REVIEWS

Hyponatraemia: more than just a marker

of disease severity?
Robert W. Schrier, Shailendra Sharma and Dmitry Shchekochikhin
Abstract | Hyponatraemiathe most common serum electrolyte disorderhas also emerged as an important
marker of the severity and prognosis of important diseases such as heart failure and cirrhosis. Acute
hyponatraemia can cause severe encephalopathy, but the rapid correction of chronic hyponatraemia can also
profoundly impair brain function and even cause death. With the expanding elderly population and the increased
prevalence of hyponatraemia in this segment of society, prospective studies are needed to examine whether
correcting hyponatraemia in the elderly will diminish cognitive impairment, improve balance and reduce the
incidence of falls and fractures. Given that polypharmacy is also common in the elderly population, the various
medications that may stimulate arginine vasopressin release and/or enhance the hormones action to increase
water absorption must also be taken into consideration. Whether hyponatraemia in a patient with cancer is
merely a marker of poor prognosis or whether its presence may alter the patients quality of life remains to
be examined. In any case, hyponatraemia can no longer be considered as just a biochemical bystander in the
ill patient. A systematic diagnostic approach is necessary to determine the specific aetiology of a patients
hyponatraemia. Therapy must then be dictated not only by recognized reversible causes such as advanced
hypothyroidism, adrenal insufficiency, diuretics or other medicines, but also by whether the hyponatraemia
occurred acutely or chronically. Information is emerging that the vast majority of cases of hyponatraemia are
caused by the nonosmotic release of arginine vasopressin. Now that vasopressin V2-receptor blockers are
available, a new era of clinical investigation is necessary to examine whether hyponatraemia is just a marker
of severe disease or whether correction of hyponatraemia could improve a patients quality of life. Such an
approach must involve prospective randomized studies in different groups of patients with hyponatraemia,
including those with advanced heart failure, those with cirrhosis, patients with cancer, and the elderly.

Schrier, R.W. et al. Nat. Rev. Nephrol. 9, 3750 (2013); published online 20 November 2012; doi:10.1038/nrneph.2012.246

Introduction
Hyponatraemia, the most frequently encountered plasma
electrolyte abnormality, is defined as a serum sodium
concentration of less than 135mmol/l, indicates excessive
total body water relative to total body sodium,1 and occurs
when urine-diluting capacity is exceeded by electrolyte-
free water intake. One study found that hyponatraemia
occurred in 21% of patients on initial presentation to
ambulatory hospital care and in 7.2% of patients on initial
presentation to a community care centre.2 Hyponatraemia
is also considered a marker of severity of illness such that
mean serum sodium concentration is 56mmol/l lower in
hospitalized patients than in healthy outpatients.3 In a large
database of 300,000 serum samples studied over 2years,
hyponatraemia (serum sodium concentration <136mmol)
was observed in 34% of the hospitalized patients.2 Another
prospective cohort study of 2,907 hospitalized patients
reported the incidence of hyponatraemia to be 30%.4
Competing interests
R. W. Schrier declares associations with the following
companies: Janssen Pharmaceuticals, Otsuka Pharmaceuticals.
See the article online for full details of the relationships. The
other authors declare no competing interests.
Critically ill patients frequently have impaired urinary
dilution and are unable to excrete electrolyte-free water.
One study found that 30% of patients in intensive care
units (ICUs) have a serum sodium concentration of
less than 134mmol/l.5 Increasing age is also associated
with impaired capacity to excrete water, which makes
the elderly population more vulnerable to developing
hyponatraemia, as will be discussed.
Acute hyponatraemia and the resultant extracellular
hypo-osmolality are known to cause brain oedema
and raise intracranial pressure.6 Acute hyponatraemic
encephalopathy is an established life-threatening medical
emergency associated with an overall morbidity and
mortality rate of 42%.7 In addition, cardiorespiratory
University of Colorado
arrest and hypoxia may contribute to brain damage in School of Medicine,
cases of severe hyponatraemia.6 Chronic asymptomatic 12700 East 19th
Avenue C281, Aurora,
hyponatraemia has also been associated with multiple CO 80045, USA
poor outcomes including, but not limited to, increased (R.W.Schrier,
mortality 8 and an increased length of hospital stay.9 Wald S.Sharma,
D.Shchekochikhin).
etal. showed that patient survival is poor and that length
of stay increases if hyponatraemia is present on admis- Correspondence to:
R.W. Schrier
sion, is exacerbated during hospitalization, is acquired robert.schrier@
while in hospital or remains uncorrected throughout ucdenver.edu

