence of anemia in patients with inflammatory bowel disease ranges from 8.8% to 73.7% depending on the patient subpopulation. Anemia, one of many extraintestinal complications of ulcerative colitis and Crohn disease, is generally defined as a hemoglobin value <120 g/L or hematocrit <0.4; severe anemia is defined as a hemoglobin level <100 g/L. Many patients have been shown to be intolerant of oral iron replacement therapy or their anemia was refractory to such supplementation. Correction of anemia through the administration of intravenous iron saccharate and/or supplemental erythropoietin has been shown to improve patient hematologic indices and quality of life. Future studies are needed to determine the type of patients at highest risk of developing severe anemia as well as the treatment interventions with the most beneficial effect.

Topics: Adolescent; Adult; Anemia; Child; Comorbidity; Erythropoietin; Female; Health Status; Hematocrit; Hemoglobins; Humans; Inflammatory Bowel Diseases; Iron Compounds; Male; Outcome Assessment, Health Care; Patient Satisfaction; Prevalence; Quality of Life; Risk Assessment; Risk Factors; Severity of Illness Index

Anemia is a common comorbidity in individuals with rheumatoid arthritis (RA). In fact, anemia of the type characterized by low serum iron concentrations in conjunction with adequate iron stores is frequently associated with RA and has served as a model for anemia of chronic disease. A systematic search of the scientific literature published since January 1966 identified 19 articles that reported findings on either the prevalence of anemia in patients with RA or outcomes for patients with anemia and RA. Ten articles addressed the prevalence of anemia in patients with RA. Estimates of the prevalence of mild anemia ranged between 33% and 60%; however, the 2 studies that examined demographics in patients with RA did not identify subpopulations at particular risk for anemia. Twelve articles assessed the impact of the resolution of anemia on symptoms and quality of life (QOL) in patients with RA. For many of the parameters assessed-including swollen, painful, and tender joints, pain, muscle strength, and energy levels-a positive correlation was observed between improvement of symptoms and the resolution of anemia. In addition, 2 studies reported a significant improvement in QOL scores in patients with RA who experienced a response to treatment for anemia. These results suggest that (1) patients with RA who have anemia are likely to have more severe joint disease and (2) if the anemia is successfully treated, the joint disease will likely respond to treatment as well. Whether improvements in QOL and/or joint symptoms occur with improvement of anemia, independent of other signs of an overall response to RA therapy, remains to be determined.

Topics: Activities of Daily Living; Adult; Age Distribution; Anemia; Arthritis, Rheumatoid; Blood Transfusion; Child; Cost of Illness; Erythropoietin; Fatigue; Female; Hand Strength; Humans; Iron; Male; Outcome Assessment, Health Care; Pain; Prevalence; Quality of Life; Risk Factors; Severity of Illness Index; Sex Distribution

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

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

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

The anemia of critical illness is a distinct clinical entity with characteristics similar to that of chronic disease anemia. Several solutions to the processes of anemia, such as blunted erythropoietin production and erythropoietin response and abnormalities in iron metabolism have been developed. The transfusion of RBCs provides immediate correction of low hemoglobin levels, which may be of value in patients with life-threatening anemia. Avoidance of RBC and blood component transfusion, however, is becoming increasingly important as data of adverse clinical outcomes in critically ill patients become clearer. Although the optimal hemoglobin in critically ill patients is not determined, this organ system has a generous reserve. Short-term compensated anemia is tolerated well, while exogenous erythropoietin allows patients to achieve higher hemoglobin concentrations without exposure to transfused blood/blood components. A recent randomized trial enrolled over 1300 critically ill patients to receive either 40,000 units of exogenous erythropoietin or placebo. These authors found that patients randomized to erythropoietin received significantly less allogeneic RBC transfusions and had significantly greater increases in hemoglobin. Although no differences were found between groups in gross clinical outcomes (ie, death, renal failure, myocardial infarction), this study did not have the power to identify small differences in outcomes. This and other studies of exogenous erythropoietin therapy in critically ill patients clearly demonstrate that the bone marrow in many of these patients will respond to the administration of erythropoietin despite their illness, suggesting a blunted production of erythropoietin rather than a blunted response to erythropoietin. Exogenous erythropoietin therefore represents a therapeutic option for treating anemia in critical illness. Acute events in medicine and surgery often lead to many patients becoming anemic. Solutions to this process of anemia should be focused on preventing such events. Anemia after surgery represents an area for prevention. Blood conservation strategies can be performed with adequate results. Monk et al randomized 79 patients undergoing radical prostatectomy to preoperative autologous donation (PAD), preoperative exogenous erythropoietin therapy plus ANH immediately following induction of general anesthesia, and ANH alone. This study concluded that all three techniques resulted in similar hemostasis outcomes

Topics: Anemia; Blood Loss, Surgical; Critical Illness; Erythrocyte Transfusion; Erythropoiesis; Erythropoietin; Humans; Inflammation; United States

Anemia may be the most common illness of critically ill patients. The majority of critically ill patients are anemic at admission to the intensive care unit (ICU), and hemoglobin concentrations typically decline during the first 3 days of ICU stay. Hemoglobin continues to decline for patients with sepsis and higher severity of illness. This patient population may be at particular risk of adverse consequences of anemia given the cardiovascular, respiratory, and metabolic compromise frequently encountered during critical illness. The etiology of anemia of critical illness is multifactorial, resulting from phlebotomy, gastrointestinal bleeding, coagulation disorders, blood loss from vascular procedures, renal failure, nutritional deficiencies,bone marrow suppression, and impaired erythropoietin response.

Topics: Anemia; Blood Substitutes; Critical Care; Critical Illness; Erythrocyte Transfusion; Erythropoietin; Hemostatics; Humans; Phlebotomy; Point-of-Care Systems

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

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

Anemia is extremely common in patients with cancer. Low hemoglobin levels are associated with diminished quality of life and possibly decreased overall survival. Successful treatment of anemia has undeniable benefits for patients, often yielding dramatic symptomatic improvement that can be very satisfying for clinicians to observe. This review focuses on evolving issues in the management of anemia in patients suffering from cancer. Topics addressed include new evidence-based guidelines concerning the use of epoetin alfa, the evolving role of darbepoetin alfa in cancer-associated anemia, the potential for concomitant iron supplementation to maximize response to erythropoietic agents, the unresolved question of whether erythropoietin use affects survival in cancer patients, new concerns about the risk of thromboembolism in cancer patients with higher hemoglobin levels who are receiving epoetin, and possible immunosuppressive effects of blood product transfusions that may have relevance to neoplasia progression.

Topics: Anemia; Chemotherapy, Adjuvant; Darbepoetin alfa; Drug Therapy, Combination; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Evidence-Based Medicine; Hematinics; Humans; Iron; Neoplasms; Practice Guidelines as Topic; Quality of Life; Radiotherapy, Adjuvant; Recombinant Proteins; Thromboembolism; Treatment Outcome

Anemia is a common condition in patients with cancer. Patients who develop severe anemia are frequently treated with red blood cell transfusions. However, the benefits are transient and associated with a number of risks (such as infection and immunosuppression). An alternative treatment option, recombinant human erythropoietin (rHuEPO) was introduced into the clinical setting more than a decade ago. Today, rHuEPO is increasingly being used to treat anemic patients with cancer. However, despite the well-documented clinical benefits of rHuEPO therapy, it has not been universally adopted as a routine treatment in the oncology setting and there remains an unmet need for an effective and convenient anemia treatment for cancer patients. Longer-acting versions of rHuEPO would avoid the need for frequent injections, increase biological activity and, potentially, the clinical efficacy of rHuEPO. One agent, darbepoetin alfa, is now available for the treatment of anemia in patients with cancer who are receiving chemotherapy, another agent, pegylated-epoetin beta, is in phase II trials, and additional compounds are in early stages of preclinical and clinical development. This review focuses on the available clinical experience with such agents and discusses how dose- and schedule-finding studies are optimizing their clinical use to maximize patient benefits.

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Humans; Neoplasms; Polyethylene Glycols; 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

The formation of red blood cells (RBCs) in the bone marrow is regulated by erythropoietin in response to a cascade of events. Anemia in the intensive care unit can be caused by a host of factors. Patients in the intensive care unit may have decreased RBC production and a blunted response to erythropoietin. Administration of recombinant human erythropoietin may stimulate erythropoiesis, increase hematocrit levels and hemoglobin concentration, and reduce the need for RBC transfusions.

Topics: Anemia; Anemia, Iron-Deficiency; Blood Specimen Collection; Bone Marrow Cells; Comorbidity; Erythrocytes; Erythroid Precursor Cells; Erythropoietin; Hemorrhage; Humans; Incidence; Intensive Care Units; Vitamin B 12 Deficiency

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

Critically ill patients receive an extraordinarily large number of blood transfusions. Between 40% and 50% of all patients admitted to intensive care units receive at least 1 red blood cell (RBC) unit during their stay, and the average is close to 5 RBC units. RBC transfusion is not risk free. There is little evidence that 'routine' transfusion of stored allogeneic RBCs is beneficial to critically ill patients. The efficacy of perioperative recombinant human erythropoietin (rHuEPO) has been demonstrated in a variety of elective surgical settings. Similarly, in critically ill patients with multiple organ failure, rHuEPO therapy will also stimulate erythropoiesis. In a randomized, placebo-controlled trial, therapy with rHuEPO resulted in a significant reduction in RBC transfusions. Despite receiving fewer RBC transfusions, patients in the rHuEPO group had a significantly greater increase in hematocrit. Strategies to increase the production of RBCs are complementary to other approaches to reduce blood loss in the intensive care unit, and they decrease the transfusion threshold in the management of all critically ill patients.

Topics: Anemia; Critical Care; Erythrocyte Transfusion; Erythropoietin; Europe; Humans; Intensive Care Units; Multiple Organ Failure; Phlebotomy; Recombinant Proteins; Treatment Outcome; United States

Preoperative anemia in a surgical patient predisposes to poor outcomes and allogeneic blood transfusions. As an alternative to transfusions, pharmacologic management of preoperative anemia with recombinant human erythropoietin (rHuEPO) has been well studied in many different types of surgery. rHuEPO, when used alone or in combination with preoperative autologous blood donation before elective surgery, stimulates erythropoiesis and helps to avoid or reduce the need for allogeneic blood transfusions. The clinical evidence on preoperative use of rHuEPO in orthopedic, cardiac, and cancer surgery, as well as in bloodless surgery, is reviewed.

Topics: Anemia; Blood Loss, Surgical; Blood Transfusion; Cardiac Surgical Procedures; Cardiovascular Diseases; Erythropoietin; Humans; Monitoring, Intraoperative; Neoplasms; Premedication; Recombinant Proteins; Treatment Outcome

Topics: Anemia; Antibodies; Clinical Trials as Topic; Erythropoietin; Hematinics; Humans; Peritoneal Dialysis, Continuous Ambulatory; Receptors, Erythropoietin; Recombinant Proteins; Renal Dialysis; Treatment Outcome

Topics: Anemia; Clinical Trials as Topic; Erythropoietin; Humans; Neoplasms; Recombinant Proteins; Renal Insufficiency

Topics: Anemia; Erythrocyte Transfusion; Erythrocytes; Erythropoietin; Fetal Blood; Humans; Infant; Infant, Newborn; Oxygen

Heart failure is defined as the inability of the heart to pump blood at an amount sufficient to meet the metabolic needs of the body. In heart failure, the inability to meet the body's metabolic needs is based on hemodynamic derangement and suboptimal oxygen-carrying capacity of the blood itself. Current pharmacologic therapy attempts to improve survival and reduce symptomatology by optimizing hemodynamics to increase oxygen delivery, but does not address oxygen-carrying capacity. Unfortunately, there is a high prevalence of anemia in patients with heart failure, which compromises oxygen-carrying capacity, is an independent predictor of mortality, and may be caused in part by pharmacologic agents that confer morbidity and mortality benefits in this population. Recombinant human erythropoietin supplementation improves the functional capacity of the failing myocardium, reverses and antagonizes the detrimental remodeling induced by autoimmune activity, and may reduce mortality and morbidity among patients receiving maximal pharmacologic therapy for heart failure. However, limited clinical data prohibit widespread recommendations for its use in patients with heart failure.

Topics: Anemia; Blood Viscosity; Erythropoietin; Heart Failure; Humans; Survival Analysis

Topics: Anemia; Diagnosis, Differential; Erythropoietin; Hematocrit; Humans; Prognosis; Recombinant Proteins; Renal Dialysis

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

Topics: Abortion, Spontaneous; Anemia; Anticoagulants; Benzamidines; Erythropoietin; Female; Guanidines; Humans; Infant, Newborn; Peritoneal Dialysis, Continuous Ambulatory; Polyhydramnios; Pregnancy; Pregnancy Outcome; Prenatal Care; Prenatal Nutritional Physiological Phenomena; Recombinant Proteins; Renal Dialysis

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

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

Anemia is a common problem in critically ill patients. As a result, blood transfusions are often used in the intensive care unit (ICU) setting. However, mounting evidence shows that blood transfusions may contribute to negative outcomes, such as transfusion-related infections, organ dysfunction, and immunosuppression. Supplementation with epoetin alfa is currently used in some medical centers to manage anemia in critically ill patients.. This review discusses the risks with blood transfusions and the clinical evidence supporting the use of epoetin alfa in managing edema during critical illness.. A search was conducted in MEDLINE and Current Contents (1966-2003) using the terms epoetin alfa, recombinant human erythropoietin, and anemia. Articles addressing anemia and the use of epoetin alfa in critically ill patients were selected and assessed. From this selection, the cited references addressing the etiology of anemia in the ICU and the risks associated with blood transfusions were manually extracted and reviewed.. Several reports have shown that critically ill patients display evidence of anemia due to a blunted erythropoietin response. One large, randomized, placebo-controlled study assessed the effect of SC epoetin alfa on blood transfusions in the ICU. In this study, 40, 000 IU administered weekly for up to 4 weeks resulted in an overall transfusion reduction (9.9% absolute risk reduction; P<0.001 ). Other, smaller studies using different dosing regimens in critically ill patients have also demonstrated that epoetin alfa can decrease the need for transfusion.. The use of epoetin alfa in critically ill patients can decrease the number of blood transfusions required during hospitalization, and potentially result in transfusion avoidance. Because of the scarce amount of evidence and the diversity of dosing regimens used used, no strict recommendations can be drawn from this review.

Topics: Anemia; Critical Illness; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Recombinant Proteins; Transfusion Reaction

To determine the occurrence of cancer-related fatigue, the methods used to assess it, and the efficacy of the available treatments, we performed literature searches that identified English-language publications on these topics. Twenty-seven studies were identified in which the quantitative estimation of the occurrence of cancer-related fatigue was an end point. Fifty-six were judged to be relevant to the assessment of fatigue, and 10 randomized controlled clinical trials of treatments of cancer-related fatigue were retrieved. The occurrence of cancer-related fatigue was found to range from 4% to 91%, depending on the population studied and the methods of assessment. Few population-based studies and no longitudinal studies of cancer-related fatigue have been performed. The methods of fatigue assessment were highly variable. Exercise programs show promise to prevent or treat fatigue in some subsets of cancer patients, and the use of epoetin alfa for correction of anemia has been shown to ameliorate fatigue. The number of subjects in the treatment trials was small and their methodologic quality was inconsistent.

Topics: Anemia; Antineoplastic Agents; Epoetin Alfa; Erythropoietin; Evidence-Based Medicine; Exercise Therapy; Fatigue; Humans; Neoplasms; Palliative Care; Radiotherapy; Randomized Controlled Trials as Topic; Recombinant Proteins

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

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

Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoietin (EPO) and red blood cell transfusions.. The aim of this systematic review was to assess the effect of erythropoietin to either prevent or treat anaemia in cancer patients.. We searched the Central Register of Controlled Trials, MEDLINE (01/1985 to 12/2001), EMBASE (01/1985 to 12/2001), other databases and reference lists of articles. We also contacted experts in the field and pharmaceutical companies.. Randomised controlled trials comparing the use of recombinant human erythropoietin (plus transfusion if needed) with red blood cell transfusions alone for the treatment or prevention of anaemia in cancer patients.. Two reviewers independently assessed trial quality and extracted data. All authors from included studies were contacted for additional information.. Twenty seven trials with 3,287 adults were included. Use of erythropoietin significantly reduced the relative risk of red blood cell transfusions (RR 0.67; 95% CI 0.62 to 0.73, 25 trials, n = 3,069). On average participants in the erythropoietin group received one unit of blood less than the control group (WMD -1.00; 95% CI-1.31 to -0.70, 13 trials, n = 2,056). For participants with baseline haemoglobin below 10 g/dL haematological response was observed more often in participants receiving EPO (RR 3.60; 95% CI 3.07 to 4.23, 14 trials, n = 2,347). There was inconclusive evidence whether EPO improves tumour response (fixed effect RR 1.36; 95% CI 1.07 to 1.72, seven trials, n = 1,150; random effects: RR 1.21; 95% CI 0.92 to 1.59) and overall survival (adjusted data: HR 0.81; 95% CI 0.67 to 0.99; unadjusted data: HR 0.84; 95% CI 0.69 to 1.02, 19 trials, n = 2,865). There were no statistically significant adverse effects. Evidence was inconclusive with respect to quality of life and fatigue.. There is consistent evidence that the administration of erythropoietin reduces the risk for blood transfusions and the number of units transfused in cancer patients. For patients with baseline haemoglobin below 10 g/dL there is strong evidence that erythropoietin improves haematological response. There is inconclusive evidence whether erythropoietin improves tumour response and overall survival. Research on side effects is inconclusive.

Topics: Anemia; Erythrocyte Transfusion; Erythropoietin; Humans; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins

Erythropoietin, a hematopoietic growth-factor possessing manifold, potent neuroprotective properties, after multiple testing in cell culture and animal studies now gradually finds its way into clinical neuroscience. The first time this took place was in 1998 with a pilot study in stroke patients, the "Göttingen EPO-Stroke-Trial". This study was able to demonstrate that EPO is perfectly well tolerated and safe with this indication. Furthermore, the EPO-treated patients showed a significantly better outcome regarding their clinical progress as well as regarding the infarct size as observed by MRI, when compared to the placebo treated patients. At the moment a multicenter study is being carried out in Germany.

Topics: Anemia; Brain Ischemia; Cerebral Infarction; Clinical Trials as Topic; Erythropoietin; Hematinics; Humans; Hypoxia, Brain; Pilot Projects; Safety; Treatment Outcome

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

To analyze the data from the literature on erythropoietin and the future indications of recombinant human erythropoietin in intensive care unit (ICU) patients.. References were obtained from computerized bibliographic research (Pubmed) from 1986 to 2003, except for some physiologic data.. Original articles, reviews, and letters to editor in French and English were selected and analyzed.. An anemia is often observed in patients hospitalized in ICU. This anemia may be due to many reasons. The management of anemia consists on the treatment of the underlying disease associated with the transfusion of red blood cells. Recent studies provided evidence of an association between transfusions and mortality in ICU patients. The anemia of ICU patients is compared to the anemia of chronic diseases, which is characterized by a blunted erythropoietin. A treatment with rHuEPO may be a future therapeutic of the anemia in such patients. A multicentric study shows the efficacy of recombinant erythropoietin therapy on a decrease in the use of red blood cell, and another clinical trial highlights a decrease of the proportion of ICU patients receiving red blood cell. Recombinant erythropoietin could be an alternative to transfusion in certain conditions and certain ICU patients. Further studies are needed to determine the consequences on mortality rate and to clarify the place of this therapy in ICU patients.

Topics: Anemia; Critical Care; Drug Utilization; Erythrocyte Transfusion; Erythropoietin; Humans; Intensive Care Units; Recombinant Proteins

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

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

Despite the availability of highly active antiretroviral therapy and the resulting reduction in severe anemia associated with HIV infection, epoetin alfa has continued to play an important role in the management of HIV-infected patients. Mild-to-moderate anemia remains common, and its correction with epoetin alfa has resulted in significant improvements in quality of life, physical functioning, and possibly prolongation of survival. New research has demonstrated that epoetin alfa may have therapeutic potential beyond its ability to stimulate erythropoiesis due to its neuroprotective and antiapoptotic properties. Current and future research will further clarify the role of epoetin alfa in the clinical management of the HIV-infected population.

Topics: Anemia; Epoetin Alfa; Erythropoietin; Hematinics; HIV Infections; Humans; Recombinant Proteins; Treatment Outcome

Anemia in patients with cancer causes fatigue, weakness, and impaired concentration, negatively impacting quality of life (QOL). In clinical trials involving patients with cancer who had varied characteristics, it has been shown that epoetin alfa treatment increased hemoglobin levels and improved QOL. A systematic review and metaanalysis of data from those trials was conducted to summarize existing knowledge on the role of epoetin alfa in improving QOL for anemic patients with cancer.. The Cochrane Library and other data bases were searched for published and unpublished, randomized/controlled and single-arm studies that included > or = 20 patients with cancer per arm, epoetin alfa treatment, and QOL assessment by Cancer Linear Assessment Score (CLAS), Functional Assessment of Cancer Therapy (FACT) scale, Eastern Cooperative Oncology Group (ECOG) scale, and/or Medical Outcomes Study Short-Form 36 (SF-36) scale.. Among 11,459 patients from 23 trials, epoetin alfa and control cohorts were indistinguishable (with regard to demographic, clinical, QOL variables) at baseline. Epoetin alfa improved CLAS (20-25%), FACT-Fatigue (17%), and FACT-Anemia (12%) scores (P = 0.05). ECOG scores worsened for control cohorts (P = 0.05); epoetin alfa cohorts remained unchanged. Four of the SF-36 subscales, Physical Function, Role Physical, Vitality, and Social Function, improved with epoetin alfa (P = 0.05). Results adjusted for confounding factors remained consistent.. This metaanalysis confirmed that epoetin alfa improves QOL significantly in patients with cancer, emphasizing the need to manage anemia in this population.

Topics: Anemia; Case-Control Studies; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Neoplasms; Placebos; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins

Anaemia is frequently diagnosed in patients with cancer, yet it is difficult to identify a single cause due to its multifactorial aetiology. We conducted a systematic literature review (1996-2003) to produce evidence-based guidelines on the use of erythropoietic proteins in anaemic patients with cancer (see ). Level I evidence exists for a positive impact of erythropoietic proteins on haemoglobin (Hb) levels when administered to patients with chemotherapy-induced anaemia or anaemia of chronic disease, when used to prevent cancer anaemia, in patients undergoing cancer surgery and following allogeneic bone marrow transplantation. The Hb level at which erythropoietic protein therapy should be initiated is difficult to determine as it varied between studies; a large number of Level I studies in patients with chemotherapy-induced anaemia or anaemia of chronic disease enrolled patients with a Hb concentration

Topics: Anemia; Bone Marrow Transplantation; Chronic Disease; Dose-Response Relationship, Drug; Erythropoietin; Hematopoietic Stem Cell Transplantation; Humans; Hypertension; Neoplasms; Quality of Life; Survival Analysis; Thromboembolism

Hematologic abnormalities such as anemia, neutropenia, and thrombocytopenia are common during combination therapy with pegylated (or standard) interferon and ribavirin for chronic hepatitis C. Ribavirin-induced hemolytic anemia is a common cause of dose reduction or discontinuation. Bone marrow suppression also contributes to the anemia and is the predominant mechanism for interferon-induced neutropenia and thrombocytopenia. Although dose reduction or discontinuation of combination therapy can reverse these abnormalities, they may reduce virologic response. Hematopoietic growth factors may provide a useful alternative for managing these hematologic side effects without reducing the optimal dose of the combination antiviral regimen. Treatment of anemia also may improve patients' health-related quality of life and their adherence to combination antiviral therapy. The impact of growth factors on sustained virologic response and their cost-effectiveness in patients with chronic hepatitis C need further assessment.

