doi: 10.1111/j.1751-7133.2010.00177.
Copeptin: A Biomarker of Cardiovascular and Renal Function
A rginine vasopressin (AVP), also
termed antidiuretic hormone
(ADH), is one of the key hormones for
cardiovascular homeostasis. Despite its
pivotal role in cardiovascular disease,
the measurement and diagnostic use of
AVP have never reached clinical practi-
cability, due to considerable technical
challenges related to AVP’s short
plasma half-life, interaction with plate-
lets in the serum, and small size.
Copeptin, which was described for
the first time by Holwerda in 1972,1 is a
glycosylated 39–amino acid long peptide
with a leucine-rich core segment. AVP
and copeptin share the same precursor
peptide, the 164–amino acid long pre-
provasopressin, which consists of a signal
peptide, AVP, neurophysin II, and co-
peptin.2 Thus, copeptin is the C-termi-
nal part of pro-AVP (CT-proAVP) and
is released together with AVP during
precursor processing. In contrast to
AVP, copeptin is very stable in the
serum or plasma at room temperature
and is easy and robust to measure.3,4
This review outlines the potential
diagnostic indications of copeptin in
cardiovascular and renal disease and
summarizes the recent progress made in
this field by measuring copeptin instead
of AVP. A more detailed review of the
problems associated with AVP measure-
ment and the technical advantages of
the copeptin assay has been reported
elsewhere.5
Synthesis of AVP and
Copeptin
Pro-AVP, the precursor peptide of AVP
and copeptin, is produced and released
by 2 endocrine mechanisms that are
distinct but may have some anatomi-
cal interaction at the neuronal level
(Figure 1).
In the first mechanism, the precursor
peptide pro-AVP is produced in the
copeptin: a new cardiovascular biomarker
REVIEW PAPER
Arginine vasopressin (AVP or antidiuretic hormone) is one of the key hormones in the
human body responsible for a variety of cardiovascular and renal functions. It has so far
escaped introduction into the routine clinical laboratory due to technical difficulties and
preanalytical errors. Copeptin, the C-terminal part of the AVP precursor peptide, was
found to be a stable and sensitive surrogate marker for AVP release. Copeptin behaves in
a similar manner to mature AVP in the circulation, with respect to osmotic stimuli and
hypotension. During the past years, copeptin measurement has been shown to be of
interest in a variety of clinical indications, including cardiovascular diseases such as heart
failure, myocardial infarction, and stroke. This review summarizes the recent progress on
the diagnostic use of copeptin in cardiovascular and renal diseases and discusses the
potential use of copeptin measurement in the context of therapeutic interventions with
vasopressin receptor antagonists. Congest Heart Fail. 2010;16(4)(suppl 1):S37–S44.

2010 Wiley Periodicals, Inc.
Nils G. Morgenthaler, MD, MBA
From the Institut für Experimentelle Endokrinologie und Endokrinologisches
Forschungszentrum, EnForCé, Charité, Berlin, Germany
Address for correspondence:
Nils G. Morgenthaler, MD, MBA, Institut für Experimentelle Endokrinologie und
Endokrinologisches Forschungszentrum, EnForCé, Charité, Campus Virchow,
Augustenburger Platz 1, 13353, Berlin, Germany
E-mail: n.morgenthaler@brahms.de
Manuscript received March 22, 2010; accepted April 4, 2010
magnocellular neurons of the supraop- produced. AVP produced by this mech-
tic and paraventricular hypothalamic anism is subsequently released into the
nuclei. During axonal transport through pituitary portal system at the eminentia
the infundibulum to the posterior lobe mediana and acts immediately on the
of the pituitary gland, AVP, neurophy- endocrine cells of the adenohypophysis
sin II, and copeptin are processed from (Figure 1). The complex stimulation of
the precursor peptide (Figure 2). Pro- the humoral stress response, resulting in
AVP is subjected to a 4-enzyme cascade adrenocorticotropic hormone (ACTH)
to reach the bioactive conformation of and cortisol release, has been attributed
mature AVP.6 During this process, co- to a synergistic effect of CRH and
peptin and neurophysin II seem to help AVP.8–11 This redundant, or ‘‘backup,’’
in the correct folding of AVP.7 Process- system of 2 hormones from the hypo-
ing is usually complete at the level of thalamus for the release of ACTH
the neurohypophysis.6 All 3 peptides are underlines the physiologic importance
subsequently secreted from the neurohy- of the endocrine stress response.
