Copeptin in the differential diagnosis of the polydipsia-polyuria syndrome – revisiting the direct and indirect water deprivation tests

Background: The water deprivation test with direct or indirect measurement of plasma vasopressin (AVP) is currently the method of choice for the differential diagnosis of the polydipsia-polyuria syndrome. Its diagnostic reliability, however, has never been evaluated in a larger series of patients, and measurement of AVP is known to be hampered by its high preanalytical instability. This study seeks to evaluate the diagnostic potential of copeptin, a highly stable and easy to measure surrogate of AVP secretion, in a large sample of patients with polyuria-polydipsia syndrome, and to compare its performance with the current diagnostic standard. Methods: Thirty healthy subjects and 50 consecutive patients with polydipsia-polyuria syndrome underwent the standard water deprivation test with additional, iterative measurements of plasma AVP and copeptin levels. A clinical reference standard and patients' response to therapeutic trials adjudicated on the final diagnosis, provided that any diagnostic discrepancies occurred between the water deprivation test and direct AVP measurement. Results: Twenty two patients (44%) were diagnosed with primary polydipsia, 17 patients (34%) with partial central diabetes insipidus (DI), 9 patients (18%) with complete central DI, and 2 patients (4%) with nephrogenic DI. The water deprivation test led to a correct diagnosis in 35/50 patients (70%), additional AVP measurement correctly diagnosed in 23 patients (46%), and additional copeptin measurement correctly identified 36 patients (72%). The ratio between delta copeptin [8h to 16h] and the serum sodium concentration at 16h yielded the best diagnostic accuracy, allowing even to discern mild forms of central DI from primary polydipsia (sensitivity and specificity of 87 and 100%, respectively). Conclusion: Baseline copeptin reliably identified patients with nephrogenic and complete central DI. The ratio of delta copeptin [8h-16h] to plasma osmolality [16h] during an osmotic stimulation holds great potential to considerably improve the differential diagnosis in this diagnostically demanding syndrome.