Introduction Of Recombinant Human Erythropoietin Research Articles

Inhibition of HIF prolyl-hydroxylase domain to correct anemia in patients with chronic kidney disease

Since the introduction of recombinant human erythropoietin in the 1980s, the anemia of chronic kidney disease (CKD) can be effectively treated with erythropoiesis-stimulating agents (ESAs) and oral or intravenous iron supplementation. The majority of patients with CKD respond to such treatment; however, some patients do not respond adequately to recommended ESA or iron doses, with higher doses exposing them to an increased risk of adverse effects.1 Although on one hand complete correction of anemia paradoxically worsens patient outcomes, undertreatment of anemia is also associated with reduced quality of life, increased hospitalization rates, more blood transfusions, and higher mortality rate.

Peginesatide for the treatment of anemia due to chronic kidney disease – an unfulfilled promise

ABSTRACTIntroduction: The introduction of recombinant human erythropoietin revolutionized the management of anemia in patients with chronic kidney disease (CKD). In order to circumvent costly recombinant DNA technology, synthetic chemistry techniques were used to manufacture peginesatide, a synthetic peptide that bore no resemblance to previous erythropoiesis-stimulating agents (ESAs), and yet was capable of stimulating erythropoiesis. Compared with other ESAs, peginesatide was deemed to have advantages related to immunogenicity, administration schedule, and cost. Marketing approval was restricted to CKD patients on dialysis because cardiovascular events were more common with peginesatide than with darbepoetin in non-dialysis CKD patients. Unfortunately, unexplained serious adverse drug reactions (sADR) led to quick withdrawal of peginesatide from the market.Areas covered: This review describes the efficacy and safety of peginesatide in pre-approval clinical trials, sADRs after marketing approval, and lessons learned during its short life-span.Expert opinion: The case of peginesatide illustrates the difficulties in detecting rare sADRs in trials with limited patient populations and the need for improved pharmacovigilance after marketing approval. However, the need for simpler drug production methods as a result of non-dependence on recombinant DNA techniques and mammalian cell lines remains. Lessons learned during the scientific development of peginesatide can be used in developing other drugs.

The Safety of Erythropoiesis-Stimulating Agents for the Treatment of Anemia Resulting from Chronic Kidney Disease.

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.

A review on pharmacological use of recombinant human erythropoietin in renal and nonrenal anemia and other potential applications in clinical practice

Abstract The introduction of recombinant human erythropoietin (rHuEPO) has revolutionized the treatment of patients with anemia of chronic renal disease. Clinical studies have demonstrated that rHuEPO is also useful in various nonuremic conditions, including hematological and oncological disorders, prematurity, HIV infection, and perioperative therapies. Since the cloning and first clinical introduction of recombinant erythropoietin (epoetin) in the late 1980s, indications and usage of epoetin have expanded significantly. It is estimated that as many as one-third of patients with substantial anemia (hemoglobin less than 10.0 g/dl) resulting from chemotherapy for cancer are treated with epoetin. Research suggests there is considerable variation in epoetin usage in practice. This review highlights the applications of rHuEPO in clinical practice and also addresses the usage of recombinant erythropoietin in situations where benefit is substantiated by high-quality studies.

Erythropoietin Potentiates The Immune System Yet Induces Bone Resorption In a Myeloma Mouse Model

