Supplementary Appendix: Quantitative Estimation of the Muscle-Mass Decline Required to Meaningfully Bias Creatinine-Based eGFR and Supplementary Methods for Detecting Treatment-Induced Changes in Endogenous Creatinine Generation

This supplementary 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 includes Box S1, which presents a quantitative estimation of the muscle-mass decline required to meaningfully bias creatinine-based estimated glomerular filtration rate (eGFR). It also includes the Supplementary Methods, providing 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 trajectories of creatinine-based eGFR and cystatin C-based eGFR. The Supplementary Methods additionally include a detectability analysis based on the longitudinal design and follow-up characteristics of the TEMPO3:4 trial.