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Anemia is a frequent complication during the later stages of chronic kidney disease. When present, it may cause symptoms such as fatigue and shortness of breath. The pathogenesis of anemia in chronic kidney disease is complex, but a central feature is a relative deficit of erythropoietin. New information has elucidated the critical role of the hypoxia-sensing system in mediating erythropoietin synthesis and release. Iron deficiency is a second important factor in the anemia of chronic kidney disease. New insights into the dynamics of iron metabolism have clarified the role of chronic inflammation and hepcidin as key mediators of impaired iron utilization. In this article, we review the epidemiology, pathobiology, clinical evaluation, and treatment of anemia in chronic kidney disease., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Little is known about epoetin alfa (EPO) dosing at dialysis centers after implementation of the US Medicare prospective payment system and revision of the EPO label in 2011., Study Design: Retrospective cohort study., Setting & Participants: Approximately 412,000 adult hemodialysis patients with Medicare Parts A and B as primary payer in 2009 to 2012 to describe EPO dosing and hemoglobin patterns; of these, about 70,000 patients clustered in about 1,300 dialysis facilities to evaluate facility-level EPO titration practices and patient-level outcomes in 2012., Predictor: Facility EPO titration practices when hemoglobin levels were <10 and >11g/dL (grouped treatment variable) determined from monthly EPO dosing and hemoglobin level patterns., Outcomes: Patient mean hemoglobin levels, red blood cell transfusion rates, and all-cause and cause-specific hospitalization rates using a facility-based analysis., Measurements: Monthly EPO dose and hemoglobin level, red blood cell transfusion rates, and all-cause and cause-specific hospitalization rates., Results: Monthly EPO doses declined across all hemoglobin levels, with the greatest decline in patients with hemoglobin levels < 10g/dL (July-October 2011). In 2012, nine distinct facility titration practices were identified. Across groups, mean hemoglobin levels differed slightly (10.5-10.8g/dL) but within-patient hemoglobin standard deviations were similar (∼0.68g/dL). Patients at facilities implementing greater dose reductions and smaller dose escalations had lower hemoglobin levels and higher transfusion rates. In contrast, patients at facilities that implemented greater dose escalations (and large or small dose reductions) had higher hemoglobin levels and lower transfusion rates. There were no clinically meaningful differences in all-cause or cause-specific hospitalization events across groups., Limitations: Possibly incomplete claims data; excluded small facilities and those without consistent titration patterns; hemoglobin levels reported monthly; inferred facility practice from observed dosing., Conclusions: Following prospective payment system implementation and labeling revisions, EPO doses declined significantly. Under the new label, facility EPO titration practices were associated with mean hemoglobin levels (but not standard deviations) and transfusion use, but not hospitalization rates., (Copyright © 2016 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The potential effects of iron-dosing strategies and erythropoiesis-stimulating agents (ESAs) on health-related quality of life (HRQoL) in the dialysis population are unclear. We examined the independent associations of bolus versus maintenance iron dosing and high versus low ESA dosing on HRQoL., Study Design: Retrospective cohort design., Setting & Participants: Clinical data (2008-2010) from a large dialysis organization merged with data from the US Renal Data System. 13,039 patients receiving center-based hemodialysis were included., Predictor: Iron and ESA dosing were assessed during 1-month (n=14,901) and 2-week (n=15,296) exposure periods., Outcomes: HRQoL was measured by the Kidney Disease Quality of Life (KDQOL) instrument (0-100 scale) during a 3-month follow-up period., Measurements: Generalized linear mixed models, adjusting for several covariates, were used to estimate associations between iron and ESA dosing and HRQoL overall and for clinically relevant subgroups., Results: For the 1-month exposure period, patients with lower baseline hemoglobin levels who received higher ESA dosing had higher physical health and kidney disease symptom scores (by 2.4 [95% CI, 0.6-4.2] and 5.6 [95% CI, 2.8-8.4] points, respectively) in follow-up than patients who received lower ESA dosing. For the 2-week exposure period, patients with low baseline hemoglobin levels who received bolus dosing had higher mental health scores (by 1.9 [95% CI, 0.0-3.8] points) in follow-up. Within the low-baseline-hemoglobin subgroup, individuals with a catheter or dialysis vintage less than 1 year who received higher ESA dosing had higher HRQoL scores in follow-up (by 5.0-9.9 points) and individuals with low baseline transferrin saturations who received bolus dosing had higher HRQoL scores in follow-up (by 2.6-5.8 points)., Limitations: Observational design; short duration of observation., Conclusions: For individuals with low baseline hemoglobin levels, higher ESA dosing and bolus iron dosing were associated with slightly higher HRQoL scores in follow-up. These differences became more pronounced and clinically relevant for specific subgroups., (Copyright © 2016 National Kidney Foundation, Inc. All rights reserved.)

