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Test Catalog

Test ID: CPAVP    
Copeptin proAVP, Plasma

Useful For Suggests clinical disorders or settings where the test may be helpful

The investigation of the differential diagnosis of patients with water balance disorders, including diabetes insipidus, in conjunction with osmolality and hydration status

 

May aid in the evaluation of cardiovascular disease in conjunction with other cardiac markers

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Arginine vasopressin (AVP) and copeptin (also known as copeptin proAVP or copeptin AVP) are derived from the same precursor peptide. Copeptin has been proposed as a more stable, potentially superior, surrogate marker of AVP in the assessment of water balance disorders. Unlike AVP, copeptin is stable in plasma. Both copeptin and AVP are responsive to osmotic stimuli and increase in response to water deprivation. In healthy subjects, water deprivation causes the plasma osmolality to rise above approximately 280-290 mOsmol/kg, leading to the release of AVP and copeptin into the circulation. Copeptin increases gradually with fasting and water deprivation and declines rapidly after intake of water and/or food.

 

Diabetes insipidus (DI) is characterized by the inability to appropriately concentrate urine in response to volume and osmolar stimuli. The main causes for DI are decreased AVP production (central DI) or decreased renal response to AVP (nephrogenic DI).

 

The determination of the underlying disease pathology in patients with polyuria and altered plasma osmolality is often difficult. Polyuria can be related to insufficient AVP (central DI), reduced sensitivity to AVP (nephrogenic DI), or excessive water intake. Measurement of plasma copeptin concentration has been shown to be useful in the investigation of these AVP-related disorders. Additionally, utilization of copeptin has been proposed in the assessment of syndrome of inappropriate antidiuretic (SIADH).

 

Copeptin is also a marker of acute hemodynamic stress, and has been reported to aid in the prognosis or diagnosis of several cardiac disorders such as acute coronary syndrome, stable coronary artery disease, congestive heart failure, and acute ischemic stroke. Some studies have demonstrated that copeptin may improve prediction of mortality and heart disease outcome when combined with natriuretic peptides such as B-type natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP).

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

Non-water deprived, non-fasting adults: <13.1 pmol/L

Water deprived, fasting adults: <15.2 pmol/L

Non-water deprived, non-fasting pediatric patients: <14.5 pmol/L

Note:

1. The reference interval for non-water deprived healthy adults is from Keller T, Tzikas S, Zeller T, et al: Copeptin improves early diagnosis of acute myocardial infarction. J Am Coll Cardiol. 2010 May 11;55(19):2096-2106. doi: 10.1016/j.jacc.2010.01.029

2. The reference interval for fasting and water deprived adults (at least 8 hours of fasting and water deprivation) was determined from an in-house Mayo study.

3. The reference interval for non-water deprived healthy pediatric individuals is from Du JM, Sang G, Jiang CM, He XJ, Han Y: Relationship between plasma copeptin levels and complications of community-acquired pneumonia in preschool children. Peptides. 2013 Jul;45:61-65. doi: 10.1016/j.peptides.2013.04.015

Interpretation Provides information to assist in interpretation of the test results

While secreted in equimolar concentrations in conjunction with arginine vasopressin (AVP), measured plasma concentrations of copeptin do not correlate strongly with AVP concentrations due to in vivo and in vitro differences in stability. Copeptin is a more stable surrogate biomarker of AVP release. The clinical utility of copeptin of differentiating polyuria and water balance disorders has been demonstrated in a number of studies, when used in conjunction with osmolality and hydration status.

 

In a prospective clinical study, an algorithm was established based on patients with polyuria-polydipsia syndrome (n=55). A nonwater deprived baseline copeptin concentration of 21.4 pmol/L or greater was found to be consistent with the presence of nephrogenic diabetes insipidus (DI). In a described algorithm(1), patients with a copeptin concentrations of under 21.4 pmol/L and a copeptin cut-off of 4.9 pmol/L after fluid deprivation, was used to distinguish between complete or partial DI (<4.9 pmol/L) and primary polydipsia (> or =4.9 pmol/L).

 

Central DI may also be differentiated from nephrogenic DI by measuring copeptin during a stimulus for AVP release such as a water deprivation test. Copeptin concentrations obtained in the process of a water deprivation test can be difficult to interpret because of variation in water deprivation protocols. Patients with psychogenic polydipsia will either have a normal response to water deprivation or, in long-standing cases, show a pattern suggestive of mild nephrogenic DI. Expert consultation is recommended in these circumstances.

