The cardiac and kidney-related adverse effects of novel hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) do not differ significantly from those of erythropoiesis-stimulating agents (ESAs) or placebo in patients with nondialysis-dependent chronic kidney disease (CKD), a new review published in the American Journal of Kidney Diseases concludes.

Current oral HIF-PHIs include roxadustat, daprodustat, vadadustat, molidustat, enarodustat, and desidustat. The results are from a systematic review and meta-analysis of data from 23 randomized controlled trials involving 15,144 patients with anemia of CKD conducted by Wei Jing Liu, MD, of Dongzhimen Hospital, Beijing University of Chinese Medicine in China, and colleagues. Cardiac disorders included cardiovascular death, myocardial infarction, unstable angina pectoris, ischemic stroke, heart failure, arrhythmia, other cardiac and valvular diseases, or major adverse cardiovascular events. Kidney-related adverse events included worsening chronic kidney disease or decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD) or dialysis initiation, acute kidney injury, nephritis, azotemia, etc. The groups taking HIF-PHI vs ESA/placebo did not differ significantly in their risks for ESKD or dialysis initiation.

Hypertension risk was a significant 35% higher with HIF-PHI use compared with placebo but a significant 11% lower compared with ESAs. Hyperkalemia risk was 25% higher with HIF-PHI use compared with placebo, but no higher compared with ESAs.

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“According to the current evidence, HIF-PHIs did not significantly increase the risk of cardiac or kidney-related AEs, kidney failure events, SAEs, or death in anemic patients with CKD not receiving dialysis,” Dr Liu’s team wrote.

The quality of the evidence comparing HIF-PHIs with ESAs was low to moderate with differing standards for outcome reporting, so future studies are still needed.


Zheng Q, Wang Y, Yang H, et al. Cardiac and kidney adverse effects of HIF Prolyl-Hydroxylase inhibitors for anemia in patients with CKD not receiving dialysis: A systematic review and meta-analysis. Am J Kidney Dis. Published online November 14, 2022. doi:10.1053/j.ajkd.2022.09.014