BackgroundMultiple myeloma (MM) is characterized by clonal expansion of malignant plasma cells and monoclonal gammopathy. It is associated with various clinical manifestations including bone disease and anemia. Clinical introduction of recombinant human erythropoietin (rHuEPO) and its derivatives has been a breakthrough in treating patients with anemia, mainly those with chronic kidney disease and cancer patients on chemotherapy. EPO was found to have additional biological effects, including potentiation of both humoral and cell-mediated immune responses. Our studies and those of others, have shown that EPO treatment for anemia in MM patients was associated with general improved immunological functions and immune-mediated modulation (suppression) of MM. A role for EPO in bone metabolism was previously suggested, but its effects were often controversial and the underlying mechanisms remain to be resolved. ObjectivesTo determine the immunological and skeletal effects as well as the underlying mechanisms of EPO signaling in the 5T33 MM mouse model. ResultsEPO administration led to a 50% decrease in the levels of the MM pathological κ light chain while attenuating the decrease in normal IgA. These immunoglobulin changes were accompanied by a 70% elevation (p=0.015) of B220+IGM+IgD- immature B cells in the BM of EPO-treated MM mice, compared to diluent-injected MM mice (9.8%±0.91 versus 5.68%±1.19 of B220-gated cells, respectively). We also found a 45% increase (p=0.01) in the level of BM macrophages (F4/80+CD11b+) following EPO administration in both healthy and MM mice. Moreover, stimulation in vitro of purified BM-derived macrophages with EPO, led to a 33% increase (p=0.01) in phagocytosis of the 5T33 MM cells.Th17 cells play an important role in MM pathobiology. Our data demonstrate that in MM mice, rHuEPO administration induces a 70% decrease (p=0.021) in the expression level of RORγt, a Th17 hallmark transcription factor. These findings were associated with a 4-fold increase (p<0.001) in the transcript levels of the Th1-associated cytokine IFN-γ, in the BM of EPO-treated MM mice versus their diluent-injected MM counterparts. As MM is typically associated with a Th2 response and since Th17-associated cytokines in MM patients are suggested to inhibit the Th1 response, EPO may thus have a beneficial role in MM, by shifting the balance towards a Th1 response. Collectively, these findings demonstrate that EPO treatment potentiates humoral immune responses, and limits MM progression.Bone disease is a major component of MM and is associated with significant morbidity. High-resolution CT analysis of the distal femurs confirmed bone loss in 5T33 MM mice. The femur bone density of 5T33 MM mice was 30% lower (p=0.04) than that of their healthy counterparts (3.1%±0.003 versus 4.4%±0.008, respectively). Unexpectedly, EPO treatment of MM mice, in comparison to diluent-injected MM mice, induced a 35% reduction (p=0.004) in trabecular bone density (3.1%±0.003 and 2%±0.007, respectively) and 41% (p<0.001) reduction in trabecular number (2.62mm-1±0.23 and 1.54mm-1±0.266, respectively). This was only partly compensated by a 19% increase (p=0.006) in trabecular thickness (0.043mm ±0.005 versus 0.036mm ±0.003 in controls) in EPO-treated MM mice. Bone loss correlated with a 50% increase in transcript levels of the osteoclastogenic nuclear factor-kappa B ligand (RANKL) in BM of EPO-treated MM mice compared to diluent-injected MM mice. In line with the premise that EPO-induced bone loss is mediated by increased osteoclastogenesis, we found an EPO-associated elevation in BM osteoclast progenitors, as determined by RANK and cFms immunostaining (cFms+/RANK−, 1.7 fold, p=0.01; cFms+/RANK+, 2.7 fold, p=0.007). ConclusionsWe show that in MM, EPO acts as a double-edged sword, by stimulating the immune response against MM on one hand, but also accelerating bone resorption on the other, which further alters the already compromised bone tissue. A better understanding of the osteoimmunological roles of EPO may advocate for the use of rHuEPO along with targeted bone protective treatment in MM patients, to attenuate the anemia and MM progression, while also preventing bone damage.ND-U and SH-B have contributed equally. Supported by the Multiple Myeloma Research Foundation (DN). Disclosures:No relevant conflicts of interest to declare.

Management of anemia with erythropoietic-stimulating agents in children with chronic kidney disease

Anemia management is an important component of the care provided to children with chronic kidney disease (CKD) and influences both morbidity and mortality risk. The introduction of recombinant human erythropoietin to the treatment regimen three decades ago revolutionized the therapy and significantly decreased the need for repeated blood transfusions and exposure to associated risks. Recent data on the efficacy and complications associated with erythropoietic-stimulating agent (ESA) usage has, however, prompted a reassessment of treatment-related recommendations. This review will address these recommendations, in addition to describing pediatric outcomes associated with current ESAs and presenting information on alternative ESAs, many of which will likely soon be incorporated into clinical practice.

