Hypoxia-inducible factor prolyl hydroxylase inhibitors: a paradigm shift for treatment of anemia in chronic kidney disease?

Abstract

Introduction: The hypoxia-inducible factor prolyl hydroxylase (HIF-PH) pathway is responsible for regulating the biosynthesis of erythropoietin (EPO) and maintaining iron homeostasis. Investigational drugs that target the HIF-PH pathway are promising alternatives for treating anemia in Chronic Kidney Disease (CKD).

Areas covered: This review summarizes recent advances focused on the clinical development of HIF-PH inhibitors (HIF-PHIs) as potentially novel therapies in the treatment of anemia in CKD based on publications available on PubMed and restricted Google searches. We provide a comparison between HIF-PHIs regarding their pharmacokinetics, dosing regimens and safety concerns, structure-activity relationships, and alterations in key laboratory parameters observed in animal models and clinical trials.

Expert opinion: HIF-PHIs may be advantageous in some aspects compared to the conventional erythropoiesis-stimulating agents (ESAs). While ESAs could increase the risk of cardiovascular events due to rapid rises in ESA blood levels, HIF-PHIs have been reported to maintain EPO concentrations at levels that are closer to the normal physiological ranges. Although HIF-PHIs have been demonstrated to be relatively safe and effective in clinical trials, long-term safety data are needed in order to establish whether these therapeutic agents will lead to a major paradigm change in the treatment of anemia of CKD.

Keywords: Anemia; chronic kidney disease; erythropoiesis stimulating agents; erythropoietin; hepcidin; hepcidin antagonists; hypoxia-inducible factor prolyl hydroxylase inhibitors; iron.