Arginine Vasopressin Deficiency, Resistance, and Primary Polydipsia: A Review of the Copeptin-Based Diagnostic Paradigm

Abstract

The differential diagnosis of polyuria-polydipsia syndromes has historically relied on the water deprivation test, a procedure subject to logistical challenges, prolonged duration, and diagnostic imprecision in cases of partial disease. Measurement of copeptin, the C-terminal segment of the arginine vasopressin (AVP) precursor, has fundamentally transformed this diagnostic landscape. Because AVP is highly unstable in vitro and extensively platelet-bound, its direct measurement is clinically impractical. Copeptin is co-secreted in equimolar amounts, demonstrates high analytical stability, and possesses a plasma half-life approximately twice that of AVP, serving as a highly reliable surrogate marker. This review examines the molecular rationale, physiological basis, and clinical utility of basal and stimulated copeptin measurement in differentiating arginine vasopressin deficiency (AVP-D), arginine vasopressin resistance (AVP-R), and primary polydipsia. We analyze hypertonic saline and arginine stimulation protocols, including direct evidence demonstrating hypertonic saline superiority over arginine from the definitive 2023 non-inferiority study, discuss integration of copeptin into recent international endocrine guidelines, and evaluate its application in special populations including pediatric patients, pregnant women, and post-pituitary surgery cases. Finally, we address current analytical limitations, including lack of standardization across commercial immunoassays, and future directions for copeptin assay standardization.