Use of Proton Pump Inhibitors Increases Risk of Incident Kidney Stones

Published:March 05, 2020DOI:

      Background and Aims

      Proton pump inhibitors (PPIs) are widely prescribed and have effects on gut ion absorption and urinary ion concentrations. PPIs might therefore protect against or contribute to development of kidney stones. We investigated the association between PPI use and kidney stones.


      We performed a retrospective study using data from the Women’s Veteran’s Cohort Study, which comprised men and women, from October 1, 1999 through September 30, 2017. We collected data from 465,891 patients on PPI usage over time, demographics, laboratory results, comorbidities, and medication usage. Time-varying Cox proportional hazards and propensity matching analyses determined risk of PPI use and incident development of kidney stones. Use of histamine-2 receptor antagonists (H2RAs) was measured and levothyroxine use was a negative control exposure.


      PPI use was associated with kidney stones in the unadjusted analysis, with PPI use as a time-varying variable (hazard ratio [HR], 1.74; 95% CI, 1.67–1.82), and persisted in the adjusted analysis (HR, 1.46; CI, 1.38–1.55). The association was maintained in a propensity score-matched subset of PPI users and nonusers (adjusted HR, 1.25; CI 1.19–1.33). Increased dosage of PPI was associated with increased risk of kidney stones (HR, 1.11; CI, 1.09–1.14 for each increase in 30 defined daily doses over a 3-month period). H2RAs were also associated with increased risk (adjusted HR, 1.47; CI 1.31–1.64). We found no association, in adjusted analysis, of levothyroxine use with kidney stones (adjusted HR, 1.06; CI 0.94–1.21).


      In a large cohort study of veterans, we found PPI use to be associated with a dose-dependent increase in risk of kidney stones. H2RA use also has an association with risk of kidney stones, so acid suppression might be an involved mechanism. The effect is small and should not change prescribing for most patients.


      Abbreviations used in this paper:

      CI (confidence interval), DDD (defined daily dose), GERD (gastroesophageal reflux disease), GI (gastrointestinal), H2RA (histamine-2 receptor antagonist), HR (hazard ratio), PPI (proton pump inhibitor), VHA (Veterans Health Administration), eGFR (estimated glomerular filtration rate)
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      Linked Article

      • Proton Pump Inhibitors, Histamine-2 Receptor Antagonists, and the Risk of Kidney Stones: Negligible or Not?
        Clinical Gastroenterology and HepatologyVol. 19Issue 3
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          We read with great interest the study from Simonov et al,1 the first study examining the association of proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) with the risk of kidney and ureteral stone development. PPIs are the mainstay of acute and long-term management of acid-related disease, especially gastroesophageal reflux disease; delay progression of Barrett’s esophagus to dysplasia; and can prevent gastrointestinal bleeding in patients on antiplatelet or anticoagulant therapy.
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