Urea-stimulated copeptin: a novel diagnostic approach in polyuria polydipsia syndrome

Distinguishing arginine vasopressin (AVP) deficiency from primary polydipsia remains challenging. While hypertonic saline-stimulated copeptin testing offers high diagnostic accuracy, it is complex and limited to specialized centers. Intravenous urea is known to stimulate AVP secretion, but the effect of oral urea on copeptin levels is unknown.

Twenty-two healthy adults were included in a randomized, double-blind, placebo-controlled cross-over trial receiving a single dose of urea (0.5 g/kg; minimum 30 g, maximum 45 g) and placebo. Serum copeptin was measured at 30-min intervals for 2.5 h. In a second step, 13 patients with AVP-deficiency and 13 patients with primary polydipsia were included in an open-label pilot study, receiving urea only. The primary endpoint was maximum copeptin within 150 min.

In healthy adults, median [IQR] copeptin significantly increased from 4.6 [3.0-5.7] pmol/L at baseline to a maximum of 10.1 [7.2-11.6] pmol/L at 120 min after ingestion of urea, while it remained stable at 3.8 [2.9-6.6] pmol/L after placebo intake (P < .001). In patients with AVP-deficiency, copeptin remained below detection limit throughout the test, while in patients with primary polydipsia the peak was seen 150 min after ingestion of urea at 7.4 pmol/L [4.3, 10.3]. The best copeptin cut-off for differentiating AVP-deficiency from primary polydipsia was 3.5 pmol/L after 120 min, with 93% sensitivity and specificity.

Oral urea stimulates copeptin in healthy adults and patients with primary polydipsia, but not in patients with AVP-deficiency, establishing the first oral copeptin-based test in differentiating primary polydipsia from AVP-deficiency.