pophysis upon hemodynamic or osmotic
stimuli. AVP Effects on the
For the second release mechanism, Cardiovascular System
the precursor peptide is synthesized and and the Kidney
processed in the parvocellular neurons While the physiologic relevance of co-
of the hypothalamus, an area where peptin is still unsolved, much is known
releasing hormones, such as corticotro- about the function of AVP. Once
pin-releasing hormone (CRH), are also released into the circulation, AVP
supplement 1 july august 2010
• • S37
 water homeostasis: first, it stimulates the
Triggers of AVP release synthesis of mRNA encoding aquaporin
• Drop in blood pressure
• Change in osmotic pressure 2; second, it increases the traffic of aqu-
• Stress (e.g. AMI) aporin 2 vesicles to the apical plasma
membrane of the collecting duct, where
aquaporin 2 allows the absorption of
most of the water present in the urine.
A third AVP receptor, termed the V3
Synthesis of pro-AVP, the
precursor hormone of AVP
Hypothalamus receptor (or V1b receptor in some litera-
and Copeptin, in the
neurons of the para-
ture) seems to be restricted to certain
ventricular and the
supraoptic nucleus
Synthesis of pro-AVP in
parvocellular neurons
cells of the adenohypophysis and is
involved in the secretion of ACTH.15
Besides the interaction with specific
Cleavage of AVP and
AVP receptors, AVP also binds to the
Copeptin and transport
down the axons
oxytocin receptor with a similar affinity
to oxytocin16 and to certain purinergic
receptors, also members of the GPCR
AVP and Copeptin release
into capillaries of the
superfamily. Oxytocin receptors are
Portal vessels carry AVP
and Copeptin directly to
portal system
located on the vascular endothelium,
the anterior pituitary
Posterior
where they mediate nitric oxide–depen-
Anterior
pituitary
pituitary
AVP and Copeptin storage
dent vasodilation.17 Binding of AVP to
in axons in the posterior
pituitary
these receptors may induce some of the
AVP stimulates endocrine
cells to release ACTH
vasodilating effects seen by AVP in cer-
tain vascular beds (see Holmes14 for
AVP and Copeptin release
AVP synthesized by para- into nearby capillaries details). AVP interactions with the 2
ventricular and supraoptic nucleus upon appropriate
AVP synthesized by stimulation latter receptors are also proposed to
neurons releasing hormones
into the anterior pituitary cause some of the AVP effects on the
ACTH heart: activation of cardiac oxytocin
receptors stimulates the release of atrial
V3 (V1b)-receptor V2-receptor V1-receptor
natriuretic peptide,18 while stimulation
of the P2 class of purinoceptors of the
heart causes coronary vasoconstriction
and negative inotropy.19

Copeptin and AVP in the

Circulation
Endocrine cells release ACTH Water retention Vasoconstriction
into the circulation which stimulates Cortisol release in the kidney While copeptin is very robust for mea-
from the adrenal gland
surement ex vivo, it behaves in a similar
way to AVP in the circulation, and the
Figure 1. Arginine vasopressin (AVP) and copeptin release in hypothalamus and pituitary
and its effects. Upper panel: Triggers of AVP release. Middle panel: Production site and 2 markers are closely correlated.4 Co-
processing of pro-AVP in the hypothalamus followed by 2 distinct release mechanism for the peptin concentrations in healthy volun-
anterior and posterior pituitary. Lower panel: Effects of AVP on 3 different types of teers range between 1 and 12 pmol ⁄ L
vasopressin receptors (V1–V3). AMI indicates acute myocardial infarction; ACTH,
adrenocorticotropic hormone (upper 97.5 percentile) with median val-
ues <5 pmol ⁄ L.4,20 Men consistently
