Clin Chem Lab Med 2014; 52(10): 1447–1456
Review Davide Bolignano, Aderville Cabassi, Enrico Fiaccadori, Ezio Ghigo, Renato Pasquali, AndreaPeracino*, Alessandro Peri, Mario Plebani, Antonio Santoro, Fabio Settanni andCarmine Zoccali
Copeptin (CTproAVP), a new tool for understanding the role of vasopressin in pathophysiology Abstract: Arginine vasopressin (AVP) plays a key role in many physiologic and pathologic processes. The most important stimulus for AVP release is a change in plasma osmolality. AVP is also involved in the response and adaptation to stress. Reliable measurement of AVP is hindered by several factors. Over 90% of AVP is tightly bound to platelets, and its estimation is influenced by the number of platelets, incomplete removal of platelets or pre-analytical processing steps. Copeptin (CTproAVP), a 39-aminoacid glycopeptide, is a C-terminal part of the precursor pre-provasopressin (pre-proAVP). Activation of the AVP *Corresponding author: Andrea Peracino, Fondazione Giovanni Lorenzini Medical Science Foundation, Milan, Italy and Houston, TX, USA, E-mail: [emailprotected] Davide Bolignano and Carmine Zoccali: CNR-Institute of Clinical Physiology and Department of Nephrology, Urology and Renal Transplantation Unit, United Hospitals, Reggio Calabria, Italy Aderville Cabassi: Internal Medicine, Cardiorenal Research Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy Enrico Fiaccadori: Clinical and Experimental Medicine Department, Renal Failure Unit, Parma University Medical School, Parma, Italy Ezio Ghigo: Department of Medical Sciences, School of Medicine, University of Turin, Turin, Italy Renato Pasquali: Division of Endocrinology, S. Orsola-Malpighi Hospital in Bologna, Bologna, Italy Alessandro Peri: Endocrine Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Center for Research, Transfer and High Education on Chronic, Inflammatory, Degenerative and Neoplastic Disorders for the Development of Novel Therapies (DENOThe), Florence, Italy Mario Plebani: Department of Laboratory Medicine, UniversityHospital of Padua, Padua, Italy Antonio Santoro: Nephrology, Dialysis and Hypertension Department, Azienda Ospedaliero-Universitaria of Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy Fabio Settanni: Laboratory of Endocrinology, Division of Endocrinology, Diabetology and Metabolism, Department of Medical Science, Turin University San Giovanni Battista Hospital, Città della Salute e della Scienza, Turin, Italy
system stimulates CTproAVP secretion into the circulation from the posterior pituitary gland in equimolar amounts with AVP. Therefore CTproAVP directly reflects AVP concentration and can be used as a surrogate biomarker of AVP secretion. In many studies CTproAVP represents AVP levels and its behavior represents changes in plasma osmolality, stress and various disease states, and shows some of the various physiologic and pathophysiologic conditions associated with increased or decreased AVP. Increased CTproAVP concentration is described in several studies as a strong predictor of mortality in patients with chronic heart failure and acute heart failure. Autosomal polycystic kidney disease (ADPKD) patients have both central and nephrogenic defects in osmoregulation and CTproAVP balance. A possibility raised by these clinical observations is that CTproAVP may serve to identify patients who could benefit from an intervention aimed at countering AVP. Keywords: chronic heart failure; copeptin; CTproAVP; diabetes insipidus; hyponatremia; osmoregulation; vasopressin. DOI 10.1515/cclm-2014-0379 Received April 7, 2014; accepted May 14, 2014; previously published online June 18, 2014
Introduction Arginine vasopressin (AVP), also known as antidiuretic hormone, plays a key role in many physiologic and pathologic processes. Both AVP and its closely related peptide oxytocin are highly conserved and appear to precede the divergence of vertebrate and invertebrate families. The main role of AVP is to induce water conservation by the kidney, thus contributing to osmotic and cardiovascular
