Long-Term Use of Proton-Pump Inhibitors Is Associated with Rapid Progression to ESKD in Patients with CKD: A Korean Nationwide Study

Background: Proton pump inhibitors (PPIs) are one of the most widely used drugs worldwide. Nevertheless, it has long been debated whether PPIs are associated with disease progression in patients with chronic kidney disease (CKD). Methods: Using the Korean Health Insurance Review and Assessment (HIRA) database encoded in the Observational Medical Outcomes Partnership – Common Data Model (OMOP-CDM) version 5.3, a total of 34,656 patients with CKD stage 3 or 4 initiating PPIs or H2 receptor antagonists (H2RAs) for more than 90 days were assembled from 2012 through 2021. ESKD progression was defined as the initiation of kidney replacement therapy (hemodialysis, peritoneal dialysis, or kidney transplantation) for more than three months. The observation period was three years, and we calculated the incidence rate (IR) as 100 person-years (PYs) in the 1:1 propensity score-matched model. Results: After 1:1 propensity score matching, we retrieved a total of 19,438 CKD stage 3 or 4 patients initiated PPIs or H2RA for more than three months. In all, 66.3% were CKD stage 3, 44.5% were aged over 75 years, 59.8% were male, and 68.3% had diabetes. During the mean follow-up of 1.2 years, ESKD progression was observed in 2,327 patients, and it was more frequent in PPI users (IR, 10.5/100PYs) compared to H2RA users (IR, 9.2/100PYs; incidence rate ratio (IRR), 1.19(1.07-1.32)). In the subgroup analysis, ESKD progression was more prominent in CKD stage 3 patients (PPI, 5.7 /100 PYs; H2RA 4.2/ 100 PYs; IRR 1.40(1.12-1.69)) than in CKD stage 4 (PPI, 19.8/100 PYs; H2RA 19.34 /100 PYs; IRR 1.03(0.91-1.18)), and non-diabetic CKD 3 or 4 patients (PPI, 7.7/100PYs; H2RA, 6.3/100 PYs; IRR, 1.32(1.07-1.64)) than in diabetic CKD 3 or 4 patients (PPI, 11.7/100PYs; H2RA, 10.80/100 PYs; IRR, 1.12(0.99-1.26)). Conclusion: In CKD stage 3 or 4 patients, the use of PPIs for more than three months is associated with a 19% higher risk of ESKD progression, and the risk is more prominent in non-diabetic and earlier-staged CKD patients.