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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0232
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 10 3973-3978
Copyright © 2007 by The Endocrine Society

Changes in Plasma Copeptin, the C-Terminal Portion of Arginine Vasopressin during Water Deprivation and Excess in Healthy Subjects

Gabor Szinnai, Nils G. Morgenthaler, Kaspar Berneis, Joachim Struck, Beat Müller, Ulrich Keller and Mirjam Christ-Crain

Division of Endocrinology, Diabetology, and Clinical Nutrition (G.S., B.M., U.K., M.C.-C.), University Hospital, CH-4031 Basel, Switzerland; Pediatric Endocrinology and Diabetology (G.S.), University Children’s Hospital, CH-4005 Basel, Switzerland; Research Department (N.G.M., J.S.), B.R.A.H.M.S. AG, D-16761 Hennigsdorf/Berlin, Germany; and Clinic of Endocrinology, Diabetes, and Clinical Nutrition (K.B.), University Hospital, CH-8091 Zurich, Switzerland

Address all correspondence and requests for reprints to: Dr. Gabor Szinnai, Pediatric Endocrinology and Diabetology, University Children’s Hospital Basel, Römergasse 8, CH-4005 Basel, Switzerland. E-mail: gabor.szinnai{at}unibas.ch.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The measurement of arginine vasopressin (AVP) is often cumbersome because it is unstable with a short half-life time. AVP is derived from a larger precursor peptide along with the more stable peptide copeptin. Copeptin is the C-terminal part of provasopressin and has been shown to be a useful tool to indicate AVP concentration in critically ill patients.

Objective: The objective of the study was to evaluate the clinical usefulness of copeptin as a new marker in disordered states of blood volume and plasma osmolality.

Design and Setting: This was a prospective observational study in a university hospital.

Participants and Main Outcome Measures: Three techniques with respective control studies were used in 24 healthy adults to produce changes in plasma osmolality and/or volume: 1) a 28-h water deprivation, 2) a 17-h hypertonic saline infusion combined with thirsting, and 3) a hypotonic saline infusion with iv desmopressin administration during free water intake.

Results: Water deprivation produced a weight loss of 1.7 kg, an increase in plasma osmolality to 294.8 ± 4.3 mosmol/kg, and an increase of copeptin from 4.6 ± 1.7 pmol/liter to 9.2 ± 5.2 pmol/liter (P < 0.0001). During hypertonic saline infusion and thirsting with a raise of plasma osmolality to 296.1 ± 3.4 mosmol/kg, copeptin increased from 4.9 ± 3.0 pmol/liter to 19.9 ± 4.8 pmol/liter (P < 0.0001). Conversely, during hypotonic saline infusion, plasma osmolality decreased to 271.3 ± 4.1 mosmol/kg, and copeptin decreased from 6.2 ± 2.4 pmol/liter to 2.4 ± 2.1 pmol/liter (P < 0.01).

Conclusion: Copeptin shows identical changes during disordered water states as previously shown for AVP. It might be a reliable marker of AVP secretion and substitute for the measurement of circulating AVP levels in clinical routine.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE ANTIDIURETIC HORMONE arginine vasopressin (AVP) is synthesized in the hypothalamus and secreted by the neurohypophysis into the blood (1). AVP acts on the distal tubule of the kidney and induces water conservation by the kidney. It is one of the key hormones of water homeostasis (1). The main stimulus for AVP secretion is hyperosmolality, but a decrease in blood volume also induces AVP secretion (2). The diagnostic use of AVP in normal and disordered states of water balance due to endocrine, cardiovascular, or renal disease has been described in detail over the last decades (1, 2, 3, 4, 5). Secondary involvement of AVP in the pathogenesis of other diseases like congestive heart failure has repeatedly been reported (6). AVP is also considered to be part of the endocrine stress response to cardiac arrest and shock (7), and this AVP effect is presently the focus of experimental and clinical trials in cardiac arrest and different shock states (8, 9). However, depending on the assay used, the methodological reliability of many laboratory assays determining plasma AVP concentrations is problematic. More than 90% of AVP in the circulation is bound to platelets (10), resulting in either underestimation or in case of prolonged storage of unprocessed blood samples in falsely elevated or varying AVP levels (10, 11). Furthermore, AVP is unstable in isolated plasma, even when stored at –20 C (3), and due to its small size, AVP cannot be measured by sandwich immunoassays but needs competitive assays, which are generally time consuming and less sensitive.

