Impact of HIF-prolyl hydroxylase inhibitors on VEGF expression and vascular adverse events in chronic kidney disease: a meta-analysis of 34 randomized controlled trials

Background Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are novel oral agents used to treat renal anemia in chronic kidney disease (CKD). While their erythropoietic effects are well-documented, the potential consequences of HIF-mediated vascular endothelial growth factor (VEGF) activation remain uncertain. This meta-analysis aimed to evaluate the effect of HIF-PHI therapy on VEGF levels and the risk of VEGF-related adverse outcomes in CKD patients. Methods We systematically analyzed 34 randomized controlled trials (RCTs) including 26 trials reporting VEGF levels and additional data on cancer, diabetic retinopathy, peripheral edema, and thrombosis. Subgroup analyses were performed based on drug type, treatment duration, dialysis status, trial phase, and comparator type. Results HIF-PHI treatment was associated with a modest but significant increase in VEGF levels (SMD = 0.23; 95% CI: 0.07–0.39) and a reproducible increase in peripheral edema risk (log RR = 0.22; 95% CI: 0.09–0.35). No significant associations were found for cancer, diabetic retinopathy, or thrombosis. Dialysis status moderated VEGF response, with greater elevation observed in dialysis-dependent patients. Conclusion HIF-PHIs modestly increase VEGF expression, with peripheral edema as the most consistent adverse signal. However, no evidence of oncologic or retinal harm was found in the short term. Long-term surveillance is recommended.