exerts its peripheral effects by binding to protein–induced inositol triphosphate show slightly higher values compared
tissue-specific G-protein–coupled recep- and diacylglycerol. V1 receptors are also with women, but the difference in med-
tors (GPCRs) (see Birnbaumer12 and present on cardiac myocytes, but the ian values is only about 1 pmol ⁄ L.4,20 In
Holmes13 for details). The 2 predomi- vasoconstrictive effect on these cells contrast to many other biomarkers, the
nant receptors are the V1 receptor, seems to be dose-dependent and is still copeptin plasma concentration was sim-
which mediates arteriolar vasoconstric- under debate.13,14 ilar in different age groups and showed
tion, and the V2 receptor, which is The V2 receptors are mainly located no correlation with age.4
responsible for the antidiuretic effect in on the cells of the renal collecting Copeptin responds to changes in
the kidneys. V1 receptors are found in tubules, where they increase intracellular plasma osmolality with a kinetic increa-
high density on vascular smooth muscle cyclic adenosine monophosphate se ⁄ decrease similar to that reported for
cells and cause vasoconstriction by an (cAMP) via the Gs signaling pathway.12 AVP.4,21 Patients with diabetes insipidus
increase in intracellular calcium via G- This increase in cAMP has 2 effects on and reduced AVP have very low plasma
S38 copeptin: a new cardiovascular biomarker supplement 1 july august 2010
• •
 AVP precursor peptide
1 20 28 32
signal
AVP Neurophysin II
Figure 2. Arginine vasopressin (AVP) precursor peptide. Numbers indicate the amino acid
positions of the pre-prohormone.
levels of copeptin,22 while patients
with hyponatremia and the syndrome
of inappropriate ADH secretion
(SIADH) have elevated copeptin in
their circulation.23
While the normal range of copeptin
mirrors the physiologic AVP secretion
needed to maintain plasma osmolality,
in severe diseases or states, such as
shock, sepsis, stroke, or cardiovascular
diseases, the nonosmotic release of AVP
is depicted by a sharp increase in plasma
copeptin, which has diagnostic and
prognostic value.
Copeptin and AVP in
Cardiovascular Shock
High AVP plasma levels of patients in
cardiovascular shock are well described,
and exogenous AVP is even considered
therapeutically in cardiac arrest and dif-
ferent shock states.24–28
The effect of experimental hemor-
rhagic shock on copeptin was studied in
a small number of baboons.29 After
induction of hemorrhagic shock, copep-
tin increased sharply from median values
of 7.5 to 225 pmol ⁄ L after the second
hour and reached a peak of 269 pmol ⁄ L
after 3 hours of bleeding. Copeptin lev-
els dropped again within 1 hour of rep-
erfusion to 123 pmol ⁄ L and continued
to decline until they reached a plateau
of 24 pmol ⁄ L at the end of the experi-
ment. The mean arterial blood pressure
followed inverse kinetics in all animals,
decreasing during bleeding and increas-
ing slowly after reperfusion.29 The
behavior of copeptin closely followed
that of mature AVP in a similar experi-
mental setting.30
The copeptin response in severe
infections, such as pneumonia, resulting
in sepsis and septic shock is reviewed in
detail elsewhere.5
copeptin: a new cardiovascular biomarker
124 126 164
Copeptin
(CT-proAVP)
Copeptin and Acute
Myocardial Infarction
A particularly interesting observation is
the response of circulating copeptin lev-
els as a result of an acute myocardial
infarction (MI). The first results were
reported by Khan and Ng.31 In 980
post–acute MI patients of the Leicester
Acute Myocardial Infarction Peptide
(LAMP) study, copeptin values were
