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  • Review Article
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Anemia and anemia correction: surrogate markers or causes of morbidity in chronic kidney disease?

Nature Clinical Practice Nephrology volume 4, pages 436–445 (2008)Cite this article

Abstract

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

Key Points

  • Contrary to common perception, the observational association of anemia with cardiovascular and all-cause mortality in patients with chronic kidney disease (CKD) does not necessarily reflect causality; rather, anemia and adverse outcomes are both caused by inflammation and oxidative stress

  • In addition to their well-known erythropoietic functions, erythropoietin and iron have many other actions that are essential when these agents are at physiological levels, but they are potentially hazardous when at high levels

  • The increased risk of adverse outcomes observed in patients with CKD assigned to higher hemoglobin targets in randomized clinical trials is probably a result of the extra-erythropoietic actions of erythropoietin and/or iron that result from excessive dosing, as opposed to anemia correction per se

  • The range of 'safe' hemoglobin levels varies widely among patients with CKD; consequently, the blanket application of arbitrary hemoglobin targets to all patients with CKD, as called for by clinical guidelines, is impractical and potentially harmful

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Figure 1: The contribution of oxidative stress and inflammation to adverse cardiovascular outcomes and anemia in patients with chronic kidney disease.

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  1. Division of Nephrology and Hypertension, UCI Medical Center, 101 The City Drive, Building 53, Room 125, Route 81, Orange, CA 92868, USA ndvaziri@uci.edu

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  1. Physiology and Biological Science and Director of the Division of Nephrology and Hypertension at the University of California, ND Vaziri is Professor of Medicine, Irvine, CA, USA.,

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Vaziri, N. Anemia and anemia correction: surrogate markers or causes of morbidity in chronic kidney disease?. Nat Rev Nephrol 4, 436–445 (2008). https://doi.org/10.1038/ncpneph0847

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