Abstract
Renal anemia in patients with stage-IV chronic kidney disease (CKD) is commonly treated with erythropoiesis-stimulating agents (ESAs), which are effective but associated with cardiovascular risks, variable responsiveness, and inflammatory complications. Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) have recently emerged as an alternative therapy that enhances endogenous erythropoietin production and improves iron metabolism. This retrospective cohort study utilized the TriNetX Global Collaborative Network to compare clinical outcomes between HIF-PHI and ESA users in non-dialysis stage IV CKD patients (estimated glomerular filtration rate 15-30 mL/min/1.73 m(2)). After 1:1 propensity score matching, 493 patients were included in each group and followed for up to three years. HIF-PHI therapy was associated with significantly lower all-cause mortality (hazard ratio [HR] 0.39; 95% confidence interval [CI] 0.26-0.58; p < 0.0001) and reduced sepsis risk (HR 0.32; 95% CI 0.14-0.74; p = 0.01) compared with ESA therapy. Subgroup analyses demonstrated consistent mortality benefit across major comorbidities, with the greatest advantage observed in patients with ferritin 100-299 ng/mL (HR 0.41; 95% CI 0.23-0.74; p = 0.002) and in comparisons against short-acting ESAs (HR 0.55; p = 0.0304). No survival difference was observed between HIF-PHI and long-acting ESA users, indicating that the observed benefit of HIF-PHIs was driven exclusively by differences versus short-acting ESAs. These findings suggest that HIF-PHIs may offer a safer and more physiologically adaptive approach to correcting anemia in advanced CKD, particularly when compared with short-acting ESA therapy. In contrast, long-acting ESAs achieve outcomes comparable to those of HIF-PHIs.