highest on day 1 after acute MI and
declined to a stable, but still elevated,
plateau, compared with healthy controls
at days 2 to 5.31 Copeptin levels were
higher in patients who died or were re-
admitted with heart failure compared
with event-free survivors. In particular,
patients with copeptin levels in the
highest quartile showed a >40% event
rate during the follow-up period.31
This observation led to the examina-
tion of the potential role of copeptin in
the diagnosis of acute MI. Reichlin and
Müller studied the role of copeptin in
the management of 487 consecutive
patients with chest pain presenting to
the emergency department (ED).32 In
those patients with the final gold stan-
dard diagnosis of acute MI (17%), co-
peptin levels were already elevated 0 to
4 hours after the onset of symptoms, at
a time when troponin T was still unde-
tectable in many patients. During the
next hours, copeptin levels declined
while troponin levels increased. These
distinct kinetics resulted in an additive
diagnostic value of both markers for the
diagnosis of acute MI. The area under
the curve (AUC) of troponin alone in
the first blood sample taken in the ED
was 0.86 and increased to 0.97 by add-
ing copeptin (Figure 3). Using this
approach, a negative troponin and co-
peptin at presentation of the patient in
the ED <14 pmol ⁄ L allowed acute MI
Figure 3. Receiver-operator characteristic
(ROC) curves at presentation for the
diagnosis of acute myocardial infarction.
Area under the ROC curves for troponin T
and copeptin at presentation, and the
combination of both markers in the diag-
nosis of acute myocardial infarction. Figure
from Reichlin et al.32
to be ruled out with a negative predic-
tive value of >99%.32
This report was independently con-
firmed by a multicenter trial in 1293
consecutive patients with suspected
acute coronary syndrome (ACS). Com-
bined measurement of copeptin and tro-
ponin T in the first blood sample taken
at ED admission improved the c-statistic
from 0.85 for troponin T alone to 0.94
for a combination of copeptin and tro-
ponin T. The effect was particularly
prominent in patients presenting within
3 hours after chest pain onset to the
ED. In this group, the combination
increased the c-statistic from 0.77 to
0.91.33
At present, it is still unclear how the
combination of copeptin and troponin
may perform in a world of highly sensi-
tive troponin assays. The present confu-
sion on the nomenclature and clinical
use of those assays34 must be sorted out
before the benefit of additional biomar-
kers can be fairly evaluated. If the diag-
nostic accuracy to identify ACS patients
(for whom rapid intervention is manda-
tory) is lost, and patients are identified
with trace amounts of troponin in their
blood that may have prognostic (but less
diagnostic) relevance, then the value of
troponin as a diagnostic biomarker may
change in the perception of the ED cli-
nician. The ongoing Copeptin Helps in
supplement 1 july august 2010
• • S39
 the Early Detection of Patients With
Acute Myocardial Infarction (CHO-
PIN) trial may address this issue.35
Why Is Copeptin Elevated
in Acute MI?
The observed elevation of copeptin after
acute MI has long been described for
AVP, but based on the complexity of
AVP measurement, this observation has
never become of diagnostic relevance.
However, despite insufficient assays
being available, several studies tried to
elucidate the AVP response in acute
MI. Although these findings were lim-
ited to a few patients, Schaller and
coworkers36 reported, back in 1986, on
elevated AVP during the early phase of
MI with a particularly poor prognosis.