Background: Adequately powered studies directly comparing hard clinical outcomes of darbepoetin alfa (DPO) versus epoetin alfa (EPO) in patients undergoing dialysis are lacking., Study Design: Observational, registry-based, retrospective cohort study; we mimicked a cluster-randomized trial by comparing mortality and cardiovascular events in US patients initiating hemodialysis therapy in facilities (almost) exclusively using DPO versus EPO., Setting & Participants: Nonchain US hemodialysis facilities; each facility switching from EPO to DPO (2003-2010) was matched for location, profit status, and facility type with one EPO facility. Patients subsequently initiating hemodialysis therapy in these facilities were assigned their facility-level exposure., Intervention: DPO versus EPO., Outcomes: All-cause mortality, cardiovascular mortality; composite of cardiovascular death, nonfatal myocardial infarction (MI), and nonfatal stroke., Measurements: Unadjusted and adjusted HRs from Cox proportional hazards regression models., Results: Of 508 dialysis facilities that switched to DPO, 492 were matched with a similar EPO facility; 19,932 (DPO: 9,465 [47.5%]; EPO: 10,467 [52.5%]) incident hemodialysis patients were followed up for 21,918 person-years during which 5,550 deaths occurred. Almost all baseline characteristics were tightly balanced. The demographics-adjusted mortality HR for DPO (vs EPO) was 1.06 (95% CI, 1.00-1.13) and was materially unchanged after adjustment for all other baseline characteristics (HR, 1.05; 95% CI, 0.99-1.12). Cardiovascular mortality did not differ between groups (HR, 1.05; 95% CI, 0.94-1.16). Nonfatal outcomes were evaluated among 9,455 patients with fee-for-service Medicare: 4,542 (48.0%) in DPO and 4,913 (52.0%) in EPO facilities. During 10,457 and 10,363 person-years, 248 and 372 events were recorded, respectively, for strokes and MIs. We found no differences in adjusted stroke or MI rates or their composite with cardiovascular death (HR, 1.10; 95% CI, 0.96-1.25)., Limitations: Nonrandom treatment assignment, potential residual confounding., Conclusions: In incident hemodialysis patients, mortality and cardiovascular event rates did not differ between patients treated at facilities predominantly using DPO versus EPO., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: 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., Study Design: Systematic review of the literature and meta-analysis., Setting & Population: Patients enrolled in randomized trials comparing EPO versus DPO for the treatment of anemia in adults with chronic kidney disease, including those requiring dialysis., Selection Criteria for Studies: 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., Intervention: DPO versus EPO., Outcome: All-cause mortality., Results: 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)., Limitations: Generalizability to nontrial populations is uncertain., Conclusions: 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., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Biologic drugs, including epoetin, continue to play an important role in the management of medical conditions. However, biologics are costly and soon many of the patents on these drugs will expire, making way for non-brand name products (ie, biosimilars). It is only by introducing competition to the marketplace that costs will de-escalate. In Europe, a specific regulatory pathway for approving biosimilars has been in place since 2005. A similar review pathway in the United States has been developed by the US Food and Drug Administration. These guidelines for approving biosimilars are stringent, requiring preclinical pharmacodynamic and toxicologic studies, clinical studies to demonstrate bioequivalence and efficacy, and long-term postmarketing studies to monitor drug safety. Biosimilar epoetin has been used in Europe since 2007, and a wealth of data has been collected. These studies and reports indicate that the efficacy and safety profiles of biosimilar epoetin are similar to those of originator epoetin alfa. Biosimilars of epoetin alfa are expected to be among the first biosimilar agents to be approved for use in the United States. The availability of lower cost epoetins may have significant impact on the treatment of anemia of chronic kidney disease., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Changes in anemia management practices due to concerns about erythropoiesis-stimulating agent safety and Medicare payment changes may increase patient risk of transfusion. We examined anemia management trends in hemodialysis patients and risk of red blood cell (RBC) transfusion according to dialysis facility-level hemoglobin concentration., Study Design: Retrospective follow-up study; 6-month study period (January to June), 3-month exposure/follow-up., Setting & Participants: For each year in 2007-2011, annual cohorts of point-prevalent Medicare primary payer patients receiving hemodialysis on January 1 with one or more hemoglobin measurements during the study period. Annual cohorts averaged 170,000 patients, with 130,000 patients and 3,100 facilities for the risk analysis., Predictor: Percentage of facility patient-months with hemoglobin level<10 g/dL., Outcome: Patient-level RBC transfusion rates., Measurements: Monthly epoetin alfa and intravenous iron doses, mean hemoglobin levels, and RBC transfusion rates; percentage of facility patient-months with hemoglobin levels<10 g/dL (exposure) and patient-level RBC transfusion rates (follow-up)., Results: Percentages of patients with hemoglobin levels<10 g/dL increased every year from 2007 (6%) to 2011 (~11%). Epoetin alfa doses, iron doses, and transfusion rates remained relatively stable through 2010 and changed in 2011. Median monthly epoetin alfa and iron doses decreased 25% and 43.8%, respectively, and monthly transfusion rates increased from 2.8% to 3.2% in 2011, a 14.3% increase. Patients in facilities with the highest prevalence of hemoglobin levels<10 g/dL over 3 months were at ~30% elevated risk of receiving RBC transfusions within the next 3 months (relative risk, 1.28; 95% CI, 1.22-1.34)., Limitations: Possibly incomplete claims data; smaller units excluded; hemoglobin levels reported monthly for patients receiving epoetin alfa; transfusions usually not administered in dialysis units., Conclusions: Dialysis facility treatment practices, as assessed by percentage of patient-months with hemoglobin levels<10 g/dL over 3 months, were associated significantly with risk of transfusions in the next 3 months for all patients in the facility, regardless of patient case-mix., (Copyright © 2014 