Red Blood Cell Transfusion Risks in Patients with End‐Stage Renal Disease

Prior to the introduction of recombinant human erythropoietin (EPO), red blood cell (RBC) transfusions were frequently required when iron and anabolic steroids failed to improve the clinical symptoms of anemia associated with hemoglobin (Hb) levels that were commonly less than 7 g/dl. After the approval of EPO in the United States in 1989, the Hb levels of patients on hemodialysis dramatically improved and the need for RBC transfusions decreased significantly. The need for RBC transfusion remains for patients who require an immediate increase in their RBC mass due to symptomatic anemia and is likely to increase due to changes in the management of anemia in dialysis patients resulting from clinical trials data, regulatory changes, and new reimbursement policies for EPO. The safety of the blood supply has greatly improved over the last few decades, and the risk of transfusion-transmitted diseases has now been dramatically reduced. Noninfectious complications of transfusion currently cause the majority of morbidity and mortality associated with transfusion in the United States. Transfusion also brings a risk of alloimmunization, a particular concern for dialysis patients waiting for kidney transplantation. Knowledge of the risks of RBC transfusions will help clinicians better assess the risks and benefits of transfusing patients with ESRD. This article reviews the modern day infectious and noninfectious risks of allogeneic RBC transfusions.

Current and Upcoming Erythropoiesis-Stimulating Agents, Iron Products, and Other Novel Anemia Medications

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

Erythropoietin Stimulating Agents and Epoetin Alfa Revisited

It has been more than 20 yr since the introduction of recombinant human erythropoietin (rHuEpO) to treat the anemia of chronic kidney disease (CKD; initially in dialysis-dependent patients but subsequently in patients with CKD-associated anemia before dialysis) (1). It heralded a very important era in the treatment and care of the patient with CKD. The first commercially available form of rHuEpO was epoetin alfa, but there are now many erythropoietin-stimulating agent (ESA) products, all of which are fundamentally very effective in correcting CKD-induced anemia and maintaining hemoglobin (Hb) levels. In this issue are three articles specifically related to epoetin alfa; two concern the pharmacokinetics and pharmacodynamics of epoetin alfa and their relevance to dosing intervals, and the third addresses patient responsiveness to epoetin alfa. The quandary for the clinician, however, remains a broader one; it concerns the provision of individualized treatment for the patients with CKD-induced anemia. This clinical dilemma has been made even more difficult by the fact that the Clinical Practice Guidelines, which have historically helped to guide care, have been characterized by incomplete and/or inadequate evidence (2). More recently, the complexity has been further amplified by the need for conservatism after meta-analysis publications indicating that using ESA to target higher levels (>13 g/dl) (3) compared with control ranges (9.5 to 11.5 g/dl) is likely to produce net harm (increased mortality and major vascular events) rather than benefit. Despite the fact that criticism of the meta-analysis data occurred (4), because of the heterogeneity in the patient demographic data (ranges of stages of CKD and associated comorbidities) and the uncertainty surrounding the effect of preexisting comorbidities, acute inflammation, and other factors on the ability to achieve Hb targets, the concern …

The (re)challenging question of erythropoiesis-stimulating agents inducing pure red cell aplasia

The introduction of recombinant human erythropoietin (EPO) into routine clinical practice in the late 1980s heralded a new dawn for the treatment of anaemia in chronic kidney disease (CKD). Apart from the financial burden, limiting its use in the developing world, the early sideeffect profile was mild. It has been shown that full correction of anaemia, requiring high doses of EPO, does not confer mortality benefit to patients suffering from CKD [1,2], and is potentially detrimental to survival [1] even in haemodialysis patients with cardiac disease; the administration of EPO to raise haematocrit to 42% is not recommended [3]. Pure red cell aplasia (PRCA), secondary to EPO, will form the basis of this review. This idiosyncratic immunological reaction involves the generation of anti-EPO antibodies (Abs) resulting in significant anaemia. The mechanisms governing this immunological response remain only partially understood. Whilst PRCA is infrequent, the disease is severe, and the aggressive treatment requirements present a significant complication to patients and a therapeutic conundrum to the treating clinician.

