Comparative efficacy of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists in preclinical renal ischemia-reperfusion injury models: Multilevel and network meta-analyses

Hypothesis/Introduction The renin-angiotensin system plays a central role in renal ischemia-reperfusion injury (IRI). We evaluated the effects of angiotensin-converting enzyme inhibitors (ACEIs) and AT1 receptor blockers (ARBs) in preclinical renal IRI models using multilevel and network meta-analyses (PROSPERO: CRD42024599859). Materials and Methods Database searches identified 55 studies. Serum creatinine data were pooled using three-level random-effects models (96 comparisons, n = 1233 animals). Publication bias was assessed using Egger and 1/√n methods. Drugs were ranked via P-scores. Results ACEIs/ARBs significantly reduced creatinine (standardized mean difference: −1.74; 95% CI: −2.22 to −1.26; p < 0.0001) with high heterogeneity. Egger's test showed asymmetry ( p < 0.0001), but 1/√n-based testing did not ( p = 0.160), suggesting mathematical artifact rather than publication bias. Multivariable meta-regression identified drug identity, dose, and route as key effect modifiers. Network analysis ranked azilsartan and telmisartan highest, though evidence remains limited (no direct comparisons, n = 2 for azilsartan). Secondary outcomes confirmed renal protection. Conclusions ACEIs/ARBs effectively reduce renal IRI in animals, with azilsartan and telmisartan ranking favorably despite limited evidence. High-dose intravenous administration enhances efficacy. Most studies used pre-ischemia protocols relevant only to transplantation. Post-injury models with comorbid animals of both sexes and direct drug comparisons are needed for clinical translation.