AVP derives from a 166-amino acid long precursor protein, preprovasopressin, which consists of a signal peptide, AVP, neurophysin II, and copeptin (12). The three components are separated during axon transport of the neurosecretory granules from the cell body to the axon terminals in the posterior pituitary. Copeptin, the C-terminal part of the AVP precursor, is a 39-amino acid-long glycosylated peptide with a leucine-rich core segment (13, 14). It is produced together with AVP in an equimolar ratio and processed on the way from the hypothalamus to the pituitary during which it may act together with neurophysin II as a carrier protein of AVP. Recent data suggest an important role of copeptin in the correct structural formation of the AVP precursor as a prerequisite for its efficient proteolytic maturation (15). In vivo, copeptin values decrease rapidly after a water load, indicating similar kinetics as described for AVP in vivo (16). Similarly, a direct site-to-site comparison of mature AVP and copeptin during a several day stay on an intensive care unit indicate similar kinetics for both peptides (17). A possible reason for the disparity in molar concentrations observed for AVP and copeptin may be the large attachment of AVP to thrombocytes. In addition, a higher molar ratio of a precursor peptide, compared with the mature peptide, is well known for other hormones that are initially secreted stoichiometrically (18). Ex vivo, bioactive AVP is rapidly degraded, whereas copeptin remains stable for several days at room temperature in serum or plasma (16). On the basis of detailed analysis of the structure of circulating copeptin, a copeptin assay to quantify AVP secretion has recently been developed (16, 19).

The aim of this study was to evaluate the reliability of this new assay for AVP activity in the context of human disorders of blood volume and osmolality in analogy with the seminal papers of Robertson and colleagues (2, 3, 20).


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study subjects

Three techniques with respective control studies were used to produce changes in plasma osmolality and/or volume (Fig. 1Go). In the first study, eight women and eight men underwent a dehydration study (i.e. hyperosmolar hypovolemia) and a control study in random order, 6–8 d apart. All female subjects were investigated during the follicular phase (2–4 d after the beginning of menstrual bleeding and 7 d later for the respective second study), when osmotic sensitivity is identical in men and women. The studies started at 0800 h on d 1 and lasted 28 h as previously described (21). On the morning of d 1, predeprivation data were obtained after a small continental breakfast with a noncaffeinated beverage and after abstaining from alcohol for at least 24 h. The participants were weighed after emptying the bladder. After a minimum of 30 min of rest in a semirecumbent position, a baseline antecubital venous blood sample was obtained. During the dehydration study, all fluids were withdrawn, and the subjects were asked to undertake normal activities in the hospital building and to consume a self-selected diet based on a list of foods containing less than 75% of water by weight according to published tables (22) for the next 28 h. During the control study, the subjects were allowed to consume nonalcoholic beverages except coffee ad libitum throughout the study period. On d 2 after breakfast and at 1200 h, blood samples for measurement of plasma sodium, plasma osmolality, and copeptin levels and data on weight were obtained in the same manner as on the first day.


Figure 1
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  		FIG. 1. Overview of the different experiments performed during the study to induce changes in osmolality and volume status.

