Complete Correction Of Anemia 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.

On both sides of the ocean.

On both sides of the ocean.

Anemia in Chronic Kidney Disease (Ckd). Do we know how to Treat it Properly

Renal anemia is one of the major complications observed in patients with chronic kidney disease (CKD). It is caused mainly by a relative erythropoietin deficiency due to progressive damage of renal parenchyma. The primary goal of anemia treatment using available today ESAs is not only to improve the quality of life of patients but, above all to reduce cardiovascular mortality. The target hemoglobin concentration during application of ESA in CKD patients treated conservatively and renal replacement therapy patients was and still is being discussed among nephrologists. Based on the clinical trials performed so far, it seems that in patients with renal anemia we should individualise treatment with ESA, seeking partial rather than complete correction of anemia.

New Strategies for Managing Anemia of Chronic Kidney Disease

Anemia is a prevalent and premature comorbidity in chronic kidney disease (CKD) and associated with multiple adverse clinical consequences including increased mortality. Today Erythropoiesis-stimulating agents (ESAs), together with iron supplementation, are the cornerstones of therapy for correcting anemia in CKD patients. As no generally accepted dosing algorithms for these agents exist, current recommendations prefer a partial but not complete anemia correction thereby favoring a more conservative and individualized ESA and iron dosing. Here we discuss in detail current evidence derived from large randomized trials about the proposed hemoglobin targets to aim at in CKD and End-Stage renal disease patients and report recent data from the thriving European market of biosimilar erythropoietins. We summarize promising investigational strategies including peginesatide and prolyl hydroxylase inhibitors for stabilization of the hypoxia inducible factor and provide a clinical review of novel high dose iron formulations like ferumoxytol or iron (III)-carboxymaltose. Taking these findings together, treatment strategies for anemia of CKD have got considerably more complicated so that a careful balance between maximization of patient`s quality of life while minimizing all risks associated with anemia treatment has become a major task of current nephrology.

ESAs in Transplant Anemia

ESAs in Transplant Anemia

Anemia na Doença Renal Crónica: da evidência à prática clínica.

Anemia in Chronic Kidney Disease (CKD) is present in approximately 90% of patients with glomerular filtration rate below 25-30 mL/min. It's impact in the quality of life makes it one of the major problems in CKD patients. Although the etiology is multifactorial the suboptimal production of erithropoietin caused by renal mass loss appears to be of major importance. After the introduction of Erythropoiesis Stimulating Agents (ESA's) the treatment of anemia in CKD has changed dramatically. Today, ESA's have a fundamental role in the increase of Hb values in CKD. Previously, severe anemia was frequent and blood transfusions were often necessary to improve patients quality of life. Small observational studies performed during the late 80's suggested that high Hb values may be benefic in CKD patients. At that time, the use of ESA's became universal. Later randomized trials tried to show the positive impact of rising Hb levels with ESA's in patient's outcome. The results of such studies were disappointing. Some of them even documented higher mortality associated with near normal Hb levels, failing to prove the real benefit of the complete correction of CKD anemia. We're still waiting for new randomized trials to be elucidated about the optimal target of Hb to achieve in CKD and the treatment algorithm with ESA's. Current evidence suggests that Hb values must be targetted at 11-12 g/dL, without reaching the complete correction of anaemia.

Complete correction of anemia by erythropoiesis-stimulating agents is associated with insulin resistance in hemodialysis patients

