Objective: The growing use of immune checkpoint inhibitors (ICIs) in cancer immunotherapy has brought attention to immune-related adverse events (irAEs), including acute kidney failure (AKF), a potentially fatal complication. This study aimed to characterize ICI-associated AKF through pharmacovigilance data and molecular pathway analyses to improve risk assessment and management. Methods: Adverse event reports from the US Food and Drug Administration Adverse Events Reporting System (FAERS) were analyzed for ICIs, including anti-PD-1, anti-PD-L1, anti-CTLA-4, and anti-LAG-3 therapies, from January 2015 to September 2024. Transcriptomic data from The Cancer Genome Atlas (TCGA) were used for pathway enrichment and gene expression analyses to investigate potential mechanisms. Results: A total of 13 542 377 unique cases were analyzed. Elderly patients showed a higher incidence of ICI-related AKF ( P < 0.001), and no AKF cases were reported for LAG-3 inhibitors due to limited data. Through disproportionality analysis using the Reporting Odds Ratio (ROR), we identified several PT signals significantly associated with ICI-induced AKF. For PD-L1 inhibitors, significant associations were observed with renal impairment, acute kidney injury, proteinuria, and renal failure. PD-1 inhibitors showed notable correlations with increased blood creatinine, renal failure, tubulointerstitial nephritis, and acute kidney injury. Similarly, CTLA-4 inhibitors demonstrated significant associations with increased blood creatinine, acute kidney injury, tubulointerstitial nephritis, and renal impairment. Tumor-specific patterns emerged: anti-PD-L1 therapy was linked to AKF in mesothelioma and melanoma, anti-PD-1 to uterine, renal, and bladder cancers, and anti-CTLA-4 to bladder, renal, and lung cancers. Pathway analysis revealed that anti-PD-L1 and anti-PD-1 therapies were associated with dysregulated cell cycle, DNA replication, and protein degradation, while anti-CTLA-4 showed enrichment in cell cycle pathways. Bladder cancer had the highest AKF risk, with neuroactive ligand-receptor interaction pathways implicated. Vascular endothelial growth factor (VEGF) was proposed as a potential core regulator in ICI-induced nephrotoxicity. Conclusion: This study identifies cancer-specific risks and mechanisms of ICI-associated AKF, offering a framework for personalized risk stratification and patient monitoring. The findings provide insights into the biological basis of AKF and suggest potential therapeutic targets for prevention and management.
Sun et al. (Fri,) studied this question.