 
In the second and third study, eight male volunteers underwent randomly three studies: hyperosmolal isovolemia, hypoosmolal hypervolemia, and a control study (i.e. isoosmolal isovolemia) in randomized order and with intervals of at least 7 d in between, as previously described (23). In the hyperosmolal isovolemia study, the subjects received 1 ml/kg·h of 2% saline infusion from 2000 to 0800 h and 200 ml/h of 5% saline infusion from 0800 to 1300 h. They were instructed not to drink during the whole study period. In the hypoosmolal hypervolemia study, the subjects received 4 µg desmopressin (Minirin) iv at 2000 h on study d 1 and at 0800 h on study d 2. Simultaneously, they were instructed to drink 2–2.5 liters of tap water during the night. From 0800 to 1300 h on study d 2, they received 200 ml/h of 0.4% saline infusion. The isoosmolal isovolemia study consisted of access to oral water ad libitum during the whole study period. Body weight, plasma sodium, plasma osmolality, and copeptin values were measured at baseline (2000 h on d 1), 1000, 1200, and 1300 on d 2 after a minimum rest of 30 min in a semirecumbent position. The saline infusion studies (hyperosmolal isovolemia and hypoosmolal hypervolemia) were combined with infusions of variable amounts of glucose 20% and mixed standard amino acid solutions for metabolic studies, explaining why serum sodium levels did not increase as high as expected by saline infusion alone (23).

Written informed consent was obtained from all subjects. Approval from the local ethics committee was obtained before the studies.

Measurements

Changes in total body water (in liters) were assessed by repeated weighing (as exactly as 0.1 kg) of the subjects at baseline and during the study period. Plasma sodium concentrations were measured by indirect potentiometry (Hitachi 917; Roche Diagnostics, Rotkreuz Switzerland; or DuPont Dimension AR, Dade, Düdingen, Switzerland). Plasma osmolality was measured by cryoscopic technique (Micro Osmometer model 3300; Advances Instruments for Switzerland Instruments, Zürich, Switzerland).

Plasma copeptin levels were measured with a new sandwich immunoassay (B.R.A.H.M.S AG, Hennigsdorf/Berlin, Germany), as described in detail previously (16). Briefly, this sandwich immunoluminometric assay uses two polyclonal antibodies to the C-terminal region (amino acid sequence 132–164) of prepro-AVP. One antibody is bound to polystyrene tubes, and the other is labeled with acridinium ester for chemiluminescence detection. The assay requires 50 µl of either serum or plasma and no extraction steps or other preanalytical procedures like addition of protease inhibitors are necessary, and results are available in approximately 3 h. The analytical detection limit is 1.7 pmol/liter and the total precision of the assay (interlaboratory coefficient of variation) is less than 20% for copeptin concentrations across the calibration curve (up to 405 pmol/liter). Copeptin plasma concentration in 359 healthy individuals were (median, range) 4.2 pmol/liter (1–13.8 pmol/liter). The 97.5th percentile was 11.25 pmol/liter, and the 2.5th percentile was 1.7 pmol/liter. Of all 359 tested volunteers, only nine (2.5%) had a plasma copeptin concentration below the detection limit of the assay of 1.7 pmol/liter. The analytical specificity of the assay is based on the epitope specificity of the antibodies used in the assay. The amino acid sequence of the peptides used for immunization in the databank (FASTA Protein Similarity Search against the UniProtKB/SwissProt Database) showed not a single other human peptide but only nonhuman homologs of copeptin with homologies down to 66%. AVP was measured from EDTA plasma once by a competitive double-antibody RIA after extraction on phenylsilica columns (Bühlmann Laboratories AG, Schönenbuch, Switzerland). This AVP assay had a detection limit of 0.35 pM/liter with an intraassay precision of 4.6% and an interassay precision of 10.0%. Another measurement of AVP was done from EDTA plasma using a RIA (DRG Diagnostics, Marburg, Germany). Thereby 0.5 ml of EDTA plasma was extracted with 2 ml of ethanol, centrifuged, the plasma fraction frozen in liquid N2, and the ethanol fraction evaporated. The dry residue was then reconstituted in 0.5 ml assay buffer, of which 0.3 ml extract were assayed. The AVP assay standard calibration curve ranged from 0.5 to 60 pmol/liter, with a detection limit of 0.5 pmol/liter.

Statistical analysis

Student’s paired t tests (Statistica 6.0; StatSoft, Inc., Tulsa, OK) for parametric, and Friedman tests for nonparametric data were used to detect differences within the different protocols. ANOVA (suitable for repeated measures) was used to assess differences between the different protocols/experiments of each study. Logarithmic transformation was performed before analysis, if response data were found to be distributed nonnormally. Correlation analyses were performed using Spearman rank correlation. Data are presented as mean ± SD.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Baseline characteristics

Twenty-four healthy nonsmoking adults (16 men, eight women) were included in the study. The mean age was 26 ± 4 yr with a body mass index of 20.9 ± 2.1 kg/m2, range 18–21 kg/m2, similar for men and women. All women were without oral contraceptives for at least 3 months. Physical examination and medical history were normal.