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Targeting higher hemoglobin levels with erythropoiesis-stimulating agents (ESAs) to treat the anemia of chronic kidney disease (CKD) is associated with increased cardiovascular risk., Study Design: Metaregression analysis examining the association of ESA dose with adverse outcomes independent of target or achieved hemoglobin level., Setting & Population: Patients with anemia of CKD irrespective of dialysis status., Selection Criteria for Studies: 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., Predictors: ESA dose standardized to a weekly epoetin alfa equivalent, and hemoglobin levels., Outcomes: All-cause and cardiovascular mortality, cardiovascular events, kidney disease progression, or transfusion requirement., Results: 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., Limitations: Use of study-level aggregated data; use of epoetin alfa-equivalent doses; lack of adjustment for confounders., Conclusions: In patients with CKD, higher ESA dose might be associated with all-cause mortality and cardiovascular complications independent of hemoglobin level., (Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Conflicting relationships have been described between anemia correction using erythropoiesis-stimulating agents and progression of chronic kidney disease (CKD). This study was undertaken to examine the impact of target hemoglobin level on progression of kidney disease in the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) trial., Study Design: Secondary analysis of a randomized controlled trial., Setting & Participants: 1,432 participants with CKD and anemia., Intervention: Participants were randomly assigned to target hemoglobin levels of 13.5 versus 11.3 g/dL with the use of epoetin alfa., Outcomes & Measurements: Cox regression was used to estimate HRs for progression of CKD (a composite of doubling of creatinine level, initiation of renal replacement therapy, or death). Interactions between hemoglobin target and select baseline variables (estimated glomerular filtration rate, proteinuria, diabetes, heart failure, and smoking history) also were examined., Results: Participants randomly assigned to higher hemoglobin targets experienced shorter time to progression of kidney disease in both univariate (HR, 1.25; 95% CI, 1.03-1.52; P = 0.02) and multivariable models (HR, 1.22; 95% CI, 1.00-1.48; P = 0.05). These differences were attributable to higher rates of renal replacement therapy and death for participants in the high hemoglobin arm. Hemoglobin target did not interact with estimated glomerular filtration rate, proteinuria, diabetes, or heart failure (P > 0.05 for all). In the multivariable model, hemoglobin target interacted with tobacco use (P = 0.04) such that the higher target had a greater risk of CKD progression for participants who currently smoked (HR, 2.50; 95% CI, 1.23-5.09; P = 0.01), which was not present for those who did not currently smoke (HR, 1.15; 95% CI, 0.93-1.41; P = 0.2)., Limitations: A post hoc analysis; thus, cause and effect cannot be determined., Conclusions: These results suggest that a high hemoglobin target is associated with a greater risk of progression of CKD. This risk may be augmented by concurrent smoking. Further defining the mechanism of injury may provide insight into methods to optimize outcomes in anemia management., (Copyright © 2012 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Hematopoietic growth factors (HGFs) continue to be the most widely prescribed class of medications for patients with myelodysplastic syndromes (MDS), despite the advent of disease-modifying therapies for MDS (eg, azacitidine, decitabine, and lenalidomide) and the current absence of an MDS-specific US Food and Drug Administration (FDA)-approved indication for any of the HGFs. Erythropoiesis-stimulating agents (ESAs: epoetin alfa, darbepoetin alfa), myeloid growth factors (MGFs: filgrastim, pegfilgrastim, sargramostim), and the newest group of HGFs, thrombopoiesis-stimulating agents (TSAs: romiplostim, eltrombopag), can increase peripheral blood counts in some patients, and may ameliorate some of the signs and symptoms of MDS-associated bone marrow failure. Although HGFs are generally considered "supportive care" measures, recent data suggest that HGFs may alter the natural history of disease in MDS, either for better or worse. This review examines data on the safety and effectiveness of HGFs for patients with MDS., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study is to identify the potential benefits or complications from the use of epoetin alfa in patients with intertrochanteric fracture., Materials and Methods: Seventy-nine patients who sustained an intertrochanteric fracture were divided into 2 groups. One group received 10 daily doses of 20 000 IU of epoetin alfa beginning from the day of trauma, whereas the control group received placebo., Results: We found a statistically significant difference in the required units of allogenic blood used between the 2 groups (P = .034). The group that received epoetin alfa also showed an elevation of hematocrit and hemoglobin values, which was statistically significant at the seventh postoperative day (P = .019 and .015, respectively) compared to the control group. No complications were evident during our study., Conclusions: Patients with intertrochanteric fractures seem to benefit from the use of epoetin alfa because it is safe and reduces the need for blood transfusions., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Treatment of the anemia of chronic kidney disease (CKD) with erythropoiesis-stimulating agents (ESAs) has been intensely debated during the past 2 years. Treatment with ESAs has transformed the lives of millions of patients with CKD, with fewer blood transfusions and improved quality of life. However, randomized trials have suggested that targeting greater hematocrits/hemoglobin levels and/or exposure to high doses of ESAs is associated with a greater risk of cardiovascular complications and mortality. The US Food and Drug Administration has inserted a boxed warning for ESAs and, along with the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (KDOQI), decreased recommended target hemoglobin ranges for ESA therapy. The Centers for Medicare & Medicaid Services has decreased ESA dosing recommendations in the Medicare claims policy for ESAs. Managing the anemia of CKD in the era of the hemoglobin level and ESA controversy has required aiming for appropriate hemoglobin levels, using the lowest effective ESA dose, and better managing the problem of ESA hyporesponsiveness.

