Acute Kidney Injury and Heart Failure Risk with Hypoxia-Inducible Factor–Prolyl Hydroxylase Inhibitors: A Network Meta-Analysis

The aim of this systematic review and network meta-analysis was to clarify the risk of acute kidney injury (AKI) and acute heart failure associated with hypoxia-inducible factor–prolyl hydroxylase inhibitors (HIF-PHIs) in patients with anemia of chronic kidney disease. The certainty of evidence for each outcome was assessed using the Confidence in Network Meta-Analysis approach. The primary outcomes were AKI and acute heart failure, while the secondary outcome was any kidney injury. Thirty-five studies, performed between 2009 and 2025, were included in the network meta-analysis. HIF-PHIs were associated with a higher risk of AKI compared with erythropoiesis-stimulating agents (ESAs) (risk ratio [RR] 1.23, 95% confidence interval [CI] 1.02–1.47, moderate certainty) and placebo (RR 1.40, 95% CI 1.11–1.75, high certainty). HIF-PHIs were also associated with an increased risk of any kidney injury compared with placebo (RR 1.13, 95% CI 1.01–1.26, moderate certainty). ESAs ranked lower in terms of acute heart failure risk than both HIF-PHIs and placebo, although the differences were not statistically significant. Vadadustat (RR 0.30, 95% CI 0.12–0.74, moderate certainty) and ESAs (RR 0.40, 95% CI 0.17–0.94, high certainty) were associated with a lower risk of acute heart failure compared with placebo. In conclusion, HIF-PHIs may be associated with an increased incidence of AKI compared with placebo and ESAs. In contrast, vadadustat and ESAs might be associated with a decreased incidence of acute heart failure compared with placebo. Further robust studies should be conducted to validate these findings.