Hyperosmolal hypovolemia

During the 28-h water restriction experiment, serum sodium increased from 139.4 ± 2.1 to 140.8 ± 2.1 mmol/liter (P < 0.01) and plasma osmolality from 289.8 ± 4.7 to 294.8 ± 4.3 mosmol/kg (P < 0.01). Water deprivation induced a weight loss of 1.7 kg (P < 0.001). Copeptin values increased form 4.6 ± 1.7 to 9.2 ± 5.2 pmol/liter (P < 0.0001). All copeptin levels measured after 24 and 28 h were higher, compared with baseline levels in all subjects. In the control experiment with isoosmolal isovolemia, neither serum sodium nor serum osmolality or copeptin levels changed significantly (Tables 1Go and 2Go, and Fig. 2AGo).


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  		TABLE 1. Sodium, osmolality, and copeptin levels at baseline and at the end of the experiments

 

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  		TABLE 2. Changes ({Delta} values) in weight, sodium, osmolality, and copeptin levels during experiments

 

Figure 2
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  		FIG. 2. A, Copeptin levels during water deprivation. CO, Control; DH, dehydration. Solid lines denote median values, boxes represent 25 to 75 percentiles, and whiskers indicate the range. Blood sampling was done at baseline (CO1, DH1), after 24 h (CO2, DH2), and after 28 h (CO3, DH3). B, Hypertonic saline infusion combined with thirsting and hypotonic saline infusion combined with desmopressin administration at baseline and after 12 h. Blood sampling was done at four time points: baseline, after 14 h, after 16 h, and after 17 h.

 
The changes in weight (P < 0.001), osmolality (P < 0.01), and circulating copeptin levels (P < 0.01) in the water deprivation experiment were different from the control experiment.

Hyperosmolal isovolemia

The 17-h hypertonic saline infusion with concomitant thirsting induced an increase in serum sodium from 141.9 ± 1.6 to 148.6 ± 1.6 mmol/liter (P < 0.0001) and serum osmolality from 284.9 ± 3.4 to 296.1 ± 3.4 mosmol/kg (P < 0.01). In contrast, no significant body weight loss occurred. During this isovolemic hyperosmolal state, a pronounced increase of copeptin levels was observed from 4.9 ± 3.0 to 19.9 ± 4.8 pmol/liter (P < 0.0001). All copeptin values measured during hyperosmolal isovolemia were higher, compared with baseline levels in all subjects. In the control experiment, neither serum sodium nor serum osmolality or copeptin levels changed significantly (Tables 1Go and 2Go, and Fig. 2BGo). Changes in osmolality (P < 0.001), plasma sodium (P < 0.001), and circulating copeptin levels (P < 0.001) in the hyperosmolal isovolemia experiment were different compared with the control experiment.

Hypoosmolal hypervolemia

Hypotonic saline infusion led to a decrease of serum sodium from 142.0 ± 1.4 to 134.1 ± 1.1 mmol/liter (P < 0.0001) and serum osmolality from 284.6 ± 3.3 to 271.3 ± 4.1 mosmol/kg (P < 0.0001), whereas body weight increased by 1.6 ± 0.5 kg (P < 0.001). This hypervolemic hypoosmolal state of water balance produced a decrease of copeptin from 6.2 ± 2.4 to 2.4 ± 2.1 pmol/liter (P < 0.01). During hypoosmolal hypervolemia, copeptin values in only one patient at one time point were as high, compared with baseline levels. All other repeated measurements were lower, compared with baseline levels.

Changes in weight (P < 0.001), osmolality (P < 0.001), plasma sodium (P < 0.001), and circulating copeptin levels (P < 0.01) in the hypoosmolal hypervolemia experiment were different, compared with the control experiment (Fig. 2BGo).