Observational studies have consistently documented independent, strong associations of anemia--even if not severe--with major adverse functional outcomes in older adults. In this chapter, recent epidemiologic evidence linking mild anemia with decline in physical and cognitive function, frailty, and disability in community-dwelling older adults is reviewed. Altogether, these biologically plausible associations provide empirical, though not conclusive, support for the notion of mild anemia as a cause of adverse functional outcomes in older adults. Randomized clinical trial data assessing the impact of anemia correction on functional outcomes are lacking at this time.

Background: Confounding-by-indication is a bias in nonexperimental studies that occurs when outcomes are compared for treated and untreated patients and the treatment or medication dose is related to predictors of the outcome. Two recent publications reported that greater epoetin alfa (EPO) doses were associated with increased mortality rates. We assessed whether confounding-by-indication might account for these results., Study Design: We used a retrospective cohort study design., Setting & Participants: Hemodialysis patients were randomly selected from a large dialysis organization from July 2000 to June 2002 and were required to have completed a 9-month baseline period., Predictor: EPO dose assessed during months 7 to 9 of the baseline period and monthly throughout the follow-up period. Hemoglobin (Hb) was assessed as average value during months 4 to 6 of the baseline period and monthly throughout the follow-up period. All other covariates were assessed during months 1 to 6 of the baseline period., Outcome: All-cause mortality during the 1 year of follow-up. Baseline Cox models were fitted with log EPO and Hb with and without adjustment for baseline patient characteristics. Time-dependent models were fitted with time-varying log EPO and Hb and, separately, lagged log EPO and Hb, with adjustment for baseline patient characteristics., Results: 22,955 patients met our inclusion criteria. In the unadjusted model, we observed increased mortality risk with increasing EPO dose (hazard ratio [HR], 1.31 per log unit increase; 95% confidence interval [CI], 1.26 to 1.36). Adjustment for baseline patient characteristics resulted in an appreciably decreased HR (HR, 1.21; 95% CI, 1.15 to 1.28). In the lagged time-dependent analyses, estimates ranged from HR of 0.93 (95% CI, 0.92 to 0.95) to HR of 1.01 (95% CI, 0.99 to 1.03) for the 1- and 2-month lagged models, respectively., Limitations: This analysis was limited to prevalent hemodialysis patients, and inhospital EPO dosing information was unavailable., Conclusions: The observed mortality risk estimates associated with EPO dose in nonexperimental studies in dialysis patients may be highly sensitive to the analytic method used. This highlights the complexity of evaluating the association between EPO dose, Hb level, and mortality in these studies.

Aims: To determine the cerebrospinal fluid concentrations and the functional and pain outcomes after a single intravenous infusion of erythropoietin at the start of a standard radiotherapy and steroid protocol., Materials and Methods: Ten paraparetic patients with malignant extradural spinal cord compression who were eligible for radiotherapy, lumbar puncture and intravenous epoetin alpha were enrolled. The patients received epoetin alpha 1500 IU/kg intravenously over 30 min followed by a standardised dexamethasone and radiotherapy protocol. A lumbar puncture and venipuncture were carried out 24-30 h after the epoetin alpha infusion. The patients were followed closely at defined intervals., Results: Erythropoietin was detectable in the cerebrospinal fluid in all eight patients sampled (median 92.5 mIU/ml, range 17.8-214.0 mIU/ml). Before treatment, eight patients were non-ambulatory and two patients were ambulatory with assistance. After treatment, eight (80%, 95% confidence interval [CI] 44-97%) improved at least one functional class and recovered or maintained ambulation. Five of seven patients (71%; 95% CI 29-96%) with objective sensory deficits and one of seven (14%; 95% CI 0-58%) catheter-dependent patients recovered. Overall, 78% (95% CI 40-97%) had a pain response., Conclusions: After an intravenous infusion of epoetin alpha, radiotherapy and steroids, high concentrations of erythropoietin were detectable in the cerebrospinal fluid. Patients with malignant extradural spinal cord compression showed encouraging improvements in neurological function and pain.