Topics: Anemia; Antiviral Agents; Clinical Trials as Topic; Darbepoetin alfa; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Hepatitis C, Chronic; Humans; Interferon alpha-2; Interferon-alpha; Interferons; Interleukin-11; Neutropenia; Patient Compliance; Polyethylene Glycols; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins; Ribavirin; Thrombocytopenia

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

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

The glycoprotein hormone erythropoietin (EPO) is an essential viability and growth factor for the erythrocytic progenitors. EPO is mainly produced in the kidneys. EPO gene expression is induced by hypoxia-inducible transcription factors (HIF). The principal representative of the HIF-family (HIF-1, -2 and -3) is HIF-1, which is composed of an O2-labile alpha-subunit and a constant nuclear beta-subunit. In normoxia, the alpha-subunit of HIF is inactivated following prolyl- and asparaginyl-hydroxylation by means of alpha-oxoglutarate and Fe(2+)-dependent HIF specific dioxygenases. While HIF-1 and HIF-2 activate the EPO gene, HIF-3, GATA-2 and NFkappaB are likely inhibitors of EPO gene transcription. EPO signalling involves tyrosine phosphorylation of the homodimeric EPO receptor and subsequent activation of intracellular antiapoptotic proteins, kinases and transcription factors. Lack of EPO leads to anemia. Treatment with recombinant human EPO (rHuEPO) is efficient and safe in improving the management of the anemia associated with chronic renal failure. RHuEPO analogues with prolonged survival in circulation have been developed. Whether the recent demonstration of EPO receptors in various non-hemopoietic tissues, including tumor cells, is welcome or ominous still needs to be clarified. Evidence suggests that rHuEPO may be a useful neuroprotective agent.

Topics: Anemia; DNA-Binding Proteins; Erythropoietin; Gene Expression Regulation; Hematinics; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Nuclear Proteins; Recombinant Proteins; Signal Transduction; Transcription Factors

Anaemia is a common problem in critically ill patients admitted to intensive care units. Many factors can be involved in its development, including rapid alterations of iron metabolism. Maintenance of iron homeostasis is a prerequisite for many essential biological processes and a central element for the development of erythroid precursors and mature red blood cells. With the inflammatory process, iron distribution is disturbed, with decreased serum iron levels and increased iron stores. Little information is available on the precise role of alterations of iron metabolism in the development of iron anaemia in critically ill patients.

Topics: Anemia; Critical Illness; Erythrocyte Transfusion; Erythrocytes; Erythropoietin; Homeostasis; Humans; Inflammation; Intensive Care Units; Iron

Critically ill patients frequently develop anemia due to several factors. Iron-withholding mechanisms caused by inflammation contribute to this anemia. The iron metabolism imbalances described or reported in all intensive care studies are similar to the values observed in anemia of inflammation. The administration of iron could be useful in the optimization of recombinant human erythropoietin activity, but this could be at the expense of bacterial proliferation. Since there is a lack of evidence to support either oral or intravenous iron administration in intensive care patients, further studies are necessary to determine the efficacy and safety of iron supplementation in conjunction with recombinant human erythropoietin in critically ill patients. We review the mechanisms leading to iron sequestration in the presence of inflammation. The present article also reviews the literature describing the iron status in critically ill patients and explores the role of iron supplementation in this setting.

Topics: Anemia; Critical Care; Critical Illness; Dietary Supplements; Erythropoiesis; Erythropoietin; Ferritins; Humans; Inflammation; Intensive Care Units; Iron; Recombinant Proteins

Anemia is a common and potentially debilitating complication of cancer. Darbepoetin alfa (Aranesp, Amgen) has been in routine clinical use for the treatment of chemotherapy-induced anemia since 2002. The extended half-life of darbepoetin alfa permits less frequent and consequently more flexible dosing than other erythropoietic therapies. Data suggest that hemoglobin levels can be effectively and safely increased with darbepoetin alfa in cancer patients who are receiving chemotherapy (patients with treatment-induced anemia), and in those who are not receiving chemotherapy (patients with tumor-induced anemia). This review provides an overview of clinical trial results, particularly those exploring flexible, extended dosing schedules.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Darbepoetin alfa; Delayed-Action Preparations; Erythropoietin; Half-Life; Hemoglobins; Humans; Neoplasms; Quality of Life

To review the use of erythropoietin for anemia in heart failure (HF).. Peer-reviewed articles in MEDLINE (1966-June 2004) were identified and citations from available articles were reviewed using the search terms anemia, erythropoietin, and heart failure.. Anemia worsens HF prognosis. Clinical studies in patients with New York Heart Association Class III/IV HF who had hemoglobin <12 mg/dL and were refractory to maximal medical management showed that erythropoietin improves symptoms. Larger scale studies with mortality endpoints are required to confirm the benefits.. In selected patients with severe, chronic HF, erythropoietin may be considered for functional improvement. However, routine use of this treatment strategy is not recommended until more data are available.

Topics: Anemia; Erythropoietin; Heart Failure; Hematinics; Humans; Randomized Controlled Trials as Topic; Treatment Outcome

Erythropoietic agents are widely used to alleviate anemia in patients with cancer receiving chemotherapy. Over the past decade, the efficacy and safety of these agents in improving hemoglobin levels and reducing transfusion requirements in an oncology setting has been demonstrated in a number of clinical trials. The overall risk-benefit relationship of treatment with erythropoietic agents is favorable, and these agents represent a tremendous advance in anemia management. This review discusses prevalent issues and addresses key questions concerning the use of erythropoietic agents for the treatment of chemotherapy-induced anemia.

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Erythropoietin; Humans; Thrombosis

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

Anemia is a significant adverse effect of current hepatitis C treatment and may be a particular problem for HIV-infected patients, in whom there is a high prevalence of disease- or drug-related anemia at baseline. Hepatitis C treatment-induced anemia in HIV-HCV-coinfected patients can lead to ribavirin dose reduction or premature discontinuation of hepatitis C therapy, limiting sustained virologic response rates. Mean decreases in hemoglobin levels during hepatitis C treatment appear to be less in HIV-HCV-coinfected patients than in HCV-monoinfected patients, but any decrease in hemoglobin level may be more of a problem for coinfected patients. Thus, close monitoring of the hemoglobin level and appropriate management of the anemia that may develop in HIV-infected patients during hepatitis C therapy is essential.

Topics: Anemia; Antiviral Agents; Drug Therapy, Combination; Erythropoietin; Hepatitis C; HIV Infections; Humans; Interferon-alpha; Recombinant Proteins; Ribavirin

Recombinant human erythropoietin (rHuEPO) is an effective treatment for the anaemia that occurs secondary to various conditions, but its role in myelofibrosis with myeloid metaplasia (MMM) is not well established. rHuEPO, at an initial dose of 10 000 U thrice a week, was given to 20 patients with MMM and anaemia. Complete response (CR) was defined as transfusion cessation with normal haemoglobin (Hb) levels and partial response (PR) as a transfusion decrease > or =50% and Hb > 10 g/dl maintained for at least 8 weeks. Nine patients (45%) showed a favourable response to treatment, including four CR and five PR, four of whom have maintained their response at a median follow-up of 12.5 months (range: 4-21 months) from the start of treatment. The pretreatment factors associated with a favourable response were lack of transfusion requirement (P = 0.002) and higher Hb at start treatment of (P = 0.01). An analysis of the present series (n = 20) and 31 patients from the literature identified 28 (55%) favourable responses to rHuEPO, including 16 CR and 12 PR. In the multivariate analysis, serum erythropoietin level <125 U/l was found to be associated with a favourable response to rHuEPO, whereas lack of transfusional support had borderline significance.

Topics: Aged; Aged, 80 and over; Anemia; Erythropoietin; Female; Humans; Male; Middle Aged; Primary Myelofibrosis; Recombinant Proteins

Anaemia develops in most patients undergoing cancer therapy and invariably induces fatigue, which is a major determinant of QOL. Blood transfusions are reserved for patients with severe anaemia, since blood is a scarce resource and provides a short-lived benefit. Epoetins are recombinant proteins capable of alleviating therapy-related anaemia in 40-60% of cancer patients. The number of patients needed to be treated with epoetins to avoid the transfusion of one unit of blood ranges from 2.6 to 5.2; however, the absolute risk reduction depends on patients' characteristics and dose-escalation. The ratio between acquisition costs of epoetins and blood transfusion requirement is very high; thus, many thousands of dollars needs to be spent on epoetins to save 1 blood unit. Despite this, epoetins have been widely adopted by industrialised countries, where cancer patients are about 2% of the total population. The resulting budget impact of epoetins can be calculated at about 10% of the overall direct cost for cancer care, and it is expected to continue growing by about 20% each year, due to the expanding cancer population and the intensification of cancer therapies. The economic burden of epoetins needs to be weighed against the improvement of patients' QOL and society's willingness to pay for a non-life-saving therapy. All published economic evaluations of epoetins invariably report that this supportive therapy is not cost effective. Society should be made aware of the opportunity cost of treatments and should be allowed to elicit preferences for healthcare interventions and prioritisation criteria. In the near future we expect that a wider range of epoetins, drug patent expiry, a more appropriate patient selection criteria and an improved dosage schedule may help increase the efficiency of cancer-related anaemia management.

Topics: Anemia; Cost-Benefit Analysis; Darbepoetin alfa; Drug Administration Schedule; Drug Costs; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Neoplasms; Quality of Life; Recombinant Proteins

Anemia is a well-known risk factor for decreased local control and survival in patients undergoing curative radiotherapy. There is clear evidence from recent clinical investigations that anemia is an independent risk factor and hemoglobin (Hb) levels during radiotherapy are important (and not pretreatment Hb levels). The most likely explanation for the prognostic impact is the association with tumor hypoxia. An "optimal" Hb range with regard to tumor oxygenation seems to exist, and Hb levels < 11 g/dl and > approximately 15 g/dl impair tumor oxygenation but have (over a broader range) no significant impact on normal tissue oxygenation. There is some evidence from retrospective and prospective studies that the response to radiotherapy and the prognosis, especially in cervical cancers, might be improved if the Hb levels during radiotherapy can be maintained in the optimal range, either by transfusions or by erythropoietin. The effect of any antianemic therapy should be analyzed according to whether or not treatment was successful with regard to achieving optimal Hb levels during irrradiation. Erythropoietin is probably more effective in steadily increasing and stabilizing Hb levels, but bears the risk of overcorrection of Hb levels. The clinical relevance of erythropoietin receptors on tumor cells remains questionable.. Treatment of anemia with the objective of improving local control and survival in radiotherapy patients is probably more difficult and sophisticated than coping with symptoms of anemia or improving quality of life. Nevertheless, the potential of antianemic treatment is high on the basis of experimental and clinical data, and further clinical trials are warranted.

Topics: Anemia; Blood Transfusion; Clinical Trials as Topic; Erythropoietin; Humans; Neoplasms; Practice Guidelines as Topic; Practice Patterns, Physicians'; Radiotherapy

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

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

Recombinant human erythropoietin (rHuEPO) and intravenous (i.v.) iron administration may be useful tools to save blood in surgery. In the perioperative period, rHuEPO should be used in slightly anemic patients for whom an autologous predonation program is not recommended (or feasible). In such cases, i.v. iron is only given if there is a functional or real iron deficiency state. In the post-operative period, i.v. iron is administered in association with rHuEPO in an attempt to rapidly correct severe post-operative anemia. The same regimen is used for patients undergoing surgery for inflammatory bowel disease and rheumatoid arthritis. Finally, other particular categories of patients, such as those with reduced body weight (< 50 kg), candidates for surgery with increased blood needs (> 5 units), or those with a too-short period of time before surgery, also benefit from the administration of these two drugs.

Topics: Administration, Oral; Adolescent; Adult; Aged; Anemia; Arthritis, Rheumatoid; Blood Loss, Surgical; Blood Transfusion, Autologous; Erythropoietin; Hemoglobins; Humans; Inflammatory Bowel Diseases; Infusions, Intravenous; Iron; Iron Deficiencies; Postoperative Care; Postoperative Complications; Preoperative Care; Randomized Controlled Trials as Topic; Recombinant Proteins; Risk Factors; Surgical Procedures, Operative; Time Factors

It has been proposed that the basis of severe malarial anaemia, a major cause of morbidity and mortality in endemic areas, is multifactorial. Inappropriately low reticulocytosis is observed in malaria patients suggesting that insufficient erythropoiesis is a major factor. Clinical studies provide conflicting data concerning the production of adequate levels of erythropoietin (EPO) during malaria. Plasmodium chabaudi AS causes non-lethal infection in resistant C57BL/6 mice, and lethal infection in susceptible A/J mice. In P. chabaudi AS infected C57BL/6 and A/J mice, which experience varying degrees of severity of anaemia, kidney EPO production is appropriate to the severity of anaemia and is regulated by haematocrit level. Neutralisation of endogenous EPO during infection leads to lethal anaemia while timely administration of exogenous EPO rescues mice although reticulocytosis is suppressed in proportion to the parasitemia level. Characterisation of alterations in splenic erythroid compartments in naive and P. chabaudi AS infected A/J mice revealed that infection, with or without EPO treatment, leads to sub-optimal increases in TER119+ erythroblasts compared to EPO-treated naive mice. A lower percentage of TER119+ erythroblasts in infected mice undergo terminal differentiation to become mature haemoglobin-producing cells. Furthermore, there is a shift in transferrin receptor (CD71) expression from TER119+ cells to a non-erythroid population. Deficiencies in the number and maturation of TER119+ erythroblasts during infection coincide with blunted proliferation to EPO stimulation in vitro by splenocytes, although a high frequency express EPO receptor (EPOR). Together, these data suggest that during malaria, EPO-induced proliferation of early EPOR+ erythroid progenitors is suppressed, leading to sub-optimal generation of TER119+ erythroblasts. Moreover, a shift in CD71 expression may result in impaired terminal maturation of erythroblasts. Thus, suppressed proliferation, differentiation, and maturation of erythroid precursors in association with inadequate reticulocytosis may be the basis of insufficient erythropoiesis during malaria.

Topics: Anemia; Animals; Disease Models, Animal; Erythropoiesis; Erythropoietin; Humans; Kidney; Malaria; Mice; Reticulocytosis

Topics: Anemia; Darbepoetin alfa; Epoetin Alfa; Erythropoiesis; Erythropoietin; Humans; Iron; Iron Deficiencies; Neoplasms; Recombinant Proteins

Hypoxia is a common feature of solid tumors that occurs across a wide variety of malignancies. Hypoxia and anemia (which contributes to tumor hypoxia) can lead to ionizing radiation and chemotherapy resistance by depriving tumor cells of the oxygen essential for the cytotoxic activities of these agents. Hypoxia may also reduce tumor sensitivity to radiation therapy and chemotherapy through one or more indirect mechanisms that include proteomic and genomic changes. These effects, in turn, can lead to increased invasiveness and metastatic potential, loss of apoptosis, and chaotic angiogenesis, thereby further increasing treatment resistance. Investigations of the prognostic significance of pretreatment tumor oxygenation status have shown that hypoxia (oxygen tension [pO(2)] value < or =10 mmHg) is associated with lower overall and disease-free survival, greater recurrence, and less locoregional control in head and neck carcinoma, cervical carcinoma, and soft-tissue sarcoma. In view of the deleterious effect of hypoxia on standard cancer treatment, a variety of hypoxia- and anemia-targeted therapies have been studied in an effort to improve therapeutic effectiveness and patient outcomes. Early evidence from experimental and clinical studies suggests the administration of recombinant human erythropoietin (rHuEPO) may enhance the effectiveness of radiation therapy and chemotherapy by increasing hemoglobin levels and ameliorating anemia in patients with disease- or treatment-related anemia. However, further research is needed in the area of hypoxia-related treatment resistance and its reversal.

Topics: Anemia; Cell Hypoxia; Combined Modality Therapy; Drug Resistance, Neoplasm; Erythropoietin; Female; Head and Neck Neoplasms; Hemoglobins; Humans; Radiation Tolerance; Sarcoma; Uterine Cervical Neoplasms

Within the past decade, clinical trials have shown that the presence of anemia can diminish the physical status, functional abilities, and overall quality of life (QOL) of cancer patients and can negatively influence the outcome of their treatment. However, recent preclinical and clinical studies have also shown that increasing hemoglobin levels by administering recombinant human erythropoietin (rHuEPO, epoetin alfa) may ameliorate anemia and, in doing so, improve QOL and possibly result in better treatment outcomes following radiotherapy, chemotherapy, or a combination of these modalities. Several mechanisms by which rHuEPO may improve treatment outcome have been proposed, including correction of tumor hypoxia, increased sensitivity of tumor cells to radiotherapy and chemotherapy, correction of anemia and its associated symptoms (particularly fatigue), and immune-modulated effects of rHuEPO on tumor growth. Improvement of tumor oxygenation by rHuEPO could affect treatment outcome in two ways. First, correction of hypoxia results in the downregulation of hypoxia-inducible factor 1 (HIF-1), a key regulator of cellular adaptive responses to hypoxia (e.g., angiogenesis), including many pathways that are important for tumor growth and metastasis. Interruption of the HIF-1 pathway not only limits growth of the primary tumor but also reduces the potential for the development of more aggressive tumors and metastatic spread, which could ultimately improve treatment outcome. Second, within the tumor, it is the hypoxic cells that are resistant to oxygen-dependent radiotherapy and chemotherapy, and improvement in their oxygenation would increase their sensitivity to the cytotoxic effects of such treatment. Correction of anemia and its associated symptoms, particularly fatigue, can have a beneficial effect on patient QOL, and this in turn may translate into greater tolerance of radiotherapy and chemotherapy, allowing patients to receive full doses and on-schedule dosing, and thus have an increased likelihood of a therapeutic response. Lastly, results of a study using a murine model of multiple myeloma have indicated that rHuEPO may induce an immune-mediated antitumor effect. Therefore, additional research is warranted to further explore the biologic actions of rHuEPO and to determine their relevance to therapeutic outcome.

Topics: Anemia; Animals; Cell Hypoxia; Clinical Trials as Topic; Combined Modality Therapy; Disease Models, Animal; Drug Interactions; Drug Resistance, Neoplasm; Erythropoietin; Fatigue; Humans; Mice; Multiple Myeloma; Neoplasms; Quality of Life; Radiation Tolerance; Recombinant Proteins; T-Lymphocytes; Treatment Outcome

Increasingly, anemia is being recognized as a negative prognostic and predictive factor for patients undergoing chemotherapy, radiation therapy, or a combination of these treatment modalities. The results of clinical studies have shown correlations between anemia and shorter survival times in patients with a wide variety of solid tumors and hematologic malignancies, including lung, ovarian, breast, and head/neck cancers, non-Hodgkin's lymphoma, Hodgkin's disease, Waldenstrom's macroglobulinemia, and chronic lymphocytic leukemia. Also, anemia has been shown to predict treatment response in patients with ovarian, cervical, and urothelial cancers, mantle cell lymphoma, and chronic lymphocytic leukemia, as well as refractory/relapsed acute myelogenous leukemia. Based on the presumed causal relationship between anemia and poor patient outcome, several studies have examined the influence of epoetin alfa (a recombinant human erythropoietin) on outcomes in anemic patients undergoing cancer treatment. The results of these studies have been encouraging, with indications of greater locoregional tumor control and higher response rates in epoetin alfa-treated patients. Additionally, epoetin alfa therapy, by correcting anemia, has been shown to improve a patient's energy level, ability to perform daily activities, and overall quality of life (QOL). Such effects not only enhance a patient's general well-being, but may also increase their tolerance of, and willingness to undergo, full courses of their cancer therapy in a timely manner. These findings support the use of epoetin alfa to achieve gains in QOL and cancer treatment outcomes in anemic cancer patients and suggest that additional studies be conducted to further investigate the potential benefits of this agent in regard to improved outcomes.

Topics: Activities of Daily Living; Anemia; Erythropoietin; Fatigue; Hemoglobins; Humans; Neoplasms; Prognosis; Quality of Life; Recombinant Proteins; Treatment Outcome

Anemia of prematurity is characterized by low reticulocyte counts and inadequate erythropoietin response, for which many premature infants receive multiple blood transfusions. To reduce the number of those transfusions, treatment with EPO and iron supplementation is routinely used in premature infants. Even if the efficacy of this treatment is demonstrated, the results are not so good in the very low birth weight infants or very small gestational age infants and the need of transfusion is still important. This is due for a large part to blood loss in these very small infants. But there are also other explanations. Thus the pharmacokinetics of EPO is different in premature infants and newborn than in adults. Best dose, best way of administration (i.v. or subcutaneous), best number of injections per week are not already known. Further study has to be done to achieve a better use and efficacy of this treatment.

Topics: Anemia; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Reproducibility of Results

Anaemia is frequent in cancer and may increase tumour hypoxia that stimulates angiogenesis. However, erythropoietin is a hypoxia-inducible stimulator of erythropoiesis which seems to improve quality of life in cancer patients. Two recent phase III randomized studies showed negative results using erythropoietin in head and neck cancer patients and in metastatic breast cancer patients with impaired specific survival. In vitro and in vivo experiments have provided erythropoietin-receptor expression in endothelial cancer cells including malignant tumours of the breast, prostate, cervix, lung, head and neck, ovary, melanoma, stomach, gut, kidney etc. Biologic effect of erythropoietin and its receptor linkage induces proliferation of human breast cancer and angiogenesis and may limit anti-tumour effect of cancer treatment, in part, by tumour vascularization improvement. In addition, the use of exogenous erythropoietin could be able to favour tumour progression by improving tumour oxygenation and nutriment supply. If erythropoietin receptor were functional in human cancer, the assessment of erythropoietin receptor expression on tumour cell may help to select patients benefiting from exogenous erythropoietin. However, the relationship between erythropoietin receptor expression, tumour growth and exogenous erythropoietin, requires more studies. The results of recent clinical trials suggest that using erythropoietin should be avoided in non-anemic patients and discussed in patients receiving curative therapy.

Topics: Anemia; Animals; Clinical Trials, Phase III as Topic; Erythropoietin; Female; Humans; Male; Mice; Neoplasms; Neoplasms, Experimental; Neovascularization, Pathologic; Prognosis; Rats; Receptors, Erythropoietin

Anemia is common among patients with cancer receiving chemotherapy (CT) and/or radiotherapy (RT) and may limit cancer treatment, clinical outcomes, and overall patient quality of life (QOL). In the United States, epoetin alfa and darbepoetin alfa are approved for the treatment of CT-induced anemia in patients with nonmyeloid malignancies. Goals of treatment are to reduce transfusions, increase hemoglobin (Hb) levels, and improve overall QOL. Results from ongoing head-to-head trials comparing these agents will allow for direct comparisons of Hb response profiles and overall QOL effects. To optimize patient benefits from erythropoietic therapy, new doses and schedules of these agents are being studied. Data from investigations of the use of a higher weekly starting dose ("front-loading") followed by maintenance dosing on a less frequent schedule (when Hb has increased to a specified level or by a specified amount after the higher initial starting dose) suggest that both agents can increase and subsequently maintain Hb levels on such schedules. This approach may lead to benefits for patients and healthcare providers, such as earlier increases in Hb and earlier identification of nonresponders. Consequently, evolving strategies with erythropoietic agents should ultimately improve overall QOL in anemic cancer patients receiving CT.

Topics: Anemia; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Erythropoietin; Humans

Understanding the tissue distribution of erythropoietin receptors and cellular actions of erythropoietic agents may facilitate the development of wider applications for these compounds. Erythropoietin receptors have been identified in the central nervous system (CNS), retina, heart, vascular endothelium, kidney, lung, liver, gastrointestinal and reproductive tracts, and erythroid bone marrow precursors. Potential benefits of erythropoietic agents in several therapeutic areas may result from actions other than hematopoiesis stimulation. Their hematopoietic effects may also have broader applications in treating anemia of the elderly and non-chemotherapy (CT)-related anemia in patients with cancer. Furthermore, because hypoxic tumor cells tend to be more resistant to radiation therapy (RT) and some forms of CT, and more aggressive than normoxic cells, increased oxygenation resulting from anemia correction may increase RT and CT sensitivity, possibly impacting treatment outcomes. However, clinical studies addressing this hypothesis have conflicting results. Preliminary evidence suggests erythropoietin has CNS neuroprotective effects, including potential clinical benefits in ischemic stroke. In addition, data suggest that erythropoietin (epoetin alfa) may attenuate declines in cognitive function during CT for early-stage breast cancer. Erythropoietin may have benefits in retinal disease, peripheral neuropathy, and myocardial ischemia. Thus, accumulating evidence suggests that erythropoietic agents may have clinical utility outside CT-related anemia.

