Kidney Week Educational Symposia-HIF-PH Inhibitors: Moving Beyond Erythropoietin and Iron Deficiency

Video Transcription

Video Summary

The session reviews hypoxia-inducible factor prolyl-hydroxylase inhibitors (HIF-PHIs) as a potential major advance in treating anemia of chronic kidney disease (CKD) beyond erythropoietin (ESAs) and iron. HIF-PHIs stabilize HIF (especially HIF-2α), preventing oxygen-dependent degradation and enabling transcription of the EPO gene. This stimulates endogenous erythropoiesis and also affects iron handling: lowers hepcidin, increases gastrointestinal iron absorption and iron mobilization/transport, and may reduce ferritin and transferrin saturation as iron is utilized.<br /><br />Early proof-of-concept studies showed oral HIF-PHIs raise plasma EPO within 8–12 hours in healthy volunteers and in hemodialysis patients, including anephric patients (suggesting hepatic EPO) and some patients with diseased kidneys.<br /><br />For non-dialysis CKD, trials of roxadustat demonstrate dose-dependent hemoglobin increases and hepcidin reductions; a China phase 3 placebo-controlled study showed clear hemoglobin improvement and reduced hepcidin, with safety signals including metabolic acidosis/hyperkalemia. Large phase 3 programs exist across agents (roxadustat, vadadustat, daprodustat). Vadadustat’s PROTECT program met efficacy endpoints versus darbepoetin but did not meet a prespecified cardiovascular non-inferiority margin in non-dialysis patients.<br /><br />For dialysis-dependent CKD, a China trial found roxadustat non-inferior/superior to epoetin alfa for hemoglobin rise, with more hyperkalemia/URIs but less hypertension, and cholesterol lowering. Vadadustat’s INNOVATE trials (≈4,000 dialysis patients, ~1.5 years follow-up) showed non-inferior cardiovascular safety (MACE HR ~0.96) and non-inferior hemoglobin efficacy versus darbepoetin, with similar adverse events. Remaining questions include long-term/off-target effects (many HIF-regulated genes), class differences, cost, iron use, adherence logistics, and ultimate clinical role.

Asset Subtitle

Jeffrey Berns, Francesco Locatelli, Kai-Uwe Eckardt
Support is provided by an educational grant from Akebia Therapeutics, Inc. and Otsuka America Pharmaceutical, Inc.

Keywords

HIF-PHI

hypoxia-inducible factor stabilization

CKD anemia treatment

roxadustat

vadadustat

daprodustat

hepcidin reduction

dialysis and non-dialysis clinical trials