Background: Published clinical guidelines advocate subcutaneous (SC) administration for epoetin therapy, although this is practiced among only 7% of all hemodialysis patients. Despite this disparity, few studies have examined factors associated with route of epoetin administration in hemodialysis patients., Methods: Data from the Centers for Medicare & Medicaid Services End-Stage Renal Disease Clinical Performance Measures Project were used to identify 13,854 patients receiving hemodialysis in 3,069 dialysis facilities from October to December in 1999 and 2000. Unadjusted associations were examined by using t-test and chi-square test. Adjusted associations were estimated by using generalized estimating equations to control for clustering of patients within the same dialysis facility., Results: In the United States, use of the SC route of epoetin administration varies widely across the country. After adjusting for patient sociodemographics and comorbidities, the greatest rates of SC therapy are found in the Midwest and West, in providers not affiliated with chains, and in hospital-based and not-for-profit freestanding units. Previous exposure to SC administration (as a predialysis or peritoneal dialysis patient) predicted subsequent SC use, for-profit and large chains were significantly less likely to use SC administration, and increased use of injectable drugs overall (to maximize income) was associated with less SC use., Conclusion: In addition to regional variation in SC use, study findings indicate that physician decision making for epoetin administration route is influenced primarily by type of ownership and financial incentives. Adherence to published clinical guidelines was not a consistent predictor of SC use. Given the similar effectiveness, but significantly decreased dose associated with SC epoetin, these findings suggest an enormous opportunity for cost savings for the Medicare program.

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

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.

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

Background: It is unknown to what degree physicians adjust erythropoietin doses to achieve hemoglobin levels (11.0 to 12.0 g/dL [110 to 120 g/L]) recommended by the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) for patients with end-stage renal disease receiving hemodialysis. Our objective is to examine epoetin alfa prescribing patterns for achieving the target hemoglobin level range in this population., Methods: Monthly hemoglobin levels and epoetin alfa doses from 2 large databases were retrospectively analyzed. One data set comprised 31,267 patients from the Fresenius Medical Care-North America (FMC-NA) database, and the other comprised 128,761 patients based on claims for Medicare services., Results: Longitudinal evaluation of the FMC-NA data set showed that hemoglobin levels in patients administered epoetin alfa cycled in and out of the NKF-K/DOQI hemoglobin target range, and doses were decreased in 98.8% of patients with persistent hemoglobin levels greater than 12.0 g/dL (> 120 g/L). Hemoglobin levels in patients from the Medicare data set that initially were outside the target range migrated into the range with epoetin alfa dose titration. FMC-NA patients with a 3-month average hemoglobin level less than 11.0 g/dL (< 110 g/L) were administered significantly greater epoetin alfa doses than those with average hemoglobin levels greater than 12.0 g/dL (> 120 g/L; 21,838 versus 13,503 U/wk; P < 0.0001). Less than 0.4% of patients administered epoetin alfa were persistently anemic (hemoglobin < 11.0 g/dL [< 110 g/L]) and were administered persistently high doses (> 30,000 U/wk), but failed to respond with a 0.5-g/dL or greater (> or = 5-g/L) increase in hemoglobin levels., Conclusion: In these analyses, few hemodialysis patients experienced persistent anemia while being administered high epoetin alfa doses. Physicians appeared to appropriately adjust doses to achieve hemoglobin levels recommended by the NKF-K/DOQI guidelines.

Major elective orthopedic surgery may be associated with significant blood loss and allogeneic transfusion risk. Identifying patients at risk for allogeneic transfusion is best accomplished with a thorough preoperative evaluation of the patient's hematopoietic system, which, unfortunately, is not always carried out. An evaluation of the hematopoietic system begins with an evaluation of the patient's hemoglobin level a minimum of 30 days before the scheduled surgical procedure. This allows for expedited diagnosis and treatment of underlying comorbidities. An unexplained low level of hemoglobin or a hemoglobin level low enough to increase the patient's allogeneic risk should cause elective surgery to be deferred until an evaluation can be preformed and blood management strategies put in place.

Pure red cell aplasia (PRCA) is a rare, but important, complication of erythropoietin (EPO) replacement therapy in patients with renal disease. There is no consensus about the best way to treat this condition; however, recent reports indicated that immunosuppressive therapy is beneficial. We report a patient with EPO-induced PRCA treated with a regimen initially designed for antifactor VIII antibodies in patients with hemophilia. This regimen consists of immunoadsorption therapy using protein A columns, followed by oral prednisolone and single bolus infusions of intravenous immunoglobulin G and cyclophosphamide. Shortly after the course, a swift and rapid increase in reticulocyte count was evident; the patient became transfusion independent and has remained so during 2 years of follow-up. By means of this report, we wish to encourage others to consider this option when first-line treatments fail.

