Anemia trials in CKD and clinical practice: refining the approach to erythropoiesis-stimulating agents

As our knowledge of managing renal anemia with recombinant human erythropoietin has grown, new clinical challenges have emerged. Although initial observational studies produced important favorable results, troubling observations later came from 4 randomized controlled trials that assigned CKD patients to intervention with an erythropoiesis-stimulating agent (ESA) to achieve high hemoglobin levels (Hb). The difference between the observational studies and these randomized controlled trials comes from the observation of higher cardiovascular events when targeting higher Hb, but lower events once patients had achieved these Hb targets. In all of the 4 RCTs, the primary intervention was 'targeting' a higher Hb, and using higher dosages of ESA as the means. Therefore, the question to be solved is: what is harmful with recombinant human erythropoietin--targeting higher hemoglobin or achieving higher hemoglobin? Evidence supporting a relationship between ESA exposure and worse outcomes is not universal, and these comorbidities would require the administration of high doses. However, increasing ESA doses in hyporesponsive patients to achieve a specific target is not reasonable. Managing anemia in CKD patients is complex. It is affected by the underlying disease, comorbid conditions, the environment and several other factors that differ among patients. Thus, anemia management in these patients needs an individualized approach. Each patient should be treated according to a Hb target with the lowest effective ESA dose, while avoiding large fluctuations in Hb levels or prolonged periods outside the target. This strategy may necessitate changes to the ESA dose, dosing frequency and iron supplementation over the course of a patient's treatment, and proactive management of conditions that can affect ESA responsiveness. While all ESAs effectively increase Hb levels, differences with respect to route of administration, pharmacokinetics, and dosing frequency and efficiency should be considered to maximize the benefits of ESA treatment for the individual patient.