Proton pump inhibitors and the risk of adverse renal events and all-cause mortality in cancer patients receiving immune checkpoint inhibitors.

Abstract

11173 Background: Immune checkpoint inhibitors (ICI) have transformed cancer treatment by improving prognosis across various malignancies, while proton pump inhibitors (PPI) are frequently prescribed as prophylaxis in cancer patients. Studies suggest long-term PPI use has higher risks of adverse outcomes, though small patient populations and short follow-up periods limit the current evidence. Pharmacoepidemiologic studies are prone to protopathic bias and, methodological limitations and heterogeneity across studies in cancer patients. We aimed to assess the impact of PPI use on adverse renal events and all-cause mortality in patients receiving ICIs. Methods: We conducted a retrospective cohort study using the TriNetX, including adult cancer patients treated with ICIs (PD-1, PD-L1, and CTLA-4 inhibitors). We used a new-user, active comparator design, which compared newly treated PPI users with nonusers and histamine2 receptor antagonists (H2RA) users. We performed 1:1 propensity score matching (PSM) to adjust for confounding factors (demographics, comorbidities, cancer type, and medications. Primary outcomes included acute kidney injury (AKI) and acute interstitial nephritis (AIN). A secondary outcome was all-cause mortality. Hazard ratios(HR) were calculated using Cox regression models. Sensitivity analysis assessed statistical robustness. Results: We identified 54763 PPI, 28090 H2RA, and 30898 nonusers among patients receiving ICIs. After PSM, the PPI vs. nonusers cohort was well matched with 27322 patients, whereas PPI vs. H2RA users had 21567 patients in each cohort. During the follow-up period (median 4.3 3 years for PPI and 5.1 years for nonusers), PPI users demonstrated a higher risk for AKI (HR 1.48) and AIN (HR 1.07) compared to nonusers. In a subgroup analysis of ICIs, for PD-1i, the HR for AKI was 1.86, and for AIN, it was 2.51. For PD-L1i, the HR for AKI was 1.81, and for AIN, it was 2.33. For CTLA-4i, the HR for AKI was 2.03, and for AIN, it was 3.87. A secondary analysis at 1-year follow-up revealed a significant difference in mortality rates between former PPI and nonusers. Compared with H2RA, the PPIs demonstrated a higher rate of all-cause mortality HR: 1.51. Long-term PPI users showed consistent risks of AKI and AIN across follow-ups at 2 to 5 years, with HRs for AKI ranging from 1.48 to 2.59. Pantoprazole users showed the highest AKI risk (HR 1.59). Sensitivity analysis results were consistent, and associations remained unchanged. Conclusions: PPI use is associated with a significantly increased risk of AREs and all-cause mortality in cancer patients receiving ICIs, with the highest risk observed in patients treated with PD-1i and CTLA-4i. These results emphasize the importance of careful prescribing of PPIs and vigilant renal monitoring for this at-risk group. Further research is warranted to explore the mechanisms underlying this association.