Background: Anemia is a frequent complication of end-stage renal disease. Poor responsiveness to epoetin therapy hampers the management of anemia. Escalating epoetin doses often are used to overcome epoetin resistance. The objective of this study is to examine the relationship between epoetin dose requirements and mortality., Methods: Using United States Renal Data System administrative claims data, we conducted a retrospective cohort study of 94,569 prevalent hemodialysis patients in 2000 and 2001. A Cox proportional hazard regression analysis, adjusted for baseline variables, and a 5-knot cubic regression spline were used to model the dose-response relationship between epoetin and all-cause mortality., Results: Significant interpatient variation exists in epoetin dose requirements to attain defined hematocrit levels. For every hematocrit cohort studied, patients administered higher doses of epoetin had significantly lower hematocrit values and greater mortality rates. Using the cubic spline function, a significant nonlinear relationship between increased epoetin dose and mortality was found regardless of hematocrit (P < 0.0001), with the steepest increase in relative risk for death found after the 72.5th dose percentile., Conclusion: Epoetin dose requirement is an independent predictor of total mortality in hemodialysis patients after adjustment for hematocrit. Poor responders who continue to have low hematocrit values despite the administration of high epoetin doses may not necessarily benefit from more epoetin, but perhaps should be considered for other adjunctive therapies. In contrast to conventional wisdom, this study suggests that epoetin dosing requirements could provide important prognostic information beyond that predicted by hematocrit alone.

An 80-year-old man with chronic renal failure (CRF) had pure red cell aplasia (PRCA) 9 months after starting the subcutaneous administration of recombinant human erythropoietin alfa (rHuEPO-alpha). Owing to the advanced renal failure, conventional immunosuppressive therapies were not practicable. It was decided to administer rituximab (4 cycles of 375 mg/m2/wk). PRCA was treated successfully with rituximab. The administration of rHuEPO-alpha then was resumed via the intravenous route with a satisfactory correction of anemia (12 months after the EPO-alpha rechallenge the patient is still transfusion independent). To the authors' knowledge, this is the first report of (1) a successful treatment with rituximab with CD20 depletion in a CRF patient with PRCA and (2) a successful intravenous resumption of the same rHuEPO-alpha.

Background: Numerous substances are administered during dialysis for anticoagulation and the treatment of anemia and iron deficiency. The availability of current dialysis membranes is diverse, but assessment of the effects of different membranes on these routinely administered substances is lacking. This prospective study appraises specific effects of 7 dialysis membranes (4 low-flux membranes, 3 high-flux membranes) on the handling of 4 commonly administered agents (epoetin alfa, darbepoetin alfa, enoxaparin, and iron sucrose) during dialysis., Methods: Using a different membrane sequentially, 6 stable hemodialysis patients were treated with epoetin alfa, enoxaparin, and iron sucrose, and 6 patients with darbepoetin alfa. Serum concentrations (predialyzer and postdialyzer) of each substance were assessed after administration and after 4 hours of dialysis (predialyzer)., Results: Overall, use of low-flux membranes resulted in similar serum concentrations for all compounds. However, use of high-flux membranes showed reduced antifactor Xa levels immediately (predialyzer, P = 0.028; postdialyzer, P = 0.027) and 4 hours after (P = 0.001) administration of enoxaparin compared with low-flux membranes. Variable changes in darbepoetin concentrations also were found between the high-flux membranes during dialysis (P = 0.009). Although peak serum concentrations of all compounds were inversely proportional to body weight, the percentage of change during dialysis was not related to dosage or body weight., Conclusion: High-flux membranes may require greater doses of enoxaparin to ensure adequate anticoagulation during dialysis and may be associated with variable changes in darbepoetin concentrations. For other compounds, no noteworthy difference among membranes was defined.

Background: Epoetin alfa (Eprex*; Johnson & Johnson, Manati, PR) has been used successfully to correct the anemia of chronic renal failure for more than 12 years. Anti-erythropoietin (anti-EPO) antibodies have been reported in a small number of patients, resulting in a blood disorder, pure red cell aplasia (PRCA). To evaluate the utility of a large-scale anti-EPO antibody screening program in patients with chronic kidney disease (CKD) administered epoetin alfa, a study involving 5 large renal centers in southern Ontario, Canada, was conducted., Methods: More than 1,500 hemodialysis, peritoneal dialysis, and predialysis patients were screened for the prevalence of anti-EPO antibodies by means of a radioimmunoprecipitation (RIP) assay. Serum samples were drawn and shipped to PPD Development (Richmond, VA) for the immunoprecipitation assay. Serum EPO levels also were measured. All samples that tested positive or borderline for antibodies were sent to MDS Pharma Services (Montreal, Canada) for the neutralization assay., Results: Of 1,531 samples tested, 1 patient tested low-positive and 3 borderline results were detected by means of RIP. PRCA previously was diagnosed in the patient with the low-positive antibody level; the patient was treated with cyclosporine and currently is being administered epoetin alfa with good response. The 3 patients with borderline antibody results manifested no clinical signs of PRCA. Neutralization assays performed on all 4 serum samples were negative for anti-EPO antibodies., Conclusion: Results from this surveillance study show that the prevalence of antibody to EPO in patients with CKD administered epoetin alfa in 5 Canadian renal centers is low, and the value of a large-scale antibody screening program for PRCA cannot be justified.

