Importance of Physiological Erythropoiesis in the Treatment of Chronic Kidney Disease-Associated Anemia

Recent large clinical trials have reported that despite the maintenance of target hemoglobin (Hb) levels, higher doses of erythropoiesis-stimulating agents (ESAs) and/or iron preparations are significantly associated with higher risks of adverse events and death in maintenance hemodialysis (MHD) patients. Higher doses of ESAs have been demonstrated to result in a higher risk for cardiovascular disease due to elevated blood pressure or increased thrombogenicity. In addition, a high dose of iron might enhance inflammatory responses to infection and impair the phagocytic function of neutrophils. Moreover, iron induces the generation of hydroxyl radicals, which accelerate atherosclerosis. Patients with hyporesponsiveness to ESAs or dysutilization of iron for erythropoiesis tend to be treated with ESAs or iron at doses exceeding the physiological level. However, the optimal doses of ESAs and iron for maintaining target Hb levels in these patients are not well established. Thus, from the perspective of long-term survival in chronic kidney disease patients, it is necessary to treat anemia with appropriate doses of ESAs and an iron that can induce physiological erythropoiesis.