Mediation Analysis of Urine Osmolality and Response to Tolvaptan in Autosomal Dominant Polycystic Kidney Disease: A Post Hoc Assessment
In brief
Early urine concentration change mediated tolvaptan's kidney-function benefit in non-Japanese patients
In this post hoc analysis of a 3-year trial, a week 3 drop in urine osmolality partly explained tolvaptan's later kidney-function benefit among 948 non-Japanese participants. The link was not significant in 138 Japanese participants, though tolvaptan directly limited kidney-volume growth in both groups. Whether early urine changes reliably predict individual patients' long-term response remains uncertain.
- Journal
- Nephrology (Carlton, Vic.) (Q1)
- Published
- 1 October 2026
- Study design
- Randomized controlled trial
- Evidence level
- Level 1, High (CEBM 1b)
- Authors
- Ryo Matsuura, Kent Doi, Zhen Zhang, Katherine Maringer, Sachin Hajarnis, Yoshifumi Hamasaki
- PMID
- 42813962
- DOI
- 10.1111/nep.70292
Why clinicians should know about it
- Picked for Nephrology (top studies of the week, 4 October 2026): Post hoc mediation of tolvaptan effect in ADPKD patients
- Picked for Urology (top studies of the week, 4 October 2026): Not urological oncology, focuses on kidney cyst disease
Abstract
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.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.