Anemia treatment in patients with chronic kidney disease.

Anemia develops in most persons with progressive chronic kidney disease. When it becomes severe, the administration of erythropoiesisstimulating agents (ESAs) is generally required, along with the repletion of iron stores and the correction of other causes of anemia. The introduction of ESAs 30 years ago markedly improved the lives of many patients with chronic kidney disease, who until then had severe, often transfusion-dependent anemia.1 Two types of recombinant human erythropoietin (epoetin alfa and epoetin beta) have been available since ESAs first came into use; both types are highly effective but short-acting (approved for dosing three times a week). Subsequently, two second-generation ESAs with an extended duration of action were developed — darbepoetin alfa, which has an altered glycosylation pattern, and a continuous erythropoietinreceptor activator called methoxy polyethylene glycol-epoetin beta (PEG-EPO) (Mircera, Hoffmann –La Roche), which contains a polyethylene-glycol moiety. Darbepoetin alfa is approved for dosing every 2 weeks worldwide, and PEG-EPO for dosing once a month in Europe. In addition to the original formulations, biologically similar and “copy” ESAs have been developed. In all cases, the production of firstand second-generation ESAs involves the use of complex recombinant DNA technology and mammalian cell lines. The Kidney Disease: Improving Global Outcomes (KDIGO) work group recently suggested that only ESAs that have been formally approved by an independent regulatory agency (level of evidence 2D) should be prescribed, a recommendation created to avoid potentially serious and unanticipated adverse events.2 On the basis of observational studies conducted during the early days of erythropoietin usage, clinicians aimed to normalize hemoglobin levels in patients with chronic kidney disease. However, randomized, controlled trials later showed that partial correction of anemia was preferable to complete correction, a practice aimed at reducing the risk of cardiovascular events and other potential adverse events. Subsequently, KDIGO suggested that in general, ESAs should not be used to maintain hemoglobin levels above 11.5 g per deciliter in adult patients with chronic kidney disease (level of evidence 2C).2 However, it is unclear whether the negative effects of the complete correction of anemia are due primarily to high hemoglobin levels per se, to excessive ESA doses, or to both.3 In the past decade, several new approaches to the correction of anemia have been tried, including erythropoietin gene therapy,4 the stabilization of hypoxia-inducible factor,5 and peptidebased erythropoietic agents, such as the dimeric pegylated peptide, peginesatide.6 Such peptidebased erythropoietic agents are not homologous with erythropoietin and therefore exhibit no antibody cross-activity. This means that patients with transfusion-dependent chronic kidney disease with antibody-mediated pure red-cell aplasia may be “rescued” upon treatment with drugs of this class.7 In this issue of the Journal, Macdougall et al.8 and Fishbane et al.9 report the results of four event-driven, randomized, controlled, open-label trials that compared the efficacy and safety of peginesatide with standard ESA therapy. In one pair of studies, PEARL 1 and 2 (Peginesatide for the Correction of Anemia in Patients with Chronic Renal Failure Not on Dialysis and Not Receiving Treatment with Erythropoiesis-Stimulating