Kidney Week Educational Symposia-Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors, CVD, and Hyporesponsiveness to Erythropoiesis-Stimulating Agents in ESKD

Video Transcription

Video Summary

The symposium introduces current debates around hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) in kidney failure, focusing on cardiovascular safety and use in ESA (erythropoiesis-stimulating agent) hyporesponsive patients. The moderator reviews the history of anemia management in dialysis: early ESA trials were small and short, emphasizing hemoglobin and transfusion reduction rather than cardiovascular outcomes. Over time, hemoglobin-targeting guidelines, financial incentives, and enthusiasm for “normalization” drove high dosing, but later randomized trials (mid-2000s onward) showed harm (e.g., cardiovascular events, stroke, faster CKD progression), leading to black-box warnings and a shift toward using ESAs mainly to avoid transfusions. Reimbursement changes later reduced ESA dosing and hemoglobin levels. In this context, HIF-PHIs emerged as promising oral alternatives, though their uptake has been complicated by existing ESA comparators, pricing expectations, and regulatory scrutiny.<br /><br />Dr. Mark Khoury explains physiology and mechanisms: kidney hypoxia signaling regulates EPO; ESKD anemia reflects low EPO, inflammation, high hepcidin (functional iron deficiency), and shortened RBC survival. HIF-PHIs stabilize HIF to induce endogenous EPO with far lower EPO exposure than injected ESAs and can improve iron mobilization (lower hepcidin, higher transferrin/TIBC). Trials suggest some benefit in ESA hyporesponsiveness, but concerns remain about broad “pleiotropic” effects (e.g., VEGF-related issues, pulmonary hypertension, malignancy risk in predisposed patients).<br /><br />Dr. Diana Jalal reviews cardiovascular evidence in dialysis: large phase 3 open-label noninferiority trials (daprodustat, vadadustat, roxadustat pooled program) generally show similar MACE and mortality versus ESAs, though the FDA found a cardiovascular risk signal with roxadustat. Meta-analyses show no clear overall excess CV risk but note possible increased vascular access complications with roxadustat. Draft KDIGO guidance favors ESAs first-line, considering HIF-PHIs for ESA hyporesponsiveness, using the lowest dose, avoiding combination therapy, and stopping for serious CV/thrombotic events or lack of response.

Asset Subtitle

Moderator(s): Marcello Tonelli

Presentation(s):

Introduction - Marcello Tonelli
Are HIF-PHIs the Solution to ESA Hyporesponsiveness in ESKD? - Mark Koury
Cardiovascular Effects of HIF-PHIs in ESKD - Diana Jalal

Support is provided by an educational grant from Akebia Therapeutics, Inc.

Meta Tag

Date 11/6/2025

Pathway 1 Dialysis

Pathway 2 Pharmacology

Session ID 518943

Keywords

HIF-PHI

hypoxia-inducible factor prolyl hydroxylase inhibitors

dialysis anemia management

ESA hyporesponsiveness

cardiovascular safety

major adverse cardiovascular events (MACE)

hepcidin and functional iron deficiency

endogenous erythropoietin induction

roxadustat daprodustat vadadustat

KDIGO draft guidance