Long-term use of proton pump inhibitors was associated with rapid progression to end stage kidney disease in a Korean nationwide study

Abstract

Proton pump inhibitors (PPIs) are among the most widely used drugs worldwide. However, their influence on the progression of end-stage kidney disease (ESKD) in established chronic kidney disease (CKD) cases is unclear. Using the Korean Health Insurance Review and Assessment database encoded by the Observational Medical Outcomes Partnership-Common Data Model (OMOP-CDM), patients with stage 3 or 4 CKD initiating PPIs or histamine-2 receptor antagonists (H2RAs) for over 90 days were enrolled from 2012 through 2021. Incidence of ESKD events between the groups were compared using a cox proportional hazard model. A total of 34,656 eligible patients were included. Of the patients, 65.1% had CKD stage 3, 44.5% aged > 75 years, 59.8% were male individuals, and 68.3% had diabetes. After 1:1 propensity score matching, ESKD progression was observed in 2327 out of 19,438 patients and it was more frequent in PPI users (incidence rate, 10.5/100PYs) than that in H2RA users (incidence rate, 9.2/100PYs; IRR, 1.14 [1.07-1.12]). Using the subgroup analysis, IRR was significantly higher in patients with CKD stage 3 (IRR 1.40 [1.21-1.60]), whereas it was not in those with CKD stage 4 (IRR 1.04 [0.94-1.15]). A similar trend was observed in patients with CKD 3 or 4 with and without diabetes. In general, PPI use is associated with a 14% higher risk of ESKD progression in patients with CKD stage 3 or 4. However, the influence of PPIs differed according to the comorbidities and risks of adverse kidney outcomes.

Keywords: Chronic kidney disease; End stage kidney disease; Follow-up studies; Incidence; Proton pump inhibitors.

Fig. 1

Diagram of cohort construction. CKD, chronic kidney disease; PPI, proton pump inhibitor; H2RA, histamine-2 receptor antagonist.

Fig. 2

Attrition diagram, showing the number of participants in the target and comparator group after various stages in the analysis.

Fig. 3

The KM survival curve shows the increased event in ESKD progression in crude (A), and the propensity score matches the (B) model. ESKD end-stage kidney disease, CKD chronic kidney disease, PPI proton pump inhibitor, H2RAs histamine-2 receptor antagonists.

Fig. 4

Differences in nephrotoxic effects of PPIs by the incidence rate of ESKD of comparator cohort. The number in each bar represents incidence rate of ESKD per 100 person years. Dotted lines represent overall incidence rate in proton pump inhibitor (PPI, orange line) and histamine 2 receptor antagonists (H2RA, green line) users. ***p < 0.001, **p < 0.01, *p < 0.05. ESKD end-stage kidney disease, CKD chronic kidney disease, PPI proton pump inhibitor, H2RA histamine-2 receptor antagonist, CHF chronic heart failure, DM diabetes, HTN hypertension, LC liver cirrhosis, IR incidence rate.