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1448 Bolignano etal.: CTproAVP to understand the role of vasopressin in pathophysiology homeostasis. It also has hemostatic, endocrine and central nervous effects. AVP is a nine-amino acid peptide with a disulfide bridge between two cysteine amino acids. It is produced primarily in the magnocellular neurons of the hypothalamus, and is stored and secreted by granules within the posterior lobe of the pituitary, primarily as a response to high plasma osmolality, low plasma volume, and/or low blood pressure. To a lesser extent, it is also produced in other tissues including the sympathetic ganglia, adrenal glands, and the testis [1]. The synthesis of AVP involves precursor peptides (pre-proAVP and proAVP) that are enzymatically cleaved by a four-enzyme cascade into the components vasopressin, copeptin (CTproAVP) and neurophysin II. These three cleavage products are all released into the circulation in equal ratios. The most important stimulus for AVP release is a change in plasma osmolality. This occurs via peripheral receptors whose afferent stimuli ascend via the vagus nerve through the medulla to the hypothalamic nuclei. A small change, of even 1%, in plasma osmolality is sufficient to change AVP concentration. Normal AVP concentrations in healthy individuals are between 1 and 5 pg/mL. AVP is also an important factor of the response and adaptation to stress. Stressful stimuli evoke complex endocrine, autonomic, and behavioral responses that are extremely variable and specific depending on the type and nature of the stressors. Adaptation to stress stimuli, either acute or chronic, largely depends on the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the catecholaminergic system [2]. Appropriate regulatory control of the HPA stress axis is essential to health and survival. The outflow of the HPA axis is therefore a summation of integrated inputs from several forebrain regions. In the hypothalamic areas, the cascade is in turn chiefly regulated by the corticotropin releasing hormone (CRH) and AVP. Hyperactivation of the sympathetic nervous system (SNS) also plays a partnership role in the body’s response to both acute and chronic stress [3]. AVP is particularly produced in response to stress or acute life-threatening events (physical stress conditions), and is involved in changes in blood pressure and volume. AVP produced under these circumstances greatly exceeds the physiological range with exponential levels 100- or 1000-fold times the normal concentration. AVP exerts its effects on three different receptors. The V1a receptors mediate strong arteriolar vasoconstriction and are localized primarily on vascular smooth muscle cells, hepatocytes, platelets, and cells in the brain and uterus. V2 receptors mediate antidiuretic effects, and are highly
expressed in the kidneys, and in endothelial cells and vascular smooth muscle. Upon stimulation, V2 receptors activation is associated with an increased intracellular level of cAMP, which in turn triggers the insertion of aquaporin-2 water channels in the apical membrane of tubular cells of the distal nephron, leading to water reabsorption into the interstitium. V3 receptors (also known as V1b receptors), found in the anterior pituitary, brain, pancreas, and heart are involved in ACTH secretion, neuromodulation, insulin synthesis and release, temperature and memory control [1, 4–7]. The plasma half-life of AVP is quite short, of about 5–20 min. Clearance of AVP usually occurs by the kidney or liver, with renal clearance estimated at approximately 50%–70% of total clearance [1]. AVP can also be degraded by several endothelial and circulating endo- and amino peptidases. Clearance is proportional to plasma levels of AVP and reaches 600 mL/min at a concentration of 10pg/ mL in humans. Urinary clearance is about 5% of the total clearance [1]. AVP action has been linked to liver glycogenolysis via V1a receptors and insulin and glucagon secretion via V1b receptors. AVP levels are markedly increased in patients with poorly controlled diabetes mellitus [8] and AVP infusion leads to increased blood glucose levels in healthy subjects [9]. AVP predicts diabetes mellitus independently of a broad range of established diabetes risk factors [10]. Finally, AVP has been suggested to regulate hypermetabolic pathways of fat in V1a receptor knockout mice [11] and promote thermogenic adipokines in brown adipose tissue [12], which imply a potential role of the AVP system in the regulation of energy expenditure and balance which, in turn, may interfere with the water balance.
