Treatment of Anemia in Kidney Disease: Beyond Erythropoietin.

Anemia is common in patients with chronic kidney disease. Treatment with erythropoiesis-stimulating agents has decreased transfusion rates, but has not been consistently shown to improve cardiovascular outcomes or quality of life. Moreover, treatment to hemoglobin levels normal for the general population (13-14 g/dL) has resulted in increased cardiovascular morbidity and mortality versus lower hemoglobin targets, and some patients with chronic kidney disease do not reach these lower hemoglobin targets despite escalating doses of erythropoiesis-stimulating agents. The pathophysiology of anemia in patients with chronic kidney disease has been informed by the discovery of hypoxia-inducible factor and hepcidin pathways. Recent innovations in anemia treatment leverage knowledge of these pathways to effectively raise hemoglobin levels independent of erythropoiesis-stimulating agent administration. Several agents that stabilize hypoxia-inducible factor are undergoing or have completed phase 3 clinical trials. These agents appear to have equal efficacy as erythropoiesis-stimulating agents in raising hemoglobin levels and have not been associated with major safety signals to date. Because of the potential for off-target effects from non-anemia-related gene transcription by hypoxia-inducible factor stabilization, longer-term follow-up studies and registries will be needed to ensure safety. Agents that modulate hepcidin have undergone early clinical trials with mixed results regarding safety and efficacy in increasing hemoglobin levels. Sodium-glucose cotransporter 2 inhibitors, which also decrease hepcidin levels, have been associated with increased hemoglobin levels among patients with chronic kidney disease in clinical trials exploring proteinuria and kidney disease progression.