 

Although the water-deprivation test is considered the reference standard for the evaluation of DI, measurement of saline stimulated copeptin was shown to be more accurate than the water-deprivation test.(2) In this indirect water deprivation test with a cutoff of 4.9 pmol/L or less indicated central DI while a concentration greater than 4.9 pmol/L indicated primary polydipsia.

 

An elevated plasma copeptin AVP concentration in a hyponatremic patient may be indicative of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). However copeptin determination alone is not typically sufficient to distinguish SIADH from other hyponatremic disorders.(3)

 

Elevations of plasma copeptin in patients with symptoms of heart failure may be prognostic of short and long term mortality. In patients with heart failure (HF) following a myocardial infarction (MI), elevations in copeptin are associated with severity of HF and poorer prognosis.(4) In a cohort of patients with class III or IV HF, copeptin concentrations of 40 pmol/L or greater significantly increased the risk of death or need for cardiac transplantation. The combination of elevated copeptin and hyponatremia was an even stronger predictor of heart failure, independent of B-type natriuretic peptide (BNP) and cardiac troponin (cTn) concentrations.(5)

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Sepsis, severe sepsis, septic shock, lower respiratory tract infections, chronic obstructive pulmonary disease (COPD), and cardiovascular diseases, ie, chronic heart failure may increase copeptin concentrations.

 

Arginine vasopressin (AVP) receptor antagonist therapies and other diseases in which AVP has been shown to play an important pathophysiologic role may also increase copeptin concentration.

 

In some cases bronchial carcinoma may lead to ectopic copeptin secretion.

 

Mixed forms of diabetes insipidus (DI) can exist, and both central and peripheral DI may be incomplete, complicating the interpretation of results.

 

Some patients who have been exposed to animal antigens, either in the environment or as part of treatment or imaging procedures, may have circulating antianimal antibodies present. These antibodies may interfere with the assay reagents to produce unreliable results.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Timper K, Fenske W, Kuhn F, et al: Diagnostic accuracy of copeptin in the differential diagnosis of the polyuria-polydipsia syndrome: A prospective multicenter study. J Clin Endocrinol Metab. 2015 Jun;100(6):2268-2274. doi: 10.1210/jc.2014-4507

2. Fenske W, Refardt J, Chifu I, et al: A copeptin-based approach in the diagnosis of diabetes insipidus. N Engl J Med. 2018 Aug 2;379(5):428-439. doi: 10.1056/NEJMoa1803760

3. Fenske W, Stork S, Blechschmidt A, Maier GK, Morgenthaler NG, Allolio B: Copeptin in the differential diagnosis of hyponatremia. J Clin Endocrinol Metab. 2009 Jan;94(1):123-129. doi: 10.1210/jc.2008-1426

4. Neuhold S, Huelsmann M, Strunk G, et al: Comparison of copeptin, B-type natriuretic peptide, and amino-terminal pro-B-type natriuretic peptide in patients with chronic heart failure: prediction of death at different stages of the disease. J Am Coll Cardiol. 2008 Jul 22;52(4):266-272. doi: 10.1016/j.jacc.2008.03.050

5. Miller WL, Grill DE, Struck J, Jaffe ASP: Association of hyponatremia and elevated copeptin with death and need for transplantation in ambulatory patients with chronic heart failure. Am J Cardiol. 2013 Mar 15;111(6):880-885. doi:10.1016/j.amjcard.2012.11.053

6. Morgenthaler NG, Struck J, Alonso C, Bergmann A: Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin Chem. 2006 Jan;52(1):112-119. doi: 10.1373/clinchem.2005.060038

7. Mueller C, Mockel M, Giannitsis E, et al: Use of copeptin for rapid rule-out of acute myocardial infarction. Eur Heart J Acute Cardiovasc Care. 2018 Sep;7(6):570-576. doi: 10.1177/2048872617710791

8. Maisel A, Mueller C, Neath SX, et al: Copeptin helps in the early detection of patients with acute myocardial infarction: primary results of the CHOPIN trial (copeptin helps in the early detection of patients with acute myocardial infarction). J Am Coll Cardiol. 2013 Jul 9;62:150-160. doi: 10.1016/j.jacc.2013.04.011

9. Keller T, Tzikas S, Zeller T, et al: Copeptin improves early diagnosis of acute myocardial infarction. J Am Coll Cardiol. 2010 May 11;55(19):2096-2106. doi: 10.1016/j.jacc.2010.01.029

10. Du JM, Sang G, Jiang CM, He XJ, Han Y: Relationship between plasma copeptin levels and complications of community-acquired pneumonia in preschool children. Peptides. 2013 Jul;45:61-65. doi: 10.1016/j.peptides.2013.04.015