Molecular mechanisms and clinical patterns of ICI-associated acute kidney failure: an integrated pharmacovigilance and pathway analysis
Year: 2026
Type: article
Abstract: 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.
Source: International Journal of Surgery
Authors: Xiaobo Sun, Dandan Guo, Ling Wang
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,450
OpenAlex ID: W7135227638