Insulin resistance and anemia secondary to erythropoietin deficiency characterize patients with end-stage kidney disease. In a cross-sectional analysis, we examined the relationship between erythropoietin-mediated correction of anemia and insulin sensitivity in nondiabetic hemodialysis patients. Insulin sensitivity (euglycemic-hyperinsulinemic clamp) and endogenous glucose production (primed-continuous infusion of [6,6-(2)H(2)]glucose) were determined in two groups of patients with normal hemoglobin (n:8; mean hemoglobin: 14.0±0.3g/dl) or with mild anemia (n:10; mean hemoglobin: 12.1±0.9g/dl). The patients with normal hemoglobin were receiving higher (P<0.05) erythropoietin doses than those with mild anemia (171±73 and 91±39Ukg(-1)wk(-1), respectively). The two groups were matched for all other potential determinants of insulin resistance. Endogenous glucose production was similar in the two groups of patients in the postabsorptive state and was completely suppressed by insulin infusion. During the hyperinsulinemic clamp, the rate of glucose infusion to maintain euglycemia was significantly lower (P<0.01) in the patients with normal hemoglobin levels [166±31mg(m(2))(-1)min(-1)] than in those with mild anemia [251±49mg(m(2))(-1)min(-1)] and in a group of matched controls [275±68mg(m(2))(-1)min(-1)]. In pooled patients, individual values of hemoglobin concentrations inversely correlated with the rates of insulin-mediated glucose infusion, both as absolute values (r=-0.58; P<0.05) and as values normalized by steady-state plasma insulin concentration (r=-0.74; P<0.001). In conclusion, this exploratory study indicates that complete correction of anemia by erythropoietin treatment in patients with end-stage kidney disease on hemodialysis is associated with impaired insulin sensitivity.

From Bench to Bedside: Hematopoietic Growth Factors (HGFs)- a Cause of Serious and Unanticipated Class Toxicities.

Abstract 4555 IntroductionHGFs have vastly improved the management of anemia, neutropenia, and thrombocytopenia, but are associated with unexpected toxicities. MethodsToxicities associated with granulocyte, erythroid, and thrombopoietic growth factors were reviewed. Data sources included systematic reviews, clinical trials, guidelines, and materials disseminated by the Food and Drug Administration (FDA), the European Medicines Agency (EMEA), and Canada Health and their advisory committees; product labels and safety notifications disseminated by manufacturers; and utilization data. Data abstracted were thromboembolic complications, immune-mediated cytopenias, bone marrow toxicities, systematic and synergistic toxicities, and regulatory responses.Results Granulopoiesis agentsPulmonary infiltrates were associated with administration of HGFs with bleomycin or chest radiation. Increased myelodysplasia (MDS) or acute myeloid leukemia (AML) risks among chemotherapy (chemo)-treated breast cancer patients were reported. ESAsIncreased mortality and tumor progression were seen when cancer patients received ESAs versus placebo; increased mortality and cardiovascular events were reported when chronic kidney disease (CKD) patients received ESAs targeted to complete anemia correction. Between 1998 and 2003, 191 CKD patients developed neutralizing antibodies and pure red cell aplasia (PRCA) following recombinant erythropoietin administration. Thrombopoietins (TPO)TPO receptor agonist administration is associated with bone marrow reticulin and collagen deposition. 3% of healthy volunteers who received repeated rHuMGDF developed neutralizing autoantibodies and severe thrombocytopenia. ConclusionsWhile ESAs, granulopoietic factors, and thrombopoietins have important clinical benefits, they also retain the potential to exhibit serious and unanticipated toxicities.ESAsGranulopoiesis agentsThrombopoietinsMortality risksIncreased risks among CKD patients targeted to complete anemia correction and ESA treated cancer patients**Increased countsPossibly related to mortality in cancer and CKD patientsSplenic rupture in peripheral stem cell donorsSeen with 2nd generation agents, no toxicityThrombosis1.6x increased risks among cancer patients, 1.3x increased risks among CKD patients randomized to complete anemia correctionRarely reported. Case reports of heart attack or stroke among healthy peripheral blood stem cell donors who received GCSF*Tumor cell stimulationDownstream and stimulatory effects identified with erythropoietin receptor activationIncreased risks of MDS/AML among breast cancer, chemo and chronic neutropenia patients who received GCSF* (TPO receptor not seen in tumors)Autoantibody formationPRCA with ESAs*Seen among 3% of 324 healthy volunteers who received rHuMGDFStem cell depletion*Severe cytopenias with granulopoiesis agents and 5-fluorouracil or radiation therapy*Bone marrow reticulin/ fibrosis**Seen with 2nd generation TPOsIncreased bone marrow collagen**Rarely seen with 2nd generation TPOsWorsening of cytopenia following treatment cessation**Seen with romiplostim and eltrombopagSystemic toxicities*Bone pain with GCSF and peg GCSF; pleural and cardiac effusions with GMCSFïz½Hepatic toxicity following eltrombopagSynergistic toxicitiesESAs and lenalidomide increase the risk of thrombosis ESAs are suspected to aid NSF pathogenesisGSCF combined with topoisomerase II inhibitors shown to increase myeloid leukemias Incidences of pulmonary toxicity when bleomycin is combined with GCSF*Toxicity among healthy individualsDeaths reported with ESA use among high performance athletes2 healthy donors developed AML after GCSF and peripheral blood donation 15 healthy peripheral blood stem cell donors had splenic ruptures with GCSF, GMCSF, or peg GCSF3% of 324 healthy volunteers developed neutralizing antibodies and severe thrombocytopenia following repeated rHuMGDF administration. 3 of the 324 volunteers developed lymphoid malignanciesToxicity with off-label administrationESA manufacturers report safety concerns with off-label ESA useHigh rates of neutropenia and thrombocytopenia when GCSF or GMCSF are administered in certain off-label settingsHigh rates of accelerated MDS or AML when TPOR activators administered off-label to MDS patients*=Not reported Disclosures:No relevant conflicts of interest to declare.