Circulating copeptin levels correlated with serum osmolality (r = 0.58, P < 0.001, Fig. 3Go). The correlation of circulating copeptin and AVP levels during water deprivation was r = 0.37, P < 0.001.


Figure 3
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  		FIG. 3. Correlation of copeptin levels with plasma osmolality. The dotted lines represent the lower and upper limits of the normal range for plasma osmolality and copeptin levels.

 
Baseline circulating copeptin levels were lower in women than men (4.2 ± 1.9 vs. 5.8 ± 3.6 pmol/liter; P < 0.05, Fig. 4AGo), in the presence of a similar serum osmolality (289.5 ± 3.6 vs. 288.8 ± 3.6 mosmol/kg). These data were not influenced by menstrual cycle because all women were studied in the follicular phase, when osmotic threshold is identical in men and women. Conversely, the copeptin increase during water deprivation was not different between men and women (Fig. 4BGo).


Figure 4
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  		FIG. 4. Baseline copeptin levels (A) and increase in copeptin concentrations (B) during water deprivation in men and women. A, Solid lines denote median values, boxes represent 25 to 75 percentiles, and whiskers indicate the range. B, The values represent mean ± SD.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Our results show a similar pattern of copeptin levels on changes in osmolality and blood volume as has been reported for AVP (2, 3, 20). This suggests a reliable diagnostic accuracy of copeptin during disorders of serum osmolality and blood volume.

The changes of AVP serum concentrations on changes in blood volume and plasma osmolality are well known. AVP secretion is stimulated by increased serum osmolality and to a lesser extent by volume depletion. However, depending on the local experience and the AVP assays used, the methodological reliability of many laboratory assays determining plasma AVP concentrations is problematic. Thus, it is difficult to implement AVP measurement in clinical routine, partly because it can reveal falsely low or falsely high levels, partly because it is unstable, even when stored at –20 C (3), and because its measurement is generally time consuming.

Recently an assay for the measurement of copeptin, the stable C-terminal part of provasopressin, has been developed and proposed as a new marker of AVP activity. Theoretically this assay detects all precursor fragments containing the copeptin sequence and the presence of larger fragments cannot completely be excluded. However, no larger fragments besides fully processed copeptin were present in the circulation of patients, indicating complete and thorough processing of the AVP precursor, even during enhanced secretion of AVP (19). The only situation for which the existence of unprocessed precursors in the circulation has been described is cancer (breast cancer or small cell lung cancer, respectively), in which AVP-Neurophysin II-copeptin is ectopically expressed and insufficiently processed, presumably due to the local absence of prohormone convertase. Copeptin is stable for days at room temperature (16) and can be detected from 50 µl of plasma or serum within 3 h. A practical and relevant property of copeptin is that it seems to be released stoichiometrically together with AVP. This is supported by several studies showing a similar behavior of copeptin and mature AVP under different situations (16, 17, 19, 24). The measurement of this very stable AVP precursor fragment could be a clinically relevant and reliable method to substitute the cumbersome assessment of AVP plasma concentration. This concept has also been applied with great success for A- and B-type natriuretic peptides, (25, 26) and other difficult-to-measure peptide hormones, like adrenomedullin (27) or endothelin-1 (28), respectively.

So far, copeptin levels have been studied only in healthy volunteers and critically ill patients. Therefore, we evaluated the reliability of this new copeptin assay in the context of disorders of blood volume and osmolality in healthy subjects.

The combination of a moderate increase of plasma osmolality with volume depletion led to a significant increase of copeptin. These results for copeptin are in accordance with the results of Robertson and Athar (2) for AVP under a comparable degree of volume depletion and increase of osmolality after fluid deprivation. During hypertonic isovolemia, copeptin showed a marked increase, being in accordance with the fact that hyperosmolality is the dominant stimulus for AVP secretion. Copeptin values obtained by this experiment exceeded the upper limit of those found in a randomly selected population of healthy individuals (16). Again, our results are very similar to the results of Robertson and Athar obtained by the AVP RIA methodology after hypertonic saline infusion. Finally, we found a significant decrease of copeptin levels during hypoosmolal hypervolemia, close to the detection limit of the assay. Again, the change in circulating copeptin levels mirrors the changes of AVP levels under comparable conditions. Also of note, the administration of desmopressin did not interfere with copeptin measurements 2, 4, 5, and 12 h after administration, indicating the usefulness of copeptin measurement even under AVP or desmopressin therapy. Taking all results of copeptin and osmolality in the three experiments together, we observed virtually a mirror image of the correlation of AVP and osmolality as shown previously by Robertson and colleagues (3, 20).