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REVIEWS

Key points
increases nonlinearly as serum sodium decreases below
134mmol/l. 11 Low serum sodium has been strongly
Hyponatraemia is the most common electrolyte disturbance in clinical
and consistently associated with increased mortality
practice and its most common mediator is the nonosmotic release of arginine
vasopressin
in patients with pneumonia,12 heart failure,13 and liver
In the elderly, hyponatraemia predisposes to falls and fractures and may cirrhosis14 and in those in the ICU.15 The prevalence of
worsen cognitive impairment; in patients with heart failure, hyponatraemia hyponatraemia in various patient populations is summa-
reflects severe haemodynamic alterations and is associated with worse rized in Table1;1648 these different populations provide
morbidity and mortality the outline for our Review of this important topic.
In patients with liver cirrhosis, hyponatraemia is associated with increased
mortality, hepatorenal syndrome, hepatic encephalopathy, and reduced quality Hyponatraemia in the elderly
of life
Epidemiological studies have confirmed the increased
Hyponatraemia carries a worse prognosis in patients with chronic kidney
disease, including those with end-stage renal disease
prevalence of hyponatraemia in the elderly popula-
Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is tion. It is estimated that 711% of healthy elderly people
classified as euvolaemic hyponatraemia, and therefore hypovolaemic or over 65years of age have serum sodium concentra-
hypervolaemic causes of hyponatremia need to be excluded tions of 137mmol/l or less.19,20 In a study of 419 elderly
In addition to fluid restriction, vasopressin-receptor antagonists are now outpatients, 46 (11%) were found to have at least one
available in some countries to treat hyponatremia in heart failure, cirrhosis and episode of hyponatraemia (defined as a serum sodium
SIADH concentration <135mmol/l) during a 24-month follow-
up period.20 Moreover, 27 of 46 (60%) of these patients
Table 1 | Prevalence of hyponatraemia in different patient populations
fulfilled the criteria for syndrome of inappropriate
secretion of antidiuretic hormone (SIADH). Although
Patient group Prevalence (%) References
most patients had one or more possible aetiologies of
ICU patients 11.029.6 Stelfox etal. (2010)16 hyponatraemia, including diseases or medications,
DeVita etal. (1990)17
in seven patients no apparent cause of hyponatraemia
Funk etal. (2010)18
was determined. More advanced age correlated with an
Elderly outpatients 7.211.0 Caird etal. (1973)19
increased occurrence of hyponatraemia. In total, 43% of
Miller etal. (1996)20
individuals aged 75years or older were hyponatraemic,
Elderly inpatients 18.053.0 Anpalahan etal. (2008)21
Miller (1998)22
and this elderly group of patients constituted 100% of
Kleinfeld etal. (1979)23 those with SIADH.
Sunderam etal. (1983)24 The elderly population living in chronic care facilities,
Miller etal. (1995)25 such as nursing homes or rehabilitation centres, have a
Patients with heart failure 10.227.0 Bettari etal. (2012)26 high prevalence of hyponatraemia.21,49,50 The prevalence
Konstam etal. (2007)27 of hyponatraemia among elderly nursing home residents
Shorr etal. (2011)28
DeWolfe etal. (2010)29
has been reported to be between 18% and 22.5% over a
Mohammed etal. (2010)30 12-month observational period.2224 However, one study
Klein etal. (2005)31 reported that as many as 53% of nursing home patients
Gheorghiade etal. (2007)32 had at least one episode of hyponatraemia during a
Patients with cirrhosis 20.849.4 Sol etal. (2012)33 12-month period. 25 Comorbidities, such as central
Shaikh etal. (2010)34 nervous system diseases, cardiovascular diseases and
Kim etal. (2009)35
Yun etal. (2009)36
diabetes mellitus did not differ significantly between the
Angeli etal. (2006)37 patients with and without hyponatraemia. Notably, all
Patients with cancer 3.747.0 Berghmans etal. (2000)38
patients with spinal cord disease had at least one episode
Doshi etal. (2012)39 of hyponatraemia that theoretically could have been
Patients with pneumonia 8.127.9 Zilberberg etal. (2008)12
caused by arterial baroreceptor failure with nonosmotic
Nair etal. (2007)40 release of arginine vasopressin (AVP).51 Many of the
Predialysis patients with CKD 13.6 Kovesdy etal. (2012)41
nursing home patients with hyponatraemia had received
hypotonic saline or glucose, and the criteria of SIADH
Patients on dialysis 29.3 Waikar etal. (2011)42
were fulfilled in 78% of all hyponatraemic patients in
Marathon runners 3.013.0 Almond etal. (2005)43 the nursing home. 25 Notably, among the 12 patients
Knechtle etal. (2011)44
Kipps etal. (2011)45 who received nutritional support via tube feeding, 11
Mettler etal. (2008)46 developed hyponatraemia. A low sodium concentra-
Elderly patients with falls 9.113.0 Gankam Kengne etal. (2008)47 tion in the tube feeding diet may have contributed to the
Sandhu etal. (2009)48 hyponatraemia, as reported elsewhere.52
Abbreviations: CKD, chronic kidney disease; ICU, intensive care unit. A study from Taipei found that 37.5% of hypo
natraemic elderly patients in long-term care facilities
fulfilled the criteria of SIADH.50 In another report from
the hospital stay.10 This group found a linear increase Australia, 51.5% of hyponatraemic patients in rehabili-
in mortality with decreases in serum sodium concen- tation hospitals had SIADH.21 Thus, as with outpatient
tration below the normal range of 138142mmol/l, hyponatraemia, advanced age is a major risk factor for
but other authors have reported that mortality inpatient hyponatraemia.21,50

