Supplementary Appendix: Sample Size Considerations for Detecting Treatment-Induced Changes in Endogenous Creatinine Generation in Trials Using Creatinine-Based eGFR Outcomes

This supplementary technical appendix accompanies the manuscript ‘Questioning the kidney-protective effects of tolvaptan: a testable hypothesis to revisit the current narrative’, which examines treatment-induced changes in endogenous creatinine generation and informative dropout in autosomal dominant polycystic kidney disease (ADPKD) trials evaluating tolvaptan. It provides the methodological assumptions, derivations, variance formulations, and worked sample size calculations underlying approaches for detecting treatment-induced changes in endogenous creatinine generation using MRI/MRS, stable isotope dilution, 24-hour urinary creatinine excretion, and discordance between eGFRcr and eGFRcys trajectories. The appendix additionally includes a detectability analysis based on the longitudinal design and follow-up characteristics of the TEMPO3:4 trial.