SAT-063 Mannitol-induced Release of Copeptin in Healthy adults

Abstract Disclosure: S. Lustenberger: None. C. Atila: None. F. Riehle: None. C. Bathelt: None. J.G. Verbalis: None. M. Christ-Crain: None. Background AND OBJECTIVES The differential diagnosis between arginine vasopressin (AVP) deficiency (formerly known as central diabetes insipidus) and primary polydipsia remains challenging. To date, the method with the highest diagnostic accuracy is osmotically-stimulated copeptin – a surrogate marker of AVP – measured during hypertonic saline infusion. However, this method is often limited to experienced hospitals, requires close monitoring, and is contraindicated in some patients. An alternative simpler osmotic stimulation test would be highly desirable. Intravenous mannitol has been shown to increase plasma osmolality and stimulate AVP release, but its effects on copeptin levels have not yet been studied. Methods: 22 healthy adults were included in a randomized double-blind placebo-controlled cross-over trial. Participants presented for two visits, each receiving either mannitol infusion (1g/kg body weight in 30 minutes, maximum 80g) or placebo (normale saline) in random order. Serum copeptin was measured at baseline and at 30, 45, 60, 90, and 150 minutes. The primary endpoint was copeptin levels after infusion of mannitol versus placebo. For the primary analysis, we estimated the treatment effect by fitting a linear mixed effect model, excluding participants with presyncope due to the known strong stimulatory effect of hypotension on AVP secretion. The mixed-effects model, with copeptin at 30 minutes as the dependent variable, included treatment, baseline copeptin, an interaction term, and a random subject effect. Results: 12 of 22 participants were female (55%). Median [IQR] age was 25 years [24, 31] and body mass index was 23.0 kg/m2 [21.4, 25.9]. Baseline copeptin was 4.5 pmol/L [<2.7, 7.0] and peaked at 30 minutes at 12.3 pmol/L [9.4, 19.6] after mannitol infusion. Concurrently, sodium levels decreased from 140 mmol/L [138, 140] to 130 mmol/L [129, 132] and osmolality increased from 289 mOsm/kg [284, 291] to 299 mOsm/kg [296, 300].In contrast, with placebo, baseline copeptin was 4.4 pmol/L [3.1, 6.7] and remained stable at 4.3 pmol/L [3.0, 6.2] after 30 minutes. Sodium and osmolality at baseline were 139 mmol/L [138, 140] and 290 mOsm/kg [285, 291], respectively, and remained stable during the test. One participant with presyncope due to catheter placement was excluded from the primary analysis. Mannitol infusion was associated with a significant treatment effect, increasing copeptin at 30 minutes by +13.9 pmol/L (95% Confidence Interval: [+12.9, +14.9], p< 0.0001). Conclusion: Mannitol infusion at doses used clinically in humans significantly stimulates copeptin levels in healthy adults. Whether mannitol infusion can be used as a diagnostic test to differentiate patients with AVP-deficiency from patients with primary polydipsia is currently being investigated. Presentation: Saturday, July 12, 2025