A post-hoc internal validation of arginine-stimulated copeptin cut-offs for diagnosing AVP deficiency (central diabetes insipidus)

BACKGROUND: Distinguishing arginine vasopressin (AVP) deficiency (central diabetes insipidus) from primary polydipsia is challenging. While hypertonic saline-stimulated copeptin testing provides the highest diagnostic accuracy, it is often restricted to specialised centres, requiring close monitoring and potentially causing patient discomfort. Initially, arginine-stimulated copeptin was proposed as a simpler alternative, but a head-to-head comparison study found it less precise than hypertonic saline stimulation. However, the same study identified two new high sensitivity and specificity cut-offs for arginine-stimulated copeptin, though these cut-offs have yet to be validated. METHODS: This is a secondary post-hoc analysis of the initial prospective multicentre study, including adult patients with confirmed AVP deficiency or primary polydipsia. Participants underwent the arginine stimulation test, with plasma copeptin measured at baseline and 60- and 90 min after arginine infusion. The primary objective was to revisit the original study to internally validate the proposed arginine-stimulated copeptin cut-offs of > 5.2pmol/L (high specificity cut-off with > 90% specificity for primary polydipsia) and ≤ 3.0 pmol/L (high specificity cut-off with > 90% specificity for AVP deficiency). FINDINGS: In total, 96 patients were included between May 2013 and June 2018: n = 38 [40%] with AVP deficiency and n = 58 [60%] with primary polydipsia. At 60 min after arginine infusion, a copeptin level ≤ 3.0 pmol/L showed a specificity of 95% (95% CI: 0.88-1.00) for AVP deficiency, while a copeptin level > 5.2 pmol/L demonstrated a specificity of 97% (95% CI: 0.92-1.00) for primary polydipsia. The ≤ 3.0 pmol/L cut-off accurately identified 71% (n = 27/38) of patients with AVP deficiency, and the > 5.2 pmol/L cut-off correctly identified 69% (n = 40/58) of patients with primary polydipsia. INTERPRETATION: This analysis validates two new copeptin cut-offs of the arginine stimulation test to distinguish AVP deficiency from primary polydipsia: >5.2 pmol/L for high specificity in diagnosing primary polydipsia and ≤ 3.0 pmol/L for high specificity in diagnosing AVP deficiency. These thresholds might offer a practical initial alternative to hypertonic saline testing. REGISTRATION: Clinicaltrials.gov (NCT00757276).