The association between proton pump inhibitor use and the risk of mortality in patients with kidney disease: a systematic review and meta-analysis

Background: Use of proton pump inhibitor (PPI) has been associated with adverse health outcomes, including increased risk of all-cause mortality. Evidence suggests that individuals with kidney disease who use PPIs may experience higher mortality, though the nature of this association is not well established. Objective: To assess the relationship between PPI use and mortality among individuals with kidney disease through a systematic review and meta-analysis. Methods: A comprehensive search of Ovid-MEDLINE, Ovid-EMBASE, and Cochrane CENTRAL was conducted through April 2025 to identify randomized controlled trials and observational studies examining mortality among PPI users versus non-users with kidney disease. Both unadjusted mortality rates and adjusted hazard ratios (aHRs) were extracted. A random-effects meta-analysis was performed using the Hartung-Knapp-Sidik-Jonkman method, with the Sidik-Jonkman estimator used for between-study variance (τ²). Study heterogeneity was evaluated using the I² statistic and Cochran’s Q test. Subgroup analyses were carried out based on follow-up length, population characteristics, geographic region, and risk of bias level. Results: The review included 24 observational studies encompassing 216,032 individuals with kidney disease. Across 20 cohorts from 17 observational studies, mortality was 23.2% among PPI users and 22.1% among non-users. Pooled adjusted estimates from 18 studies (20 cohorts) indicated a significantly increased risk of death in PPI users (aHR 1.26; 95% CI, 1.11–1.42). Considerable heterogeneity was observed, but subgroup analyses revealed consistent trends. Conclusions: Our meta-analysis showed that PPI use was linked to elevated mortality risk in kidney disease populations. Careful consideration is advised when prescribing PPIs, and further research is needed.