CTproAVP (copeptin) in physiological conditions Reliable measurement of AVP is hindered by several factors. Over 90% of AVP is tightly bound to platelets, and its estimation is influenced by the number of platelets, incomplete removal of platelets or pre-analytical processing steps [4]. In addition, AVP is also highly unstable in isolated plasma – even when stored at –20 °C. CTproAVP (copeptin), a 39-aminoacid glycopeptide, is a C-terminal part of the precursor pre-provasopressin (preproAVP). Activation of AVP system stimulates CTproAVP secretion into the circulation from the posterior pituitary gland in equimolar amounts with AVP. Therefore, CTproAVP directly reflects AVP concentration and can be
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used as surrogate biomarker of AVP secretion. Even mild to moderate stress situations contribute to the release of CTproAVP. These reasons have led to several different lines of research in various disease states. To overcome some of these disadvantages, CTproAVP can be used as a surrogate for AVP since it is very stable in plasma and during storage. Unlike AVP, it does not require any pre-analytical processing and can be easily determined with several manual and automated assays. A large study using healthy volunteers recruited from a local heart failure screening showed that the median CTproAVP levels are slightly, but significantly higher in males compared to females [4.3 (0.4–44.3) vs. 3.2 (1.0–14.8) pmol/L]. There is a stronger correlation of CTproAVP with the estimated glomerular filtration rate (eGFR) in males compared to females and left atrial size correlated with higher CTproAVP levels [13]. Levels of CTproAVP are not strongly correlated with age [13, 14], however, strenuous exercise causes a moderate increase in CTproAVP [14]. Studies have shown that CTproAVP mirrors AVP levels under diverse physiologic and pathophysiologic conditions such as changes in plasma osmolality, stress and various disease states [15–17]. The measurement of CTproAVP can be used to reflect AVP concentrations as it is produced in equimolar amounts as AVP and released into the circulation at the same time as AVP secretion [15].
Vasopressin and CTproAVP in pathogenetic conditions Diabetes insipidus Diabetes insipidus (DI) is a clinical syndrome characterized by polyuria due to a defect in the urinary concentrating mechanism [18]. There is also an associated compensatory polydipsia. The prevalence in the general population is estimated at 1 per 25–35,000. The syndrome comprises three main types central, nephrogenic and gestational, and a related syndrome, primary polydipsia [19]. Central (neuro-hypophyseal) DI is associated with impaired production or secretion of AVP, such as in pituitary injury after head trauma or surgery. It is estimated that 20%–30% of pituitary operations are associated with transient central DI, and that 2%–10% lead to permanent disease [20, 21]. Central DI is also sometimes observed in course of infection or malignancy. The other type of central DI is due to a very rare congenital condition, i.e., as familial
neuro-hypophyseal DI associated with autosomal dominant, recessive or X-linked recessive mutation of the AVP gene. Nephrogenic DI is characterized by impaired AVPinduced water adsorption [19]. Acquired nephrogenic DI is most commonly associated with electrolyte abnormalities (such as hypokalemia or hypercalcemia) or the therapeutic use of drugs, such as lithium or cisplatin. Gestational DI, is due to an increased degradation of AVP from vasopressinase, a placental enzyme [22, 23]. Although it is not very commonly observed, it can be under diagnosed, as polyuria is considered normal during pregnancy. DI should be differentiated from primary polydipsia. The latter differs from DI as it is not associated with variants of AVP secretion or activity – but rather from excessive fluid intake over extended periods of time. However, CTproAVP may help in the differential diagnosis of primary polydipsia and DI, although further studies are needed in the area. An accurate differentiation of the underlying pathology is necessary for effective treatment of DI. If the patient has central diabetes insipidus, the AVP concentration will not increase – even though there has been a significant decrease in body weight or increase in plasma osmolarity. However, if the patient has nephrogenic DI, AVP will appropriately increase in parallel to dehydration status progression and the increase in plasma osmolarity. Desmopressin (an exogenous synthetic vasopressin analog) is commonly administered as a challenge after water deprivation to see if there is a further change in urine osmolality. CTproAVP has been used in several recent studies as a novel approach for the diagnosis of DI [24–26]. This method evaluates osmotically stimulated CTproAVP after an 8-h water withdrawal period. The first blood sample is able to aid in the distinction between central complete and nephrogenic DI by comparing the plasma levels of CTproAVP. Concentrations of CTproAVP that are 20 pmol/L indicate nephrogenic DI. Patients with intermediate values between 2.6 and 20 pmol/L undergo a further 8h of fluid deprivation. A CTproAVP index is derived by the following equation: Delta CTproAVP [8 − 16 h]×1000 [pmol/L/mmol/L] S-Na+ [16 h] Patients with a CTproAVP index of 20 have primary polydipsia [16].
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1450 Bolignano etal.: CTproAVP to understand the role of vasopressin in pathophysiology
Hyponatremia and SIADH (SIAD) Hyponatremia, defined as serum sodium levels