Our study has limitations. First, we also attempted to determine AVP concentrations from our assessed samples. However, we found only a weak correlation of AVP with plasma osmolality and copeptin levels. This suggests a substantial preanalytical degradation of AVP and methodological unreliability of the AVP assays used in the present study. We subsequently tested the entire samples in a second laboratory for AVP, again with a weak correlation to copeptin. Moreover, the correlation between the two AVP methods was poor (r = 0.19). These results point to the difficulties in the reliable measurement of AVP. A third measurement with another assay might have provided more reliable results. Unfortunately, we did not have a third batch of samples to remeasure AVP levels. Other studies in critically ill patients have shown a highly significant correlation between AVP and copeptin values (16). In addition, similar kinetics for AVP and copeptin have been shown in different clinical situations (16, 17). Second, changes in body weight reflect changes of total body water but not osmotically driven redistribution of water between the intracellular and extracellular water compartment. Thus, a shift of water along the osmotic gradient between extracellular and intracellular water cannot be excluded during hyperosmolal isovolemia in the context of unchanged total body water.

In women, lower copeptin values have been described compared with men (16). In our study, we confirmed significant gender differences for pooled baseline levels of copeptin. Conversely, we found no significant difference in the copeptin increase between men and women on changes in osmolality or volume status. We investigated women during the follicular phase of the menstrual cycle, when osmolal sensitivity is comparable between men and women (29).

The measurement of AVP release through copeptin may be of relevance for a variety of clinical situations. Besides the classical endocrine indication of diabetes insipidus and syndrome of inappropriate secretion of antidiuretic hormone SIADH (1, 4, 30, 31), copeptin measurement may also be of relevance in those diseases in which electrolyte disturbances are present. Some electrolyte disturbances (e.g. hyponatremia) are relatively common and the underlying pathophysiology requires complex diagnostic procedures. Often the reason for the disturbance remains unclear, despite a thorough evaluation. AVP levels are elevated in different etiologies of hyponatremia; thus, until now AVP measurements could not improve the diagnostic approach in hyponatremia. Whether copeptin concentrations can differentiate more subtly between different etiologies of hyponatremia due to its more precise measurement or whether it may be of use in tracking the response to therapy remains to be shown and is currently investigated in a prospective study (http://www.controlled-trials.com/ISRCTN48080544/).

In conclusion, the C-terminal provasopressin peptide copeptin behaves similar to mature AVP and seems to mirror AVP release during changes of blood volume and plasma osmolality.


   Acknowledgments
 
We thank the staff of the Departments of Endocrinology and Clinical Chemistry, notably Dr. Lilly Linder, Maya Kunz, Vreni Wyss, and Ursula Schild, for most helpful support during the study; Dr. Dieter Burki (Viollier AG, Allschwil, Switzerland), Dr. Marc Beineke (Ingelheim, Germany), and Dr. Siegfried Schwartz (Innsbruck, Austria) for the helpful and rapid measurement of circulating AVP levels; and Dr. Maurice J. Arnaud for the support by an unrestricted grant from Nestlé Water Institute, Vittel, France.


   Footnotes
 
This work was supported by an unrestricted grant from Nestlé Water Institute, Vittel, France, and grants from the Swiss Foundation of Medical and Biological Stipends (PASMA-114617/1 to M.C.-C.).

Disclosure Statement: G.S., K.B., B.M., U.K., and M.C.-C. have nothing to declare. N.G.M. and J.S. are employees of B.R.A.H.M.S. AG, the manufacturer of the copeptin assay.

First Published Online July 17, 2007

Abbreviation: AVP, Arginine vasopressin.

Received January 31, 2007.

Accepted July 6, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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