Left Ventricular Geometry Predicts Cardiovascular Outcomes Associated with Anemia Correction in CKD

Partial correction of anemia in patients with chronic kidney disease (CKD) reduces left ventricular hypertrophy (LVH), which is a risk factor for cardiovascular (CV) morbidity, but complete correction of anemia does not improve CV outcomes. Whether LV geometry associates with CV events in patients who are treated to different hemoglobin (Hb) targets is unknown. One of the larger trials to study the effects of complete correction of anemia in stages 3 to 4 CKD was the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) trial. Here, we analyzed echocardiographic data from CREATE to determine the prevalence, dynamics, and prognostic implications of abnormal LV geometry in patients who were treated to different Hb targets. The prevalence of LVH at baseline was 47%, with eccentric LVH more frequent than concentric. During the study, LVH prevalence and mean left ventricular mass index did not change significantly, but LV geometry fluctuated considerably within 2 yr in both groups. CV event-free survival was significantly worse in the presence of concentric LVH and eccentric LVH compared with the absence of LVH (P = 0.0009 and P < or = 0.0001, respectively). Treatment to the higher Hb target associated with reduced event-free survival in the subgroup with eccentric LVH at baseline (P = 0.034). In conclusion, LVH is common and associates with poor outcomes among patients with stages 3 to 4 CKD, although both progression and regression of abnormal LV geometry occur. Complete anemia correction may aggravate the adverse prognosis of eccentric LVH.

Negative effects of anemia on quality of life and its improvement by complete correction of anemia by administration of recombinant human erythropoietin in posttransplant patients

Anemia is a common complication in posttransplant patients (posttransplant anemia: PTA). We tested the hypothesis that targeting hemoglobin (Hb) over 13.3 g/dl by administration of recombinant human erythropoietin (rHuEPO-ad) has positive impact on quality of life (QOL). Twenty-four patients, whose initial Hb and estimated glomerular filtration rate (eGFR) were 10.5 +/- 0.2 g/dl and 48.5 +/- 2.7 ml/(min 1.73 m2), respectively, were enrolled in the present study. Physical and mental QOL in these patients before and after rHuEPO-ad were acquired and summarized as physical summary sore (PSC) and mental summary sore (MSC), respectively, by the 36-item Short Form (SF-36), an international questionnaire for analysis of QOL. Before rHuEPO-ad, posttransplant patients had preserved MSC (54.1 +/- 2.3) but impaired PSC (32.6 +/- 3.2). rHuEPO-ad for 6 months increased their Hb to 13.7 +/- 0.3 g/dl. This was accompanied by improvement of PSC (49.1 +/- 2.1: P < 0.01 versus before rHuEPO-ad). MSC was preserved during rHuEPO-ad (54.4 +/- 1.6: NS versus before rHuEPO-ad). There was inverse correlation between initial PSC or MSC and responses of these parameters to rHuEPO-ad (PSC, P = 0.007; MSC, P = 0.009). Patients whose initial PSC was lower than 39.6 or whose initial MSC was lower than 39.4 were expected to improve their PSC or MSC by more than 10 by rHuEPO-ad. Anemia in posttransplant patients has negative impacts on their QOL. Scoring mental and physical QOL by SF-36 in posttransplant patients is useful to identify groups of patients whose QOL could be improved by rHuEPO-ad.