McAlpine and colleagues37 studied
AVP and other neuroendocrine hor-
mones after acute MI and found ele-
vated plasma levels within 6 hours of
onset of symptoms. Donald and cowork-
ers examined the response of the entire
hypothalamus-pituitary-adrenal axis to
the stress of MI within 6 hours of onset
of symptoms and found plasma AVP,
CRH, and cortisol highly elevated,
while ACTH was suppressed compared
with a reference population of healthy
volunteers. During the follow-up period
of 72 hours, the 3 elevated hormones
declined irrespective of treatment with
angiotensin-converting enzyme inhibi-
tors, while ACTH values increased.38
The same group studied the neuroendo-
crine response after acute MI more clo-
sely in an animal model using sheep.
They found that all 3 hormones, AVP,
ACTH, and cortisol, were increased
within 2 hours after inducing micro-
embolization in the animals. In a subset
of more frequently sampled animals, the
peak response of AVP, ACTH, and cor-
tisol occurred at 40 min after emboliza-
tion. While ACTH and cortisol
returned to baseline within 6 hours,
AVP was elevated for more than
12 hours.39
Despite the very early rise of AVP
and other hormones related to stress
response, none of these markers was fol-
lowed up as a potential candidate for
the diagnosis of acute MI due to severe
limitations in the measurement of these
S40 copeptin: a new cardiovascular biomarker
hormones. Neither AVP nor ACTH
nor cortisol are available in rapid and
sensitive assay technology, which would
allow a fast enough ‘‘vein-to-brain time’’
to influence the early diagnosis in an
ED.
What triggers the rapid release of
AVP ⁄ copeptin after acute MI is still
under debate. There are several possible
explanations, but 2 hypotheses seem to
be most likely. First, as described above,
AVP is a substantial part of the endo-
crine stress response, resulting in ACTH
and cortisol release. Therefore, it is not
surprising that the body responds to
acute and life-threatening diseases, such
as MI or stroke, by a rapid AVP ⁄ copep-
tin release. This hypothesis is favored by
some endocrinologists (including the
author of this review), and copeptin is
discussed to be a rapid and immediate
biomarker of the individual stress
response.40 However, following the
release mechanism of AVP ⁄ copeptin for
ACTH stimulation, this would strictly
mean that the measurable copeptin in
the circulation is the spillover of copep-
tin released in the portal system of the
pituitary. Therefore, a second trigger is
likely that leads to AVP ⁄ copeptin secre-
tion from the posterior pituitary. This
could be cardiac underfilling resulting in
baroreceptor stimulation as a result of
the MI or even direct damage to the
cardiac baroreceptors. This speculation
is supported by the fact that the highest
copeptin elevation after MI is seen in
patients with electrocardiographic signs
of cardiac damage.32
Copeptin and AVP in
Heart Failure
Involvement of AVP in the pathogene-
sis of congestive heart failure has repeat-
edly been reported.41–43 In chronic
congestive heart failure, AVP, through
its V1 and V2 receptor–mediated effects,
seems to contribute to the progression of
left ventricular (LV) dysfunction by
aggravating systolic and diastolic wall
stress and by directly stimulating ven-
tricular hypertrophy and myocardial
remodeling.44 Moreover, selective block-
ade of specific AVP receptors has been
suggested to offer new clinical perspec-
tives for treatment45 (see below).
The prognostic role of mature AVP
in heart failure is well described. Studies
looking at the neurohumoral activation
in patients with acute MI found an ele-
vation that lasted for more than 12 days,
and those patients with elevated AVP
and other neurohormones had a poorer
prognosis.46,47
More recently, data on the role of co-
peptin as a biomarker in patients with
CHF have been described in several
studies. Patients with chronic heart
failure and high levels of copeptin had a
significantly poorer long-term prognosis
than patients who had low plasma co-
peptin concentrations.48,49 Combined
measurement of plasma copeptin
together with B-natriuretic peptide con-
centrations could further improve out-
come prediction in these patients.48,49
As mentioned previously, Khan and
colleagues31 examined the role of copep-
tin in 980 consecutive patients after
acute MI. In the follow-up of those
patients, the prognostic value of copep-
tin was assessed alone or in combination
with N-terminal prohormone B-type
natriuretic peptide (NT-proBNP). Co-
peptin was elevated in patients who died
or were readmitted with heart failure
compared with survivors (median, 18.5
pmol ⁄ L vs 6.5 pmol ⁄ L; P<.0005). In a
logistic regression analysis, copeptin and
NT-proBNP were significant indepen-
dent predictors of death or heart failure
at 60 days. Consideration of both mark-
ers gave added prognostic information
beyond existing clinical characteristics,
enabling patients to be stratified into
low-, intermediate-, or high-risk groups.
