Hypoxia-inducible factor prolyl hydroxylase inhibitor in the treatment of anemia in chronic kidney disease

Curr Opin Nephrol Hypertens. 2020 Jul;29(4):414-422. doi: 10.1097/MNH.0000000000000617.

Abstract

Purpose of review: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are orally active small molecules and are launched as novel therapeutic agents for anemia in chronic kidney disease (CKD). In contrast to conventional exogenous erythropoietin (EPO) administration, HIF-PHIs stimulate endogenous EPO production and improve iron metabolism via stabilization of hypoxia-inducible factor (HIF). This review summarizes the mechanism of action, the results of clinical trials, and future perspectives of HIF-PHIs.

Recent findings: Six HIF-PHIs are currently under phase III studies, some of which have been already completed. According to the results of clinical trials, HIF-PHIs increased and maintained hemoglobin levels in both nondialysis-dependent and dialysis-dependent CKD patients with physiological EPO concentrations. HIF-PHIs also improved iron utilization and were comparably effective regardless of underlying inflammation and iron status.

Summary: HIF-PHIs have several advantages including oral administration, physiological EPO secretion, and improved iron utilization. Undoubtedly, HIF-PHIs will pave the new way in the field of treatment of anemia in CKD, but it should be noted that HIFs have pleiotropic effects on a plethora of cellular functions, which might lead to either beneficial or undesirable off-target effects. Intensive postmarketing surveillance is crucially important to identify unexpected consequences.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Anemia / drug therapy*
  • Anemia / etiology*
  • Erythropoietin / metabolism
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases / antagonists & inhibitors*
  • Hypoxia-Inducible Factor-Proline Dioxygenases / metabolism
  • Iron / metabolism
  • Prolyl-Hydroxylase Inhibitors / therapeutic use*
  • Renal Insufficiency, Chronic / complications*
  • Renal Insufficiency, Chronic / drug therapy*

Substances

  • EPO protein, human
  • Prolyl-Hydroxylase Inhibitors
  • Erythropoietin
  • Iron
  • EGLN2 protein, human
  • Hypoxia-Inducible Factor-Proline Dioxygenases