Topics: Anemia; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Drug Evaluation, Preclinical; Erythropoietin; Humans; Models, Biological

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

In spite of recent advances in the treatment of myelodysplastic syndromes (MDS), supportive care remains a very important part of the therapy. Red blood cells transfusions are the most important component of this supportive care. They transiently relieve anemia symptoms and alleviate their effects on quality of life and daily functioning. Platelet transfusion therapy is less frequently needed, at least in low-risk MDS. Dealing with an increased risk of infections linked to neutropenia, mainly by broad spectrum antibiotics, is also needed, more often in advanced stages of [dict: MDS] or when the MDS evolves to acute myeloid leukemia. Chronic red blood cell transfusions expose patients to various side-effects, including blood components intolerance reactions and alloimmunization risks, but also increased frequency of iron overload, a more significant problem in low-risk heavily transfused MDS patients, who have prolonged life expectancy. The use of growth factors is becoming a more and more important part of current supportive care. High-dose erythropoietin is able to reduce or suppress red blood cell transfusions needs in selected subgroups of MDS. The short-term use of granulocyte colony-stimulating factor is also often proposed in infections, although not formally established by prospective trials. Although trials of growth factors with thrombopoeitic activity have been performed with interleukin 11 and are underway with thrombopoeitin, none of them are available for routine use.

Topics: Anemia; Erythrocyte Transfusion; Erythropoietin; Growth Substances; Hemorrhage; Humans; Myelodysplastic Syndromes; Neutropenia; Recombinant Proteins; Thrombocytopenia

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

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

Anemia is a common complication in patients with multiple myeloma (MM) and occurs in more than two thirds of all patients. The most frequent underlying pathophysiological mechanism is anemia of chronic disease (ACD), relative erythropoietin (EPO) deficiency (due partly to renal impairment) and myelosuppressive effects of chemotherapy, but many other factors may account for or contribute to anemia in myeloma. In patients who achieve complete remission after chemotherapy, anemia usually normalizes. Nonresponders and relapsing myeloma patients often continue to suffer from anemia. Treatment options for anemic myeloma patients include red blood cell (RBC) transfusions and recombinant human erythropoietin (rHuEPO). Red blood cell transfusions convey an immediate effect and rapidly increase the patient's hemoglobin level. Unfortunately, effects of RBC transfusions are only transient and can be associated with several risks, including infections and mild to even life-threatening immunologic reactions. rHuEPO is biologically equivalent to the human endogenous hormone EPO, and its application leads to an increase of hemoglobin levels over an extended time without the risks of blood transfusions. Several studies reported a significant improvement of erythropoiesis, reduction in transfusion need, and improved quality of life by using rHuEPO as long-term treatment of myeloma-associated anemia. Recently, an international expert panel recommended the use of rHuEPO for anemic myeloma patients where other possible causes of anemia have been eliminated.

Topics: Anemia; Cell Hypoxia; Clinical Trials as Topic; Erythropoietin; Fatigue; Humans; Models, Biological; Multiple Myeloma; Neovascularization, Pathologic; Recombinant Proteins; Transfusion Reaction; Treatment Outcome

Recombinant human eythropoietin (rh-epo) is a well established treatment for many kinds of anemia including the anemia of cancer with or without myelosuppressive chemotherapy. This review considers the effects of rh-epo in humans, tumour-bearing and healthy experimental animals treated with cisplatin with or without rh-epo, and proposes that the ability of rh-epo to improve the quality of life in cancer patients may also be due to interference with the prostaglandin pathways.

Topics: Anemia; Animals; Antineoplastic Agents; Cisplatin; Erythropoietin; Humans; Models, Biological; Neoplasms; Prostaglandins; Quality of Life; Rats; Recombinant Proteins

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

This minireview is an update of a 1997 review on erythropoietin (EPO) in this journal. EPO is a 30,400-dalton glycoprotein that regulates red cell production. In the human, EPO is produced by peritubular cells in the kidneys of the adult and in hepatocytes in the fetus. Small amounts of extra-renal EPO are produced by the liver in adult human subjects. EPO binds to an erythroid progenitor cell surface receptor that includes a p66 chain, and, when activated, the p66 protein becomes dimerized. EPO receptor activation induces a JAK2 tyrosine kinase, which leads to tyrosine phosphorylation of the EPO receptor and several proteins. EPO receptor binding leads to intracellular activation of the Ras/mitogen-activated kinase pathway, which is involved with cell proliferation, phosphatidylinositol 3-kinase, and STATS 1, 3, 5A, and 5B transcriptional factors. EPO acts primarily to rescue erythroid cells from apoptosis (programmed cell death) to increase their survival. EPO acts synergistically with several growth factors (SCF, GM-CSF, 1L-3, and IGF-1) to cause maturation and proliferation of erythroid progenitor cells (primarily colony-forming unit-E). Oxygen-dependent regulation of EPO gene expression is postulated to be controlled by a hypoxia-inducible transcription factor (HIF-1alpha). Hypoxia-inducible EPO production is controlled by a 50-bp hypoxia-inducible enhancer that is approximately 120 bp 3' to the polyadenylation site. Hypoxia signal transduction pathways involve kinases A and C, phospholipase A(2), and transcription factors ATF-1 and CREB-1. A model has been proposed for adenosine activation of EPO production that involves protein kinases A and C and the phospholipase A(2) pathway. Other effects of EPO include a hematocrit-independent, vasoconstriction-dependent hypertension, increased endothelin production, upregulation of tissue renin, change in vascular tissue prostaglandins production, stimulation of angiogenesis, and stimulation of endothelial and vascular smooth muscle cell proliferation. Recombinant human EPO (rHuEPO) is currently being used to treat patients with anemias associated with chronic renal failure, AIDS patients with anemia due to treatment with zidovudine, nonmyeloid malignancies in patients treated with chemotherapeutic agents, perioperative surgical patients, and autologous blood donation. A novel erythropoiesis-stimulating factor (NESP, darbepoetin) has been synthesized and when compared with rHuEPO, NESP has a higher carbohydra

Topics: Anemia; Animals; Erythropoietin; Gene Expression; Humans; Oxygen; Receptors, Erythropoietin; Signal Transduction

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

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

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

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

Recombinant human erythropoietin (rHuEPO) is an effective treatment for anemia in patients with cancer, and recent studies show that over two-thirds of patients can be expected to respond with a large increase (>2 g/dl) in hemoglobin concentration. However, it would be helpful to identify likely responders and nonresponders before initiating treatment. Previous studies have suggested that high pretreatment endogenous erythropoietin levels are associated with a lower response to erythropoietin, especially in certain patient groups, such as patients with hematological malignancies, non-chemotherapy patients, or patients with myelodysplastic syndrome. Various algorithms have therefore been developed to predict patient response to rHuEPO using baseline serum erythropoietin levels and other baseline factors. We performed an analysis of data pooled from four randomized clinical trials of 604 patients with non-myeloid malignancies, examining the clinical usefulness of pretreatment and early treatment factors for predicting response to erythropoietin. The analysis confirms several other reports that the most predictive models combined pretreatment and early treatment factors, including change in hemoglobin at 4 weeks, but even these models did not increase sensitivity above 85% (total response in unselected patients was 68.1%), while specificity remained poor. We conclude that clinically useful prediction of response to erythropoietin is not possible using baseline or early response variables because of poor sensitivity and specificity of prediction compared with generally accepted clinical tests.

Topics: Anemia; Erythropoietin; Hemoglobins; Humans; Models, Theoretical; Predictive Value of Tests; Prognosis; Randomized Controlled Trials as Topic; Recombinant Proteins; Sensitivity and Specificity; Treatment Outcome

The prevalence of tumour anaemia in patients with multiple myeloma is greater than 80%. At the time of diagnosis 20% of these patients are already anaemic. In about 70% of patients with multiple myeloma, recombinant human erythropoietin (r-HuEPO) leads to a reduction in transfusion frequency, resulting in a drop in transfusion- related side-effects like infections and immune reactions, iron overload and hyperviscosity which often negatively influence the course of disease. A further reason for the use of erythropoietin is to achieve and maintain high haemoglobin levels (11-12 g/dl), which are of considerable prognostic significance in patients with multiple myeloma. Increasing Hb levels with r-HuEPO also improve the quality of life of patients, thus leading to better therapy compliance. The trade-off between high costs of an erythropoietin treatment and lower indirect costs (infusion material, personal equipment, patient transport costs, etc.) should be evaluated. Nevertheless, an exact definition of patients for whom the use of erythropoietin is beneficial is warranted. The pathogenesis of anaemia and the clinical experiences of erythropoietin in patients with multiple myeloma are discussed.

Topics: Anemia; Contraindications; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythropoietin; Hemoglobinometry; Humans; Multiple Myeloma; Recombinant Proteins; Treatment Outcome

Haematological disorders of pregnancy are common reasons for referral. It is reasonable then to devote a review to recent publications on these issues.. Several narrative reviews on the management of venous thromboembolic disease in pregnancy provide exceptional guidance. They highlight, however, that most of what is done is still based on opinions from highly qualified people, extrapolated from the non-pregnant literature but not involving randomized trials on pregnant patients. It is apparent that a consensus is nearing on the management of both pregnancy-related thrombocytopenia and idiopathic (immune) thrombocytopenic purpura. Several randomized controlled trials are reported on the treatment of non-deficiency anaemia, using oral iron, intravenous iron and erythropoietin, which contribute to the debate on the appropriate and best intervention for this common problematic issue.. This review demonstrates the need for appropriately sized randomized trials on haematological issues in pregnancy. With heparin becoming the most common medication being administered prophylactically and therapeutically in pregnancy, it is important that quality trials are performed to guide its sensible utilization.

Topics: Anemia; Erythropoietin; Female; Heparin; Humans; Iron, Dietary; Pregnancy; Pregnancy Complications, Hematologic; Prenatal Care; Prenatal Diagnosis; Randomized Controlled Trials as Topic; Thrombocytopenia; Thromboembolism

Anemia occurs frequently in patients with cancer and is associated with impaired health-related quality of life (HRQOL). Treatment of anemia results in significant improvements in energy, activity and overall HRQOL, particularly among patients with mild-to-moderate anemia. Importantly, studies have indicated that anemia may have a negative impact on the success of radiotherapy, reducing survival and locoregional control. Recent preclinical and preliminary clinical data have also suggested that anemia may be associated with poorer outcomes following chemotherapy or surgery.. Data for review were identified and selected from searches of the literature published from January 1990 through to October 2002 using Medline, and searches of proceedings from key international oncology and hematology meetings.. A wealth of data indicate that treatment of anemia improves HRQOL in patients with cancer. Prospective studies exploring survival and/or treatment outcomes in anemic cancer patients are currently in their early stages, preventing any firm conclusions from being drawn, although they do indicate a benefit in treating anemia.. Recent studies support the use of erythropoietic agents in anemic cancer patients as a means of raising their hemoglobin levels and consequently improving their HRQOL. Randomized, controlled trials are needed to determine whether treating anemia with erythropoietic agents will improve other outcomes following therapy.

Topics: Anemia; Darbepoetin alfa; Erythropoietin; Fatigue; Health Status; Humans; Neoplasms; Quality of Life; Randomized Controlled Trials as Topic; Survival; Treatment Outcome

Insulin resistance is a characteristic feature of uremia. As long as the hyperinsulinemia adequate to overcome the insulin resistance, glucose tolerance remains normal. In patients destined to develop type 2 diabetes, the beta cell compensatory response declines, and relative, or absolute, insulin deficiency develops. At this point glucose intolerance and eventually frank type 2 diabetes occur. Insulin resistance and concomitant hyperinsulinemia are present irrespective of the type of renal disease. Several studies have confirmed that hemodialysis (HD) treatment significantly improves insulin resistance. Both CAPD and CCPD are shown to improve insulin resistance in uremic patients. Comparing the effect of PD and HD treatment, it was found that the CCPD group has significantly higher insulin sensitivity than the HD group with the CAPD group similar to HD. Treatment of calcium and phosphate disturbances, including vitamin D therapy, significantly reduces insulin resistance in uremia. Treatment with recombinant human erythropoietin (EPO) is an efficient way to increase hematocrit, to reverse cardiovascular problems and to improve insulin sensitivity. Angiotensin-converting enzyme inhibitors have been shown to improve insulin resistance, hyperinsulinemia and glucose intolerance in uremic patients. Thiazolidinediones (TZDs), the new insulin-sensitizing drugs, provide the proof that pharmacologic treatment of insulin resistance can be of enormous clinical benefit. The great potential of insulin resistance therapy illuminated by the TZDs will continue to catalyze research in this area directed toward the discovery of new insulin-sensitizing agents that work through other mechanisms.

Topics: Anemia; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Diabetes Mellitus, Type 2; Erythropoietin; Humans; Hyperparathyroidism; Hypoglycemic Agents; Insulin Resistance; Phosphoric Diester Hydrolases; Pyrophosphatases; Recombinant Proteins; Renal Dialysis; Thiazoles; Thiazolidinediones; Uremia

Topics: Anemia; Animals; Erythropoietin; Gene Expression Regulation; Genetic Therapy; Hypoxia; Mice

Significant progress has been made in the prevention and management of many symptoms associated with cancer and its therapy. Anemia in cancer may be secondary to blood loss, displacement of normal bone marrow cells by malignant cells, myelotoxic therapy, or the tumor itself. Practitioners may not always adequately assess anemia unless it represents a source of significant symptoms or patient distress. Risk factors include platinum-based treatment regimens, specific tumor types, and low baseline hemoglobin levels. Anemia may have an impact on patient performance status, quality of life, clinical symptoms, and possibly therapeutic efficacy and survival. Treatment interventions, directed toward the underlying etiology of the anemia, involve iron supplementation, blood transfusion, and administration of recombinant human erythropoietin. Future advances may include new tools to assess physical or functional symptoms and predict therapeutic response more accurately, and more cost-effective, convenient agents to prevent or treat anemia in cancer. Novel approaches that may add to the armamentarium of strategies designed to address anemia in patients with cancer currently are being developed.

Topics: Anemia; Blood Transfusion; Erythropoietin; Hematinics; Humans; Neoplasms; Nurse's Role; Nursing Assessment; Oncology Nursing; Prevalence; Quality of Life; Risk Factors; Treatment Outcome

Topics: Anemia; Blood Transfusion; Clinical Trials as Topic; Erythropoietin; Hematologic Neoplasms; Humans; Lymphoproliferative Disorders; Myelodysplastic Syndromes; Prognosis; Quality of Life; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome

Topics: Anemia; Blood Component Removal; Blood Preservation; Blood Transfusion, Autologous; Erythropoietin; Fibrin Tissue Adhesive; Forecasting; Humans; Recombinant Proteins; Time Factors

Topics: Anemia; Diabetic Nephropathies; Diabetic Retinopathy; Erythropoietin; Humans; Recombinant Proteins

Darbepoetin alfa, novel erythropoiesis stimulating protein closely related to human erythropoietin, has been developed for the treatment of chemotherapy-related anaemia in patients with non-myeloid malignancies. In three 12-week, phase II studies in patients with cancer and chemotherapy-related anaemia, subcutaneous darbepoetin alfa, administered in once-weekly or 2-, 3- or 4-weekly regimens, dose-dependently increased the mean haemoglobin levels. In a randomised, double-blind, phase III study in 320 patients with lung cancer and chemotherapy-related anaemia, recipients of subcutaneous darbepoetin alfa 2.25 micro g/kg once weekly, received red blood cell (RBC) transfusion approximate, equals 2-fold less frequently than placebo recipients (p < 0.001). In the same study, patients receiving darbepoetin alfa also received fewer standard units of RBC for transfusion and had greater haematopoietic response rate than placebo recipients (both p < 0.001). Subcutaneous darbepoetin alfa 2.25 micro g/kg once weekly also reduced patient-reported fatigue (assessed by a quality-of-life questionnaire) [p = 0.019 vs placebo]. black triangle Darbepoetin alfa was generally well tolerated in clinical trials. The most frequent darbepoetin alfa-related adverse events were: body oedema, arthralgia and skin rash.

Topics: Anemia; Animals; Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Darbepoetin alfa; Double-Blind Method; Drug Administration Schedule; Erythropoiesis; Erythropoietin; Humans; Randomized Controlled Trials as Topic; Receptors, Erythropoietin; Treatment Outcome

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

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

Chemotherapy-induced anaemia has important consequences on the quality of life and social function of cancer patients. The finding of erythropoietin (EPO) deficiency in these patients led to the therapeutic development of erythropoietic proteins. Darbepoetin alfa (Aranesp), Amgen Inc, Thousand Oaks, California), a new erythropoietic growth factor, has eight more sialic acids than epoetin alfa. The increased sialic acid content confers a three-fold longer half-life and allows the drug to be administered less frequently than epoetin alfa. Darbepoetin alfa affects the same early haematopoietic cells as epoetin alfa and the endogenous hormone EPO. Preclinical pharmacokinetic studies suggest that the intrinsic pharmacological properties of darbepoetin alfa are comparable to those of epoetin alfa, but that the increased sialic acid content allows for less-frequent administration with superior performance. Darbepoetin alfa has been shown to have safe clinical efficacy in a variety of tumour settings and with several types of chemotherapy.

Topics: Anemia; Animals; Antineoplastic Agents; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Humans; Neoplasms

In moderately anaemic patients, Autologous Blood Donation is much less effective than Erythropoïetin (EPO) at constituting a pre-operative RBC reserve. Indeed, the ability to give blood is limited or even impossible for anaemic individuals. EPO lowers the risks associated with autologous and allogeneic transfusions, while improving probably the quality of life of the patients. EPO therapy is efficient, in moderate anaemic patients, to reduce allogeneic transfusion when iron supplementation is associated. All blood conservation techniques carry their own efficiency limits, constraints and risks that, in addition to institutional considerations and individual patient characteristics, are determinant to settle a blood conservation strategy. But to optimise benefit/cost/effectiveness of this technique, it is important to take into account the delay before surgery, the anticipated blood loss for the procedure that varies among institutions and the tolerable blood loss without transfusion for the patient. To reduce the cost, a strategy according to baseline haematocrit and to blood loss has to be adapted at each patient. Furthermore, when the delay between the first EPO injection and the surgical procedure is sufficient, the number of injections can be easily reduced to obtain the same Ht the day prior to surgery.

Topics: Anemia; Blood Transfusion, Autologous; Erythrocyte Count; Erythropoietin; Hemoglobins; Humans; Intraoperative Care; Recombinant Proteins; Safety; Transfusion Reaction; Transplantation, Homologous

Chronic heart failure (CHF) is a leading cause of morbidity and mortality. Although a precise definition for a cut-off value of hemoglobin level for anemia is still lacking, it has recently been found to be a common complication in CHF, occurring in 10-20% of patients. There are several possible pathogenetic mechanisms for anemia in CHF, and a precise underlying cause is found in only a minority of patients. In CHF, more than 50% of anemia cases are considered to be 'anemia in chronic illness'. In CHF patients, low hemoglobin values directly relate to poor peak oxygen consumption, disabling symptoms, and impaired survival. Recent pilot studies showed that correction of anemia with erythropoietin and iron may lead to improvement in symptoms and exercise capacity. These issues need to be tested in larger, double-blind, randomized, placebo-controlled trials before anemia treatment becomes routine in patients with CHF.

Topics: Anemia; Erythropoietin; Heart Failure; Hemoglobins; Humans; Iron

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

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

Cardiac disease represents a major cause of morbidity and mortality in dialysis patients, and is also a well-established feature of chronic kidney disease (CKD). Anaemia has also been shown to be a key component not only of dialysis and CKD but also of cardiac disease, including congestive heart failure (CHF). Furthermore, published clinical and laboratory data suggest that anaemia, CHF and CKD are interrelated, each causing the other to worsen and thus resulting in a 'vicious cycle' of disease progression which we have called the Cardio-Renal Anaemia syndrome. In this syndrome anaemia may cause CKD or be caused by CKD, anaemia may cause CHF or be caused by CHF and CHF may cause CKD or be caused by CKD. Numerous publications have borne out the fact that anaemia correction through epoetin treatment provides great benefit to CKD patients. Additionally, there is evidence to suggest that these benefits may be extended to patients with cardiac disease. Uncontrolled and controlled studies of the effect of subcutaneous epoetin treatment in anaemic patients with both CHF and CKD show significant improvements in both cardiac and renal function. Despite these findings, however, it is apparent that anaemia correction is not implemented rigorously within both CHF and CKD populations. Greater awareness of the need for early anaemia correction therapy is therefore required. Cooperation between nephrologists and others who are caring for CHF patients, especially cardiologists, is crucial.

Topics: Anemia; Erythropoietin; Heart Diseases; Humans; Recombinant Proteins; Renal Insufficiency; Treatment Outcome

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

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

For previously untreated patients receiving most chemotherapy regimens, primary prophylactic administration of granulocyte colony-stimulating factor (G-CSF) cannot be recommended. Secondary prophylactic G-CSF administration can lessen incidence of febrile neutropenia (FN) in subsequent cycles of chemotherapy in patients with a prior episode of FN. Physicians should consider chemotherapy dose reduction after neutropenic fever or severe or prolonged neutropenia after the previous cycle of treatment. Intervention with G-CSF in afebrile neutropenic patients is not recommended. For the majority of patients with FN, the available data do not clearly support the routine initiation of G-CSF as an adjunct to antibiotic therapy. However, certain FN patients may have prognostic factors that are predictive of clinical deterioration, such as pneumonia, hypotension, multiorgan dysfunction (sepsis syndrome), or fungal infection. The therapeutic use of G-CSF together with antibiotics may be reasonable in such high-risk patients. Empirical antifungal therapy is effective, especially for patients with neutropenia who were treated for seven days with empirical antibiotic therapy but remained febrile, or became afebrile but then had recurrent fever. The patient's overall clinical status and laboratory parameters are both considered when deciding to transfuse a patient. Epoetin may be available for use in the future as a treatment option for patients with chemotherapy-associated anemia with a hemoglobin level less than 10 g/dl. Giving prophylactic platelets at a threshold of 10,000/microliter compared with 20,000/microliter can decrease the total utilization of platelets with only a small adverse effect on bleeding, and no statistically significant effect on morbidity.

Topics: Anemia; Anti-Bacterial Agents; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Erythropoietin; Fever; Granulocyte Colony-Stimulating Factor; Guidelines as Topic; Humans; Neoplasms; Neutropenia; Platelet Transfusion; Recombinant Proteins; Risk

Anemia is a real and frequent complication during the management of cancer patients. It is define as a decrease of the erythrocyte mass. The hemoglobin rate (which was an estimation of this erythrocyte mass) is the most often using criteria. The inferior threshold change with the sex and the age of the patients. This is 13 g/dl for the men and 11.5 g/dl for the women. This rate would be however decrease without any other associated pathology. This anemia is due to nutritional context of the patients and complications of the cancer pathology or his management (treatments). Anemia due to the chemotherapy toxicity is a real problem to investigate, to quantify, to prevent or to treat. The chemotherapy toxicity worsened previous anemia (inflammatory ethiology) which physiopathology is multifactoriel and depends on drugs, patients' characteristics, and sort of cancer. Anemia is also a therapeutic problem. Whatever is the severity of the anemia, impact on the quality of life with physical and social consequences is clear. In addition, anemia could relieve of specific treatment such as blood transfusion or preventive treatment with recombinant erythropoietin.

Topics: Age Factors; Anemia; Antineoplastic Agents; Erythrocyte Transfusion; Erythropoietin; Female; Hemoglobins; Humans; Male; Neoplasms; Quality of Life; Recombinant Proteins; Severity of Illness Index; Sex Factors

Anemia is a frequent symptom encountered in hematological malignancies at diagnosis or in the course of the disease. Allogeneic transfusions were, until recently, the only treatment available and used only for severe anemia. Erythropoietin is currently an important alternative especially for treatment and even to prevent severe anemia. It has been assessed for the treatment of chemotherapy related anemia in NHL, myeloma and CLL with a significant reduction of blood transfusions and prevention of grade 3-4 anemia in 51% of patients. In myelodysplasia, the more effective regimen is the association of G-CSF and Epo. In the setting of allogeneic bone marrow transplantation, it reduces the time to red cell engraftment and probably the number of blood cell unit per patient in contrast with autologous stem cell transplant. All these studies assessed the efficacy of Epo in hematological malignancies but needs further trials including the assessment of the quality of life and economical parameters.

Topics: Anemia; Erythropoietin; Hematologic Diseases; Hematologic Neoplasms; Hematopoietic Cell Growth Factors; Hematopoietic Stem Cell Transplantation; Humans; Myelodysplastic Syndromes; Recombinant Proteins

The role of oxygen as an enhancer of the biological effect of ionising radiation is crucial for radiotherapy. Most of the solid tumours have an inadequate vasculature (neo-angiogenesis) leading to hypoxic areas, favoured by anaemia. Many clinical approaches have been used to overcome this problem with oxygen breathing, radiosensitizing drugs or anaemia correction. All these parameters will be developed together with the methods available for measuring tumour oxygenation and the biological consequences of anaemia and hypoxia on tumour physiology.

