Comparison of Renal Adverse Events Between Intravitreal Anti-Vascular Endothelial Growth Factor Agents: A Meta-Analysis

Purpose: To assess the risk of renal adverse events, particularly acute kidney injury (AKI), between intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents.

Design: Meta-analysis.

Methods: A systematic literature search was conducted on Ovid Medline, Embase and the Cochrane Library for randomized controlled trials (RCTs) published from January 2005 to February 2024 involving adult patients receiving anti-VEGF intravitreal injections for agerelated macular degeneration, diabetic macular edema, and macular edema secondary to retinal vein occlusion. The primary outcome was the comparative risk of AKI between anti-VEGF agents and sham injections. Secondary outcomes involved other renal adverse events. Subgroup analyses were conducted by specific disease indications. A random-effects model was used for meta-analysis to estimate risk ratios (RR) and their 95% confidence intervals (CI), with a p-value of less that 0.05 representing statistical significance. Risk of bias was assessed using the Cochrane Risk of Bias 2 (ROB2) tool, and the certainty of evidence was evaluated through the GRADE framework.

Results: A total of 10,031 eyes from eleven RCTs were included. No significant differences were found in the risk of acute or chronic renal conditions, obstructive uropathies, neoplasia, or infectious processes between anti-VEGF agents as well as sham therapy. AKI was reported in 5.4% (n=10/185) of patients treated with bevacizumab, 1.3% (n=6/456) with sham, 1.0% (n=48/4,724) with aflibercept, 0.8% (n=15/1,929) with faricimab, 0.5% (n=5/1,098) with brolucizumab, and 0.3% (n=5/1,639) with ranibizumab. No significant differences in AKI risk were observed between any of the anti-VEGF agents and sham (p>0.05 for all comparisons). However, there was an increased risk of patient-reported symptoms with 1.25mg bevacizumab compared to 2mg aflibercept (RR=3.26, 95% CI=1.07-9.93, p=0.04), primarily driven by reports of hematuria: 4.3% (bevacizumab), 0.7% (sham), 0.2% (aflibercept), 0.1% (faricimab), and 0.1% (ranibizumab).

Conclusions: FDA-approved intravitreal anti-VEGF agents do not significantly increase the risk of AKI compared to sham injections. Nevertheless, variations in patient-reported renal symptoms were observed across different anti-VE F drugs. These variations were primarily influenced by differences in hematuria events, which may be a result of differential systemic absorption by these agents. These results underscore the importance of continuous monitoring and pharmacovigilance.