Triumph and tragedy: anemia management in chronic kidney disease

Recent trial data have resulted in a reevaluation of the management of anemia in chronic kidney disease, including the use of erythropoiesis-stimulating agents, intravenous iron, and novel pharmaceuticals. In this review, we evaluate the latest research on anemia management in chronic kidney disease. Clinical trials of erythropoiesis-stimulating agents indicate that targeting the complete correction of anemia in patients with chronic kidney disease results in a greater risk of morbidity and mortality despite improved hemoglobin and quality of life. Conversely, intravenous iron has been found effective and relatively well tolerated in treating anemia in chronic kidney disease, even in patients with elevated ferritin. New agents to manage anemia, including long-acting erythropoietin derivatives, are also in active development. Erythropoiesis-stimulating agents should be used to target hemoglobin 11-12 g/dl in patients with chronic kidney disease. Intravenous iron may be beneficial for patients with hemoglobin less than 11 g/dl and transferrin saturation less than 25% despite elevated ferritin (500-1200 ng/ml). An upcoming placebo-controlled trial of darbepoetin should help to define the role of erythropoiesis-stimulating agents in chronic kidney disease.

The Effect of Hemoglobin Level on Arteriovenous Fistula Survival in Iranian Hemodialysis Patients

Objective End-stage renal disease (ESRD) poses steadily growing challenges to health care systems worldwide. Renal replacement therapy with hemodialysis (HD) or kidney transplantation is the only possibility for ESRD patient survival. A complete correction of anemia in HD patients may lead to an increased risk of vascular arteriovenous fistula (AVF) primary failure; some studies have demonstrated that decreased levels of hemoglobin (Hb) had adverse effects on cardiac and brain function. This study was designed to evaluate the impact of different risk factors, especially the Hb level on AVF survival. Methods Prospective observational data were analyzed from a non-randomized sample (n=100) of HD patients who were referred for first AVF creation between April 2005 and December 2006 with &lt;1 month on HD. The relative risk (RR) of access primary failure was evaluated in four different groups of patients divided according to their Hb levels (&lt;8, 8–10, 10–12, and &gt;12 g/dL). Other factors possibly influencing vascular access (VA) survival were also considered including gender, age, smoking, diabetes, hypertension, parathyroid hormone levels, ACE inhibitor intake and triglyceride levels. The analyses were performed using SPSS v.11.5, Kaplan-Meier analysis, Cox's regression and log rank test. Results There was a statistically significant higher risk of AVF primary failure in patients with Hb &lt;8 g/dL (RR=1.41; p=0.01), diabetes (RR=1.21; p=0.05), age&gt;60 yrs (RR=1.41; p=0.06) were identified as predictive factors for AVF primary failure. ACE inhibitor intake (RR=0.45; p=0.01) was found to be protective. Conclusion Correction of serum Hb level can lead to a better result in VA survival and ACE inhibitor intake was found to be a protective factor.

Latest US KDOQI Anaemia Guidelines update what are the implications for Europe?

