Proton Pump Inhibitors May Cause a Decline in eGFR by Inhibiting Organic Cation Transporter 2–Dependent Creatinine Secretion

We read with great interest the recent investigation outlined in JASN by Pyne et al., which extends on previous observational findings by conducting a post hoc analysis of a clinical trial.1 Their results reveal a modest yet significant increase in the rate of decline in eGFR associated with the use of proton pump inhibitors (PPIs). We concur with the authors regarding the necessity for future investigations to establish causality in these associations. We wish to highlight that the potential involvement of tubular creatinine secretion in the eGFR decline observed with PPI usage has not been adequately considered. Tubular secretion plays a pivotal role in the elimination of endogenous metabolites and pharmaceutical agents. Notably, creatinine undergoes substantial tubular secretion, leading to an overestimation of GFR by 10%–20% when using creatinine clearance. Studies in both human subjects and rodent models have definitively elucidated the function of organic cation transporter 2 (OCT2, encoded by the SLC22A2 gene) in the basolateral tubular uptake and subsequent secretion of creatinine. OCT2 is a versatile transporter involved in the tubular secretion of commonly prescribed medications, such as metformin, cisplatin, and cimetidine. Inhibition of OCT2-mediated creatinine secretion can occur in the presence of either a drug that is a substrate, such as cimetidine, or a drug that inhibits OCT2 function, such as CDK4/6 kinase inhibitors. Several frequently used medications are recognized as OCT2 substrates and or inhibitors, and their administration is often associated with minor yet noteworthy elevations in plasma creatinine levels. Previously, we demonstrated that CDK4/6 kinase inhibitors employed in breast cancer therapy are potent inhibitors of OCT2,2 which was subsequently confirmed as the cause of elevated serum creatinine levels after abemaciclib administration in human subjects.3 It has been established for over a decade that PPIs, such as pantoprazole, are potent inhibitors of OCT2.4 This raises the possibility that the decline in eGFR associated with PPI usage may result from impaired tubular secretion rather than a true decrease in GFR or impaired renal function. In line with this perspective, we concur with the proposal that future investigations should explore alterations associated with PPI administration in other markers of GFR, such as cystatin C, in addition to creatinine.