Mediation Analysis of Urine Osmolality and Response to Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: A Post Hoc Assessment

AIM: Tolvaptan delays growth in total kidney volume (TKV) and decline in estimated glomerular filtration rate (eGFR) among individuals with autosomal dominant polycystic kidney disease (ADPKD) at elevated risk of rapid progression. We evaluated changes in urine osmolality (Uosm) after treatment initiation as a potential biomarker of long-term response. METHODS: This was a post hoc analysis of TEMPO 3:4, a 3-year, randomized, placebo-controlled trial of tolvaptan. Causal mediation analysis assessed if the effect of tolvaptan on longer-term outcomes of change in eGFR and TKV at month 36 was mediated by change in Uosm at week 3. Analyses were performed separately for non-Japanese and Japanese participants. RESULTS: The average causal mediation effect (ACME) of change in Uosm on eGFR at month 36 was statistically significant (2.4; 95% quasi-Bayesian confidence interval [CI] 1.2, 3.6) in the non-Japanese cohort (n = 948). In the Japanese cohort (n = 138), whereas the ACME for change in Uosm was non-significant (-0.3 [95% CI: -2.3, 1.7]), the average direct effect (ADE) of tolvaptan on eGFR was statistically significant (8.4 [95% CI 3.1, 12.4]). For percentage change in TKV, the ADE of tolvaptan was statistically significant in both the non-Japanese (-8.3 [95% CI: -10.5, -6.3]) and Japanese cohorts (-12.0 [95% CI: -17.4, -7.5]). CONCLUSION: This study supported short-term change in Uosm as a predictive biomarker of longer-term kidney function in a non-Japanese cohort; the relationship was not significant in the smaller Japanese cohort. Tolvaptan exhibited a direct treatment effect on the growth of kidney volume in both cohorts of ADPKD patients.