Kidney Week 2025 Annual Meeting-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-PHIs

hypoxia-inducible factor prolyl hydroxylase inhibitors

dialysis anemia management

erythropoiesis-stimulating agents (ESAs)

ESA hyporesponsiveness

cardiovascular safety

major adverse cardiovascular events (MACE)

hepcidin and iron mobilization

roxadustat daprodustat vadadustat

KDIGO anemia guidelines