What is Copeptin?
Copeptin is a 39-amino-acid glycopeptide that serves as a stable surrogate marker for arginine vasopressin (AVP), secreted in equimolar amounts with AVP but with superior stability and ease of measurement, making it the primary diagnostic tool for differentiating types of diabetes insipidus in patients presenting with polyuria and polydipsia. 1, 2
Biochemical Properties and Measurement Advantages
- Copeptin is the C-terminal fragment of pre-pro-vasopressin, cleaved during vasopressin synthesis and released in a 1:1 ratio with AVP 1, 3
- The peptide has an estimated half-life approximately twice as long as AVP, providing greater stability for clinical measurement 1
- Unlike AVP, which is unstable ex vivo and requires complex handling, copeptin remains stable in vitro and can be measured using automated immunofluorescent assays 1, 3
- Copeptin responds to the same physiological stimuli as AVP—osmotic changes, hemodynamic stress, and volume depletion—and correlates strongly with AVP across a wide osmolality range 1, 2
Diagnostic Role in Diabetes Insipidus
Nephrogenic Diabetes Insipidus (AVP Resistance)
- A baseline copeptin level >21.4 pmol/L is diagnostic for nephrogenic diabetes insipidus with 100% sensitivity and specificity, eliminating the need for water deprivation testing in these cases 4, 5, 1, 6
- This threshold indicates markedly elevated vasopressin levels that the kidneys are failing to respond to, definitively establishing AVP resistance 4
Central Diabetes Insipidus (AVP Deficiency) vs. Primary Polydipsia
- Baseline copeptin levels <21.4 pmol/L require further testing to distinguish between central diabetes insipidus and primary polydipsia 4, 5
- Stimulated copeptin measurement after hypertonic saline infusion is superior to the classical water deprivation test, with a threshold of 4.9 pmol/L differentiating central DI from primary polydipsia with high diagnostic accuracy 2, 6
- Meta-analysis demonstrates stimulated copeptin achieves 93% sensitivity and 96% specificity for diagnosing AVP deficiency 6
- Arginine-stimulated and glucagon-stimulated copeptin protocols have also been explored as alternative stimulation methods 1
Clinical Utility Beyond Diabetes Insipidus
- Copeptin measurement aids in early goal-directed management of post-operative AVP deficiency 1
- The marker has prognostic value in cardiovascular disease, chronic kidney disease progression, stroke, and autosomal dominant polycystic kidney disease 7, 1, 3
- Copeptin shows limited diagnostic utility in hyponatremia and SIAD due to wide overlap in levels and nonspecific elevations from acute stress 2
Important Caveats for Clinical Use
- Small amounts of oral fluid intake may significantly decrease copeptin levels, while food intake does not appear to affect measurements 1
- Separate validation studies are required before applying copeptin thresholds from one assay platform to another, as different immunoassays may yield different results 1
- Copeptin has little value in differentiating between primary polydipsia and central DI when measured at baseline without stimulation 2, 6, 8
- The test should only be performed after confirming the characteristic triad of diabetes insipidus: polyuria (>3 L/24h in adults), inappropriately dilute urine (osmolality <200 mOsm/kg), and high-normal or elevated serum sodium 4, 9