The same research group subsequently
reported on an association between co-
peptin and LV dysfunction in the very
early stages after acute MI, which was
maintained in the survivors during fol-
low-up. Furthermore, copeptin was asso-
ciated with the degree of LV remodeling
after the acute event.50 Thus, the AVP
system may have progressive effects on
LV impairment beyond the acute phase
of MI. Several actions of AVP on the
heart may account for the remodeling
process, including myocyte protein syn-
thesis via the V1 receptor51; increased
peripheral vasoconstriction, afterload,
and ventricular stress52; and stimulation
supplement 1 july august 2010
• •

Figure 4. Quartiles of copeptin in heart
failure patients. Kaplan–Meier plots of
survival in heart failure patients grouped
according to quartiles of plasma copeptin.
Figure from Neuhold et al.57
of cardiac fibroblasts.53 These observa-
tions were strengthened by the increased
risk of elevated copeptin levels and clin-
ical heart failure in those patients. This
risk stratification at an early stage after
acute MI remains important and may be
useful to select treatment regimes in the
future, such as the use of AVP receptor
antagonists (vaptans). Although mixed
reports on those drugs exist for conges-
tive heart failure Efficacy of Vasopressin
Antagonism in Heart Failure Outcome
Study With Tolvaptan [EVEREST]),54,55
no study has yet examined the use of
vaptans in the human post–acute MI
patient, although animal data on
improved cardiac hemodynamics exist
for conivaptan.56
Neuhold and Pacher, following up on
their first report,48 examined the role of
copeptin in 786 patients across the
whole spectrum of heart failure based on
systolic dysfunction (LV ejection frac-
tion ranging from 5% to 65%) and B-
type natriuretic peptide values (ranging
from 3 to 8536 pg ⁄ mL).57 They showed
a strong and independent correlation
between plasma copeptin levels and all-
cause mortality. This was seen in the
entire cohort of symptomatic (New
York Heart Association class II, III, and
IV) patients, but it was most compelling
in functional classes II and III. Patients
with copeptin values <5.75 pmol ⁄ L
had the lowest mortality rate (<12%)
in the 24-month follow-up period, while
patients in the highest quartile (>21.7
copeptin: a new cardiovascular biomarker
pmol ⁄ L) had mortality rates >50%
(Figure 4).57
Voors and the Optimal Trial in Myo-
cardial Infarction With the Angiotensin
II Antagonist Losartan (OPTIMAAL)
investigators examined the prognostic
role of copeptin in patients after acute
MI in a subset of patients of OPTI-
MAAL.58 They confirmed the report by
Khan,31 in a multicenter setting, dem-
onstrating that copeptin is a strong mar-
ker for mortality and morbidity in
patients with heart failure after acute
MI, with an even stronger predictive
value than B-type natriuretic peptide
and NT-proBNP. Again, patients in the
highest quartile (>25.9 pmol ⁄ L) had
significantly increased mortality com-
pared with the other groups (about 40%
during the follow-up of 337 months).
Furthermore, they could also demon-
strate that serial measurements of copep-
tin during follow-up added predictive
value over a single determination at
baseline.58
Copeptin in Stroke
Besides the reported association in car-
diac disease, copeptin seems to play a
useful role in other areas of cardiovascu-
lar disease. A recent report showed that
copeptin is elevated in patients with
ischemic stroke.59 The authors addressed
3 important clinical issues.