Background & Aims: Combination therapy with interferon alpha (IFN-alpha) and ribavirin (RBV) or pegylated IFN-alpha (PEG-IFN-alpha)/RBV for chronic hepatitis C virus (HCV) infection often causes anemia, prompting RBV dose reduction/discontinuation. This study assessed whether epoetin alfa could maintain RBV dose, improve quality of life (QOL), and increase hemoglobin (Hb) in anemic HCV-infected patients., Methods: HCV-infected patients (n = 185) on combination therapy who developed anemia (Hb < or = 12 g/dL) were randomized into a U. S. multicenter, placebo-controlled, clinical trial of epoetin alfa, 40,000 U subcutaneously, once weekly vs. matching placebo. The study design used an 8-week, double-blind phase (DBP) followed by an 8-week, open-label phase (OLP), in which placebo patients were crossed over to epoetin alfa., Results: At the end of the DBP, RBV doses were maintained in 88% of patients receiving epoetin alfa vs. 60% of patients receiving placebo (P < 0.001). Mean QOL scores at the end of the DBP improved significantly on all domains of the Linear Analog Scale Assessment (LASA) and on 7 of the 8 domains of the Short Form-36, version 2 (SF-36v2). Mean Hb increased by 2.2 +/- 1.3 g/dL (epoetin alfa) and by 0.1 +/- 1.0 g/dL (placebo) in the DBP (P < 0.001). Similar results were demonstrated in patients who switched from placebo to epoetin alfa in the OLP. Epoetin alfa was well tolerated; the most common adverse effects were headache and nausea., Conclusions: Epoetin alfa maintained RBV dose and improved QOL and Hb in anemic HCV-infected patients receiving combination therapy.

Treatment with recombinant human erythropoietin (epoetin alfa) has been shown to enhance quality of life and cognitive function. The mechanism of action for these changes appears to involve more than the alleviation of cancer treatment-induced anemia. Rather, there is increasing evidence that epoetin alfa treatment may modulate a series of cascading events that involve hypoxia-induced activation of vascular endothelial growth factor and an induction in the expression of vascular endothelial growth factor receptors via a hypoxia-inducible factor-1-mediated transcription among several other hypoxia-related events. The use of epoetin alfa to interfere with this hypoxia-induced cascade could provide significant benefits for cancer patients by enhancing survival through a direct modulation of tumor angiogenesis and effectiveness of cancer therapy. The enhanced quality of life seen with erythropoietin treatment may also involve a modulation of hypoxia-induced decrement in cognitive functioning. It appears that epoetin alfa is a useful addition to the treatment of breast cancer.

Background: Membrane biocompatibility has long been thought to be relevant to hemodialysis outcomes and, possibly, renal anemia., Methods: We performed a randomized, controlled, single-center study comparing the consequences on renal anemia of 2 dialyzers of equivalent performance, but different composition, during 7 months. Two hundred eleven patients of an unselected dialysis population of 235 patients gave informed consent to undergo random assignment to either group A (SF170E; modified cellulose triacetate/midflux membrane; Nipro, Osaka, Japan) or group B (HF80LS; polysulfone/high-flux membrane; Fresenius, Bad Homburg, Germany). Anemia management was identical in both treatment groups and followed strict clinical protocols managed by computer algorithms. Dialysis adequacy, hemoglobin (Hb) level, ferritin level, percentage of red blood cell hypochromicity, C-reactive protein (CRP) level, and intravenous iron and epoetin doses were monitored monthly., Results: One hundred seventy-seven patients completed the 7-month study. Equilibrated Kt/V increased in both groups. Hb outcome improved overall, but did not differ between the 2 study groups. Epoetin dose was not significantly different after 7 months compared with baseline in either group. Hb level, epoetin dose, iron status, CRP level, dialysis Kt/V, and residual renal function did not differ between the 2 groups. A slight but significant negative correlation was identified between dialysis Kt/V and Hb level in the population as a whole (Spearman's correlation, -0.16; P = 0.04)., Conclusion: No significant epoetin-sparing effect was identified through the use of the high-flux polysulfone HF80LS membrane over the modified cellulose triacetate SF170E membrane. Although not a primary outcome for this study, there was a suggestion of benefit of improved Hb level, without increased need for epoetin, through increasing delivered dialysis dose.

Human recombinant erythropoietin is the main treatment for anemia in renal patients. Recently, there have been case reports of pure red blood cell aplasia (PRCA) developing in renal patients administered erythropoietin, probably because of neutralizing antibodies detected in all these patients. All reports were from the West, and most patients were treated with erythropoietin-alpha. Cyclosporine is an immunosuppressive agent used to treat a spectrum of autoimmune conditions. We report a series of Chinese renal patients who developed PRCA after treatment with erythropoietin-alpha, suggesting that this is a problem worldwide. They were treated successfully with cyclosporine and became transfusion independent., (Copyright 2003 by the National Kidney Foundation, Inc.)

