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

We thank Pabla and Sparreboom for their insightful comments1 highlighting the possibility that the excess eGFR decline seen with pantoprazole in our post hoc analysis2 of the COMPASS trial could be due to reduced creatinine secretion rather than causing kidney injury. The evidence that proton pump inhibitors inhibit organic cation transporter 2 comes primarily from in silico and in vitro experiments,3,4 and its existence/magnitude of the effect is uncertain in humans. Additional analyses of the COMPASS trial suggest that the effect of pantoprazole compared with placebo on rate of eGFR change was attenuated in patients who discontinued treatment before eGFR reassessment (−0.04 ml/min per 1.73 m2 per year, 95% confidence interval, −0.26 to 0.17) compared with those who remained on treatment (−0.60 ml/min per 1.73 m2 per year, 95% confidence interval, −0.85 to −0.34). We reported the mean effect across subgroups given the high risk of presenting biased treatment effects based on postrandomization subgroups,5 but this disparity could support a reversible effect of pantoprazole on eGFR, possibly due to inhibition of creatinine secretion. However, this finding could also be explained by lower total drug exposure, thereby suggesting a dose-response or threshold exposure effect (i.e., those who stopped treatment early avoided measurable pantoprazole-induced kidney injury because they had less drug exposure). These possibilities could be further explored in future proton pump inhibitor studies by serial measurements of kidney function beginning early after starting treatment to understand potential acute effects and continuing until after study drug discontinuation to understand reversibility of effects. In addition, the use of analytes that are less affected by organic cation transporter 2 inhibition, such as cystatin C, may be beneficial. The potential adverse effect of proton pump inhibitors on renal function remains relevant, particularly for those at higher risk for progressive kidney disease and/or who have weak indications for chronic proton pump inhibitor use.