Topics: Anemia; Blood Transfusion; Cell Hypoxia; Erythropoietin; Hemoglobin A; Humans; Neoplasms; Oxygen; Oxygen Consumption; Partial Pressure; Radiation-Sensitizing Agents

Anemia is a reduction in the oxygen-carrying capacity of red blood cells that results in a variety of symptoms, including dyspnea, headaches, light-headedness, and fatigue. Although anemia has been associated with reduced health-related quality of life (HRQoL), its treatment has not yet been consistently shown to improve HRQoL.. This systematic review of the literature was conducted to determine whether the treatment of anemia improves HRQoL domains, regardless of the type of underlying disease.. Data for this review were drawn from the clinical trial databases from 2 previous systematic literature reviews of erythropoiesis-stimulating protein treatment for renal insufficiency- and cancer-related anemia, both spanning the period January 1, 1980, through December 31, 2001. MEDLINE, Cancerlit, and Current Contents/Clinical Medicine were searched using the combined terms erythropoietin, kidney failure, neoplasms, and anemia. The reference lists of all identified articles were searched manually for additional relevant papers. The review included prospective studies that reported both HRQoL and hematocrit (Hct) in patients with cancer or renal insufficiency who received treatment for anemia with an erythropoiesis-stimulating protein. HRQoL was categorized by domain (overall, energy/fatigue, physical, activity); changes in HRQoL domains were expressed as effect sizes and meta-analyzed, as were correlation coefficients. The effects on HRQoL of dropout rate, study duration, baseline Hct, and change in Hct were examined in meta-regression analyses.. Sixteen studies each were identified in patients with renal insufficiency (N = 2253) and patients with cancer (N = 10,695). The treated groups included 11,710 patients, and the control groups included 1238 patients. The baseline Hct in all treated groups averaged 26.0%: 28.3% in the group with cancer and 24.4% in the group with renal insufficiency. The mean improvement in Hct from baseline to the end of treatment was 8.3% (range, 1.0%-16.5%) in treated patients and 1.0% (range, 0.0%-3.3%) in controls. The Hct changes were similar in treated patients with cancer and treated patients with renal insufficiency, as was the HRQoL effect size (0.43). Dropout rate and study duration were not significant predictors of HRQoL changes, but change in Hct was a significant predictor in both conditions. Meta-analysis of the correlation coefficients, adjusting for HRQoL domains, showed a consistent and significant positive correlation between change in Hct and change in HRQoL (P < 0.001).. The consistency in both direction and magnitude of effect across many studies and thousands of patients supports the hypothesis that treatment of anemia with erythropoiesis-stimulating protein improves selected HRQoL domains in patients with renal insufficiency- or cancer-related anemia.

Topics: Anemia; Clinical Trials as Topic; Epoetin Alfa; Erythropoietin; Hematocrit; Humans; Neoplasms; Quality of Life; Recombinant Proteins; Renal Insufficiency; Treatment Outcome

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

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

The transfusion of red blood cells is still associated with possible adverse effects and a residual risk of transmission of viral and nonviral diseases. In addition, there is an increasing shortage of blood supply worldwide. These two facts together with the success experienced in the treatment of various types of anemia with recombinant human EPO, have recently led to an increasing interest in the anemia of critically ill patients. As in the anemia of chronic diseases there are several reasons that contribute to the development of anemia in patients on intensive care units: pre-existing anemia, blood loss, reduced red cell life span, impaired iron availability and a direct inhibition of erythropoiesis by inflammatory cytokines. The implications of anemia for the progression and prognosis of critical illness are still unclear and the optimal treatment, including optimal "transfusion triggers" remains controversial. Recombinant human EPO has been proven to be effective in ameliorating the anemia of critical illness in several pilot studies and is currently being tested in larger trials.

Topics: Adult; Anemia; Blood Loss, Surgical; Child; Critical Care; Critical Illness; Cytokines; Double-Blind Method; Drug Therapy, Combination; Erythrocyte Transfusion; Erythropoiesis; Erythropoietin; Hemoglobins; Humans; Iron Compounds; Jehovah's Witnesses; Middle Aged; Multicenter Studies as Topic; Pilot Projects; Placebos; Randomized Controlled Trials as Topic; Recombinant Proteins; Reticulocyte Count; Time Factors; Transfusion Reaction

Despite therapeutic improvements and ongoing efforts to develop more efficacious therapies, the majority of lung cancer patients face a poor prognosis. Therefore, the primary goal of current treatment is palliation, improvement and maintenance of quality of life (QOL), and (modest) prolongation of survival. Anemia frequently occurs in lung cancer patients and has been associated with decreased QOL, impaired treatment outcomes, and shortened survival time. Furthermore, anemia is a causative factor of tumor hypoxia, which compromises the efficacy of chemotherapy and radiotherapy. Thus, correction of even mild anemia seems to have a beneficial effect on QOL and cancer treatment outcomes. The current article describes the basis and mechanism for the use of recombinant human erythropoietin (rHuEPO, epoetin alfa), a molecular targeted therapy, for the treatment of cancer-related anemia, with a focus on lung cancer. Epoetin alfa has proven efficacy and safety in correcting anemia and improving QOL based on numerous clinical studies and over a decade of clinical practice. In addition, emerging data show that epoetin alfa may offer potential benefits beyond treating anemia, specifically in terms of treatment outcomes and cognitive function. Future research needs to be conducted to explore the potential for epoetin alfa to improve survival time in lung cancer patients.

Topics: Anemia; Clinical Trials as Topic; Cognition; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Lung Neoplasms; Palliative Care; Quality of Life; Recombinant Proteins; Survival Analysis; Treatment Outcome

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

Anemia in children after renal transplantation is more common than previously appreciated. Multiple factors appear to play roles in the development of post-transplant anemia, the most common of which is absolute and/or functional iron deficiency anemia. Most experts recommend that iron limited anemias in transplant patients should be diagnosed using the same criteria as for chronic renal failure patients. Serum erythropoietin (EPO) levels are expected to normalize after a successful renal transplantation with a normal kidney function, yet both EPO deficiency and resistance have been reported. While no large controlled trials comparing the effect of different immunosuppressive agents on erythropoiesis after transplantation have been performed, generalized bone marrow suppression attributable to azathioprine (AZA), mycophenolate mofetil (MMF), tacrolimus, antithymocyte preparations has been reported. Pure red cell aplasia (PRCA) occurs rarely after transplantation and is characterized by the selective suppression of erythroid cells in the bone marrow. PRCA has been reported with the use of AZA, MMF, tacrolimus, angiotensin converting enzyme inhibitors (ACEI), but not with cyclosporine (CSA) use. Post-transplant hemolytic uremic syndrome has been reported with orthoclone anti T-cell antibody (OKT3), CSA and tacrolimus therapy. Viral infections including cytomegalovirus, Epstein-Barr virus and human parvovirus B19 have been reported to cause generalized marrow suppression. Management of severe anemia associated with immunosuppressive drugs generally requires lowering the dose, drug substitution or, when possible, discontinuation of the drug. Because this topic has been incompletely studied, our recommendation as to the best immunosuppressive protocol after renal transplantation remains largely dependent on the clinical response of the individual patient.

Topics: Anemia; Anemia, Iron-Deficiency; Azathioprine; Bone Marrow; Child; Erythropoiesis; Erythropoietin; Hemolytic-Uremic Syndrome; Humans; Immunosuppressive Agents; Liver Transplantation; Mycophenolic Acid; Tacrolimus

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

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

Anemia is a common finding in patients with hematologic malignancies and most commonly can be attributed to the anemia of chronic disease compounded by the myelotoxic effects of chemotherapy. Symptoms of anemia include fatigue, and the patient's quality of life may be impaired. Possible treatments for the anemia are to do nothing, to transfuse with red cells, or to treat with recombinant human erythropoietin (rhEPO). rhEPO has become standard treatment for the anemia in chronic renal failure and has been successfully used in anemia secondary to malignancy. In patients with lymphoproliferative diseases, rhEPO increases the hemoglobin concentration, decreases the need for transfusion, and improves the patients' quality of life. Disadvantages of rhEPO include its cost, efficacy in only around 60% of patients, and delay of 4 to 8 weeks before maximum benefit is achieved. The anemia in patients with myelodysplasia responds less well to rhEPO. Misuse of rhEPO is common in the clinical setting but usually not of clinical importance. Misuse to enhance sporting prowess is probably rare but has potentially serious consequences.

Topics: Anemia; Doping in Sports; Erythropoietin; Humans; Lymphoproliferative Disorders; Medication Errors; Myelodysplastic Syndromes; Primary Myelofibrosis; Treatment Outcome

The anemia of chronic disease (ACD) is a hypoproliferative anemia defined by a low serum or plasma iron concentration in the presence of adequate reticuloendothelial iron stores. It is been established that ACD results from the effects of cytokines that mediate the immune or inflammatory response. During the past 3 years, the clinical scope of this syndrome has been expanded beyond the traditional chronic infectious, inflammatory, or neoplastic diseases to include other, often acute, syndromes in which the same pathogenetic mechanisms are operating. An improved understanding of the use of the soluble transferrin receptor concentration in clinical medicine has enhanced the ability to diagnose ACD, and further experience with the use of recombinant human erythropoietin in the management of severely affected patients with ACD has provided a basis for rational and effective management. Ongoing studies of the mechanisms contributing to the development of ACD continue to elucidate the pathogenesis of this common and clinically significant syndrome.

Topics: Anemia; Chronic Disease; Erythropoietin; Humans; Receptors, Transferrin; Syndrome

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

The use of recombinant human erythropoietin (rHuEpo) has revolutionized anemia management of early and late stages of chronic kidney disease. Darbopoietin is also now available for the treatment of anemia of chronic kidney disease. In addition, rHuEpo has been used for the treatment of anemia observed in critical illness. Unfortunately, the existing clinical studies of anemia in critically ill patients do not distinguish between those with and without acute renal failure (ARF). This review summarizes the existing experimental and clinical studies supporting the use of rHuEpo in ARF due to ischemic/nephrotoxic injury and conclusions are drawn on the rationale for further research into the use of this drug in ARF.

Topics: Acute Kidney Injury; Anemia; Animals; Critical Illness; Erythropoietin; Humans; Recombinant Proteins

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

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

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

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

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

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

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

Topics: Anemia; Erythropoietin; Exercise; Heart Failure; Humans

Topics: Androgens; Anemia; Drug Therapy, Combination; Erythropoietin; Humans; Recombinant Proteins; Renal Insufficiency

Anemia has been reported in approximately 40%-70% of patients with hematologic malignancies, with severity depending on the type and stage of disease and whether the patient has received myelosuppressive chemotherapy. Growing evidence supports the role of epoetin alfa in correcting anemia and improving quality of life (QOL) in patients with hematologic malignancies. Clinical practice guidelines recommend the use of epoetin alfa in patients with cancer-related anemia (including patients with hematologic malignancies) and hemoglobin levels < or =10 g/dL. Epoetin alfa treatment is optional for patients with cancer-related anemia and hemoglobin levels>10 g/dL and <12 g/dL, depending on clinical circumstances. A prospective, open-label, randomized trial evaluating hematologic response, transfusion use, and QOL after immediate or delayed epoetin alfa treatment in mildly anemic patients (hemoglobin< or =12 g/dL) undergoing chemotherapy for chronic lymphocytic leukemia, multiple myeloma, or lymphoma was recently completed. Study objectives included determining any correlation between changes in hemoglobin level and QOL and assessing any correlation between QOL measures and health care resource use. Interim results suggest that epoetin alfa treatment in patients with hematologic cancers and hemoglobin< or =12 g/dL who are receiving chemotherapy increases hemoglobin, functional capacity, well-being, work and productivity, and health resource use. Further evaluation of alternative epoetin alfa dosing schedules and use of epoetin alfa in treating anemia in patients with specific hematologic malignancies is ongoing.

Topics: Anemia; Clinical Trials as Topic; Dose-Response Relationship, Drug; Epoetin Alfa; Erythropoietin; Hematinics; Hematologic Neoplasms; Hemoglobins; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Linear Models; Multiple Myeloma; Myelodysplastic Syndromes; Quality of Life; Random Allocation; Recombinant Proteins

Although erythropoietin (EPO) deficiency is not responsible for the anemia of myelodysplasia, pharmacologic doses of recombinant human EPO (rHuEPO, epoetin alfa) and epoetin beta have been studied extensively as treatment of anemia in myelodysplastic syndrome (MDS). When an epoetin is used as a single growth factor in patients with MDS, clinically meaningful responses occur in only a small minority of patients (16%). Patients who are transfusion-dependent are less likely to respond than patients who are transfusion-independent. Serum EPO level has a weak association with response rate and cannot be used to select or exclude patients from empirical trials of epoetins. The dose schedule commonly used as initial treatment 40,000 U/week, is consistent with clinical observations, but an optimal dose schedule has not been determined. The combination of an epoetin and granulocyte colony-stimulating factor (G-CSF) produces a higher erythroid response rate (36%) than the regimen of epoetin alone, but we have found no randomized trial data to support this point. However, the design of the clinical trials, which included adding G-CSF after epoetin alone had failed, supports the hypothesis that combined use of growth factors, rather than just higher doses of epoetin, is responsible for the high response rate observed with the combination of epoetin and G-CSF. Unfortunately, as in the case of epoetin alone, patients who are transfusion-dependent (> or =2 U red blood cells/month) are less likely to respond to combined growth factor therapy. Although the ability of patients with MDS to show an erythroid response to epoetin is of biologic interest, because of high costs and the limited response rate in transfusion-dependent patients, epoetin therapy, with or without G-CSF, cannot be regarded as a definitive therapy for the anemia of MDS.

Topics: Anemia; Blood Transfusion; Clinical Trials as Topic; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Myelodysplastic Syndromes; Neutrophils; Time Factors

Multiple myeloma (MM) is commonly associated with anemia. Several causes have been implicated, but anemia of chronic disease with inadequate erythropoietin (EPO) production related to the inflammatory cytokines appears to be of utmost importance. Interleukin-1 and tumor necrosis factor are capable of suppressing erythropoiesis. Anemia has broad implications. First, the low hemoglobin and hematocrit are associated with poor quality of life and performance and affect daily activity. Second, anemia has an impact on the cardiovascular system. Considering that most MM patients are elderly, this may be even more important. Anemia has been shown to induce or aggravate hypoxia and ischemic complications. Third, anemia has been shown to be a poor prognostic factor in MM. Traditionally, patients with symptomatic anemia were treated with red blood cell transfusions as needed. The introduction of epoetin alfa and epoetin beta into clinical practice opened new avenues to these patients. The administration of epoetins to patients with MM and anemia have been shown to be very useful. Several studies in more than 1000 patients have demonstrated a high response rate (range, 25%-85%; mean, 60%). This response is characterized by a significant increase of hemoglobin, hematocrit, and the number of red blood cells together with a reduction in the blood transfusion requirements. This is also associated with an improved quality of life. Although there is no complete agreement about the role of pretreatment serum EPO levels, many investigators believe that relatively low levels may help in predicting response, thereby limiting the number of potential candidates to receive this expensive therapy. The epoetins are safe and well tolerated with minimal toxicity; however, some concern has been recently raised regarding several dozen patients who developed pure red cell aplasia while on epoetin therapy. However, this adverse effect appears to be extremely rare. Recent data suggest that EPO has additional biologic effects, such as longer-than-expected survival in patients with MM. This observation is further supported by animal studies, demonstrating an antimyeloma effect of EPO in mice models. This effect has been shown to be immune mediated. If these exciting data are confirmed in future clinical trials, this may have significant implications on the treatment of MM.

Topics: Anemia; Animals; Cytokines; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Hemoglobins; Humans; Hypoxia; Mice; Mice, Inbred BALB C; Multiple Myeloma; Prognosis; Quality of Life; Recombinant Proteins; Time Factors

Anaemia is a common finding in critically ill patients. There are often multiple causes. Obvious causes include surgical bleeding and gastrointestinal haemorrhage but many patients have no overt bleeding episodes. Phlebotomy can be a significant source of blood loss. In addition, critically ill patients have impaired erythropoiesis as a consequence of blunted erythropoietin production and direct inhibitory effects of inflammatory cytokines. The ability of a patient to tolerate anaemia depends on their clinical condition and the presence of any significant co-morbidity; maintenance of circulating volume is of paramount importance. There is no universal transfusion trigger. Current guidelines for critically ill and perioperative patients advise that at Hb values <70 g/L red blood cell transfusion is strongly indicated and at Hb values >100 g/L transfusion is unjustified. For patients with Hb values in the range 70 to 100 g/L the transfusion trigger should be based on clinical indicators. Most stable critically ill patients can probably be managed with a Hb concentration between 70 and 90 g/L. Uncertainties exist concerning the most appropriate Hb concentration for patients with significant cardio-respiratory disease.

Topics: Anemia; Critical Illness; Erythrocyte Transfusion; Erythropoiesis; Erythropoietin; Humans; Recombinant Proteins

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

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

A review of the incidence and management of anemia in elderly patients with head and neck carcinoma treated with systemic chemotherapy. The role of recombinant human erythropoietin in preventing or correcting chemotherapy-related anemia has been focused. Data concerning the prospective use of recombinant human erythropoietin (rhEpo) in a series of unfit elderly patients (EPs) treated with carboplatin plus 5-fluorouracil. Patients were randomly assigned to receive subcutaneous rhEpo 10,000U three times per week (TIW) (23 elderly patients) or no treatment (22 control patients). Recombinant hEpo was able to prevent anemia and to reduce transfusional requirements in treated patients as compared to untreated controls with a statistically significant difference. rhEpo also caused a positive effect on quality of life (QoL) parameters.

Topics: Aged; Anemia; Antineoplastic Agents; Carcinoma, Squamous Cell; Erythropoietin; Head and Neck Neoplasms; Humans; Incidence; Recombinant Proteins

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 has a high prevalence in patients with lung cancer. Its frequency and severity depend on tumor stage, duration of disease, and previous and current treatment. Anemia affects the health-related quality of life and impacts prognosis and outcome of therapy. Despite this clinical relevance, anemia is often underrecognized and undertreated. Treatment options include the administration of hematopoietic growth factors and red blood cell transfusions. Blood transfusions result in rapid but often transient improvement of anemia. Administration of epoetin or darbepoetin alfa increases hemoglobin levels, decreases blood transfusions, and improves quality of life in patients with lung cancer. Trials determining the exact association of anemia with response to chemotherapy/radiation therapy and survival are ongoing. Oncologists must be aware of the clinical relevance of anemia and offer adequate treatment options to their patients.

Topics: Anemia; Erythrocyte Transfusion; Erythropoietin; Health Status; Humans; Lung Neoplasms; Prognosis; Quality of Life; Treatment Outcome

The National Health Service (NHS) Cancer Plan published in 2000 has a short-term focus on the most pressing problems of improving survival rates and replacing equipment. It also mentioned as a target 'improved quality of life for those affected by cancer'. Continuity of care for longer-term care programmes was seen predominantly in terms of palliative care. Recent National Institute for Clinical Excellence (NICE) reports may have reinforced this approach by focussing on the clinical and cost effectiveness of chemotherapy for late-stage cancer. The impact on local decision-makers has been that drug funds have been prioritised for use on survival-enhancing interventions, with few resources left for short and longer-term supportive care targeted primarily on improving quality of life. Within supportive care, resources are particularly limited for funding treatments such as erythropoietin for the management of cancer-related anaemia, a common and very debilitating side-effect of intensive therapy. The need for a re-focusing on supportive care is associated with cancer becoming, in many instances, a longer-term illness. The prevalence of cancer is rising markedly due to increased survival rates. However, this creates a new challenge of reducing disability and improving quality of life. In surveys, patients have rated fatigue associated with anaemia as one of the most debilitating effects of their cancer and its treatment with chemotherapy. This paper reviews the evidence demonstrating the quality of life benefits of erythropoietin, and then considers the policy constraints that have limited the adoption of this treatment within the NHS. Through co-ordinated planning there are opportunities for cancer networks and primary care trusts (PCTs) working with cancer centres to develop more support in ways which are feasible and fundable. The case is argued that PCTs and cancer networks, in implementing the Cancer Plan locally, need to integrate short- and longer-term supportive care into their cancer service development plans, and recognise the importance of anaemia management as an integral part of this. Lessons can be learnt from UK renal services where anaemia management with erythropoietin is standard practice.

Topics: Anemia; Blood Transfusion; Community Networks; Erythropoietin; Fatigue; Humans; Neoplasms; Practice Guidelines as Topic; Primary Health Care; Quality of Life; Recombinant Proteins; State Medicine; United Kingdom

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

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

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

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

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

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

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

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

Anaemia in cancer patients is multifactorial. Anaemia of chronic disease due to the effects of cancer, as well as side effects of cancer treatment, are important factors. The impact of anaemia on the quality of life and social function of cancer patients has recently become more acknowledged. The traditional treatment for chemotherapy-induced anaemia (CIA) has been the use of red blood cell transfusions, with only short-lived effects and all their inherent risks. The finding of deficiency in erythropoietin, the endogenous hormone responsible for the production and maintenance of red blood cells in these patients, was the basis for the therapeutic development of erythropoietic proteins. With the introduction of epoetins (recombinant forms of human erythropoietin) in oncology and more recently, the novel long-acting darbepoetin alpha, physicians gained new pharmacotherapeutic approaches to treat CIA. Several forms of erythropoietic proteins are available in various regions of the world. Their characteristics, clinical evidence for use, guidelines for clinical administration and their safety are described in this review.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Neoplasms; Recombinant Proteins

As the population ages, a dramatic increase in the number of cases of cancer is expected and the need for supportive-care agents, those used to ameliorate some of the side effects of cancer or its treatment, becomes more urgent. At present, supportive-care products are available and new agents are being developed with novel mechanisms of action or modifications of existing agents that improve performance. Because of the urgent need for such products, efficient development is required to deliver useful products to patients as rapidly as possible. This chapter uses actual examples to illustrate the stages of drug development, phase I through phase 3.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Darbepoetin alfa; Drug Approval; Drug Design; Drug Evaluation; Erythropoietin; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Neoplasms; Neutropenia; Palliative Care; Polyethylene Glycols; Quality of Life; Recombinant Proteins; Stomatitis; United States

EPO is a hematopoietic growth factor produced in the kidney that stimulates erythropoiesis. It effectively treats hypoproliferative anemia associated with CRF, improving quality of life in these patients. Other uses that are poorly characterized in veterinary medicine include treatment of cancer patients on chemotherapy, hematologic disorders, and anemic FeLV-infected cats as well as preoperative conditioning for elective surgeries that may involve significant blood loss. Careful monitoring of therapy is necessary for optimal results. Several complications are associated with rHuEPO therapy. The production of anti-rHuEPO antibodies is the most significant and can be a life-threatening event. Alternatives to human EPO are being sought to provide beneficial effects while avoiding antibody formation.

Topics: Anemia; Animals; Cat Diseases; Cats; Chemotherapy, Adjuvant; Dog Diseases; Dogs; Erythropoietin; Recombinant Proteins

Antiprogestin-controlled gene regulation systems, initially developed by Bert O'Malley and colleagues, are based on the unusual properties of certain truncated progesterone receptor ligand-binding domains (PR-LBDdelta19). These modified PR-LBDs have lost the ability to respond to progestins, but have gained the ability to respond to antiprogestins as agonists, rather than as antagonists. When a modified PR-LBD is joined to specific DNA-binding and transcription activator domains, the resultant chimeric protein functions as an antiprogestin-inducible transcription factor for transgenes linked to promoters with specific DNA-binding sites. Antiprogestin-inducible gene regulation systems have been used to regulate transgene expression in cultured cells, transgenic animals, and for in vivo gene transfer studies using viral- or plasmid-based vectors. We have designed a plasmid-based, muscle-specific GeneSwitch system that is delivered to skeletal muscle by electroporation and provides regulated erythropoietin (EPO) expression in mice and rats in a manner that is dependent on orally administered mifepristone (MFP). Regulation was effective at low doses of MFP and provided regulated biological responses (hematocrit changes) for more than 6 months. This plasmid-based, antiprogestin-inducible EPO/GeneSwitch system has the potential to be a convenient, long-lasting and effective gene-based therapy for the treatment of anemia.

