BACKGROUND Whether correction of anemia in patients with stage 3 or 4 chronic kidney disease improves cardiovascular outcomes is not established. METHODS We randomly assigned 603 patients with an estimated glomerular filtration rate (GFR) of 15.0 to 35.0 ml per minute per 1.73 m 2 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. RESULTS 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. CONCLUSIONS In patients with chronic kidney disease, early complete correction of anemia does not reduce the risk of cardiovascular events. (ClinicalTrials.gov number, NCT00321919.)

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

KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease.

KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target.

Although treating anemia of chronic kidney disease by erythropoiesis-stimulating agents (ESA) may improve survival, most studies have examined associations between baseline hemoglobin values and survival and ignored variations in clinical and laboratory measures over time. It is not clear whether longitudinal changes in hemoglobin or administered ESA have meaningful associations with survival after adjustment for time-varying confounders. With the use of time-dependent Cox regression models, longitudinal associations were examined between survival and quarterly (13-wk averaged) hemoglobin values and administered ESA dose in a 2-yr (July 2001 to June 2003) cohort of 58,058 maintenance hemodialysis patients from a large dialysis organization (DaVita) in the United States. After time-dependent and multivariate adjustment for case mix, quarterly varying administered intravenous iron and ESA doses, iron markers, and nutritional status, hemoglobin levels between 12 and 13 g/dl were associated with the greatest survival. Among prevalent patients, the lower range of the recommended Kidney Disease Quality Outcomes Initiative hemoglobin target (11 to 11.5 g/dl) was associated with a higher death risk compared with the 11.5- to 12-g/dl range. A decrease or increase in hemoglobin over time was associated with higher or lower death risk, respectively, independent of baseline hemoglobin. Administration of any dose of ESA was associated with better survival, whereas among those who received ESA, requiring higher doses were surrogates of higher death risk. In this observational study, greater survival was associated with a baseline hemoglobin between 12 and 13 g/dl, treatment with ESA, and rising hemoglobin. Falling hemoglobin and requiring higher ESA doses were associated with decreased survival. Randomized clinical trials are required to examine these associations.

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Associations Between Changes in Hemoglobin and Administered Erythropoiesis-Stimulating Agent and Survival in Hemodialysis Patients

It is unclear whether physiologic hemoglobin targets lead to cardiac benefit in incident hemodialysis patients without symptomatic heart disease and left ventricular dilation. In this randomized, double-blind study, lower (9.5 to 11.5 g/dl) and higher (13.5 to 14.5 g/dl) hemoglobin targets were generated with epoetin α over 24 wk and maintained for an additional 72 wk. Major eligibility criteria included recent hemodialysis initiation and absence of symptomatic cardiac disease and left ventricular dilation. The primary outcome measure was left ventricular volume index (LVVI). The study enrolled 596 patients. Mean age, duration of dialysis therapy, baseline predialysis hemoglobin, and LVVI were 50.8 yr, 0.8 yr, 11.0 g/dl, and 69 ml/m 2 , respectively; 18% had diabetic nephropathy. Mean hemoglobin levels in the higher and lower target groups were 13.3 and 10.9 g/dl, respectively, at 24 wk. Percentage changes in LVVI between baseline and last value were similar (7.6% in the higher and 8.3% in the lower target group) as were the changes in left ventricular mass index (16.8 versus 14.2%). For the secondary outcomes, the only between-group difference was an improved SF-36 Vitality score in the higher versus the lower target group (1.21 versus −2.31; P = 0.036). Overall adverse event rates were similar in both target groups; higher ( P

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Double-Blind Comparison of Full and Partial Anemia Correction in Incident Hemodialysis Patients without Symptomatic Heart Disease

BACKGROUND: The optimal haemoglobin concentration ([Hb]) for patients with end-stage renal failure is uncertain. In particular, it is unclear whether Hb normalization may be an advantage to such patients who are otherwise well. METHODS: A prospective, randomized, double-blind cross-over study was completed in 14 haemodialysis patients (12 male) aged between 23 and 65 years over a period of 18 months, using a variety of measures to examine the effect of epoetin at target [Hb] of 10 g/dl ([Hb](10)) and 14 g/dl ([Hb](14)). Patients were randomized to maintain one or other of the target levels for 6 weeks before being crossed over to the alternative [Hb]. Baseline data (mean [Hb]: 8.5+/-0.2 g/dl) were also included selectively. Six patients were known to be hypertensive. Comparisons were made between 24-h ambulatory blood pressure levels (ABP), echocardiographic findings and estimates of blood volume (BV), plasma volume (PV) and Hb mass. Quality of life estimates were obtained using the Sickness Impact Profile (SIP), and epoetin dosage requirements at target [Hb] were assessed. RESULTS: Daytime and nocturnal ABP (systolic and diastolic) were not different at the respective target [Hb], although nocturnal diastolic levels were higher compared with baseline (73+/-4 mmHg) at both [Hb](10) (83+/-3, P:<0.01) and [Hb](14) (81+/-6, P:<0.05). Significant reductions in cardiac output (5.2+/-0.3 vs 6.6+/-0.5 l/min, P:<0.01) and left ventricular end-diastolic diameter (4.8+/-0.2 vs 5.2+/-0.2 cm, P:<0. 001) were found at [Hb](14) compared with [Hb](10). Left ventricular mass index was correlated with both PV (P:<0.001) and BV (P:<0.01), but not with Hb mass. The PV decreased as the [Hb] rose (P:<0.001) but BV remained unchanged. Quality of life was significantly improved at [Hb](14) compared with [Hb](10) for both total score (6. 5+/-1.7 vs 13.4+/-3.0, P:=0.01) and psychosocial dimension score (5. 4+/-1.9 vs 15.4+/-4.0, P:<0.01). The maintenance weekly dose of epoetin required was 80% higher at [Hb](14) compared with [Hb](10) (P:<0.001). CONCLUSION: These data suggest there may be a significant haemodynamic and symptomatic advantage in maintaining a physiological [Hb] in haemodialysis patients. Although untoward effects were not identified in this study at [Hb](14), a substantially higher dose of epoetin is required to maintain this level.

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Leanne E. Grigg

Papers

Effects of haemoglobin normalization on quality of life and cardiovascular parameters in end‐stage renal failure