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

Hasegawa, Sho; Tanaka, Tetsuhiro; Nangaku, Masaomi

Current Opinion in Nephrology and Hypertension: September 2018 - Volume 27 - Issue 5 - p 331–338
doi: 10.1097/MNH.0000000000000431
PHARMACOLOGY AND THERAPEUTICS: Edited by Sankar D. Navaneethan

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.

Division of Nephrology and Endocrinology, the University of Tokyo Graduate School of Medicine, Tokyo, Japan

Correspondence to Masaomi Nangaku, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel: +81 3 3815 5411 (ext. 35154); e-mail:

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