First, copeptin was associated with
the severity of the stroke, as defined by
the National Institutes of Health Stroke
Scale (NIHSS) score. The NIHSS score
is a standardized measure of stroke sever-
ity, but it requires a specially trained
doctor to use it and has large interob-
server variations. Furthermore, it is
biased by certain forms of stroke. Med-
ian copeptin values doubled from
8.6 pmol ⁄ L in patients with an NIHSS
score of 0 to 6 points to 15.8 pmol ⁄ L in
patients with 7 to 15 points and doubled
again to 30.1 pmol ⁄ L in patients with
>15 points. In patients where MRI data
of the brain were available, copeptin
levels paralleled the lesion size caused by
the stroke.
Second, copeptin predicted the func-
tional outcome of the stroke patients
and was initially higher at presentation
in those patients who remained disabled
(19.4 pmol ⁄ L) compared with those
with a favorable outcome (8.2 pmol ⁄ L).
Third, copeptin was also predictive of
death within 90 days, and median levels
were more than 3 times higher in
patients who died (35.6 pmol ⁄ L) com-
pared with survivors (9.5 pmol ⁄ L).
More than 25% of patients died in the
highest tertile (>17.8 pmol ⁄ L) of co-
peptin, while fewer than 5% of patients
died in the 2 lower tertiles. The prog-
nostic information was independent
after adjusting for a variety of clinical
risk factors or other significant outcome
predictors.
Taken together, copeptin is the first
reported circulating biomarker that
improves the prognosis accuracy of the
NIHSS score.59
Copeptin and Renal
Function
At normal concentrations, the role of
AVP is to regulate the plasma osmolality
by eliminating free water in the kidney.
Like mature AVP, copeptin is regulated
within a certain normal range but may
fluctuate according to individual physio-
logic conditions. Copeptin increases to
upper normal values during fasting and
shows a rapid decline in vivo to low nor-
mal values after oral water load.4 In a
study of 24 healthy volunteers, copeptin
showed identical changes during disor-
dered water states or osmolality to those
previously shown for AVP: water depri-
vation, which resulted in weight loss
and an increase in plasma osmolality,
increased serum copeptin. Additional
infusion of hypertonic saline increased
copeptin even further to plasma values
not usually seen in healthy individuals.
Conversely, during hypotonic saline
infusion, plasma osmolality decreased
and copeptin decreased to values in the
very low normal range.21
Electroloyte disturbances are common
in cardiovascular and renal diseases,
including the most commonly seen,
hyponatremia, and the pathophysiology
is complex and the diagnostic approach
is challenging.60 Copeptin plasma con-
centrations might be valuable in the
diagnostic work-up of hyponatremic
conditions, which have been reported in
up to 15% of hospitalized patients,61
supplement 1 july august 2010
• • S41
 sometimes with a poor prognosis. In
patients with SIADH, determination of
copeptin together with urine sodium
helped in the differential diagnosis.23
Furthermore, in many hospital situa-
tions, such as after surgery, the release of
AVP is nonosmotic, due to pain, anxi-
ety, nausea, or the use of pharmacologic
agents. Often, hypotonic fluids are given
without prior assessment of AVP levels,
potentially resulting in hyponatremia, a
scenario quite common in pediatric
medicine.62 Here, copeptin measure-
ments may offer additional information
for the fluid therapy in the postsurgical
patient.
