Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease
In the REPRISE trial, tolvaptan slowed the decline in estimated GFR over one year in patients with later-stage autosomal dominant polycystic kidney disease, at the cost of more reversible liver enzyme elevations.
Background
Autosomal dominant polycystic kidney disease is a common hereditary cause of kidney failure. An earlier trial in patients with early-stage disease showed that the vasopressin V2-receptor antagonist tolvaptan slowed kidney volume growth and GFR decline but increased aminotransferase and bilirubin elevations. The efficacy and safety of tolvaptan in patients with later-stage disease were unknown, prompting the REPRISE trial.
Study design
REPRISE was a phase 3, randomized-withdrawal, multicenter, placebo-controlled, double-blind trial. After an 8-week prerandomization period with placebo and tolvaptan run-in phases to assess tolerability, 1370 patients were randomized 1:1 to tolvaptan or placebo for 12 months. Eligible patients were 18 to 55 years old with an estimated GFR of 25 to 65, or 56 to 65 years old with an estimated GFR of 25 to 44 ml per minute per 1.73 m2. The primary endpoint was the change in estimated GFR from baseline to follow-up.
Key findings
The change from baseline in estimated GFR was -2.34 ml per minute per 1.73 m2 in the tolvaptan group versus -3.61 in the placebo group (difference 1.27 ml per minute per 1.73 m2, 95% CI 0.86 to 1.68; P<0.001). Alanine aminotransferase elevations to more than three times the upper limit of normal occurred in 5.6% of tolvaptan-treated patients versus 1.2% of placebo patients; these elevations were reversible after stopping the drug, and no bilirubin elevations of more than twice the upper limit of normal were detected.
Clinical implications
REPRISE extended evidence of tolvaptan's benefit to patients with later-stage ADPKD, showing a slower one-year decline in estimated GFR than placebo. The associated risk of reversible liver enzyme elevations underscores the need for hepatic monitoring and careful patient selection, and the findings informed updated guidance on using tolvaptan in those at risk of rapid progression.
Category
Research
Source
N Engl J Med
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