Copeptin

Copeptin is a peptide derived from the cleavage of the precursor of arginine vasopressin (AVP).^7-10 AVP, also known as antidiuretic hormone (ADH), is a neuropeptide that is secreted from the hypothalamus in response to hypovolemia and elevated plasma osmolality.^10-12 AVP has two primary functions: to retain water in the body and to constrict blood vessels.¹¹ The measurement of AVP has been employed in the differential diagnosis of a variety of disorders related to the physiologic response to changes in plasma osmolality and non-osmotic stress.^13-15 Unlike AVP, copeptin is a stable molecule and can be readily measured using an automated immunoassay.⁶ Because copeptin and AVP are produced simultaneously through a common proteolytic process, they are secreted into the circulation in an equimolar ratio.16 Serum copeptin concentrations correlate significantly with AVP levels¹⁷ and the levels of the two molecules respond equally to changes in blood volume.^9,18

The assessment of circulating AVP levels is challenging because it is released in a pulsatile pattern and is rapidly cleared from plasma. Measurement of AVP is further complicated by the high ex vivo instability of the peptide.^13,19 Copeptin levels tend to be relatively constant in plasma and this peptide is much more stable ex vivo, making sample handling more straight forward.⁹ As a consequence, copeptin can serve as a superior, surrogate marker of physiological AVP release in the assessment of patients with water balance disorders. The correlation of plasma copeptin with plasma osmolality has been shown to be stronger than the correlation of AVP with plasma osmolality,⁴ in great part due to the complexity and methodological drawbacks of the AVP assay. Copeptin is a stable surrogate marker of AVP and its measurement has proved to be convenient and sensitive diagnostic in a number of clinical applications.^13,19

Diabetes insipidus (DI) is a rare disorder of water homeostasis characterized by the excretion of abnormally large volumes of hypotonic urine due to the inability to appropriately concentrate urine in response to volume and osmolar stimuli.^7,20 The primary causes for DI are decreased AVP production (central DI) or decreased renal response to AVP (nephrogenic DI), both of which lead to hypotonic polyuria which is usually accompanied by polydipsia. Along with these etiologies, the differential diagnosis of hypotonic polyuria includes primary polydipsia.⁸ In primary polydipsia, there is no initial compromise in AVP secretion or renal action and instead, excessive fluid intake leads to a drop in plasma osmolality and a suppression of AVP synthesis. Primary polydipsia can be caused by an abnormality in the thirst center (dipsogenic polydipsia) or, more commonly, as the result of one of a number of psychiatric disorders (psychogenic polydipsia).⁷

Historically, the primary diagnostic test for the evaluation of polyuria-polydipsia syndrome has been the standard water deprivation test.^14,21,22 In healthy subjects, water deprivation causes the plasma osmolality to rise, leading to the release of AVP (and copeptin) into the circulation. In this test, insufficient AVP secretion or effect is revealed by insufficient concentration capacity of the kidneys on osmotic stimulation which is achieved by a prolonged period of thirsting and followed by assessment of the response to exogenous AVP administration (Desmopressin). Recent studies aimed at validating the classical water deprivation revealed a diagnostic accuracy of only around 70%, with an even lower diagnostic accuracy in patients with primary polydipsia.^21,22 Direct measurement of arginine vasopressin (AVP) upon osmotic stimulation has been proposed as an alternative to measuring 24-hour urine osmolality,²³ but this method failed to enter clinical practice in large part due to technical limitations of AVP testing.^13,22

The utility of copeptin measurement in assessing polyuria and water balance disorders has been evaluated.^14,15,24 A baseline copeptin concentration of 21.4 pmol/L or greater (consistent with pathogenic overproduction of AVP) has been shown to accurately differentiate nephrogenic DI from other causes of polyuria, with a sensitivity and specificity of 100%.^14,16 The distinction between central diabetes insipidus and primary polydipsia is not as straightforward because of the considerable overlap in baseline copeptin levels. In particular, distinguishing partial central diabetes insipidus from primary polydipsia is very challenging.²² Two copeptin-based test procedures have been proposed to overcome these difficulties: the hypertonic saline stimulation test²¹ and the arginine stimulation test.²⁵

Katan and coworkers found that the measurement of copeptin after insulin induced hypoglycemia could be used to assess posterior pituitary function in patients after pituitary surgery.³ They found that a significant induction of copeptin levels was seen in patients with normal posterior pituitary function, but copeptin levels remained low in patients with postsurgical DI.³ This same group went on to demonstrate, in a prospective multicenter study, that a copeptin concentration of less 2.5 pmol/L after trans- sphenoidal surgery (without the need for induction of hypoglycemia) had a predictive value of 81% for central DI, with a specificity of 97%.²⁵