Hypoxia-inducible factor stabilizers for treating anemia of chronic kidney disease

Curr Opin Nephrol Hypertens. 2018 Sep;27(5):331-338. doi: 10.1097/MNH.0000000000000431.


Purpose of review: Small-molecule inhibitors of prolyl hydroxylase domain enzymes (PHD inhibitors) are novel renal anemia therapies that increase endogenous erythropoietin (EPO) production by stabilizing hypoxia-inducible factor (HIF). This review summarizes recent findings and future perspectives of PHD inhibitors (HIF stabilizers) in chronic kidney disease (CKD)-associated anemia.

Recent findings: Clinical trials have demonstrated that HIF stabilizers effectively increase hemoglobin levels of both nondialysis and dialysis CKD patients without causing serious adverse effects. HIF stabilizers not only restore EPO production but also optimize iron metabolism by reducing hepcidin levels. Considering the pleiotropic roles of the PHD-HIF pathway, HIF stabilizers might have both advantageous and disadvantageous effects in humans, in addition to erythropoiesis. Results of studies in animal models have suggested that HIF stabilizers alleviate ischemia-reperfusion injury and play protective roles against metabolic diseases. In contrast, a theoretical concern exists regarding the potential for tumorigenesis due to HIF stabilization.

Summary: At least five HIF stabilizers are now in phase III trials and may appear on the market in 1-2 years. The long-term effects and safety of HIF stabilization should be carefully examined in future basic and clinical studies.

Publication types

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

MeSH terms

  • Anemia / drug therapy*
  • Anemia / etiology
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Erythropoietin / biosynthesis
  • Humans
  • Kidney / drug effects
  • Kidney / metabolism
  • Prolyl-Hydroxylase Inhibitors / pharmacology
  • Prolyl-Hydroxylase Inhibitors / therapeutic use*
  • Renal Insufficiency, Chronic / complications*


  • Basic Helix-Loop-Helix Transcription Factors
  • EPO protein, human
  • Prolyl-Hydroxylase Inhibitors
  • Erythropoietin