Topics: Anemia; Animals; Electroporation; Erythropoietin; Gene Transfer Techniques; Genetic Therapy; Humans; Mice; Mifepristone; Models, Genetic; Plasmids; Rats; Time Factors; Transgenes

Recombinant human erythropoietin (epoetin alfa) has proven beneficial for the treatment of various anemias. The mechanism of action of endogenous erythropoietin and the therapeutic use of epoetin alfa to stimulate red blood cell production and improve the quality of life in cancer patients are reviewed here. Epoetin alfa may also attenuate the cognitive dysfunction associated with cancer therapy. Interestingly, functional endogenous erythropoietin receptor signaling pathways have been demonstrated in numerous nonerythropoietic tissues. Of particular importance, epoetin alfa confers neurotrophic and neuroprotective effects in cultured neurons and in several animal models for neurologic disease. In one clinical trial, epoetin alfa appeared to limit functional and histologic damage in patients with stroke. Therefore, in cancer patients receiving chemotherapy, the beneficial effects of epoetin alfa could be mediated not only through enhanced erythrocyte production but also via direct effects on the nervous system. Further investigation into the nonerythropoietic effects of epoetin alfa could broaden its clinical utility for patients with cancer and also provide new therapies for various neurologic disorders.

Topics: Anemia; Apoptosis; Epoetin Alfa; Erythropoiesis; Erythropoietin; Humans; Neoplasms; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Recombinant Proteins; Signal Transduction

Topics: Anemia; Contraindications; Erythropoietin; Humans; Recombinant Proteins; Treatment Outcome

To describe the management of fatigue and anemia in patients with cancer.. Published literature and clinical experience.. Anemia is a common cause of cancer-related fatigue. Epoetin alfa increases hemoglobin, decreases transfusion requirements, and improves energy and quality of life in patients with cancer-related anemia. Nonpharmacologic treatment options include exercise, nutrition optimization, and psychosocial interventions. Effective management of fatigue improves overall cancer treatment, quality of life, and functional status.. Fatigue and anemia are commonly undertreated complications of cancer and its treatment. Oncology nurses play a key role in identifying and managing these conditions.

Topics: Activities of Daily Living; Anemia; Antineoplastic Agents; Epoetin Alfa; Erythropoietin; Fatigue; Female; Hematinics; Humans; Male; Neoplasms; Nursing Assessment; Nursing Methodology Research; Oncology Nursing; Patient Care Planning; Quality of Life; Recombinant Proteins

Chemotherapy-associated cognitive dysfunction occurs in a subset of patients treated with adjuvant chemotherapy. Recent data suggest that development of chemotherapy-related anemia predisposes patients to cognitive dysfunction. Endogenous erythropoietin (EPO) is well recognized for its central role in erythropoiesis, and recombinant human EPO (epoetin alfa) is established as a safe and effective treatment for chemotherapy-related anemia. Treatment with epoetin alfa also improved health-related quality of life in anemic cancer patients undergoing chemotherapy, and several controlled studies have documented increases in quality-of-life scores correlated with increases in hemoglobin. Erythropoietin also plays a role in neuroprotection, presumably by activation of antiapoptotic genes. Erythropoietin and its receptor are expressed in neural cells of the human brain, and their expression is upregulated after hypoxic or ischemic injury. In animal models, systemic administration of epoetin alfa protects against such neural injury. Ongoing and future studies will determine whether epoetin alfa can provide neuroprotection with respect to the development of cognitive dysfunction in patients undergoing adjuvant chemotherapy treatment for breast cancer.

Topics: Anemia; Animals; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cognition Disorders; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Quality of Life; Rats; Recombinant Proteins

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

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

Reduction in red blood cell mass, as well as structural and functional alterations of erythrocytes, occurs in critical illness. This review discusses these changes in red blood cell physiology, emphasizing the pathogenesis of anemia in intensive care unit patients.. Studies published in biomedical journals.. Anemia in intensive care unit patients resembles the anemia of chronic disease, being characterized by diminished erythropoietin production relative to decreased hematocrit, altered iron metabolism, and impaired proliferation and differentiation of erythroid progenitors in the bone marrow. Inflammatory mediators play a major role in the development of insufficient erythropoiesis and altered iron metabolism. Furthermore, a proinflammatory milieu promotes structural and functional alterations of erythrocytes, impairing their deformability and possibly impairing microvascular perfusion. Collectively, these changes in red blood cell physiology can impair oxygen transport to tissues and, thereby, might contribute to the development of multiple organ failure in critical illness.

Topics: Anemia; Critical Care; Erythrocytes; Erythroid Precursor Cells; Erythropoietin; Hemolysis; Hemorrhage; Humans; Iron; Occult Blood; Phlebotomy

Anemia in the critically ill patient population is common. This anemia of critical illness is a distinct clinical entity characterized by blunted erythropoietin production and abnormalities in iron metabolism identical to what is commonly referred to as the anemia of chronic disease.. As a result of this anemia, critically ill patients receive an extraordinarily large number of blood transfusions. Between 40% and 50% of all patients admitted to intensive care units receive at least one red blood cell unit, and the average is close to five red blood cell units during their intensive care unit stay. There is little evidence that "routine" transfusion of stored allogeneic red blood cells is beneficial for critically ill patients. Most critically ill patients can tolerate hemoglobin levels as low as 7 mg/dL, so a more conservative approach to red blood cell transfusion is warranted.. Practice strategies should be directed toward a reduction of blood loss (phlebotomy) and a decrease in the transfusion threshold in critically ill patients.

Topics: Anemia; Critical Care; Erythrocyte Transfusion; Erythropoietin; Hemorrhage; Humans; Iron; Outcome and Process Assessment, Health Care; Phlebotomy

Topics: Adult; Anemia; Child; Critical Care; Erythrocyte Transfusion; Erythropoietin; Humans; Infant; Outcome and Process Assessment, Health Care; Risk Factors

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

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

This paper presents the role of erythropoietin application in diabetic patients with accompanying renal failure. The main cause of anemia in diabetics are: nephropathy, structural lesions of erythrocyte membrane and blood loss connected with diagnostic and therapeutic actions. There are publications which demonstrate that in patients with diabetes type 1 or 2 with accompanying nephropathy, anemia appears more frequently than in the group of patients with chronic renal failure caused by other factors. It is supposed, that the impaired erythropoietin synthesis in diabetics can be caused by autonomic neuropathy. Erythropoietin administration in case of diabetic nephropathy has a beneficial influence on fat metabolism, immune response and reduction of insuline resistance. Erythropoietin because of reduction of vascular endothelial growth factor synthesis blocks the development of diabetic retinopathy and macroangiopathy. Erythropoietin reduces the risk of the left-ventricular hypertrophy caused by anemia. Very important is that the erythropoietin resistance is lower in diabetics. Scientists who are adverse to erythropoietin administration in patients with diabetic nephropathy maintain, that it can lead to vascular complications and the deterioration of glycemia control.

Topics: Anemia; Diabetes Complications; Erythropoietin; Humans

Myelosuppression associated with cancer chemotherapy may lead to neutropenia, anemia, or both, resulting in an increased risk for infection, fatigue, diminished quality of life, and reduced survival. In addition, neutropenia specifically has been shown to result in dose reductions, treatment delays, or both in subsequent chemotherapy cycles. Hematopoietic growth factors have been used effectively as supportive therapy to reduce chemotherapy-associated neutropenia and anemia. New preparations have the potential to improve treatment outcome dramatically. Results from recently reported studies indicate that patients at risk for neutropenia can be safely and effectively treated with pegfilgrastim once per chemotherapy cycle, and that those with anemia can be managed with weekly or biweekly darbepoetin alfa therapy. These new treatments have the potential to reduce the morbidity and mortality associated with opportunistic infections, decrease the requirement for potentially dangerous blood transfusions, and improve the quality of life for patients undergoing cancer chemotherapy. The longer dosing intervals offered by these new preparations may decrease healthcare expenses and enhance patient adherence.

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Neutropenia; Polyethylene Glycols; Recombinant Proteins

Cancer-related anemia often develops from the infiltration of marrow by malignant cells, impaired hemoglobin (Hb) production related to chemotherapy or radiation therapy, iron deficiency, or low endogenous erythropoietin levels. Patients with cancer-related anemia may experience cognitive dysfunction including decreased mental alertness, poor concentration, and memory problems. Anemia-mediated cerebral hypoxia may cause symptoms such as headache, vertigo, tinnitus, and dizziness. These symptoms often are exacerbated in the elderly patient with cancer and related to underlying low Hb concentrations. Restoring Hb levels via the administration of iron supplements, blood transfusions, or, more recently, erythropoiesis-stimulating therapy (epoetin alfa) results in significant improvement of cognitive function. The use of epoetin alfa as a treatment option for patients with chemotherapy-associated anemia and an Hb concentration less than 10 g/dL has been recommended by the American Society of Clinical Oncology and the American Society of Hematology. Erythropoiesis-stimulating therapies are a promising treatment option for cancer-related anemia that may improve cognitive function and quality of life for patients with cancer.

Topics: Aged; Aged, 80 and over; Anemia; Antineoplastic Agents; Cognition Disorders; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Male; Neoplasms; Recombinant Proteins

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

Multiple myeloma (MM) and chronic lymphocytic leukemia (CLL) patients often develop anemia due to the disease process and effects from disease therapy. Blood transfusion, the established treatment, has an immediate effect in improving patients' hemoglobin levels. However, this effect is transient and transfusion is associated with several risks, including infections and mild to life-threatening immunologic reactions. A newer option is recombinant human erythropoietin (epoetin); a biological treatment that leads to increased hemoglobin levels over an extended time without the risks of blood transfusion. Extensive evidence has shown that epoetin is effective in the treatment of cancer-associated anemia. An international expert panel met to develop treatment recommendations for the use of epoetin in MM and CLL patients. Based on the available data, it is recommended that treatment be initiated only after other possible causes of anemia are eliminated. Epoetin should be administered to any patient with hemoglobin < or=10 g/dl. Patients with hemoglobin 10-12 g/dl should receive epoetin if they suffer from significant symptoms of anemia and/or have progressively decreasing hemoglobin values. Dosage should be initiated at 10 000 IU three times/week or 40 000 IU once/week and be titrated to maintain hemoglobin at 12 g/dl. Nonresponsive patients (<1 g/dl increase over four weeks) may have their dose increased to 20 000 IU three times/week or 60 000 IU once/week, respectively. Epoetin treatment should be discontinued if there is no response to the increased dosage, or hemoglobin >14 g/dl. Treatment should resume for patients who exceed 14 g/dl, at a reduced dosage, if their hemoglobin falls below 12 g/dl.

Topics: Anemia; Disease Management; Epoetin Alfa; Erythropoietin; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Multiple Myeloma; Practice Guidelines as Topic; Recombinant Proteins

Topics: Adult; Anemia; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Postpartum Hemorrhage; Postpartum Period; Recombinant Proteins

Erythropoietin, in its standard role for the treatment of anemia, is often mechanistically regarded simply as increasing blood oxygen-carrying capacity and hence decreasing tumor hypoxia. In reality, erythropoietin (a member of the cytokine superfamily) is expressed in a multitude of tissues/cell types including erythroid and cancer cells, and the liver and central nervous system. Erythropoietin expression is induced by hypoxia-inducible factor-1, which itself is induced during hypoxia. Whereas it has no endogenous tyrosine kinase activity of its own, erythropoietin, via constitutively associated JAK2, can activate several signaling pathways including STAT5, RAS, and phosphoinositol 3-kinase. An increased understanding of these pathways is already opening up new clinical indications, particularly in terms of oncology and neurology. Current arrays/molecular endpoint studies in clinical trials should identify key components of the particular signaling pathways that will guide further use in the development of both better synergistic therapies as well as new molecular targets.

Topics: Anemia; Cognition Disorders; Erythropoietin; Humans; Neoplasms; Oligonucleotide Array Sequence Analysis; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Controlled Clinical Trials as Topic; Energy Metabolism; Erythropoietin; Fatigue; Female; Humans; Male; Neoplasms; Patient Satisfaction; Prognosis; Quality of Life; Recombinant Proteins; Retrospective Studies; Treatment Outcome

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

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

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

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

Many unanswered issues regarding rhEPO therapy in prematurity remain, including which premature infants best respond to rhEPO, what the long-term effect of decreased erythrocyte transfusions is, how nutritional supplementation optimizes the effect of rhEPO, whether or not rhEpo therapy causes iron deficiency later in life, and whether or not it is safe to supplement with parenteral iron. Further study of rhEPO therapy and iron status in prematurity is necessary.

Topics: Anemia; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Newborn; Infant, Premature, Diseases; Iron; Recombinant Proteins

Clinical and pharmacokinetic studies have shown that target hemoglobin or hematocrit levels can be maintained using a reduced recombinant human erythropoietin (epoetin) dosage by switching from intravenous (IV) to subcutaneous (SC) administration.. We conducted a meta-analysis of comparative studies of epoetin administered IV versus SC to assess the relative costs of these administration routes. Twenty-seven prospective clinical studies involving 916 patients were included in the analysis. The average difference between IV and SC doses of epoetin and average difference in drug costs between administration routes were determined.. The average reduction in dose in patients treated with SC versus IV epoetin was 48 IU/kg/wk (P < 0.001), representing an average annual cost savings with SC administration of US $1,761 +/- $1,080 (SD) per patient. The difference between SC and IV doses was similar in both parallel- and crossover-design studies. A retrospective US survey showed a dose reduction of 26 IU/kg/wk (P < 0.001) with SC administration, translating to an annual savings of $946 per patient.. This study indicates that the cost of epoetin is reduced substantially when administered SC in comparison to IV. Recommendations of current US and European guidelines, which encourage the use of SC administration, not only have a sound rationale in terms of efficacy and safety, but also have a sound economic basis.

Topics: Anemia; Cost-Benefit Analysis; Cross-Over Studies; Erythropoietin; Europe; Health Planning Guidelines; Humans; Injections, Intravenous; Injections, Subcutaneous; Prospective Studies; Recombinant Proteins; Renal Dialysis; Retrospective Studies; United States

Children with cancer frequently develop anemia both from the disease and from chemo- and radiotherapy. Considered a manageable complication, anemia is often not treated until it becomes severe, i.e., hemoglobin (Hb) level

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Child; Child, Preschool; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Infant; Infant, Newborn; Male; Neoplasms; Recombinant Proteins; Retrospective Studies; Risk Assessment; Treatment Outcome

Numerous reports on recombinant human erythropoietin (rHuEPO, epoetin alfa) treatment of cancer-related anemia in adult patients have been published to date. These have shown that epoetin increases hemoglobin levels, significantly ameliorates symptoms of anemia, and improves adult patients' quality of life. Unfortunately, less is known about the impact of epoetin on anemia in pediatric cancer patients.. It is the objective of this review to summarize and analyze data of clinical trials of epoetin treatment of anemia in pediatric cancer patients.. A total of 15 studies were reviewed; eight were considered for detailed analysis and demonstrated important variabilities in study methods. Four of the eight were controlled, randomized trials and four were open label.. These studies suggested an overall beneficial effect of epoetin alfa for treating anemia in children with cancer. Three large, multicenter clinical trials of the efficacy and safety of epoetin alfa in anemic children with cancer are currently underway, one in Europe and two in North America.

Topics: Anemia; Child; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Medical Oncology; Multicenter Studies as Topic; Neoplasms; Pediatrics; Randomized Controlled Trials as Topic; Recombinant Proteins

Anemia is common in patients with lung carcinoma, particularly among those undergoing platinum-based cytotoxic chemotherapy. Evidence is growing that anemia can have a profound impact on the patient's quality of life, often manifested as the patient's inability to function normally.. A literature review was conducted to provide a current picture of the incidence and impact of anemia in patients with lung carcinoma and the usage and limitations of current treatment.. The incidence of anemia (a hemoglobin [Hb] level < 11g/dL) in lung carcinoma patients is approximately 50-60%, varying according to treatment regimen. However, despite evidence supporting the treatment of anemia, many clinicians only intervene when Hb levels fall below 8 g/dL. This may be because of a lack of awareness of the incidence and impact of anemia on cancer patients, but most likely is because of limitations of current treatment options (blood transfusion and recombinant human erythropoietin [epoetin-alpha]). Darbepoetin-alpha represents a new generation of erythropoiesis-stimulating proteins. Biochemically distinct from epoetin-alpha, darbepoetin-alpha has a greater sialic acid content and biologic half-life than epoetin-alpha, but stimulates erythropoiesis in the same manner. Clinical trials involving patients with cancer-related anemia have shown that darbepoetin-alpha has a threefold longer half-life than epoetin-alpha, which may allow less frequent dosing. The results from an ongoing clinical trial dedicated to testing the clinical benefits of darbepoetin-alpha in treating anemia in lung carcinoma patients will provide a valuable insight into its full potential in this setting.. Anemia is common but is reported to be undertreated in patients with lung carcinoma. The introduction of darbepoetin-alpha into clinical practice may overcome some of the limitations of current treatments and facilitate improvement in the management of cancer-related anemia.

Topics: Anemia; Blood Transfusion; Darbepoetin alfa; Erythropoietin; Hemoglobins; Humans; Lung Neoplasms; Platinum Compounds; Quality of Life

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

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

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

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

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

Cancer-associated anemia is common and has many causes, including the effects of the underlying disease and cancer treatment. The effect of anemia on patients with cancer was not appreciated fully until relatively recently. Several well-designed studies have demonstrated the relationship between anemia and fatigue, and the effect of fatigue on quality of life. These data have resulted in a greater awareness of anemia in cancer and have increased the use of recombinant human erythropoietin (r-HuEPO, epoetin alfa) therapy for the treatment of anemia. Recombinant HuEPO produces a hemoglobin response in 50-60% of patients with cancer; however, to obtain this response rate, frequent dosing is required. Darbepoetin alfa, a recently developed erythropoietic protein, has a longer half-life than that of r-HuEPO, enabling less frequent dosing, and has a greater in vivo activity. In studies of patients with cancer who develop anemia, darbepoetin alfa has proved to be well tolerated and effective, and its advantages make it a potential improved treatment option for anemia in these patients.

Topics: Anemia; Clinical Trials as Topic; Darbepoetin alfa; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Neoplasms; Recombinant Proteins

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

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

Myelodysplastic syndromes (MDS) are a heterogeneous group of hemopoietic progenitor cell disorders, and patients with MDS regularly develop anemia and frequently become transfusion-dependent. Treatment with erythropoietin (EPO) has been tried to correct anemia with only limited success with response rates ranging from 16% to 25%. However, it is becoming evident that the generally rather low response rate of EPO in patients with MDS will be improved by the combination of EPO with either G-CSF or GM-CSF.. Here, we analyzed the results from the literature (six papers and one abstract using EPO plus G-CSF, and seven papers using EPO plus GM-CSF).. Among all trials the cytokine dose and schedule varied, and the response criteria were not uniform. The average response rate for improving anemia was 41% in 207 patients treated with EPO and G-CSF, and 26% in 154 patients treated with EPO and GM-CSF. There were higher response rates for refractory anemia (RA) (45%), ringed sideroblasts (RARS) (47%), and excess of blasts (RAEB) (38%) compared with blasts in transformation (RAEBT) (17%) for the treatment with EPO plus G-CSF. The corresponding response rates for treatment with EPO plus GM-CSF were 30% (RA), 29% (RARS), 16% (RAEB), and 0% (RAEBT), respectively. Prolonged administration even showed a higher increment in the response rates.. In conclusion, the combination of EPO with G-CSF is probably superior to EPO plus GM-CSF. There seems to be a positive correlation between the duration of cytokine treatment and response rates, and higher response rates in early MDS stages compared to advanced entities. However, controlled studies are mandatory to evaluate the role of the combined cytokine treatment in patients with MDS.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Erythropoietin; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-3; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Anemia; Erythropoietin; Humans; Hypotension, Orthostatic

Erythropoietin has been successfully used in the treatment of cancer-related anaemia. About two-thirds of patients with the 'anaemia of chronic disorders', anaemia due to neoplastic bone marrow infiltration or therapy-related anaemia, are expected to respond to high doses of erythropoietin with a haemoglobin increase of at least 2 g/dl. In the myelodysplastic syndromes, about one-third of patients will show a response when very high doses of erythropoietin are combined with granulocyte colony-stimulating factor. The response to erythropoietin is slow, requiring several months to develop. Various factors have been reported to predict a response, but the prediction models proposed are contradictory and have not been prospectively validated. Therefore, the most common strategy to determine the responsiveness of cancer-related anaemia to erythropoietin is to subject the patient to a treatment trial of several months' duration. Treatment with erythropoietin needs to be compared with the transfusion of red blood cells, which has similar effects on the patient's haemoglobin level. Erythropoietin is a generally well tolerated drug, but it is slow to exert an effect and ineffective in a substantial proportion of patients. Red blood cell transfusion is associated with a small risk of infectious, allergic or toxic complications, but it leads to a rapid haemoglobin increase in virtually all patients treated. Cost and cost-benefit analyses from several countries indicate that, in patients with cancer-related anaemia, treatment with erythropoietin is considerably more expensive than the transfusion of allogeneic red blood cells. Thus, the choice between the two treatment options will be influenced by the financial resources of the respective healthcare systems.

Topics: Anemia; Cost-Benefit Analysis; Erythropoietin; Humans; Neoplasms; Patients

This study was designed to evaluate if erythropoietin (EPO) is effective in the treatment of cancer related anemia, and if its effect remains unchanged when data are analyzed according to various clinical and methodological characteristics of the studies. We also wanted to demonstrate that cumulative meta-analysis (CMA) can be used to resolve uncertainty regarding clinical questions.. Systematic Review (SR) of the published literature on the role of EPO in cancer-related anemia. A cumulative meta-analysis (CMA) using a conservative approach was performed to determine the point in time when uncertainty about the effect of EPO on transfusion-related outcomes could be considered resolved.. Patients included in randomized studies that compared EPO versus no therapy or placebo.. Number of patients requiring transfusions.. Nineteen trials were included. The pooled results indicated a significant effect of EPO in reducing the number of patients requiring transfusions [odds ratio (OR) = 0.41; 95%CI: 0.33 to 0.5; p < 0.00001;relative risk (RR) = 0.61; 95% CI: 0.54 to 0.68]. The results remain unchanged after the sensitivity analyses were performed according to the various clinical and methodological characteristics of the studies. The heterogeneity was less pronounced when OR was used instead of RR as the measure of the summary point estimate. Analysis according to OR was not heterogeneous, but the pooled RR was highly heterogeneous. A stepwise metaregression analysis did point to the possibility that treatment effect could have been exaggerated by inadequacy in allocation concealment and that larger treatment effects are seen at hb level > 11.5 g/dl. We identified 1995 as the point in time when a statistically significant effect of EPO was demonstrated and after which we considered that uncertainty about EPO efficacy was resolved.. EPO is effective in the treatment of anemia in cancer patients. This could have already been known in 1995 if a CMA had been performed at that time.

Topics: Anemia; Erythrocyte Transfusion; Erythropoietin; Humans; Kinetics; Neoplasms; Randomized Controlled Trials as Topic; Recombinant Proteins

Topics: Anemia; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Autonomic Nervous System Diseases; Diabetic Nephropathies; Diabetic Neuropathies; Erythropoietin; Humans; Recombinant Proteins

The anemia of chronic disease traditionally is defined as a hypoproliferative anemia of no apparent cause that occurs in association with an inflammatory, infectious, or neoplastic disorder, and resolves when the underlying disorder is corrected. Disordered iron metabolism as manifested by a low serum iron, decreased serum transferrin, decreased transferrin saturation, increased serum ferritin, increased reticuloendothelial iron stores, increased erythrocyte-free protoporphyrin, and reduced iron absorption, is a characteristic feature of the anemia of chronic disease and has been thought to be a major factor contributing to the syndrome. A mild shortening of red cell life span also occurs. However, we now know that impaired erythropoietin production and impaired responsiveness of erythroid progenitor cells to this hormone are also important abnormalities contributing to the anemia of chronic disease, and appear to be due to the effects of inflammatory cytokines. Increased intracellular iron may also have a role in the inhibition of erythropoietin production, since the oxygen sensor is a hemoprotein. While the role of inflammatory cytokines in the pathogenesis of anemia of chronic disease appears unequivocal, it has become apparent that disordered iron metabolism, while characteristic of this form of anemia, may not be central to its pathogenesis. It is undisputed that iron absorption is reduced, and that iron administered intravenously is rapidly sequestered in the reticuloendothelial system; however, iron delivery to the bone marrow is not impaired, and erythroid iron utilization is not markedly depressed in anemia of chronic disease. Importantly, recombinant erythropoietin therapy can correct the anemia of chronic disease, but it cannot correct the anemia due to iron deficiency. This refutes the concept that the lack of available iron is central to the pathogenesis of the syndrome. Indeed, it is highly likely that abnormalities such as reduced iron absorption and decreased erythroblast transferrin-receptor expression largely result from decreased erythropoietin production and inhibition of its activity by inflammatory cytokines.

