What are alternatives to erythropoiesis-stimulating agents (ESAs) for management of anemia of chronic disease and renal failure?

Updated: Apr 13, 2020
  • Author: Gates B Colbert, MD, FASN; Chief Editor: Emmanuel C Besa, MD  more...
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An alternative to the administration of exogenous ESAs is the use of agents that stimulate endogenous erythropoietin production in renal and nonrenal tissues. One class of investigational agents under development works to stabilize hypoxia-inducible factor (HIF) by inhibiting prolyl hydroxylase (PH) enzymes. [36] HIF is a key regulator of erythropoietic gene expression, iron absorption, energy metabolism, pH, and angiogenesis; as its name indicates, HIF is induced by hypoxia.

HIF-PH inhibitors improve iron mobilization to the bone marrow and induce considerably lower but more consistent blood erythropoietin levels than ESAs. These agents are administered orally.

Four HIF-PH inhibitors are currently under development: roxadustat, vadadustat, daprodustat, and molidustat. [36] In a phase 2a trial, vadadustat increased hemoglobin levels and improved biomarkers of iron mobilization and utilization in patients with anemia secondary to stage 3 or 4 CKD. Phase 3 trials of vadadustat in non–dialysis-dependent and dialysis-dependent patients are ongoing.

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