In renal disease, albuminuria is a pow-
erful predictor of progressive cardiovas-
cular and renal failure. Administration
of an AVP agonist to rats and humans
induced albuminuria,63,64 and lowering
AVP by drinking or a V2 receptor antag-
onist reduced proteinuria in rats with
renal failure.65–67 It is still unclear
whether this is due to a direct effect of
AVP on albumin excretion or is second-
ary to the AVP effect on circulating
blood volume and blood pressure. In a
recent population study (Prevention of
Renal and Vascular End-Stage Disease
[PREVEND]), which included adults
with and without kidney dysfunction,
Meijer and Gansevoort report on an
association between copeptin and micro-
albuminuria that suggests a direct effect
of AVP on urinary albumin excretion.68
Microalbuminuria (urinary albumin
excretion of at least 30 mg ⁄ 24 hours)
was about 2 times more prevalent in
individuals with copeptin plasma levels
in the highest quintile (>10.5 pmol ⁄ L)
compared with individuals with copep-
tin levels in the lowest 2 quintiles
(<5.3 pmol ⁄ L). This association was
independent of age and other potential
confounders. If this hypothesis is con-
firmed in other studies, it may have
direct implications on the prevention
and control of renal disease.69
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transplant, as seen by a decrease in
glomerular filtration rate during a med-
ian follow-up of 3.6 years. Again, this
association seemed to be independent of
other risk factors for renal function
decline in renal transplant recipients,
and the association was similar in mag-
nitude to other well-known factors of
renal function decline, such as baseline
mean arterial pressure or glucose. Inter-
vention studies using V2 receptor antag-
onists seem to be justified, and copeptin
may serve as a biomarker to identify
patients with renal transplant who may
benefit from treatment with those
drugs.71
Copeptin and AVP
Receptor Antagonist
Drug Therapy
AVP receptor antagonists have been
successfully applied in experimental
congestive heart failure45,72 and hypo-
natremia,73 but first clinical trials
reported mixed results in heart failure
therapy, with no effect on mortality .54,55
Knowledge of copeptin plasma concen-
trations may be important for the intro-
duction of such novel therapies, as it
follows simple reasoning that it is of
value to know the level of the circulat-
ing substance that one intends to block
by a specific therapy. Future studies
should evaluate whether treatment with
AVP receptor antagonists is most
effective if the vasopressinergic system is
activated, as can now easily be assessed
by copeptin plasma concentrations.
physin II precursor. Nature. 1982;295:299–
303.
3 Struck J, Morgenthaler NG, Bergmann A.
Copeptin, a stable peptide derived from the
vasopressin precursor, is elevated in serum of
sepsis patients. peptides. 2005;26:2500–
2504.
Measurement of copeptin levels may be
useful in determining whether AVP
receptor antagonist therapy is appropri-
ate not only in patients with chronic
heart failure and hyponatremia but also
in patients with other diseases, such as
cirrhosis74 or renal failure,65–67 in which
AVP has been shown to play a patho-
physiologic role.
Furthermore, since AVP receptor
antagonists may be ineffective in up to
30% of patients, it needs to be examined
whether this lack of effect is related
to the level of circulating AVP. Co-
peptin measurements could help in this
assessment.
Conclusions
Copeptin is a stable fragment of the
AVP precursor. Physiologically, it con-
tributes to the correct structural forma-
tion of AVP prior to release into the
circulation. The measurement of copep-
tin appears to be a clinically relevant
method for reliably assessing AVP
plasma concentrations, which cannot be
determined in routine practice. This
would be particularly helpful in diseases
where disturbances of the vasopressiner-
gic system contribute to or are the
immediate result of the pathogenesis.
Future studies should evaluate the clini-
cal relevance of copeptin as a diagnostic
and prognostic laboratory parameter in
acute MI, heart failure, and stroke, and
its role in therapy monitoring of AVP
receptor antagonists in heart failure,
hyponatremia, and renal failure.
Disclosure: Dr Morgenthaler is emp-
loyed by B.R.A.H.M.S. Biomarkers, part of
Thermo Fischer Scientific, a company
involved in the development of in vitro
diagnostics that has developed an assay
for the measurement of copeptin. Dr
Morgenthaler also received an honorarium,
funded by Abbott Laboratories and Otsuka
America Pharmaceuticals for time and
expertise spent in the writing of this article.
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