Cellular Protection by Erythropoietin: New Therapeutic Implications?

Erythropoietin (EPO), the principal hematopoietic hormone produced by the kidney and the liver in fetuses, regulates mammalian erythropoiesis and exhibits diverse cellular effects in nonhematopoietic tissues. The introduction of recombinant human EPO (rhEPO) has marked a significant advance in the management of anemia associated with chronic renal failure. At the same time, experimental studies have unveiled its potential neuroprotective and cardioprotective properties, occurring independently of its hematopoietic action. As with other cytoprotective agents, administration of exogenous rhEPO can confer cerebral and myocardial protection against ischemia-reperfusion injury in terms of reduction in cellular apoptosis and necrosis, as well as improvement in functional recovery. Very recent studies even suggest that this drug could have beneficial applications in oncology, protecting against chemotherapy cardiotoxicity. The purpose of this letter is to review current information regarding the various conditions in which rhEPO and its derivates could confer cellular protection. We also address clinical perspectives and novel therapeutic strategies that could be developed based on these studies. Thus, EPO seems to be a very promising agent for protecting cellular survival during both acute and chronic diseases, and its future should be considered with enthusiasm.

Therapeutic implications of recombinant human erythropoietin in anaemic related clinical manifestations

The introduction of recombinant human erythropoietin (RHUEPO) has revolutionised the treatment strategies for patients suffering with anaemia of chronic renal disease and chronic heart failure. Clinical studies and several observational evidences have demonstrated that RHUEPO is also useful in various non-uraemic conditions including haematological and oncological disorders, prematurity, HIV infection and preoperative therapies. The successful treatment of all the anaemic related malfunctions with recombinant human erythropoietin (RHUEPO) has become a standard treatment tool for dialysis patients and as an interesting therapeutic option for several forms of non-renal anaemia. As a conesquence of both, RHUEPO has achieved the highest annual sales worldwide and the potential of it increases its scope in the future prospective also.

Antibody-mediated pure red cell aplasia in a dialysis patient receiving darbepoetin alfa as the sole erythropoietic agent

The introduction of recombinant human erythro-poietin (epoetin) transformed the management ofanaemia for the vast majority of dialysis patients.The immediate benefit of transfusion-independencewas a lower risk of contracting blood-borne infectionsand iron overload. The raised haematocrit ledto improvements in quality of life, which in turn hasbeen associated with improved long term survival [1,2].For the first decade or so, various brands orformulations of epoetin were available, includingepoetin alfa (Epogen, Procrit in the US; Eprex,Erypro in Europe). A second-generation erythropoieticagent (darbepoetin alfa) was developed by incorporat-ing an additional two glycosylation chains to theerythropoietin molecule, resulting in a product with alonger half-life and a consequent reduced dosingfrequency [3].Since 1998, there has been a rapid increase in theincidence of epoetin therapy-associated pure red cellaplasia (PRCA), largely associated with the Eprexbrand of epoetin, but described with the Epogen andNeoRecormon brands of epoetin. In 2002, Casadevallet al. [4] described a new complication of epoetintherapy, that of PRCA associated with anti-erythropoietin antibodies.To date, however, no cases of anti-erythropoietinmediated PRCA has been described with darbepoetinalfa, and indeed it has been suggested that theadditional glycosylation may cause this molecule tobe more resistant to antibody generation than epoetin.We describe what we believe to be the first case ofantibody-mediated PRCA associated with the admin-istration of darbepoetin alfa alone.

