- Design
- Post hoc causal mediation analysis of a randomised placebo-controlled trial
- Population
- 1086 participants with ADPKD in TEMPO 3:4
- Primary outcome
- Mediation of 36-month eGFR effect by week-3 urine osmolality change
- Effect
- Non-Japanese ACME 2.4 (1.2–3.6); Japanese −0.3 (−2.3 to 1.7)
This post hoc analysis of TEMPO 3:4, the three-year placebo-controlled tolvaptan trial in autosomal dominant polycystic kidney disease, used causal mediation analysis to ask whether the change in urine osmolality at week 3 explained effects on eGFR and kidney volume at 36 months.
In 948 non-Japanese participants, the early osmolality change significantly mediated the eGFR effect (average mediation effect 2.4, 95% CI 1.2–3.6). In 138 Japanese participants it did not, though tolvaptan still had a significant direct effect on eGFR. Tolvaptan reduced kidney volume growth directly in both groups.
A cheap urine test that predicts long-term response would help decide whether continuing an expensive, poorly tolerated drug is worthwhile. This analysis supports exploring that, but it is post hoc and not yet a basis for stopping tolvaptan in patients whose osmolality falls little.
- Consider measuring urine osmolality a few weeks after starting tolvaptan as a marker of drug effect.
- A larger fall in osmolality was linked to greater eGFR preservation in non-Japanese patients.
- Do not stop tolvaptan on osmolality alone; this is exploratory.
- Continue liver function monitoring as required on tolvaptan.
Why it matters
Clinicians need a way to judge early whether tolvaptan is working for an individual patient.
Don't overread it
This is a post hoc mediation analysis; it did not hold in the smaller Japanese cohort.
The statistics, in plain English
A mediation effect estimates how much of a drug's benefit passes through an intermediate change. It relies on assumptions that cannot be fully tested in a trial not designed for it.
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