Nephrotoxicity in immune checkpoint inhibitor therapy: a pharmacovigilance study

Background Immune checkpoint inhibitor (ICI) therapy has demonstrated impressive clinical benefits across cancers. However, adverse drug reactions (ADR) occur in every organ system, often due to autoimmune syndromes. We sought to investigate the association between ICI therapy and nephrotoxicity using a pharmacovigilance database, hypothesizing that inflammatory nephrotoxic syndromes, would be reported more frequently in association with ICIs. Methods We analyzed VigiBase, the WHO pharmacovigilance database, to identify renal ADRs (rADRs), such as nephritis, nephropathy, and vascular disorders, reported in association with ICI therapy. We performed a disproportionality analysis to explore if rADRs were reported at a different rate with one of the ICI drugs compared to rADRs in the entire database, using an empirical Bayes estimator as a significance screen and defining the effect size with a reporting odds ratio (ROR). Results We found 2,341 rADR for all examined ICI drugs, with a disproportionality signal solely for nephritis (ROR 3.67, 95% CI: 3.34-4.04). Examining the different drugs separately, pembrolizumab, nivolumab, and ipilimumab+nivolumab combination therapy had significantly higher reporting odds of nephritis than the other ICI drugs (ROR 4.54, 95%CI: 3.81-5.4; ROR 3.94, 95%CI: 3.40-4.56; ROR 3.59, 95%CI: 2.71-4.76; respectively). Conclusions Using a pharmacovigilance method, we found increased odds of nephritis when examining renal ADRs associated with ICI therapy. Pembrolizumab, nivolumab, and a combination of ipilimumab plus nivolumab showed the highest odds. Clinicians should consider these findings and be aware of the increased risk of nephritis, especially in patients treated with pembrolizumab, when administering ICI therapy.