Mannitol-stimulated Copeptin for diagnosing Arginine Vasopressin Deficiency: a randomized controlled proof of concept and a single-arm pilot study

Abstract Differentiating arginine vasopressin (AVP) deficiency from primary polydipsia is challenging. The most accurate test, hypertonic saline–stimulated copeptin, requires intensive monitoring. Intravenous mannitol stimulates AVP release and may provide a simpler alternative. In a randomized double-blind crossover trial, 22 healthy adults received mannitol and placebo in random order, of whom 21 were included in the primary analysis. In a pilot study, 10 patients with AVP deficiency and 10 with primary polydipsia received mannitol. The primary outcome was copeptin after mannitol infusion. Mannitol resulted in a 2.29-fold higher copeptin at 90 minutes (+6.4 pmol/L (95% CI: +5.2, +7.7; p <0.001)) than after placebo at mean baseline copeptin levels in healthy adults. In patients, copeptin after 30 minutes was 11.7 pmol/L (95% CI: 6.5, 17.0) higher in primary polydipsia than in AVP deficiency. Mannitol infusion shows promise as a new diagnostic approach. Larger confirmatory studies are required to validate both the optimal diagnostic cut-off and patient safety. Trial Registration number: NCT06542198 .