UNRESOLVED ISSUES IN DIALYSIS: Managing Erythropoietin Hyporesponsiveness

ABSTRACTThe anemia of chronic kidney disease is associated with cardiovascular disease, decreased quality of life, and mortality. The introduction of recombinant human erythropoietin (rHuEPO) has transformed the management of this condition. However, a significant proportion of patients fail to respond to even high doses of rHuEPO. Several factors have been implicated in the hyporesponsiveness to rHuEPO. Iron deficiency, whether absolute or functional, is considered the most important, and maintenance of adequate iron stores reduces rHuEPO requirements among patients on hemodialysis. However, traditional indices of iron that are currently utilized may not reflect iron stores accurately, and there is also increasing concern regarding the potential long‐term toxicity of parenteral iron therapy. Infection and inflammation also influence the response to rHuEPO, both by disruption of iron metabolism and by eliciting the release of cytokines that inhibit erythropoiesis. Oxidative stress may contribute to rHuEPO hyporesponsiveness directly by promoting lipid peroxidation in cell membranes, leading to increased erythrocyte fragility and reduced life span and also through its strong association with inflammation. Severe hyperparathyroidism can lead to a reduced number of erythroid progenitor cells. Inadequate dialysis dose, aluminum overload, nutritional factors such as deficiencies of carnitine, vitamin B12, folic acid, and vitamin C can also reduce the efficacy of rHuEPO therapy. Hyporesponsiveness to rHuEPO presents a challenge to both diagnosis and management in an era where optimizing response to rHuEPO is critical both in limiting the burgeoning costs of anemia management and improving clinical outcomes in the dialysis population.

Epoetin alfa: basic biology and clinical utility in cancer patients

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.

Current and future challenges in anaemia management

The introduction of recombinant human erythropoietin (rhEPO; epoetin) nearly 20 years ago revolutionized the management of renal anaemia. The correction of anaemia with epoetin is associated with improvements in the quality of life of patients with chronic kidney disease (CKD), and reductions in morbidity and mortality. In this supplement, the authors present an overview of pertinent issues in renal anaemia management that were tackled during two satellite symposia held on June 9 and 10, 2003 at the World Congress of Nephrology in Berlin, Germany: ‘Current and future challenges in anaemia management’ and ‘Who wants to defeat anaemia? An interactive insight into anaemia management today’. All recombinant human proteins can potentially induce an immune response, especially when administered repeatedly over prolonged periods. A multitude of factors, including structural properties, storage and handling, contaminants and impurities, administration and formulation, may affect immunogenicity. In recent years, a peak was noted in the number of cases of pure red cell aplasia (PRCA) associated primarily with one particular epoetin-a product available outside of the USA, Eprex /Erypo . As a result, regulatory authorities in Europe restricted the administration of this product to the intravenous (i.v.) route. Currently there is no evidence for an increasing trend in antibody-mediated PRCA for this or other epoetin formulations. The optimal route of epoetin administration has been explored in numerous studies. Current European Best Practice Guidelines and K/DOQI Guidelines on renal anaemia management recommend subcutaneous (s.c.) administration as the preferred route for epoetin in CKD patients not on dialysis, in haemodialysis, peritoneal dialysis and transplanted patients, when not contraindicated. These recommendations take into account the efficacy, frequency of dosing, cost and convenience of epoetin treatment, alongside the safety and tolerability of specific products. Target haemoglobin (Hb) levels can be maintained with much lower doses of epoetin when administered by the s.c. route. Clearly, therefore, s.c. administration of epoetin is associated with economic advantages in terms of direct drug cost and may also provide cost benefits by relieving the burden on health care services. In the case of epoetin-b, s.c. administration allows for reduced dosing frequencies at once weekly and even once every 2 week intervals during the maintenance phase of treatment in stable peritoneal dialysis patients, without compromising safety or efficacy. Reduced dosing frequency and the availability of a pen device, specifically designed for the self-administration of s.c. epoetin-b, should increase patients’ readiness to self-administer treatment and should facilitate the early initiation of anaemia treatment in patients with CKD not yet requiring dialysis. Anaemia contributes to the progression of cardiovascular disease. Detrimental effects begin at an early stage of CKD, well before kidney function deteriorates to the point when dialysis is required. Indeed, low Hb is an independent risk factor for left ventricular (LV) growth in CKD patients not needing dialysis, as well as in patients receiving dialysis, and in those who have undergone renal transplantation. Data suggest that management of anaemia can significantly reduce the cardiovascular risks associated with CKD; early correction of anaemia may be especially important in improving patient outcomes. The ability of epoetin to reverse changes in LV geometry may be limited in patients with advanced renal and cardiac disease. In this regard, the ongoing Cardiovascular risk Reduction by Early Anaemia Treatment with Epoetin b (CREATE) study, which is investigating the benefits of early, complete anaemia correction with epoetin-b on cardiovascular events in patients with CKD not receiving renal replacement therapy, will provide important information. The risk of developing cardiovascular disease is even higher in patients with CKD who also have diabetes. Diabetes is now the most common primary diagnosis associated with end-stage renal disease (ESRD), and a Correspondence and offprint requests to: Professor Eberhard Ritz, Department of Internal Medicine, Bergheimer Str. 56a, D-69115 Heidelberg, Germany. Email: Prof.E.Ritz@t-online.de

