Urine osmolality fall at three weeks partly explained tolvaptan's kidney benefit, in non-Japanese patients

Design

Post hoc causal mediation analysis of a randomised placebo-controlled trial (TEMPO 3:4)

Population

1,086 adults with ADPKD at risk of rapid progression (948 non-Japanese, 138 Japanese)

Primary outcome

Mediation of 36-month eGFR and kidney volume effects by week-3 urine osmolality change

Effect

Mediation effect on eGFR 2.4 (1.2–3.6) non-Japanese; −0.3 (−2.3 to 1.7) Japanese

This post hoc analysis of TEMPO 3:4, a three-year placebo-controlled trial of tolvaptan in autosomal dominant polycystic kidney disease, asked whether the early drop in urine osmolality predicts long-term response. Japanese and non-Japanese participants were analysed separately.

In 948 non-Japanese participants, the week-3 change in urine osmolality mediated part of tolvaptan's effect on eGFR at 36 months (mediation effect 2.4, 95% CI 1.2–3.6). In 138 Japanese participants it did not, although tolvaptan still had a direct effect on eGFR. In both cohorts, the effect on kidney volume growth was direct rather than through urine osmolality (−8.3% and −12.0%).

This supports checking urine osmolality a few weeks after starting tolvaptan as a sign the drug is acting, at least in non-Japanese patients. It does not provide a threshold for stopping, and the Japanese result shows the relationship may not hold in every population. Tolvaptan availability and cost in India limit its use, and liver monitoring requirements apply.

• Consider measuring urine osmolality a few weeks after starting tolvaptan as a marker of drug effect.
• Do not stop tolvaptan on urine osmolality alone; no stopping threshold has been validated.
• Continue regular liver function monitoring as required for tolvaptan.
• Counsel on thirst and polyuria, which drive discontinuation.

Why it matters

It offers a cheap early signal for a costly drug whose benefit takes years to show.

Don't overread it

This was a post hoc mediation analysis; the relationship did not hold in the Japanese cohort.

The statistics, in plain English

A mediation analysis estimates how much of a treatment's effect travels through a particular pathway. Here, part of tolvaptan's eGFR benefit in non-Japanese patients was 'explained' by the early urine osmolality change; the rest, and all the effect on kidney size, came through other routes.

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