The expanding role of copeptin in the differential diagnosis of polyuria-polydipsia syndrome in children: a review

The etiology of the polyuria-polydipsia syndrome (PPS) in children includes primary polydipsia (PP), arginine vasopressin (AVP) deficiency (AVP-D), and AVP resistance (AVP-R). Differentiating these conditions is essential to prevent unnecessary or harmful treatments and exclude serious intracranial pathology. Though still considered the gold standard in pediatrics, the water deprivation test (WDT) has drawbacks, including patient discomfort, prolonged duration, and inadequate diagnostic accuracy. Copeptin, the C-terminal peptide of the AVP precursor, has emerged as a stable and practical surrogate marker of AVP secretion. Both random and stimulated copeptin measurements have been investigated to better differentiate the etiology of PPS. In addition to osmotic stimulation protocols, several non-osmotic stimuli, including arginine, glucagon, insulin-induced hypoglycemia, and levodopa, have been shown to induce copeptin release. Prior pediatric studies from our group indicated that dual-agent stimulation, specifically intravenous arginine combined with oral levodopa/carbidopa [arginine-levodopa/carbidopa stimulation test (ALD-ST)] produced robust copeptin responses in control children and was valuable in differentiating AVP-D from PP in a cohort of 20 children with PPS. This review summarizes the physiological basis of copeptin release, pre-analytical and analytical considerations supporting its measurement over AVP quantitation, and the performance and limitations of available diagnostic tests for PPS. We propose a stepwise, pediatric-centered diagnostic framework that integrates clinical context, baseline biochemical assessment, and judicious use of outpatient copeptin-based testing. This approach could reduce reliance on prolonged inpatient testing (the WDT) while highlighting areas where further pediatric validation is needed.