Erythropoietin and myocardial protection: what's new?

Erythropoietin (EPO), the principal hematopoietic cytokine produced by the kidney and the liver in fetuses, regulates mammalian erythropoiesis and exhibits diverse cellular effects in non-hematopoietic tissues. The introduction of recombinant human EPO (rhEPO) has marked a significant advance in the management of anemia associated with chronic renal failure. At the same time, experimental studies have unveiled its potential cardioprotective actions. As with other preconditioning agents, administration of exogenous rhEPO can confer myocardial protection against ischemia-reperfusion injury, in terms of reduction in cellular apoptosis and necrosis as well as improvement in myocardial functional recovery. The purpose of this study is to review current information regarding the various protocols used to investigate the effects of rhEPO administration as well as its cardioprotective properties. We also address the potential mechanisms underlying the protective effects of EPO. A better understanding of these mechanisms is essential for the development of clinical applications and the design of novel therapeutical strategies.

Hyporesponsiveness to erythropoietic therapy in uraemic patients with secondary hyperparathyroidism: what is the evidence base?

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

The effects of higher hemoglobin levels on mortality and hospitalization in hemodialysis patients

The introduction of recombinant human erythropoietin for the treatment of anemia of chronic renal failure provided the opportunity to correct anemia in this patient population. The optimal target hemoglobin for patients with end-stage renal disease (ESRD) remains controversial. A large database of hemodialysis patients was analyzed to determine whether increasing hemoglobin level above the current Kidney Dialysis Outcomes Quality Initiative (K/DOQI) recommendations was associated with increased risk of mortality and hospitalization. A longitudinal study of hemodialysis patients in Fresenius Medical Care-North America facilities was performed. Selection was restricted to patients in the census for 6 consecutive months from July 1, 1998 through June 30, 2000. Patient mean hemoglobin and other covariates measured during the initial 6 months were related to survival, number of hospitalizations, and length of stay over the subsequent 6 months of follow-up. Patients with hemoglobin <9 g/dL had an adjusted relative risk of death of 2.11 compared to those patients with 11 </= hemoglobin < 12 g/dL (P < 0.0001). The adjusted relative risk of death was 0.84 for 12 </= hemoglobin < 13 g/dL (P = 0.007). These data suggest there is no increased risk of mortality associated with hemoglobin above the current recommended values. Both number of hospitalizations and length of stay decreased as hemoglobin increased. Patients with hemoglobin >/=13 g/dL had an adjusted length of stay of 9.6 days compared to 10.9 days for those with 11 </= hemoglobin < 12 g/dL (P < 0.0001). These data indicate the relative risk of death and hospitalization are inversely associated with hemoglobin levels, with no apparent additional risk associated with hemoglobin levels> 12 g/dL.

Anemia of hematologic malignancies: what are the treatment options?

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.