Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience

Adv Chronic Kidney Dis. 2019 Jul;26(4):253-266. doi: 10.1053/j.ackd.2019.04.004.

Abstract

Prolyl hydroxylase domain oxygen sensors are dioxygenases that regulate the activity of hypoxia-inducible factor (HIF), which controls renal and hepatic erythropoietin production and coordinates erythropoiesis with iron metabolism. Small molecule inhibitors of prolyl hydroxylase domain dioxygenases (HIF-PHI [prolyl hydroxylase inhibitor]) stimulate the production of endogenous erythropoietin and improve iron metabolism resulting in efficacious anemia management in patients with CKD. Three oral HIF-PHIs-daprodustat, roxadustat, and vadadustat-have now advanced to global phase III clinical development culminating in the recent licensing of roxadustat for oral anemia therapy in China. Here, we survey current clinical experience with HIF-PHIs, discuss potential therapeutic advantages, and deliberate over safety concerns regarding long-term administration in patients with renal anemia.

Keywords: Anemia; Chronic kidney disease; Erythropoietin; Hypoxia-inducible factor; Prolyl hydroxylase domain.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Anemia / drug therapy*
  • Anemia / etiology
  • Anemia / metabolism
  • Barbiturates / therapeutic use
  • Glycine / analogs & derivatives
  • Glycine / therapeutic use
  • Humans
  • Isoquinolines / therapeutic use
  • Picolinic Acids / therapeutic use
  • Prolyl-Hydroxylase Inhibitors / therapeutic use*
  • Renal Insufficiency, Chronic / complications*
  • Treatment Outcome

Substances

  • Barbiturates
  • FG-4592
  • GSK1278863
  • Isoquinolines
  • Picolinic Acids
  • Prolyl-Hydroxylase Inhibitors
  • vadadustat
  • Glycine