Keywords: anaemia; clinical guidelines; EBPG;KDIGO; KDOQI; CREATE; CHOIR; TREATIn medicine, large randomized controlled trials arepowerful entities; not only do they influence clinicalpractice and impact on clinical practice guidelines, butthey also have the ability to confuse the medical andnon-medical community by producing surprising oralarming results that question current concepts ofclinical management. Examples of this in the non-nephrological literature include the Women’s HealthInitiative trial of hormone replacement therapy forcardiovascular protection in post-menopausal women[1]. This very large placebo-controlled randomized trialin over 16000 post-menopausal women showedbeyond doubt that combined oestrogen and progester-one replacement did not reduce cardiovascular risk,but in fact increased it. Similarly, in the CAST trial(Cardiac Arrhythmia Suppression Trial), the hypoth-esis was that anti-arrhythmic drugs such as flecainideand encainide would reduce the incidence of ventri-cular arrhythmias post-myocardial infarction [2].In fact, mortality was increased with the use of suchagents. Closer to home, in nephrological practice, theresults of the HEMO study countermanded theprevious belief that more dialysis was better, and thathigh-flux dialysis was better than low-flux dialysis [3].Similarly, the 4D (Die Deutsche Diabetes Dialyse)study of atorvastatin in diabetic haemodialysispatients confused the issue regarding the cardiovascu-lar protective role of statin therapy in this patientpopulation [4].In the renal anaemia field, the US NormalHematocrit Trial by Besarab and colleagues [5] beganto discredit the hypothesis that aiming fornormalization of haemoglobin in dialysis patientswith symptomatic cardiovascular disease was betterthan aiming for incomplete correction of anaemia byepoetin therapy. Although this addressed patients withsevere cardiac disease only [6], a subsequent rando-mized double-blind trial in dialysis patients withoutsymptomatic cardiac disease, reported by Parfrey et al.[7], also showed no benefit of a haemoglobin targetwithin the normal range, in comparison with partialanaemia correction, on left ventricular hypertrophy.More recently, we have seen the publication ofthe CREATE and CHOIR studies in the sameissue of the New England Journal of Medicine [8,9].Both of these studies yielded useful data addressing theissue of optimal target haemoglobin ranges in chronickidney disease patients not on dialysis, an area thatpreviously lacked high-quality evidence to supportclinical practice recommendations. The CREATEstudy suggested that early and complete correction ofanaemia does not improve cardiovascular outcomescompared with later and incomplete correction ofanaemia [8]. Moreover, the number of patients startingchronic dialysis was higher in the higher haemoglobinarm. The main limitation of the CREATE study wasthat it ended up under-powered, due to a lower annualevent rate incidence of 6% compared with the 15%used for the sample size calculation.Of even greater concern, however, were the datafrom the CHOIR study [9]. This large prospectiverandomized trial in the United States suggestedthat aiming for a target haemoglobin of 13.5g/dl isharmful compared to targeting a haemoglobin of11.3g/dl, in terms of the composite end-point ofdeath, myocardial infarction, stroke and hospitaliza-tion for cardiac failure. Although the CHOIR data areimportant and informative, one should be aware of thefeatures of this study, which may limit the general-izability and the strength of its results. These have beenextensively discussed elsewhere [10,11], but in short,these include: 50% of the patient population, diabetic,imbalances in the patient groups at baseline [the higher

Hemoglobin Normalization Studies

Correspondence to: D. Reddan, Department of Nephrology, National University of Ireland, Galway, Unit 1, Merlin Park Hospital, Merlin Park, Galway, Ireland. donal.reddan@mailn.hse.ie Received 12 April 2007; accepted 24 May 2007. Anemia is highly prevalent among chronic kidney disease (CKD) patients (1) and patients receiving renal replacement therapy. Since erythropoiesis-stimulating agent (ESA) therapy became routinely available in the late 1980s, anemia of CKD has been treated with various ESAs, such as erythropoietin (EPO) alfa (Procrit, Johnson & Johnson, New Brunswick, New Jersey, USA; Epogen, Amgen, Thousand Oaks, California, USA), erythropoietin beta (Neorecormon, Hoffmann-La Roche, Basel, Switzerland), and darbepoetin alfa (Aranesp, Amgen). Anemia of CKD is clearly associated with reduced quality of life (QOL) and an increase in risk of death and cardiovascular events (2–4); this observation led to the hypothesis that aggressive correction of anemia might lead to improved mortality and better cardiovascular and QOL outcomes. Over recent years, average hemoglobin levels and EPO doses have been increasing, and higher targeted levels of Hb have been recommended in clinical guidelines. The rationale for these gradual increases in dose and targets was supported by extensive retrospective evidence (2–5) and QOL data that suggested a benefit to higher Hb levels. Surprisingly, however, trial evidence has contradicted conclusions made from retrospective data. The Besarab trial, published in 1998 (6), suggested a potential cardiovascular risk from complete correction of anemia among ESRD patients, and three trials during intervening years have not demonstrated a significant benefit in terms of changes in left ventricular (LV) geometry for varying levels of anemia correction with EPO (7–9).