Topics: Anemia; Chronic Disease; Cytokines; Erythropoiesis; Erythropoietin; Humans; Iron

Anemia in cancer patients is associated with a decline in energy levels, activity levels, and quality of life, and these variables improve when hemoglobin levels rise. Importantly, the impact of improved hemoglobin levels on response to chemotherapy, radiation therapy, and survival time is under study. This line of research follows favorable preliminary data in clinical studies suggesting improved treatment outcomes with reversal of anemia. It is estimated that there are 10 million people in the United States with cancer. Of the 1.3 million cancer patients who are anemic with hemoglobin levels less than 12 g/dL, about 800,000 are receiving chemotherapy and 500,000 are not. The predominant treatable cause of anemia in these patients is a relative lack of erythropoietin; overall, only 20% of anemic cancer patients receive a trial of erythropoietic therapy. About one-fourth (26%) of patients whose hemoglobin is less than 12 g/dL and who are receiving chemotherapy for cancer are currently receiving erythropoietic therapy. A review of the patients in our oncology practice revealed that 37% were anemic (hemoglobin < 12 g/dL) prior to chemotherapy, and an additional 41% became anemic during chemotherapy. Overall, 63% of our cancer patients on chemotherapy received erythropoietin; 6% of these patients received red cell transfusions. Only 7% of our patients had a hemoglobin level < 10 g/dL before chemotherapy; overall, 80% of our patients maintained hemoglobin levels > or = 10 g/dL at all times. Barriers to the use of erythropoietic agents include cost and reimbursement issues, inconvenience of frequent injections, limitations in efficacy, and indication restrictions. An understanding of the importance of anemia and newer agents requiring less frequent dosing, such as darbepoetin alfa (Aranesp), may help physicians and patients overcome some of these barriers.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Neoplasms; Recombinant Proteins; United States

The clinical development of recombinant human erythropoietin (rHuEPO) has had a remarkable impact on the clinical practice of oncology. A decade ago, randomized, placebo-controlled trials in anemic cancer patients demonstrated that rHuEPO resulted in an improvement in hemoglobin and hematocrit, a reduction in transfusion requirements, and improvement in quality-of-life (QOL) end points. Based on these trials, recombinant erythropoietin was approved for the treatment of anemia in patients with nonmyeloid malignancies in whom the anemia was caused by the effect of chemotherapy. The clinical indication was to decrease the needfor transfusion in patients for whom anemia was not due to other reversible causes. Despite this broad indication, the incorporation of rHuEPO in clinical practice was limited because of a variety of factors, including physician perception that mild-to-moderate anemia in the cancer patient was generally asymptomatic and did not warrant intervention. Subsequently, three large open-label, prospective trials of recombinant erythropoietin were performed in the community setting in anemic cancer chemotherapy patients. All three trials replicated the results of the original randomized study, but with a much larger database of more than 7,000 patients. Importantly, these trials were able to define the major impact of hemoglobin level on quality of life. Patients on these trials who improved their hemoglobin > 2 g/dL or achieved a hemoglobin > or = 12 g/ dL had the greatest improvement in symptoms of energy, activities of daily living, and overall quality of life. Furthermore, a once-per-week dosing schedule was found to be comparable to three-times-weekly administration of rHuEPO. A European randomized, placebo-controlled trial confirmed these QOL results, and a meta-analysis of other randomized clinical trials firmly supports the role of erythropoietin therapy in improving hemoglobin levels and reducing transfusion requirements. Based on this aggregate of data, the use of erythropoietin in the treatment of mild-to-moderate anemia has become a standard of care. These studies have also expanded our understanding of the problem of fatigue and the study of interventions that can improve quality of life for cancer patients.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Male; Middle Aged; Neoplasms; Quality of Life; Recombinant Proteins

Anemia is the most common hematologic abnormality seen in patients with cancer. Anemia is associated with debilitating symptoms and poorer health-related quality of life and may result in less than optimal disease/treatment outcomes. The high prevalence of anemia and the potential clinical and prognostic impact make it important to have a systematic approach to the diagnosis and treatment of cancer-related anemia. A rigorous diagnostic evaluation should be undertaken to identify the cause of anemia and guide appropriate treatment. Treatment of anemia with erythropoiesis stimulating proteins offers an alternative treatment to red blood cell transfusions and has been shown to improve quality of life for patients being treated for cancer. In addition, recent studies suggest improved cancer treatment outcomes. Data indicate that treatment with darbepoetin alfa, a novel erythropoiesis stimulating protein, improves hemoglobin levels and quality of life in anemic patients with cancer who are not receiving chemotherapy or radiotherapy. Symptoms of anemia, when searched for properly, are identified often at hemoglobin levels less than 12 g/dL. As the understanding of the importance of anemia grows, and more convenient methods of therapy become available, patients will benefit with a more proactive approach to early treatment or prevention of this complication of cancer and its treatment.

Topics: Anemia; Blood Transfusion; Clinical Trials as Topic; Darbepoetin alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Neoplasms; Physician's Role; Quality of Life

Barriers to use of erythropoietic therapy in cancer patients include nonresponse in a sizable proportion, resultant lowering of cost-effectiveness, and inconvenience. Darbepoetin alfa represents the outcome of efforts to develop agents with improved erythropoietic potency. This agent has been shown to produce high dose-related response rates, reduce risk of transfusion, and produce dose-related rapidity of response in cancer patients; no loss in dose-efficiency is observed with once-every-2-week dosing compared with weekly dosing, and the feasibility of every-3-week dosing has been demonstrated. In addition, the characteristics of this agent may permit a treatment schedule consisting of front loading with an optimal dose followed by low-dose maintenance, which may further improve dose-efficiency and cost-effectiveness of treatment. The characteristics of darbepoetin alfa suggest the ability to improve overall quality of erythropoietic therapy, which may increase its utilization in patients who would benefit from such treatment.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Hemoglobins; Humans; Neoplasms; Recombinant Proteins

This article examines the relationships between chemotherapy-induced anemia, fatigue, and psychological distress among anemic cancer patients with solid tumors. Patients participating in two randomized clinical trials evaluating the efficacy of darbepoetin alfa (Aranesp) completed a questionnaire at baseline, at the beginning of each chemotherapy cycle, and at the end of the 12-week treatment period. The questionnaire included four psychological distress outcomes: Brief Symptom Inventory (BSI) Depression and Anxiety, Functional Assessment of Cancer Therapy (FACT)-Emotional Well-Being, numeric rating scale of Overall Health, and the FACT-Fatigue subscale. Patients with a hemoglobin response of at least a 2 g/dL increase were more likely to experience meaningful improvements (at least 3 points) in FACT-Fatigue scores than nonresponders (55.0% vs 39.8%; P = .0004). Patients with meaningful improvements in FACT-Fatigue scores reported significantly greater improvements in each of the psychological outcomes relative to those without improved fatigue (P <.0001). For BSI Depression and Anxiety, the differences in mean change scores between patients with and without improved fatigue were 8.2 and 7.7, respectively. Improving the hemoglobin levels of patients undergoing chemotherapy and suffering from anemia-related fatigue has the potential to produce significant positive effects on patients' fatigue, depressive symptoms, anxiety, feelings of helplessness, and overall health.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Darbepoetin alfa; Erythropoietin; Fatigue; Female; Humans; Male; Mental Disorders; Neoplasms; Quality of Life

Anemia, common in people with cancer, can be due to the disease itself or to the associated therapy. Fatigue, the most prevalent of all symptoms experienced by cancer patients, is the primary symptom of anemia. Caused by many factors,fatigue, regardless of etiology, has an adverse impact on health-related quality of life. Anemia is among the more treatable of those causes. Prior to the development of recombinant human erythropoietin, red blood cell transfusion was the standard treatment for cancer-related anemia. Erythropoietic agents are an effective alternative to blood transfusion: they improve hematocrit, reduce transfusion dependency, and eliminate transfusion-related risks. Although studies are mixed, most clinical trials have also suggested that erythropoietic agents have a positive impact upon cancer patients' quality of life. However, the cost of drug supply is quite high in the oncology setting, where much higher doses are required relative to the nephrology setting. Thus, although few challenge the treatment's effectiveness, cost-effectiveness remains an open question. The data collected over the years to address these questions have helped define and clarify the relationship between anemia and health-related quality of life in people with cancer. That relationship is summarized in this article.

Topics: Anemia; Clinical Trials as Topic; Erythropoietin; Fatigue; Female; Hemoglobins; Humans; Male; Middle Aged; Neoplasms; Quality of Life

To support evidence-based clinical guidelines on erythropoietin use for anemia in oncology, we conducted systematic reviews of controlled trials on four patient groups. These were patients with treatment-related anemia; patients with disease-related anemia; patients transplanted with allogeneic hematopoietic stem cells; and those transplanted with autologous hematopoietic stem cells. Two reviewers followed a prospective protocol to select studies, abstract relevant outcomes, evaluate study quality, and conduct meta-analysis where data sufficed. For treatment-related anemia, meta-analysis of available evidence (22 trials; N = 1,927) demonstrated reduced odds of transfusion after erythropoietin, but higher-quality trials reported smaller odds reductions. In several trials, erythropoietin improved quality of life for groups with mean baseline hemoglobin < or = 10 g/dL. However, evidence was insufficient to determine whether initiating erythropoietin treatment earlier for newly anemic patients reduced the odds of transfusion or improved quality of life more than waiting until hemoglobin approached l0 g/dL. Limited evidence (6 trials; N= 693) suggested that erythropoietin decreased the risk of transfusion for patients with disease-related anemia. For those undergoing allotransplants, evidence (7 trials; N = 493) showed erythropoietin modestly decreased time to red cell engraftment and transfusions. Studies on erythropoietin after autologous transplants (6 trials; N = 321) did not support a beneficial effect of erythropoietin.

Topics: Anemia; Controlled Clinical Trials as Topic; Erythropoietin; Humans; Practice Guidelines as Topic

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

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

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

Topics: Anemia; Apoptosis; Clone Cells; Disease Progression; Erythropoiesis; Erythropoietin; Female; Growth Substances; Hematologic Tests; Hematopoietic Stem Cells; Humans; Iron; Leukemia, Myeloid; Male; Myeloproliferative Disorders; Phlebotomy; Phosphorus Radioisotopes; Polycythemia Vera; Pregnancy; Pregnancy Complications, Hematologic; Receptors, Erythropoietin; Receptors, Growth Factor; Thrombocytosis; Thrombosis

The majority of cancer patients suffer from chronic anemia. While recombinant human erythropoietin (rHuEPO) offers many of the advantages of blood transfusions, response rates to this treatment are variable and in some trials a large proportion of patients (30 50%) did not respond. This failure may be due to factors related to the underlying disease, the chemotherapy given or functional iron deficiency. An accurate means of predicting response to rHuEPO would be beneficial to both healthcare providers and patients.. Data were identified by searches of the published literature, including PubMed, references from relevant reviews, and abstracts presented at recent international oncology and hematology meetings. Only papers in English published between 1990 and 2002 were included. References were selected according to direct relevance to the topic discussed and availability.. The best algorithms for predicting response appear to be those combining an assessment of the adequacy of endogenous erythropoietin production together with some early indicators of erythropoietic marrow response. Further characterization of the dose-response relationship of erythropoietic agents may allow better understanding of ways in which response may be enhanced. Adequate iron availability could also contribute to better response rates.. Further characterization of the predictors of response for current and upcoming erythropoietic agents may enhance the management of anemia associated with cancer, and provide more convenient, effective, and flexible therapy.

Topics: Algorithms; Anemia; Data Collection; Dose-Response Relationship, Drug; Erythropoietin; Humans; Neoplasms; Prognosis; Recombinant Proteins; Treatment Outcome

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

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

Cancer-related anemia, in addition to having detrimental effects on quality of life and adding the risk and inconvenience of blood transfusions, may also be associated with decreased survival or time to progression. Yet despite increasing awareness of the value of treating cancer-related anemia, over 60% of US cancer patients receiving chemotherapy who have hemoglobin values below 10 g/dL are not treated for this condition. Current treatment options include red blood cell transfusions, iron supplementation for iron deficiency, or erythropoietic agents, including recombinant human erythropoietin (rHuEPO) and darbepoetin alfa (Aranesp). The articles in this supplement describe the basic scientific research and clinical development of darbepoetin alfa--another safe, effective, and approved treatment for chemotherapy-induced anemia.

Topics: Anemia; Antineoplastic Agents; Clinical Trials as Topic; Darbepoetin alfa; Erythropoietin; Humans; Neoplasms

Anemia is prevalent among cancer patients with hematologic malignancies, with fatigue and weakness, major symptoms of anemia, contributing to diminished quality of life (QOL). Data from several randomized, placebo-controlled clinical trials and three large community-based studies in patients with hematologic malignancies indicate that recombinant human erythropoietin (r-HuEPO, epoetin alfa) can correct anemia, reduce transfusion requirements, and improve QOL. Moreover, a positive relationship has been found between increased hemoglobin (Hb) levels and improvements in QOL assessments, regardless of disease state, with the greatest incremental improvement occurring when Hb increases from 11 g/dL to 12 g/dL (range, 11 to 13 g/dL). This suggests that patients with mild-to-moderate anemia may achieve the greatest QOL benefit from epoetin alfa therapy. Evidence from community-based studies suggests that epoetin alfa administered once weekly has a similar safety and efficacy profile as three-times-weekly administration. Further research is ongoing with less frequent dosing regimens. The beneficial effects of epoetin alfa therapy have been reported in studies involving patients with chronic lymphocytic leukemia (CLL), multiple myeloma, and lymphomas. Evidence also exists that epoetin alfa can benefit patients with myelodysplastic syndromes (MDS), although these results have not been as impressive. Combining epoetin alfa with other cytokine growth factors may confer some additional benefit in these patients, but more rigorous investigation is required.

Topics: Anemia; Epoetin Alfa; Erythropoietin; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Multiple Myeloma; Recombinant Proteins; Treatment Outcome

Topics: Anemia; Darbepoetin alfa; Drug Administration Schedule; Erythropoietin; Humans; Peritoneal Dialysis, Continuous Ambulatory; Renal Dialysis; Renal Insufficiency

Many cancer patients suffer from anemia, which has a major detrimental effect on their quality of life. Recombinant human erythropoietin (rHuEPO) is now widely used in cancer patients, as it improves hematocrit, lowers blood transfusion requirements, and improves quality of life. Recent research indicates that EPO has pleiotropic effects on the body well beyond the maintenance of red cell mass, but the mechanisms involved in relieving fatigue and improving quality of life in cancer patients are poorly understood. EPO receptors (EPO-Rs) have been detected in many different cells and tissues, providing evidence for autocrine, paracrine, and endocrine functions of EPO. Apart from its endocrine function, EPO may have a generalized role as an antiapoptotic agent that is associated with enhancement of muscle tone, mucosal status, and gonadal and cognitive function. The recent discovery of EPO-Rs in breast tumor vasculature, while raising important questions about the possible effects of pharmacological doses of rHuEPO on tumor cells, also suggests that the receptors could provide a useful target for drugs attached to EPO.

Topics: Anemia; Endocrine System; Erythropoietin; Humans; Neoplasms; Recombinant Proteins

As the antitumor activity of radiation is mediated via its interaction with oxygen to form labile free radicals, the intratumoral oxygen level has an important influence on the ability of radiation therapy to kill malignant cells. By decreasing the oxygen-carrying capacity of the blood, anemia may result in tumor hypoxia and may have a negative influence on the outcome of radiotherapy for various malignancies, even for small tumors not normally assumed to be hypoxic. In addition, anemia also has a negative effect on the quality of life of cancer patients, as evidenced by worsening fatigue. As a high proportion (about 50%) of cancer patients undergoing radiotherapy are anemic prior to or during treatment, strategies to correct anemia and/or the resultant tumor hypoxia are increasingly being considered an important component of treatment. In particular, epoetin alfa (recombinant human erythropoietin), which has proved an effective and well-tolerated means of raising hemoglobin levels in anemic patients receiving radiotherapy, potentially could reverse the negative prognostic influence of a low hemoglobin in patients with certain malignancies. Radiation oncologists need to be aware of the possibility of anemia in cancer patients undergoing radiotherapy so that timely intervention can be instituted whenever anemia is diagnosed.

Topics: Anemia; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Neoplasms; Peripheral Nervous System Diseases; Predictive Value of Tests; Prevalence; Prognosis; Quality of Life; Radiotherapy; Recombinant Proteins; Survival Analysis; Treatment Outcome

Although the association between low hemoglobin levels and poorer outcomes in radiation oncology has long been recognized, anemia is often overlooked and untreated. However, a growing body of clinical evidence now indicates that low hemoglobin levels during radiation treatment are associated with decreased response and survival following radiotherapy. For example, a large Canadian retrospective study in patients receiving radical radiotherapy for cervical cancer showed that the 5-year survival rate was 19% higher in those whose hemoglobin during radiation treatment was =12 g/dl compared to those with levels <12 g/dl. The data suggest that clinical trials need to be performed to determine whether increasing hemoglobin levels leads to improved local control and survival. The mechanism by which low hemoglobin levels could cause poorer outcomes is not well understood and needs further elucidation. It is postulated that lower hemoglobin levels resulting in decreased oxygen carrying capacity may lead to increased tumor hypoxia, radiation resistance and increased tumor angiogenesis. The interrelationship of low hemoglobin levels, hypoxia, tumor angiogenesis and survival is explored in this article.

Topics: Anemia; Cell Hypoxia; Chemotherapy, Adjuvant; Epoetin Alfa; Erythropoietin; Female; Head and Neck Neoplasms; Hematinics; Hemoglobins; Humans; Neoplasms; Neovascularization, Pathologic; Radiotherapy, Adjuvant; Recombinant Proteins; Survival Analysis; Survival Rate; Uterine Cervical Neoplasms

Topics: Anemia; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Erythropoietin; Forecasting; Humans; Lung Neoplasms; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Recombinant Proteins

Growth is a fundamental process of mammalian development. Several observations regarding regulation of erythropoiesis during growth are not easily explained by the hypoxia-erythropoietin (Epo) concept. This review focuses primarily on this aspect of the physiology of Epo. The question is raised of whether this regulation during growth is based on the hypoxia-Epo mechanism alone, or whether Epo acts in concert with general growth-promoting factors, particularly growth hormone (GH) and the insulin-like growth factors (IGF-I and -II). Supporting the latter hypothesis is the observation that the Epo and GH/IGF systems are activated by hypoxia and share similar receptors and pathways. Recent studies indicate that human fetal and infant growth is stimulated by GH, IGF-I and IGF-II. Epo, GH and IGFs are expressed early in fetal life. Although the rate of erythropoiesis in the fetus is high, serum Epo levels are low. The Epo response to hypoxia in the fetus and neonate is reduced compared with adults. Following delivery the Epo levels vary between species, probably related to the oxygen transport capacity of the hemoglobin (Hb) mass. IGF-I levels are low in the fetus and increase slowly following birth, except in preterm infants in whom the levels decline. In all mammals Hb declines following birth, giving rise to "early anemia". Except in the human, Epo levels increase proportionally with the fall in Hb, but there is a discrepancy between the curves for serum immunoreactive Epo (siEpo) and for erythropoiesis stimulating factors (ESF): the latter include other stimulatory factors in addition to Epo. Hypertransfusion of mice in the period of "early anemia" suppresses siEpo, but not ESF and erythropoiesis, as it does in adult mice. GH and IGF-I have direct effects on erythropoiesis in vitro and act particularly at the later stages of red cell differentiation. IGF-I acts synergistically with Epo, and its effects are most marked when Epo levels are low. Human recombinant (rhu) IGF-I stimulates erythropoiesis in neonatal rats, but not in newborn mice and lambs. In adult mice, in hypophysectomized rats and in mice with end-stage renal failure, however, a stimulatory effect of this growth factor was found on red cell production. RhuGH stimulates erythropoiesis in GH-deficient short children.. Fetal and early postnatal erythropoiesis are dependent on factors in addition to Epo. The likely candidates are GH and IGF-I. The in vitro stimulating effects of these factors on erythropoiesis are convincing, but more data are needed on the in vivo effects.

Topics: Anemia; Animals; Blood Physiological Phenomena; Embryonic and Fetal Development; Erythropoiesis; Erythropoietin; Female; Humans; Mice; Pregnancy; Pregnancy, Animal; Rats; Sensitivity and Specificity; Sheep; Species Specificity; Swine

Cancer patients frequently experience anemia as a complication of chemotherapy. Recent advances in assessing the relationships between anemia, fatigue and quality of life (QOL) in such patients have resulted in a new multidimensional perspective of these parameters. Clinical data suggest that even a mild-to-moderate chemotherapy-induced anemia results in a significant reduction in a patient's energy level and QOL. As recombinant human erythropoetin has recently become available for the treatment of this condition, we performed a review of the incidence and severity of anemia associated with commonly employed chemotherapy regimens in the major non-hematologic malignancies. Although evident flaws in the grading and reporting of treatment-related anemia have limited analysis, the results clearly indicate a relatively high incidence of mild-to-moderate anemia. Research in progress is likely to result in a new classification of chemotherapy-induced anemia that can guide therapeutic interventions on the basis of outcomes and hemoglobin levels. The once widespread belief that lesser degrees of anemia must be endured without treatment may be overcome as greater emphasis is placed on the QOL of the oncology patient. Further insights into the relationships between hemoglobin levels, patient well-being and symptoms may lead to a refinement of current strategies of approaching the treatment of anemia.

Topics: Anemia; Antineoplastic Agents; Erythropoietin; Humans; Incidence; Neoplasms; Recombinant Proteins; Severity of Illness Index

Topics: Anemia; Erythropoietin; Humans; Janus Kinase 2; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Receptors, Erythropoietin; Signal Transduction

Most of cancer patients experience anemia. It's a main cause of fatigue and it leads to a decrease of the quality of life. It may have an impact on prognostic too, mainly when radiotherapy is concerned. Apart from etiologic treatments, anemia can be treated with transfusion and/or erythropoietin. Their respective pros and cons are discussed. There are few guidelines available on this topic and an algorithm of decision is proposed.

Topics: Anemia; Blood Transfusion; Erythrocyte Transfusion; Erythropoietin; Fatigue; Humans; Practice Guidelines as Topic; Quality of Life

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

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

Although anemia is apparently tolerated in most patients, particularly those who are relatively healthy, the ICU population must be thought of differently. Anemia in the ICU may be due to acute blood loss, phlebotomy, or to the presence of inflammatory disease. The anemia in critically ill patients resembles anemia of chronic disease, which is believed to result from a poor endogenous erythropoietin response or erythropoietin deficiency. The risks of blood transfusions are many and ICU patients may not tolerate infusions of older, stored blood. Nonetheless, hemoglobin levels at or above 100 g/L may be important for oxygen delivery to vital organs, especially in critically ill patients with increased oxygen demands. The appropriate transfusion trigger for critically ill patients in this setting remains unknown. Blood transfusions in the ICU may not improve outcomes, and numerous studies have been published to suggest the contrary, that transfusions may actually worsen patients' outcomes in certain ICU settings. Recombinant human erythropoietin (rHuEPO, epoetin alfa) has been shown to reduce transfusion needs and increase hemoglobin levels in multiple settings and now, it appears to also do so in the ICU.

Topics: Anemia; Critical Care; Critical Illness; Erythropoietin; Humans; Risk; Transfusion Reaction

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

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

Topics: Anemia; Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans

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

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

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

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

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

Anemia in cancer patients is frequent but often under-recognized and under-treated. This may be related to misconceptions about the impact of anemia on cancer patients and ill-defined guidelines for treatment, as well as the inadequacies of current therapy. Darbepoetin alfa, a novel erythropoiesis-stimulating protein with a longer serum half-life than epoetin (alpha and beta), is approved to treat anemia in patients with chronic kidney disease. Most recently darbepoetin alfa has received approval by the FDA in USA for the treatment of anemia associated with myelosuppressive chemotherapy and approval in the EU is expected soon. Clinical trials in cancer patients indicate that darbepoetin alfa effectively and safely alleviates anemia in patients receiving chemotherapy. A Phase II trial also indicates that darbepoetin alfa is effective in patients who are not receiving chemotherapy. Thus, darbepoetin alfa has the potential to improve supportive care and thereby, cancer patients' quality of life, and might also impact on treatment outcome.

