Potential mechanisms of adverse outcomes in trials of anemia correction with erythropoietin in chronic kidney disease

Abstract

Advanced chronic kidney disease (CKD, stages 3–5) is almost invariably associated with anemia that is primarily caused by depressed production of erythropoietin (EPO), oxidative stress and inflammation [1,2]. This can be compounded by iron deficiency that is caused by loss of blood from repetitive laboratory tests, residual blood remaining in the hemodialysis circuits, fistula puncture site bleeding and uremic platelet dysfunction. In addition, when present, hemolytic disorders, bone marrow suppression, nutritional deficiencies, drug toxicities and hereditary diseases exacerbate the CKD-associated anemia. The EPO-deficiency and iron-deficiency components of anemia are routinely corrected with the use of recombinant human EPO and iron preparations. However, presence of severe oxidative stress and inflammation hampers efficacy of EPO and iron in promoting erythropoiesis. In this context, severe persistent anemia despite high doses of EPO and iron is commonly due to oxidative stress and inflammation that may actually be intensified by intravenous iron and EPO administration [3–5]. Observational studies have revealed a strong association between severity of anemia and risk of morbidity and mortality from cardiovascular disease and other causes in CKD patients [6–10]. These findings have been widely interpreted as evidence for the causal role of anemia in the pathogenesis of adverse outcomes in this population. Contrary to expectations, randomized clinical trials of anemia correction revealed either no effect or increased morbidity and mortality in patients assigned to normal hemoglobin (Hb) targets [11–13]. In fact, meta-