Complete Correction of Anemia Caused by Renal Disease May Increase Mortality

The optimal target hemoglobin level in erythropoietin-treated patients with chronic renal disease has long been a source of controversy. Current

Complete Correction of Anemia of Renal Failure Is Not Advised

Anemia is a major complication of renal failure, but it usually is correctable by administration of erythropoietin (EPO). However, if hemoglobin (Hb)

Anemia and Cardiovascular Risk

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

Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia

Whether correction of anemia in patients with stage 3 or 4 chronic kidney disease improves cardiovascular outcomes is not established. We randomly assigned 603 patients with an estimated glomerular filtration rate (GFR) of 15.0 to 35.0 ml per minute per 1.73 m2 of body-surface area and mild-to-moderate anemia (hemoglobin level, 11.0 to 12.5 g per deciliter) to a target hemoglobin value in the normal range (13.0 to 15.0 g per deciliter, group 1) or the subnormal range (10.5 to 11.5 g per deciliter, group 2). Subcutaneous erythropoietin (epoetin beta) was initiated at randomization (group 1) or only after the hemoglobin level fell below 10.5 g per deciliter (group 2). The primary end point was a composite of eight cardiovascular events; secondary end points included left ventricular mass index, quality-of-life scores, and the progression of chronic kidney disease. During the 3-year study, complete correction of anemia did not affect the likelihood of a first cardiovascular event (58 events in group 1 vs. 47 events in group 2; hazard ratio, 0.78; 95% confidence interval, 0.53 to 1.14; P=0.20). Left ventricular mass index remained stable in both groups. The mean estimated GFR was 24.9 ml per minute in group 1 and 24.2 ml per minute in group 2 at baseline and decreased by 3.6 and 3.1 ml per minute per year, respectively (P=0.40). Dialysis was required in more patients in group 1 than in group 2 (127 vs. 111, P=0.03). General health and physical function improved significantly (P=0.003 and P<0.001, respectively, in group 1, as compared with group 2). There was no significant difference in the combined incidence of adverse events between the two groups, but hypertensive episodes and headaches were more prevalent in group 1. In patients with chronic kidney disease, early complete correction of anemia does not reduce the risk of cardiovascular events. (ClinicalTrials.gov number, NCT00321919 [ClinicalTrials.gov].).

Effect of Early Correction of Anemia on the Progression of CKD

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

Managing a fateful alliance: anaemia and cardiovascular outcomes

Cardiovascular disease (CVD) is a significant complication in chronic kidney disease (CKD) and a major cause of death in dialysis patients. Clinical studies have shown that anaemia is associated with reduced survival in patients with renal disease, heart failure or both. There is also evidence that, even in otherwise healthy individuals, anaemia is independently associated with an increased risk of CVD. The body adapts to anaemia by increasing cardiac output, which may result in cardiac remodelling and progression of left ventricular (LV) growth. Indeed, low haemoglobin (Hb) has been identified as an independent risk factor for LV growth in CKD patients, suggesting that there is a direct link between anaemia and adverse cardiac outcomes. This suggests that correction of anaemia with recombinant human erythropoietin (rhEPO; epoetin) may improve prognosis. Partial correction of anaemia produces partial regression of LV hypertrophy, while complete correction of anaemia can help to prevent LV dilatation in haemodialysis patients with normal LV volumes. Moreover, in non-dialysis patients with advanced CVD, pilot studies showed that a moderate increase in Hb improved cardiac function and reduced hospitalization rates. In addition, consistent epoetin treatment before the start of dialysis was associated with a reduced risk of developing cardiac disease in CKD patients. In contrast, in dialysis patients with advanced cardiac disease, Hb normalization increased mortality risk. Therefore, early correction of anaemia appears important. The Cardiovascular risk Reduction by Early Anaemia Treatment with Epoetin beta (CREATE) study is investigating whether this approach is associated with a measurable reduction in cardiovascular risk.