Topics: Anemia; Antineoplastic Agents; Darbepoetin alfa; Drug Interactions; Erythropoietin; Humans; Neoplasms; Quality of Life

In this review the authors present data on biological and medical properties and high therapeutic efficacy of recently produced recombinant drugs of alfa and beta erythropoietin in the treatment of erythropoietin-deficient anaemia in patients with malignancies, diabetes mellitus, and nephropathies of other genesis. The article contains materials of international congresses held in 2001 addressing the above issues besides the newest publications.

Topics: Anemia; Clinical Trials as Topic; Erythropoietin; Humans; Recombinant Proteins; Treatment Outcome

Erythropoietin (EPO) is a 165 amino-acid sequence glycoprotein which plays an important role in maintaining regular generation of erythrocytes, Jacobs et al. describe the cloning of the human EPO and recombinant EPO has been introduced for the treatment of anemia in patients with renal diseases. The extensive utilization of EPO can induce the production of neutralizing EPO antibodies, which have been proved in patients with the non-infectious form of pure red cell aplasia (NI-PRCA), an autoimmune disease characterized by a sudden inhibition of erythrocyte maturation and production. In this review, the literature concerning the molecular structure and the genetic profile of EPO as well as the relationship between neutralizing EPO antibodies and NI-PRCA have been analyzed.

Topics: Anemia; Animals; Autoantibodies; Autoimmune Diseases; Epitopes; Erythropoietin; Glycosylation; Growth Substances; Humans; Isoantibodies; Protein Conformation; Protein Processing, Post-Translational; Rabbits; Recombinant Proteins; Red-Cell Aplasia, Pure

Anemia is a frequent clinical feature with adverse prognostic effects in patients with chronic lymphocytic leukemia (CLL). It may complicate CLL at any time during the course of the disease. Different factors concur to the occurrence of anemia in CLL, as in other lymphoproliferative diseases: leukemic bone marrow infiltration, the myelosuppressive effect of chemotherapy and inhibiting cytokines, autoimmune phenomena, hypersplenism, a poor nutritional status that leads to folic acid, vitamin B12 and iron deficiency. In addition, a defective endogenous erythropoietin (EPO) production has also been described in patients with lymphoproliferative diseases. The severity of anemia, which may be worsened by an impaired cardiopulmonary function, may profoundly compromise the patients' quality of life and, indirectly, the outcome of cancer bearing patients. Several Authors have reported the clinical activity of recombinant human (rHu)EPO in anemic patients with lymphoproliferative diseases, including CLL. Low serum EPO levels at baseline and EPO levels inappropriately low for the degree of anemia help to identify patients who are likely to respond to EPO. A clear dose-dependent response to EPO has been reported by different Authors and it has been suggested that 5,000 IU should be considered as an appropriate initial dose for the majority of patients. rHuEPO represents a potentially effective and safe therapy for the management of anemia associated with lymphoproliferative diseases. The reduction of red blood cell transfusion requirement, the improvement of quality of life through the remission of fatigue-related anemia are two important results that should be considered in the management of patients with CLL. In prospect, the availability of new rHuEPO molecules with a more prolonged half-life may open new therapeutic avenues.

Topics: Anemia; Anemia, Hemolytic, Autoimmune; Antineoplastic Agents; Bone Marrow; Cytokines; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hypersplenism; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoproliferative Disorders; Multicenter Studies as Topic; Nutrition Disorders; Radiotherapy; Randomized Controlled Trials as Topic; Recombinant Proteins; Red-Cell Aplasia, Pure; Treatment Outcome

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

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

Chronic anemia of variable severity occurs in more than two-thirds of patients with multiple myeloma (MM) as a consequence of the B cell malignancy. Its pathogenesis is multifactorial. Besides the altered inflammatory cytokine network, other events are held responsible, namely persistent defect of erythropoietin due to the kidney failure, shortening of red cell survival, accumulation of the serum monoclonal component and platelet dysfunction. Our recent studies have demonstrated that excessive erythroblast apoptosis promoted by myeloma cells drives the appearance of anemia, in particular in patients with severely progressive disease. A number of clinical trials have provided evidence for the effectiveness of recombinant human erythropoietin (rHuEPO-alpha: epoetin alpha) in improving the deregulated erythropoiesis in MM, since it acts as a major erythroid growth factor by exerting a specific anti-apoptotic effect. In the majority of these studies, the long-term treatment of MM-associated anemia with rHuEPO-alpha induced a significant improvement of erythropoiesis, as shown by a stable increase of hemoglobin values (> or = 2g/dL) and reduction of transfusion requirements. In a recent trial which included both a double-blind and an open-label phase, we have documented that rHuEPO-alpha induces a stable improvement of anemia in more than 75% of patients and a significant decrease of fatigue, with an overall recovery of the quality of life. Patients receiving a placebo also achieved similar results in the open-label phase, when they were switched to rHuEPO-alpha.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blood Transfusion; Cell Differentiation; Chronic Disease; Clinical Trials as Topic; Cytokines; Epoetin Alfa; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Humans; Multiple Myeloma; Quality of Life; Recombinant Proteins; Treatment Outcome

Anemia of variable severity occurs in more than two-thirds of patients with multiple myeloma (MM). Besides the altered cytokine network, chronic erythropoietn deficiency, blood loss and hemolysis, we have shown that deregulated myeloma cell apoptosis contributes to progressive destruction of the erythroid matrix by inducing erythroblast cytotoxicity. To exert this effect, highly malignant plasma cells overexpress both Fas-L and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which efficiently trigger the death of immature erythroblasts. However, this Fas-L/TRAIL-based anemia occurs in particular in patients with severely progressive MM, thus suggesting that these apoptogen receptors may characterize a peculiar cytotoxic-apoptogenic phenotype of malignancy. Immunophenotyping of myeloma cells could help to identify patients with a higher risk of erythropoiesis exhaustion.

Topics: Anemia; Apoptosis; Apoptosis Regulatory Proteins; Bone Marrow; Cell Communication; Cell Differentiation; Coculture Techniques; Cytokines; Disease Progression; Drug Resistance; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Fas Ligand Protein; Humans; Membrane Glycoproteins; Multiple Myeloma; Plasma Cells; Recombinant Proteins; TNF-Related Apoptosis-Inducing Ligand; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Erythropoetin therapy has been approved for treatment of medical anemia since 1989. The adoption of this strategy has been rapid in some settings (e.g., renal failure patients) and progressive in others (e.g., cancer patients). Although the risks of blood transfusion have declined substantially, risks associated with (untreated) anemia have undergone new scrutiny. Options such as novel erythropoiesis-stimulating protein bring new alternatives to blood transfusion. Erythropoietin therapy is undergoing renewed scrutiny in the management of anemia, not only because of traditional concerns regarding blood risks but because emerging evidence suggests that improved patient outcomes result from management of anemia.

Topics: Anemia; Chronic Disease; Erythrocytes; Erythropoietin; Growth Substances; Humans

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

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

Anaemia occurs in a significant number of patients with cancer, and is associated with symptoms of fatigue, dizziness, headache and decreased health-related quality of life. Clinical trials have demonstrated the ability of epoetin alfa to increase haemoglobin concentrations and reduce transfusion requirements in patients with cancer. Data from three large, open-label, community-based trials of >7000 patients, as well as a series of smaller, randomized, placebo-controlled studies, have confirmed the efficacy of treatment with epoetin alfa in patients undergoing chemotherapy. In two of the community-based studies (>2000 patients in each), patients undergoing chemotherapy received epoetin alfa, 150-300 IU/kg or 10,000-20,000 IU, three times weekly. Significant (P<0.01) increases in haemoglobin concentrations and reductions in transfusion rates were seen in both studies. Significant improvements in quality of life were also reported, as measured by the Linear Analogue Scale Assessment and the Functional Assessment of Cancer Therapy-Anaemia. Importantly, the increases in quality of life were independent of tumour response. These findings were also observed in randomized, placebo-controlled studies. The third study, in approximately 3000 patients, evaluated the efficacy of once-weekly dosing, which significantly (P<0.01) increased haemoglobin concentrations, reduced transfusion requirements and improved quality of life. Greater increases in haemoglobin concentration were associated with greater improvements in quality-of-life scores. The safety and efficacy profile of the once-weekly regimen was comparable with that of the three times weekly regimen. Maintaining optimal quality of life, while achieving tumour stabilization or regression, is essential to the successful management of patients with cancer. Epoetin alfa has been shown to increase haemoglobin concentration, decrease transfusion requirements and increase quality of life. Given the frequency of adverse sequelae associated with anaemia, its aggressive management should become an integral and routine part of cancer treatment.

Topics: Anemia; Epoetin Alfa; Erythropoietin; Humans; Neoplasms; Quality of Life; Recombinant Proteins

In order to be transmitted by their mosquito vector, malaria parasites undergo sexual reproduction, which occurs between specialized male and female parasites (gametes) within the blood meal in the mosquito. Nothing was known about how Plasmodium determines the sex of its gametocytes (gamete precursors), which are produced in the vertebrate host. Recently, erythropoietin, the vertebrate hormone controlling erythropoiesis in response to anaemia, was implicated in Plasmodium sex determination in animal models of malaria. This review examines the available information and addresses the relevance of such a sex determining mechanism for Plasmodium falciparum transmission to mosquitoes, with special reference to low gametocytaemias.

Topics: Anemia; Animals; Chronic Disease; Culicidae; Environment; Erythropoietin; Female; Germ Cells; Humans; Malaria; Male; Plasmodium; Plasmodium falciparum; Sex Determination Processes; Sex Ratio

There are many causes for carnitine depletion during maintenance hemodialysis. Supplementation with L-carnitine in animals has been associated with improvement in some abnormalities also present in chronic renal failure. However, it is still controversial whether restoring plasma or tissue carnitine will correct clinical or biologic symptoms observed in maintenance hemodialysis. A systematic review is here performed to determine the effects of L-carnitine in maintenance hemodialysis patients. Eighty-three prospective trials were identified from 1978 to 1999 in which L-carnitine was randomly allocated in 21 trials. Change in serum triglycerides, cholesterol fractions, hemoglobin levels, erythropoietin dose, and other symptoms (muscle function, exercise capacity, and quality of life) were examined. A total of 482 patients in 18 trials were considered for analysis. There was no effect of L-carnitine on triglycerides, total cholesterol, or any of its fractions. Before the erythropoietin (EPO) era, L-carnitine treatment was associated with improved hemoglobin (P < 0.01) and with a decreased EPO dose (P < 0.01) and improved resistance to EPO when patients routinely received EPO. Muscle function, exercise capacity, and quality of life could not be reliably assessed because of the noncombinable nature of end points and the limited number of trials. In conclusion, L-carnitine cannot be recommended for treating the dyslipidemia of maintenance hemodialysis patients. By contrast, this review suggests a promising effect of L-carnitine on anemia management. The route of L-carnitine administration should be evaluated because there is no evidence as to the most efficient method of administration in maintenance hemodialysis.

Topics: Anemia; Carnitine; Erythropoietin; Humans; Lipids; Randomized Controlled Trials as Topic; Renal Dialysis

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

Over the past decade an increasing number of studies have supported the use of recombinant human erythropoietin (epoetin) in cancer patients, suggesting that it improves haemoglobin concentrations for some. There is also evidence that this treatment may lead to improvement in quality of life for cancer patients. This systematic review examines the issue. We identified and critically reviewed 13 trials. Although some of the results indicate that epoetin has positive effects on quality of life, methodological limitations inherent in most of the studies hamper interpretation of data. Evidence from this review suggests that more robust designs are required to show any significant quality-of-life benefits for cancer patients undergoing epoetin treatment.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Controlled Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Epoetin Alfa; Erythropoietin; Female; Hematinics; Humans; Injections, Subcutaneous; Male; Neoplasms; Quality of Life; Recombinant Proteins; Sensitivity and Specificity

Anemia is a common disorder in patients with cancer and can be caused by the disease itself or by cancer-related therapy. The cardinal symptom of anemia, fatigue, is the most commonly reported symptom in patients with cancer and has profound effects on patient well-being and quality of life. Until recently, blood transfusions were the mainstay of management of cancer-related anemia, despite attendant risks of transfusion-related reactions and transmission of infection. Recombinant human erythropoietin (epoetin-alpha), an effective alternative to blood transfusion, has been shown to improve hematologic parameters, including hemoglobin levels, Hematocrit, and transfusion requirements. Clinical trials have also suggested that this intervention has a positive impact on the quality of life of patients with cancer. The literature published between November 2000 and October 2001 continues to support a positive effect of epoetin-alpha therapy on the quality of life of patients with cancer and includes investigations of dosing schedules more convenient for patients and trials of longer-acting versions of epoetin-alpha, such as the novel erythropoiesis-stimulating protein. Future studies that incorporate measures of patient-reported outcomes and rigorous methodologic designs are needed to strengthen and elucidate this association between these pharmacologic therapies for cancer-related anemia and quality of life.

Topics: Anemia; Erythropoietin; Humans; Neoplasms; Quality of Life

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

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

Topics: Anemia; Blood Transfusion; Blood Transfusion, Autologous; Critical Care; Erythropoietin; Hemodilution; Humans; Infections; Transfusion Reaction

Anemia is the most commonly encountered hematologic abnormality in human immunodeficiency virus (HIV)-positive patients, occurring with increasing frequency as the disease progresses. Several factors play a role in the development of anemia in patients with HIV, including chronic disease, opportunistic infections, and certain nutritional deficiencies. Despite the high prevalence of anemia in this population, the symptoms of anemia are frequently overlooked, although anemia can significantly affect a patient's ability to carry on even normal activities of daily living. Therefore, approaches--including the treatment of causative infections, discontinuation of certain drugs, or use of recombinant human erythropoietin (epoetin alfa)--aimed at increasing hemoglobin levels to normal or near-normal levels would be expected to improve quality of life (QOL). The purpose of this article is to describe the effects of anemia on QOL and to provide an overview of several studies showing that QOL improves with the alleviation of anemia.

Topics: Anemia; Antiretroviral Therapy, Highly Active; Clinical Trials as Topic; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; HIV Infections; Humans; Quality of Life; Recombinant Proteins

Three large observational cohort studies suggest that, after controlling for virus load and CD4 cell count, anemia is related to disease progression and survival in patients with human immunodeficiency virus (HIV) infection. Recovery from anemia has been linked to improved survival outcomes. Blood transfusion has been associated with accelerated disease progression and mortality in patients with HIV infection, and review of related literature suggests that the mechanism for negative transfusion-associated outcomes may be transfusion-related immunosuppression. Therefore, the use of transfusion should be restricted to patients with acute or severe anemia. Prescription of epoetin alfa has been associated with increased survival in an observational cohort among patients with HIV infection and anemia. In the absence of data from a clinical trial documenting the effect of treating anemia on survival, clinicians should consider non-transfusion options for management of anemia on the basis of clinical status and patient functional ability.

Topics: Anemia; Blood Transfusion; Disease Progression; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; HIV Infections; Humans; Quality of Life; Recombinant Proteins; Survival Analysis

To review the literature concerning the role of recombinant human erythropoietin (rHuEPO) in reducing the need for transfusion in critically ill patients.. Articles were obtained through searches of the MEDLINE database (from 1990 to June 2001) using the key words erythropoietin, epoetin alfa, anemia, reticulocytes, hemoglobin, critical care, intensive care, critical illness, and blood transfusion. Additional references were found in the bibliographies of the articles cited. The Cochrane library was also consulted.. Controlled, prospective, and randomized studies on the use of rHuEPO in critically ill adults were selected.. Anemia is a common complication in patients requiring intensive care. It is caused, in part, by abnormally low concentrations of endogenous erythropoietin and is mainly seen in patients with sepsis and multiple organ dysfunction syndrome, in whom inflammation mediator concentrations are often elevated. High doses of rHuEPO produce a rapid response in these patients, despite elevated cytokine concentrations. There have been 3 studies on rHuEPO administration in intensive care and 1 trial in acutely burned patients. Only 2 of these studies looked at the impact of rHuEPO administration on the need for transfusion.. Few randomized, controlled trials explore the role of rHuEPO in critical care. Only 1 was a large, randomized clinical trial, but it presents many limitations. Future outcome and safety studies comparing rHuEPO with placebo must include clinical endpoints such as end-organ morbidity, mortality, transfusion criteria, and pharmacoeconomic analysis. rHuEPO appears to provide an erythropoietic response. Optimal dosage and the real impact of rHuEPO on the need for transfusion in intensive care remain to be determined. Currently, based on the evidence available from the literature, rHuEPO cannot be recommended to reduce the need for red blood cell transfusions in anemic, critically ill patients.

Topics: Anemia; Blood Transfusion; Critical Care; Critical Illness; Erythropoietin; Humans; Randomized Controlled Trials as Topic; Recombinant Proteins

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

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

Ovarian cancer is one of the most aggressive gynecologic cancers. It shows its symptoms late and is consequently often diagnosed at an advanced stage. The search for a more effective chemotherapy regimen, therefore, is of great importance. Since 1996, the combination of cisplatin and paclitaxel has been proven to prolong survival in comparison with older regimens containing cisplatin and cyclophosphamide. In addition, the introduction of carboplatin in combination with paclitaxel showed similar efficacy but preferable toxicity profiles when compared with cisplatin in combination with paclitaxel. Representative studies evaluating paclitaxel combination therapies as well as new trends in the treatment of ovarian cancer are summarized in this article.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Erythropoietin; Female; Hematinics; Humans; Ovarian Neoplasms; Paclitaxel; Recombinant Proteins

Anemia is a frequent complication of cancer and its treatment. It often impairs the functional status of patients and results in decreased functional capacity and quality of life. Its etiologies are multiple, including chronic inflammation, hemorrhage, nutritional deficiencies, hemolysis, bone marrow suppression by chemotherapy, or infiltration by tumor. It can manifest as feelings of weariness, tiredness, muscular weakness, dysphoric mood, somnolence, or impaired cognitive functioning. In gynecologic patients, the incidence of anemia has been reported to be as high as 80% depending on chemotherapy regimen. Given the various consequences of a low hemoglobin level, the importance of increasing or maintaining hemoglobin levels and ameliorating the symptoms is apparent. Clinical studies have demonstrated that the administration of recombinant human erythropoietin (rHuEPO, epoetin alfa) is effective and safe in increasing hemoglobin levels and improving the overall quality of life in patients with gynecologic cancers undergoing chemotherapy. Therefore, epoetin alfa treatment should be considered in this patient population.

Topics: Anemia; Antineoplastic Agents; Epoetin Alfa; Erythropoietin; Female; Genital Neoplasms, Female; Hematinics; Hemoglobins; Humans; Quality of Life; Recombinant Proteins

A Consensus Conference on the use of recombinant human erythropoietin (rHuEPO, epoetin alfa) in gynecologic tumors was held in Rome in March 1999, and an associated consensus paper has been published in Italian. The current paper updates several discussions that took place at the 1999 meeting concerning epoetin alfa treatment in breast, ovarian, and cervical cancers; the role of epoetin alfa in mobilizing progenitor hematopoietic cells; administration of epoetin alfa in combination with granulocyte colony-stimulating factor; and the effect of hemoglobin levels on outcome of radiation or chemoradiation treatment.

Topics: Anemia; Antineoplastic Agents; Blood Transfusion; Breast Neoplasms; Epoetin Alfa; Erythropoietin; Female; Genital Neoplasms, Female; Granulocyte Colony-Stimulating Factor; Hematinics; Hematopoietic Stem Cell Mobilization; Hemoglobins; Humans; Ovarian Neoplasms; Quality of Life; Radiotherapy, Adjuvant; Recombinant Proteins; Uterine Cervical Neoplasms

Breast cancer patients undergoing therapeutic regimens of high-dose chemotherapy (HDCT) with circulating progenitor cell support often develop anemia. As a general consideration in the transplantation setting, red blood cell transfusions are normally required in patients who have passed the myeloablative phase after HDCT. In the initial 30-day period immediately following HDCT, the number of red blood cell units that are transfused will usually depend on a number of factors, including whether the transplantation was allogeneic or autologous. Observations and results from clinical studies have shown that the establishment of normal erythropoiesis varies depending on the source of the transplanted cells, resulting in different transfusion requirements. Several studies support the use of recombinant human erythropoietin (rHuEPO, epoetin alfa) after HDCT to ameliorate anemia and reduce transfusion requirements. Studies have also shown that administration of epoetin alfa prior to the myeloablative phase is an effective method for reducing red blood cell transfusion requirements in breast cancer patients receiving HDCT. Epoetin alfa in combination with other cytokines has been shown to positively affect the mobilization phase of hematopoietic progenitor cells for autografting. Furthermore, treatment with epoetin alfa could prove useful in bone marrow transplant recipients who experience delayed anemia. Recent studies that have addressed these topics in breast cancer indicate that, when used in the appropriate setting, epoetin alfa may play a role as a tool to decrease the need for red blood cell transfusion in patients undergoing HDCT plus autologous circulating progenitor cell support.

Topics: Anemia; Antineoplastic Combined Chemotherapy Protocols; Blood Transfusion; Bone Marrow Transplantation; Breast Neoplasms; Epoetin Alfa; Erythropoietin; Hematinics; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Humans; Recombinant Proteins

During the past 40 years substantial progress has been made in the treatment of hematologic malignancies, particularly in some subgroups of patients. Today, cure is attainable for patients with Hodgkin's disease and a considerable proportion of patients with high-grade non-Hodgkin's lymphoma. Prognosis is improving in patients with acute promyelocytic leukemia and, to some extent, those with acute lymphoblastic and myeloid leukemias. However, the majority of patients who suffer from a hematologic malignancy live with incurable disease. In CLL, outside the setting of a clinical trial, it is advisable to postpone treatment until the manifestation of clinical symptoms. It is yet to be determined whether treatment strategies based on new prognostic parameters such as cytogenetics can change the course of disease. In indolent lymphomas, cure is not attainable for the vast majority of patients; the median survival of 9 to 10 years has remained unchanged for several decades. Nevertheless, there has been a dramatic change in therapeutic paradigms in the past few years. For the first time, with the use of new cytostatic drugs and recombinant monoclonal antibodies, it is possible to achieve molecular remissions. Whether this will translate into cure or prolonged survival is still to be determined. In Hodgkin's disease, which is curable when treated with radiotherapy, chemotherapy, or combined therapy, depending on the stage of disease, the focus of future studies must be on prevention of early relapse and on primary resistant disease, both of which present a very poor prognosis. Finally, regardless of underlying malignancy and prognosis, the preservation of quality of life is of major consideration in the setting of hematologic malignancies.

Topics: Anemia; Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Epoetin Alfa; Erythropoietin; Hematinics; Hodgkin Disease; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Follicular; Prognosis; Quality of Life; Recombinant Proteins; Vidarabine

Anemia is a common complication in patients with hematologic malignancies, and is caused by a variety of mechanisms, including neoplastic cell infiltration into the bone marrow, hemolysis, nutritional deficiencies, and defects in erythropoiesis as a result of the disease itself or cytotoxic therapy. The anemia associated with multiple myeloma is caused by inadequate erythropoietin levels consequent to renal impairment and the effect of inflammatory cytokines. The degree of anemia can have prognostic importance, as is the case with multiple myeloma, or be a significant indicator of disease stage, as noted with chronic lymphocytic leukemia. Anemia results in fatigue, exhaustion, dizziness, headache, dyspnea, and decreased motivation, seriously affecting a patient's quality of life. Since anemia is so prevalent in hematologic malignancy patients, its treatment must be an integral part of disease management, to improve quality of life and to possibly increase potential survival. Clinical studies have shown that effectively treating anemia and increasing hemoglobin levels using recombinant human erythropoietin (rHuEPO, epoetin alfa) has a significant effect on transfusion requirements and quality of life.

Topics: Anemia; Epoetin Alfa; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Multiple Myeloma; Myelodysplastic Syndromes; Prognosis; Quality of Life; Recombinant Proteins; Survival Rate

Anemia is a common complication in patients with hematologic malignancies, with incidence rates ranging up to 63%. In myelodysplastic syndromes, anemia is an essential feature of the disease. The decrease in hemoglobin may lead to several symptoms such as fatigue, exhaustion, and impaired quality of life, and it may worsen prognosis. Before the introduction of recombinant human erythropoietin (rHuEPO, epoetin alfa), red blood cell transfusions were the traditional treatment for improvement of Hb levels. Transfusions, however, are associated with several adverse events and risks, have only transient effects, and have a limited capacity to ameliorate the symptoms of anemia. Epoetin alfa represents a physiologic treatment option, especially in the long-term treatment of cancer- and cancer treatment-associated anemia, and is well tolerated, with response rates as high as 80%. Epoetin alfa is less effective in the treatment of the anemia of myelodysplastic syndrome, but appears to be synergistic with granulocyte-colony stimulating factor. However, not every patient responds to epoetin alfa; to avoid unnecessary interventions and costs, predictors of response have been proposed. This article outlines the advantages and disadvantages of the two major treatment forms of anemia: transfusions and epoetin alfa. Representative studies on the efficacy of epoetin alfa in anemic patients with hematologic malignancies as well as models to predict response to epoetin alfa treatment are summarized.

