Risk of Kidney Stone Formation with Proton Pump Inhibitors
Based on the most recent and highest quality evidence, proton pump inhibitors (PPIs) are associated with approximately a 19-46% increased risk of kidney stone formation, with the absolute risk being relatively small.
Evidence on PPI Use and Kidney Stone Risk
Recent research demonstrates a clear association between PPI use and kidney stone formation:
- A large retrospective study found that PPI use was associated with a 46% increased risk of kidney stones (HR 1.46; 95% CI 1.38-1.55) 1
- Another study of patients with GERD showed a 19% higher risk of incident kidney stones with PPI use (HR 1.19; 95% CI 1.06-1.34) 2
- Meta-analysis data indicates an overall hazard ratio of 1.34 (95% CI 1.28-1.40) for incident nephrolithiasis with PPI use 3
- The risk appears to be dose-dependent, with higher doses associated with greater risk (HR 1.11; CI 1.09-1.14 for each increase in 30 defined daily doses over a 3-month period) 1
Mechanisms of PPI-Associated Kidney Stone Formation
The increased risk of kidney stones with PPI use appears to be related to several mechanisms:
- PPIs are associated with decreased urinary citrate excretion (12% lower 24-hour urine citrate) 4, which is an important inhibitor of stone formation
- PPI-exposed patients have significantly lower urinary magnesium levels (mean 3.6 vs 4.3 mmol, p < 0.001) 2, another inhibitor of stone formation
- The risk increases with duration of exposure, becoming apparent after three months of PPI use (HR 1.78; 95% CI 1.39-2.25) 5
Clinical Implications and Recommendations
Despite these findings, current gastroenterology guidelines do not recommend avoiding PPIs solely due to kidney stone risk. The American Gastroenterological Association (AGA) states that "the decision to discontinue PPIs should be based solely on the lack of an indication for PPI use, and not because of concern for PPI-associated adverse events" 6.
When prescribing PPIs:
- Use the lowest effective dose and shortest duration possible to minimize risks 7
- Consider monitoring urinary citrate and magnesium levels in patients with history of kidney stones who require long-term PPI therapy
- Be aware that the risk appears to be dose-dependent and increases with longer duration of use
- H2-receptor antagonists may also increase kidney stone risk (HR 1.47; CI 1.31-1.64) 1, suggesting acid suppression itself may be an involved mechanism
Conclusion
While PPIs are associated with a modest increased risk of kidney stones (approximately 19-46% relative risk increase), the absolute risk remains small for most patients. This risk should be considered in the context of the clear benefits of PPI therapy for appropriate indications.