Questioning the kidney-protective effects of tolvaptan: a testable hypothesis to revisit the current narrative

Tolvaptan is the only approved therapy for slowing disease progression in autosomal dominant polycystic kidney disease (ADPKD). Its use necessitates balancing kidney-protective effects against burdensome aquaretic side effects that limit long-term adherence. Both clinical and real-world data highlight that many eligible patients decline or discontinue therapy, complicating estimation of the true magnitude of kidney protection inferred from pivotal trials. In this perspective article, we hypothesise that two distinct sources of bias may influence estimates of treatment efficacy in opposite directions and explore the implications for the interpretation of trial results. First, we consider how treatment-related effects, particularly changes in creatinine generation, could bias creatinine-based estimated glomerular filtration rate (eGFR), potentially exaggerating the apparent benefit. Second, we evaluate how selective treatment discontinuation in the TEMPO3:4 trial may have distorted estimated treatment effects by altering which participants remain under observation over time, potentially attenuating the apparent benefit. Taken together, these considerations motivate a reassessment of placebo-adjusted treatment effects on eGFR using cystatin C measurements from TEMPO3:4, thereby enabling a within-trial, trajectory-based evaluation of potential treatment-induced changes in creatinine generation, supported by analytical approaches that better account for selective dropout. More broadly, our analysis extends beyond ADPKD, highlighting the need to re-evaluate existing clinical trials in which treatment may change creatinine generation, including those with sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists. Future trials should incorporate complementary filtration markers to assess treatment-related changes in creatinine generation. Across all trials, sensitivity analyses using contemporary modelling strategies are warranted to strengthen confidence in eGFR slope as a regulator-endorsed clinical endpoint. Improving the methodological rigour with which treatment effects are estimated is essential to ensure that clinical decisions accurately reflect therapeutic benefit relative to treatment burden and patient experience.