Long-Term Proton Pump Inhibitor Use and Incident Chronic Kidney Disease: A Prospective Cohort Analysis of the UK Biobank
Background
Proton pump inhibitors (PPIs) are among the most widely prescribed medications globally, with over 15 million long-term users in the United States alone. Observational studies have suggested associations between PPI use and adverse renal outcomes, but many were limited by confounding by indication, short follow-up, and inability to assess dose-response relationships. We leveraged the UK Biobank to evaluate the association between long-term PPI use and incident chronic kidney disease (CKD) with detailed adjustment for confounders.
Methods
We conducted a prospective cohort study of 172,456 UK Biobank participants aged 40 to 69 years without prevalent CKD at enrollment (2006-2010). PPI use was ascertained from self-reported medication records at baseline and during follow-up visits, supplemented by primary care prescription data. The primary outcome was incident CKD defined as two estimated glomerular filtration rate (eGFR) values below 60 mL/min/1.73m2 at least 90 days apart, or incident CKD diagnosis codes. Cox proportional hazards models were adjusted for age, sex, ethnicity, BMI, diabetes, hypertension, cardiovascular disease, NSAID use, and baseline eGFR.
Results
During a median follow-up of 12.4 years, 8,247 incident CKD events occurred. Regular PPI users (n=31,489) had a significantly higher risk of incident CKD compared with non-users (adjusted HR 1.19; 95% CI, 1.12-1.27; P<0.001). A dose-response relationship was observed: low-dose PPI users had an HR of 1.10 (95% CI, 1.01-1.20), while high-dose users had an HR of 1.31 (95% CI, 1.18-1.45; P for trend <0.001). The association persisted after excluding the first 2 years of follow-up (HR 1.17; 95% CI, 1.09-1.25) and in propensity score-matched analyses (HR 1.15; 95% CI, 1.06-1.24). The risk was consistent across subgroups defined by age, sex, diabetes status, and baseline eGFR. H2 receptor antagonist users showed no increased CKD risk (HR 1.02; 95% CI, 0.92-1.13).
Conclusions
In this large prospective cohort, long-term PPI use was independently associated with increased risk of incident CKD in a dose-dependent manner. These findings support clinical recommendations to use PPIs at the lowest effective dose for the shortest necessary duration.
Long-term proton pump inhibitor use is independently associated with a 19% increased risk of incident chronic kidney disease, with a dose-response relationship suggesting that the lowest effective dose for the shortest duration should be prescribed.