Genetic causal association between kidney stones and proton pump inhibitors.

Kidney stone disease is a common metabolic disorder with high recurrence rates and an associated risk of chronic kidney disease, while proton pump inhibitors (PPIs) are widely used medications with potential links to renal complications. Previous observational studies have suggested an association between PPI use and kidney stones, but the causal relationship remains unclear. This study aimed to investigate the causal effect of PPIs on kidney stones using the Mendelian randomization (MR) analysis. We utilized large-scale genome-wide association study (GWAS) data to construct genetic instruments for PPI use (including esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole) from the UK Biobank, with kidney stone outcomes derived from the FinnGen Consortium. Additionally, a drug target MR (DTMR) analysis was performed using genetic proxies of the H⁺/K⁺-ATPase (encoded by ATP4A and ATP4B), the core target of PPIs. Five MR models were applied to assess causality, with sensitivity analyses to validate robustness. The results showed no significant causal association between genetically predicted PPIs use and kidney stone risk (esomeprazole: OR = 0.99, 95% CI 0.90-1.09, p = 0.884; lansoprazole: OR = 1.04, 95% CI 0.92-1.17, p = 0.559; omeprazole: OR = 1.03, 95% CI 0.91-1.17, p = 0.628; rabeprazole: OR = 1.02, 95% CI 0.99-1.05, p = 0.088; pantoprazole: OR = 1.01, 95% CI 0.97-1.05, p = 0.687). DTMR analysis also revealed no significant association between genetic proxies of ATP4A/ATP4B and kidney stones across multiple sensitivity thresholds. In conclusion, this study found no evidence supporting a causal role for PPIs in increasing kidney stone risk, providing genetic-level evidence to support the safe use of PPIs in patients with gastric ulcers or gastroesophageal reflux disease.