Opinion
Copeptin: clinical use of a new biomarker

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Arginine vasopressin (AVP) is a key hormone in the human body. Despite the clinical relevance of AVP in maintaining fluid balance and vascular tone, measurement of mature AVP is difficult and subject to preanalytical errors. Recently, copeptin, a 39-amino acid glycopeptide that comprises the C-terminal part of the AVP precursor (CT-proAVP), was found to be a stable and sensitive surrogate marker for AVP release, analogous to C-peptide for insulin. Copeptin measurement has been shown to be useful in various clinical indications, including the diagnosis of diabetes insipidus and the monitoring of sepsis and cardiovascular diseases. Here we review recent findings regarding the relationship between AVP and copeptin, and affirm the value of AVP as a surrogate marker for AVP.

Section snippets

The multifarious activities of AVP

Arginine vasopressin (AVP), also known as the antidiuretic hormone, is a peptide hormone with osmoregulatory, hemodynamic, hemostatic, endocrinologic, and central nervous effects [1]. It is produced in the magnocellular neurons of the hypothalamus and, after axonal transport to the eminentia mediana and the posterior lobe of the pituitary gland, is secreted in response to hemodynamic and osmotic stimuli. Once released into the circulation, AVP exerts its peripheral effects through three

AVP: pathophysiologic and clinical considerations

Disturbances of the AVP system can primarily or secondarily contribute to the pathogenesis of several diseases. Diminished or absent AVP secretion can be the result of a defect at one or more sites involving the hypothalamic osmoreceptors, supraoptic or paraventricular nuclei, or the supraopticohypophyseal tract [4]. Central diabetes insipidus is characterized by decreased secretion of AVP leading to polyuria and polydipsia caused by diminished renal ability to concentrate urine. Nephrogenic

Characterizing copeptin

Copeptin, also known as the AVP-associated glycopeptide, was first described by Holwerda in 1972 [19]. It consists of 39 amino acids, is glycosylated, and contains a leucine-rich core segment. Together with AVP, copeptin is derived from a 164-amino acid precursor termed preprovasopressin, which consists of a signal peptide, AVP, neurophysin II and copeptin [20]. Thus, copeptin is the C-terminal part of pro-AVP (CT-proAVP) (Figure I in Box 2). The processing of copeptin and its physiologic

Determination of copeptin

One way to improve the problematic measurement of a bioactive, rapidly cleared peptide hormone like AVP is to measure a presumably nonfunctional, stable peptide derived from its cognate precursor. This has been applied with great success for the A- and B-type natriuretic peptides 21, 22, 23, 24, 25, adrenomedullin [26] and endothelin-1 27, 28, but is probably best known from the measurement of C-peptide of the insulin precursor. As a result of their stoichiometric generation, the amounts of

Copeptin in healthy volunteers

When measured in 359 healthy volunteers, median copeptin plasma concentrations were 4.2 pmol/L (range: 1–13.8 pmol/L). The 97.5th percentile was 11.25 pmol/L, and the 2.5th percentile was 1.7 pmol/L. Although a significant difference in median copeptin concentration between males and females (5.2 vs 3.7 pmol/L, P < 0.0001) was described, the range in the healthy subjects was comparable in both subgroups. In contrast to many other biomarkers, the copeptin plasma concentration was similar in different

Copeptin in disease

A summary is presented in Table 1.

Other potential indications for clinical determination

Determination of copeptin levels, and thus indirect estimation of AVP plasma concentrations, could theoretically be helpful in clinical situations where disturbances of the vasopressinergic system are suspected. Because of the rapidity of copeptin measurements, this assay could be especially important in answering urgent clinical questions in the acute and critical care setting.

Concluding remarks

Copeptin is a stable fragment of the AVP precursor. The measurement of copeptin seems to be a clinically relevant method of reliably assessing AVP plasma concentrations, which cannot be determined directly in routine practice. This would be particularly helpful in diseases where primary (e.g. electrolyte disturbances) or secondary (e.g. cardiovascular instability, chronic heart failure, sepsis) disturbances of the vasopressinergic system contribute to the pathogenesis. Future studies should

Disclosure statement

N.G.M. and J.S. are employed by B.R.A.H.M.S. AG, which is involved in the development of in vitro diagnostics, and has developed an assay for the measurement of copeptin. No other author has a conflict of interest with regard to drugs or reagents discussed in this manuscript.

Glossary

AUC
Area under curve. The area under the receiver operating characteristic (ROC) curve. This is a summary index for the ROC curve. A perfect diagnostic test, with the perfect ROC, has an AUC = 1.0, whereas an uninformative test has an AUC = 0.5. The AUC can be interpreted as an average true positive fraction (proportion of test positives among the true positives).
CURB65
A scoring system used to assess risk in patients presenting to the emergency room with community-acquired pneumonia. This simpler

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