Mechanism of increased mortality risk with erythropoietin treatment to higher hemoglobin targets.

Recent randomized, controlled trials indicate that there is a strong trend for increased risk for death or adverse composite outcomes with erythropoiesis-stimulating agent treatment in kidney disease to hemoglobin targets higher than those currently recommended. The failure of these trials to find a benefit of higher hemoglobin is in stark contrast to findings from large, observational, population-based studies that continue to demonstrate the association of low hemoglobin with adverse outcomes. The mechanisms for the adverse effect of higher hemoglobin targets that are seen in the randomized, controlled trials are poorly understood. This review explores hypotheses involving (1) the effect of achieved hemoglobin itself, (2) the role of erythropoiesis-stimulating agent treatment, (3) the use of iron supplementation, (4) increased blood pressure, and (5) erythropoiesis-stimulating agent hyporesponsiveness. Because the causal pathway has yet to be determined, further research is strongly encouraged. Clinical practice, however, should avoid erythropoiesis-stimulating agent treatment to higher hemoglobin targets, particularly in those with significant cardiovascular morbidity and those who require disproportionately high dosages of erythropoietin-stimulating agents to achieve recommended hemoglobin levels.