Topics: Anemia; Blood Transfusion; Epoetin Alfa; Erythropoietin; Hematinics; Hematologic Neoplasms; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Multiple Myeloma; Myelodysplastic Syndromes; Prevalence; Recombinant Proteins

Epoetin alfa has been in use for over a decade to increase hemoglobin in patients with cancer who develop chemotherapy-associated anemia. Early placebo-controlled, randomized studies, as well as recent large, community-based trials in thousands of patients, have consistently shown recombinant human erythropoietin (rHuEPO, epoetin alfa) to be effective and safe in the treatment of chemotherapy-associated anemia. Patients experienced an improved quality of life (QOL) related to the magnitude of the hemoglobin increase. As measured by a Linear Analog Scale Assessment, mean energy level, ability to do daily activities, and overall QOL improved significantly in patients who received epoetin alfa. The improvement in QOL was similar when anemia-specific instruments (Functional Assessment of Cancer Therapy-Anemia) were used. A large community-based trial has demonstrated that the more convenient once-weekly dosing schedule resulted in good efficacy and safety profiles. A recent double-blind placebo-controlled study that compared the efficacy of epoetin alfa versus placebo in patients receiving nonplatinum-based chemotherapy has confirmed epoetin alfa's efficacy, safety, and beneficial QOL effects. These findings should challenge current anemia management practices and encourage aggressive treatment of anemia in cancer patients receiving chemotherapy.

Topics: Aged; Anemia; Antineoplastic Agents; Clinical Trials as Topic; Epoetin Alfa; Erythropoietin; Female; Hematinics; Hemoglobins; Humans; Male; Middle Aged; Neoplasms; Quality of Life; Recombinant Proteins

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

The myelodysplastic syndromes (MDS) are clonal hematological disorders characterized by ineffective hematopoiesis manifested by anemia, neutropenia, thrombocytopenia or a combination. Correction of these cytopenia is a priority in MDS without excess of blasts. Treatment of anemia depends mainly on erythrocyte transfusions. However with the ability of recombinant human hematopoietic growth factor many trials have been promoted. In vitro, erythroid progenitors from MDS patients are able to differentiate but they require much higher concentrations of erythropoietin than normal progenitors. Trials using rHu-Epo alone are disappointing. Combining rHu-Epo and rHu-G-CSF induces more encouraging results showing a synergistic effect particularly clear in sideroblastic anemia. Patients with low endogenous Epo level and low transfusion need are more likely to respond. Clinician should be able in the future to identify MDS patients with a chance of reversal of anemia or transfusion dependency.

Topics: Anemia; Erythropoietin; Growth Hormone; Growth Substances; Humans; Myelodysplastic Syndromes; Recombinant Proteins

Topics: Anemia; Child; Erythropoietin; Humans; Kidney; Nephrotic Syndrome

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

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

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

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

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

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

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

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

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

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

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

The prospect of a shortage of blood for transfusions, increasing awareness of the adverse effects of transfusions, and the availability of human recombinant erythropoietin (rHuEPO) have stimulated interest in the pathogenesis of the anaemia of intensive care unit (ICU) patients. As in the anaemia of chronic illness or chronic renal failure (CRF), the anaemia of ICU patients is a multifactorial process. Blood loss, inappropriately low erythropoietin production, reduced red cell lifespan, reduced iron availability, and inhibition of erythropoiesis by cytokines all contribute to the anaemia of critical illness, although the contributions of the various elements differ depending on the disease aetiology. Evidence is accumulating that use of rHuEPO can induce stimulation of erythropoiesis in critical illness, but at doses that are usually several-fold higher than those used to define resistance to rHuEPO in the current guidelines for the management of anaemia in CRF. Available data suggest that these high doses are well tolerated, at least in the short term. These observations, as well as demonstrating the potential benefits of rHuEPO therapy in critically ill patients, have practical implications for non-ICU patients with CRF who do not respond sufficiently to the usual doses of rHuEPO. Although the risk-benefit ratio relationship for very high doses of rHuEPO needs further consideration, demonstration of rHuEPO efficacy in critical illness should result in a re-evaluation of the 'dose-response relationship' for rHuEPO in patients with less acute and severe illness, including CRF patients hyporesponsive to current dosing regimens.

Topics: Anemia; Critical Care; Critical Illness; Drug Resistance; Erythropoietin; Humans; Recombinant Proteins

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

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

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

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

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

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

Anaemia is common in patients with haematological malignancy, occurring in the majority of patients with malignant disease who are treated with chemotherapy. Most patients will have their anaemia attributed to the cytokine-mediated anaemia of chronic disease. Many of these patients with anaemia will be symptomatic with fatigue, which is the single most important symptom reported. Data from many studies indicate that treatment of patients with anaemia with recombinant human erythropoietin (rHuEpo) will increase their haemoglobin level, decrease transfusion need and also improve their quality of life. Recent clinical and experimental work suggest that improving the haemoglobin level may improve the patients' prognosis but this finding needs to be confirmed. Treatment of anaemia with rHuEpo in patients with cancer may produce many benefits. Unfortunately, rHuEpo is effective in only around 60% of patients, is slow acting and is expensive. These drawbacks have restricted its use in many healthcare systems. However, a failure to treat anaemia may have important adverse effects for the patient both in terms of their quality of life and, just possibly, in terms of their life expectancy.

Topics: Anemia; Anemia, Iron-Deficiency; Antineoplastic Agents; Blood Transfusion; Erythropoietin; Humans; Neoplasms; Quality of Life; Recombinant Proteins; Survival Analysis

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

Topics: Anemia; Blood Viscosity; Critical Care; Erythrocytes; Erythropoietin; Hematocrit; Hemodynamics; Humans; Oxygen; Reference Values

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

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

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

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

The use of erythropoietin (EPO) for the treatment of anemia associated with urological malignancies is not well defined. The rate of anemia is dependent on the type of cancer and on the different types of treatment. Only with a substantial risk for blood transfusion is substitution treatment by EPO justified. Additionally, the long-term risks of blood transfusions have to be balanced against the costs of EPO treatment.. Different experts have reviewed the literature on anemia and EPO regarding the four main tumor entities.. In prostate cancer, EPO treatment may be justified before radical prostatectomy and in patients with advanced, hormone-refractory disease. In bladder cancer, significant treatment-related anemia mainly occurs in patients who have to undergo radical cystectomy and in patients who will be treated with polychemotherapy for metastatic disease. Patients with renal cell carcinoma rarely suffer from anemia and thus are usually not candidates for EPO treatment. Testis cancer patients only have a substantial risk for blood transfusions if they belong to the intermediate or poor prognosis group according to IGCCCG or if they need salvage chemotherapy or salvage surgery. However, in testis cancer patients EPO treatment should generally be preferred to blood transfusions since cure rates are excellent and thus the potential risks of transfusion-related infections are significant.

Topics: Anemia; Carcinoma, Renal Cell; Erythropoietin; Germinoma; Humans; Male; Testicular Neoplasms; Urologic Neoplasms

The recombinant human cytokines granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), erythropoietin, and interleukin-2 (IL-2) have been manufactured and licensed. Studies have been carried out that investigate the use of G-CSF and GM-CSF to reverse leukopenia, as adjunctive therapy for HIV-associated infections and for novel approaches to treat HIV infection, including stem cell mobilization. In addition, studies that identified the role of erythropoietin in the management of anemia have been performed. Furthermore, the abilities of G-CSF and erythropoietin to permit the continued use of marrow suppressive agents that are key in managing HIV infection have been assessed. The aim of this review is to summarize these studies and to describe the reports that evaluate the use of IL-2 to enhance elevation of CD4 cell counts mediated by highly active antiretroviral therapy. This summary is important to the treating clinician in that it identifies the optimal use of these cytokines in current clinical practice as well as their potential future roles.

Topics: Anemia; Colony-Stimulating Factors; Erythropoietin; HIV Infections; Humans; Interleukin-2; Neutropenia; Recombinant Proteins

Topics: Anemia; Erythropoietin; Heart; Humans; Hypertrophy, Left Ventricular; Recombinant Proteins; Renal Circulation

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

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

Anemia is a frequent finding, particularly in the elderly population, and usually indicative of a serious disease. The main causes of preoperative anemia are acute or chronic hemorrhage, iron deficiency, renal insufficiency, inflammatory and neoplastic diseases. A preexisting mild anemia may be enhanced or unmasked by surgically induced bleeding or repeated diagnostic phlebotomies, and by a postoperative erythropoietic dysfunction caused by the surgical trauma, irrespective of any hemorrhage. Low hemoglobin values are associated with a distinct increase of mortality and morbidity, both in the normal population and perioperatively and in the critically ill patients. The anemia-associated risk is exacerbated by preexisting cardiovascular disease, important intraoperative blood loss and advanced age. In contradiction to established therapeutical concepts, the administration of allogeneic blood beyond hemoglobin levels of 8-10 g/dl has not been found to decrease perioperative or intensive care morbidity or mortality. Rather, in addition to the inherent long-term risks of transfusions, a liberal transfusion strategy seems to increase the incidence of postoperative complications. Thus, current transfusion guidelines tend to be interpreted in an increasingly restrictive manner. Depending on the urgency of the clinical situation, the primary goal should be to diagnose and treat the underlying disease, rather than to focus on the symptom anemia. Time permitting, the patient's cardiovascular and pulmonary status should be optimized preoperatively. Furthermore, iron should be substituted to treat and prevent deficiency. Recombinant human erythropoietin has successfully been used to treat anemia of chronic renal failure and chronic disease, as well as in the perioperative and intensive care setting, and to support the efficiency of autologous programs.

Topics: Aged; Anemia; Erythropoietin; Humans; Intraoperative Complications; Intraoperative Period; Recombinant Proteins

Anemia is a frequent finding in patients treated in ICUs and results in a high number of red blood cell transfusions. Many patients are already admitted to ICUs with subnormal hemoglobin values. Surgery, frequent phlebotomies and overt bleeding episodes are obvious reasons for continuous blood loss during the ICU stay. However, these causes are usually not sufficient to explain the total blood consumption of critically ill patients, which may amount to several liters. Reduced red cell life span and occult gastrointestinal bleeding are possibly important contributory factors. Irrespective of the cause the erythropoietic response to anemia is severely blunted, as a consequence of an inappropriate increase in erythropoietin production, diminished iron availability and direct inhibitory effects of inflammatory cytokines. The importance of anemia for the course and outcome of critically ill patients and its optimal therapy remain to be defined. Considering red blood cell transfusions recent evidence indicates that a target range of 7-9 g/dl hemoglobin is at least as safe and may even be superior compared to a more liberal transfusion strategy. However, the optimal transfusion trigger in relation to patient comorbidity requires further investigation. Rigorous strategies of blood conservation may help to avoid transfusions. Red blood cell substitutes and recombinant erythropoietin are promising treatment options that are currently under investigation.

Topics: Anemia; Blood Transfusion; Clinical Trials as Topic; Critical Care; Critical Illness; Erythrocyte Transfusion; Erythropoiesis; Erythropoietin; Hemoglobins; Humans; Iatrogenic Disease; Inflammation Mediators; Iron; Length of Stay; Prospective Studies; Recombinant Proteins; Risk Factors; Time Factors

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

Recombinant human EPO (rHuEPO) has not gained broad acceptance in the treatment of the anemia of prematurity, because its efficacy in diminishing RBC transfusions is questionable. Meta-analysis was used to investigate the extent and reasons for variation in the results of published clinical trials.. Prospective controlled trials published from 1990 through 1999 were retrieved; 21 met the criteria for meta-analysis. Calculated across these studies were the summary OR of RBC transfusion in treated neonates as compared with controls and the summary mean difference between controls and treated neonates in the volume of RBCs transfused and the number of RBC transfusions per infant. Twelve study descriptors were examined as possible reasons for the variation in results.. Results of 21 eligible studies varied widely (p<0.001 for the Q test statistic), and this variation persisted in most analyses when studies were stratified by individual study descriptors. When the difference in volume of RBCs transfused was the outcome measure, variation was modest across the four studies with highly desired characteristics (i.e., high blindness and design quality scores, "conservative" transfusion criteria, and the majority of neonates weighing <1 kg at birth), and treatment with rHuEPO reduced RBC transfusions by an average of 11.0 mL per kg (p<0.001).. Benefit from rHuEPO is detected across high-quality studies using conservative RBC transfusion criteria. However, there is extreme variation overall in the findings of available trials, and-until this variation is accounted for-it is premature to recommend rHuEPO as standard treatment for the anemia of prematurity.

Topics: Anemia; Blood Transfusion; Controlled Clinical Trials as Topic; Erythropoietin; Humans; Infant, Newborn; Odds Ratio; Recombinant Proteins

Anemia is common in patients with hematological malignancy. Most patients will have their anemia attributed to the anemia of chronic disease. The anemia of chronic disease is caused by cytokine mediated suppression of erythropoiesis and low serum erythropoietin levels are found in the majority of patients with cancer. Many of these anemic patients will be symptomatic with fatigue. Data from many studies indicates that treatment of anemic patients with erythropoietin will increase their hemoglobin concentration, decrease transfusion need and also improve their quality of life. A recent study also suggests that improving the hemoglobin level may improve the patients' prognosis but this finding needs to be confirmed.

Topics: Anemia; Erythropoietin; Hematologic Neoplasms; Hemoglobins; Humans; Quality of Life; Recombinant Proteins

Topics: Anemia; Erythropoietin; Granulocyte-Macrophage Colony-Stimulating Factor; Humans

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

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

Anemia is a frequent complication in cancer, occurring in more than 50% of patients with malignancies. Several factors can cause anemia in these patients, such as blood loss, hemolysis, bone marrow infiltration, hypersplenism, and nutrient deficiencies. However, in a considerable number of patients, no cause other than malignant disease itself can be implicated. This cancer-related anemia is similar to the anemia observed in other chronic diseases, such as rheumatoid arthritis and some chronic infections. The syndrome of anemia of chronic disease is characterized by a hyporegenerative, normocytic, normochromic anemia associated with reduced serum iron and transferrin saturation but elevated (or normal) ferritin levels. Cancer-related anemia results from activation of the immune and inflammatory systems, leading to increased release of tumor necrosis factor, interferon-gamma, and interleukin-1. The cytokine-mediated relative failure of erythropoiesis has been further investigated, and three different mechanisms of action are proposed: (1) impaired iron utilization; (2) suppression of erythroid progenitor cells differentiation; and (3) inadequate erythropoietin production. In addition, the life span of red blood cells is shortened in cancer-related anemia and production cannot compensate sufficiently for the shorter survival time. Administration of recombinant human erythropoietin (r-HuEPO, epoetin alfa) can not only correct inadequate endogenous erythropoietin production, but also can overcome the suppression of erythroid progenitor cells and impairment of iron mobilization.

Topics: Anemia; Erythropoiesis; Erythropoietin; Hemoglobins; Humans; Neoplasms

Acute or chronic anemia, a common complication in cancer patients, is associated with the development of tumor hypoxia. It has been shown in several trials that decreased hemoglobin (Hb) levels inducing tumor hypoxia adversely impact radiotherapy or combined radiochemotherapy outcome. For example, pre- and post-treatment Hb levels can be predictive factors for the outcome of radiotherapy, locoregional tumor control, and survival. Two strategies have been established to correct cancer-related anemia and improve radiotherapy outcome: immediate increase of Hb levels with transfusions, or treatment with recombinant human erythropoietin (r-HuEPO, epoetin alfa), which slowly but steadily increases Hb levels to within normal range. As transfusions are associated with severe risks and adverse events, the use of epoetin alfa to treat pre-existing anemia or prevent therapy-induced anemia represents an attractive strategy. The ability of epoetin alfa to maintain or to increase Hb levels in patients undergoing radiotherapy or radiochemotherapy have been shown in several studies in different tumor types. In addition to improving the results of radiotherapy and radiochemotherapy, anemia intervention with epoetin alfa may impact overall survival.

Topics: Anemia; Cell Hypoxia; Epoetin Alfa; Erythropoietin; Hematinics; Hemoglobins; Humans; Neoplasms; Prognosis; Recombinant Proteins

Clinical trials and surveys have shown that a majority of patients with cancer have low hemoglobin levels as a result of the disease and/or treatment. Clinical trials also have shown that the impact of anemia may be more insidious and far-reaching than generally appreciated. Specifically, studies have shown that low hemoglobin levels have significant impact on treatment outcomes, including survival. The mechanisms by which treatment efficacy and survival are compromised have not been fully elucidated but may include cellular compromise (eg, impaired tumor oxygenation), or more general patient compromise (eg, decreased quality of life and treatment delivery). Recent studies have suggested that increasing hemoglobin levels with recombinant human erythropoietin (r-HuEPO, epoetin alfa) have resulted in better outcomes following radiotherapy, chemotherapy, and the combined-treatment modality.

Topics: Anemia; Cell Hypoxia; Epoetin Alfa; Erythropoietin; Hemoglobins; Humans; Neoplasms; Recombinant Proteins; Treatment Outcome

Hysterectomy is the second-most-common surgical procedure among premenopausal women. The conditions that lead to the need for a hysterectomy often are accompanied by chronic blood loss that can lead to anemia. Moreover, hysterectomy and myomectomy may result in significant blood loss, which exacerbates the anemia. The presence of fatigue associated with anemia has a substantially negative impact on quality of life and the ability to perform activities of daily living. Options for alleviating perioperative anemia include minimizing surgical blood loss, blood transfusion, supplementation with hematinics, such as iron and folic acid, and treatment with recombinant human erythropoietin. Treating preoperative anemia is expected to help correct anemia prior to surgery and may have a positive impact on anemia-related symptoms and surgical outcomes.

Topics: Anemia; Blood Loss, Surgical; Blood Transfusion; Elective Surgical Procedures; Epoetin Alfa; Erythropoietin; Fatigue; Female; Gonadotropin-Releasing Hormone; Gonadotropins; Hematinics; Hematocrit; Humans; Hysterectomy; Preoperative Care; Recombinant Proteins

Erythropoietin, a glycoprotein hormone, is synthesized predominantly in the kidney and secreted by renal cortical interstitial cells in response to tissue hypoxia. Erythropoietin is the main regulator of the production of red blood cells. It functions in the recruitment and differentiation of erythroid progenitor cells and aids in their maintenance and survival. Erythropoietin also stimulates the synthesis of hemoglobin. In the last 15 years, the ready availability of recombinant human erythropoietin (r-HuEPO, epoetin alfa) has permitted the clinical investigation and application of this hormone to the treatment of anemia in various patient populations. Epoetin alfa has been shown to accelerate erythropoiesis and reduce allogeneic blood transfusion in major elective, noncardiac, nonvascular surgery and in certain anemic patients with chronic renal failure, nonmyeloid malignancies and human immunodeficiency virus infection. In addition to improving hematologic parameters, epoetin alfa therapy can enhance health-related quality of life in these patients. The success of epoetin alfa in treating anemia in other surgical populations suggests that it may be of benefit in treating the perioperative anemia that is highly prevalent in gynecologic surgery patients. Further investigation of the use of epoetin alfa in patients undergoing gynecologic surgery would increase awareness of its benefits for this patient population.

Topics: Anemia; Elective Surgical Procedures; Epoetin Alfa; Erythropoiesis; Erythropoietin; Female; Gynecologic Surgical Procedures; Hematinics; Humans; Perioperative Care; Quality of Life; Recombinant Proteins

Recombinant human erythropoietin (r-HuEPO, epoetin alfa) is used for treatment of anemia associated with chemotherapy for non-myeloid malignancies, chronic renal failure and zidovudine treatment in patients infected with the human immunodeficiency virus and for anemic patients undergoing elective, noncardiac, nonvascular surgery. Epoetin alfa has been shown to safely increase preoperative hemoglobin (Hb) levels in anemic patients undergoing elective noncardiac, nonvascular surgery and is more effective than preoperative autologous blood donation in reducing the need for perioperative blood transfusions in orthopedic surgery patients. Epoetin alfa was shown to significantly increase Hb levels and decrease transfusion requirements in gynecologic cancer patients undergoing chemotherapy. A once-weekly regimen of 40,000 IU per dose was effective in these patients. In addition to decreasing transfusion requirements and increasing Hb, epoetin alfa for relieving anemia-related fatigue and improving quality of life was demonstrated in clinical trials in anemic cancer patients receiving chemotherapy. With regard to quality of life in orthopedic surgery patients, a novel instrument to measure the effect of Hb management on postoperative recuperative power (i.e., vigor, functional ability) has been validated and may prove to be useful in optimizing rehabilitation and discharge planning. Extensive clinical experience with epoetin alfa in anemic patients undergoing major elective orthopedic surgery or those with gynecologic cancer provides a strong basis for its use in gynecologic surgery.

Topics: Anemia; Blood Transfusion; Elective Surgical Procedures; Epoetin Alfa; Erythropoietin; Fatigue; Female; Gynecologic Surgical Procedures; Hematinics; Hemoglobins; Humans; Neoplasms; Orthopedics; Quality of Life; Recombinant Proteins; Safety; Treatment Outcome

Perioperative anemia is a common complication of major surgery that may lead to prolonged and debilitating fatigue and reduction in health-related quality of life (QOL). Treatment with recombinant human erythropoietin (r-HuEPO, epoetin alfa) has been shown to increase perioperative hemoglobin (Hb) and hematocrit (HCT) levels, thereby facilitating postoperative recovery in orthopedic surgery patients. Treatment with epoetin alfa has also been shown to increase Hb and HCT levels and improve QOL in anemic cancer patients undergoing chemotherapy. The clinical and QOL benefit of using epoetin alfa in these patient populations provides the rationale for its use in patients undergoing gynecologic surgery. Because persistent fatigue is the most common complaint of patients following hysterectomy, the use of epoetin alfa should be considered to preoperatively correct anemia in this patient population. Research has been initiated to increase our understanding of the role of epoetin alfa in treating anemic patients (Hb levels < or = 13 g/dL) undergoing surgery for benign gynecologic disease, especially as it relates to postoperative QOL. Future studies should investigate the use of epoetin alfa in patients with gynecologic cancers. These studies should confirm the role of epoetin alfa in combination with iron supplementation to improve perioperative Hb/HCT levels and overall QOL in patients undergoing gynecologic surgery.

Topics: Anemia; Elective Surgical Procedures; Epoetin Alfa; Erythropoietin; Fatigue; Female; Forecasting; Gynecologic Surgical Procedures; Hematinics; Humans; Perioperative Care; Quality of Life; Recombinant Proteins; Safety; Treatment Outcome

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

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

At the time of first diagnosis, patients with squamous cell carcinoma in the head and neck are often in the advanced stage of their disease, therefore surgery is not a viable option for treatment. These patients also present frequently a high grade of anaemia as a result of either the malignant process itself or of the following therapy. The incidence of anaemia and the need for transfusion depends on several factors, such as the type and intensity of radiotherapy and radiochemotherapy. Multimode therapeutic concepts such as radio-chemotherapy are being applied with increasing frequency, resulting in an ever increasing need for transfusion with great effects on the patient's quality of life. Even more important to tumour patients is the role of the haemaglobin (Hb) value as a prognostic factor for survival and/or local tumour control. A large number of studies show that recombinant human erythropoietin (r-HuEPO) is effective in the treatment of tumour-induced anaemia and prevention and correction of chemotherapy and radiotherapy-induced anaemia. The simultaneous application of r-HuEPO with chemotherapy can prevent patients with head and neck tumours from developing anaemia or can reduce the extent of the anaemia and the need for transfusion. Comparable effects were observed both in patients undergoing platinum-based and non-platinum-based chemotherapy. The direct correlation between anaemia, tumour hypoxia and poor response to radio and/or chemotherapy has been clinically proven. Recombinant human erythropoietin administration improves the therapeutic outcome and the patients' prognosis.

Topics: Anemia; Carcinoma, Squamous Cell; Erythropoietin; Head and Neck Neoplasms; Hemoglobins; Humans; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Quality of Life; Recombinant Proteins; Survival Rate; Treatment Outcome