Use of Proton Pump Inhibitors Increases Risk of Incident Kidney Stones

Abstract

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.

Methods: 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.

Results: 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).

Conclusions: 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.

Keywords: Acid Suppression; Calcium; Nephrolithiasis; Pharmacoepidemiology.

Conflict of interest statement

Conflict of Interest: FPW reports receiving consulting fees from a law firm that represented PPI manufacturers in litigation regarding chronic kidney disease and PPI use. Details of this report and activities surrounding the report were in no way communicated or discussed with that firm who had no role in the funding, design, conduct, writing, editing, or decision to publish this manuscript. LL has served as a consultant for Phathom Pharmaceuticals. We do not report other personal or financial conflicts of interest for the other authors of the manuscript.

Published by Elsevier Inc.

Figures

Figure 1.

Cohort construction flow diagram with exclusion criteria and final cohort size.

Figure 2.

Kaplan-Meier curve for PPI and non-PPI propensity-matched cohort with respect to percentage free from nephrolithiasis. Log-rank test p−16.