Background: The Predialysis Survey on Anemia Management was designed to assess the care given to predialysis patients within 3 months of the start of hemodialysis or peritoneal dialysis (PD) therapy. In this presentation, we focus on demographic data and patient referral practices of patients who enter kidney centers., Methods: We conducted a retrospective chart review of patients who had started hemodialysis or PD therapy between August 1999 and April 2000. All patients (age, 16 to 99 years) who entered 1 of the 779 centers in 21 European countries, Israel, or South Africa were included, except those for whom dialysis therapy was only started during an acute episode. Demographic characteristics, referral to kidney centers, comorbidities, drug treatments, major clinical events, and use of epoetin were documented., Results: Mean creatinine clearance rate at the first visit to the kidney center was 18.2 mL/min (0.303 mL/s). Of all patients, greater than 35% had a creatinine clearance less than 10.0 mL/min (<0.167 mL/s) at their first visit. Overall, 87% of patients were initiated on hemodialysis therapy, and 13% were started on PD therapy. PD was used more often the longer a patient was under the care of a nephrologist. Of 4,333 new dialysis patients, 68% had a hemoglobin concentration of 11.0 g/dL or less (< or =110 g/L) at the first visit., Conclusion: The majority of patients in the survey had been under the care of a nephrologist for more than 12 months before the start of dialysis therapy. Nevertheless, most of these patients were anemic, and only a minority were on epoetin treatment., (Copyright 2003 by the National Kidney Foundation, Inc.)

Background: Anemia is a common complication of advancing chronic kidney disease, yet little is known about the consistency of anemia treatment before end-stage renal disease (ESRD) and mortality on dialysis therapy., Methods: We studied 89,193 incident Medicare patients with ESRD in 1995 to 1997 aged 67 plus years with claims 2 years before their dialysis therapy initiation. Patients were classified as follows: no epoetin, 25% or less (least consistent), greater than 25% to 50%, greater than 50% to 75%, and greater than 75% (most consistent) epoetin treatment in the available months from the first pre-ESRD epoetin dose to the first ESRD service date. Cox regression modeled the risk for 1-year death in the post-ESRD period, adjusting for age, sex, race, diabetic status, albumin level, and incidence year., Results: Sixty percent of patients had hematocrits less than 30% at ESRD initiation, yet only 15.6% (N = 13,877) had epoetin claims before ESRD. The most consistent epoetin treatment group had hematocrits increase from 27.5% to 30.8% (P < 0.0001) by month 4 of treatment. Patients with the most consistent epoetin treatment had a greater mean hematocrit (29.2% +/- 0.11%; P < 0.0001) and albumin level (3.31 +/- 0.01 g/dL [33.1 g/L]) at initiation than those with the least consistent treatment (28.1% +/- 0.10% and 3.21 +/- 0.01 g/dL [32.1 g/L], respectively). The relative risk for death in patients with the least consistent versus the most consistent (the reference) epoetin treatment was 1.460 (95% CI, 1.245 to 1.713; P < 0.0001) 1 year after the first ESRD service date., Conclusion: Elderly patients with consistent pre-ESRD epoetin treatment had lower risks for death in the first year of dialysis therapy after ESRD initiation., (Copyright 2002 by the National Kidney Foundation, Inc.)

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., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Background: Darbepoetin alfa (Aranesp; Amgen, Thousand Oaks, CA) is a new erythropoiesis-stimulating protein with a threefold longer terminal half-life than recombinant human erythropoietin (epoetin) in patients with chronic kidney disease (CKD). The purpose of this randomized, double-blind, noninferiority study is to determine whether darbepoetin alfa is as effective as epoetin for the treatment of anemia in hemodialysis patients when administered at a reduced dosing frequency., Methods: Patients receiving epoetin therapy were randomized to continue epoetin administered intravenously (IV) three times weekly (n = 338) or change to darbepoetin alfa administered IV once weekly (n = 169). The dose of darbepoetin alfa or epoetin was individually titrated to maintain hemoglobin concentrations within -1.0 to +1.5 g/dL (-10 to +15 g/L) of patients' baseline values and within a range of 9.0 to 13.0 g/dL (90 to 130 g/L) for up to 28 weeks (20-week dose-titration period followed by an 8-week evaluation period). The primary end point was change in hemoglobin level between baseline and the evaluation period (weeks 21 to 28)., Results: Mean changes in hemoglobin levels from baseline to the evaluation period were 0.24 +/- 0.10 (SE) g/dL (2.4 +/- 1.0 g/L) in the darbepoetin alfa group and 0.11 +/- 0.07 g/dL (1.1 +/- 0.7 g/L) in the epoetin group, a difference of 0.13 g/dL (95% confidence interval [CI], -0.08 +/- 0.33 [1.3 g/L; 95% CI, -0.8 to 3.3]). This difference was not statistically significant or clinically relevant despite the reduced frequency of darbepoetin alfa administration. The safety profile of darbepoetin alfa was similar to that of epoetin, and no antibody formation to either treatment was detected., Conclusion: These results show that darbepoetin alfa maintains hemoglobin concentrations as effectively and safely as epoetin in patients with CKD, but with a reduced dosing frequency., (Copyright 2002 by the National Kidney Foundation, Inc.)