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These observations support the concept of a SIADH-
like condition related to ageing.20,50,53 Hyponatraemia is
generally modest in elderly patients with SIADH, but this
population may be at increased risk of developing symp-
tomatic hyponatraemia with intercurrent illnesses and
medication use. Moreover, hyponatraemia in the elderly
would predispose to falls and fractures and could worsen
cognitive impairment.47,54,55 So-called asymptomatic
hyponatraemia has been shown to be associated with
unstable gait and decreased reaction times.54
Another factor in the capacity to excrete solute-free
water is the rate of urinary solute excretion. In a healthy
individual with AVP suppressed, a minimal urinary
osmolality of 50mOsm/l and daily solute intake of
600mOsm, 12l of solute-free water is excreted to main-
tain daily solute balance. With this maximal urinary dilu-
tion, a patient with primary polydipsia would therefore
have to drink more than 12l per of water day to become
hyponatraemic. By contrast, with the same minimal
urinary osmolality of 50mOsm, and a 300mOsm
daily solute intake, 6l of water is excreted to maintain
daily solute balance. Therefore, a patient with primary
polydipsia and a decreased solute intake can become
hyponatraemic when only drinking in excess of 6l daily.
It is known that beer drinkers, who ingest very little
solute, may become hyponatraemic in spite of maximal
suppression of AVP and maximal urinary dilution; this
phenomenon has been termed potomania.56 Whether
very elderly individuals who have lost their appetite can
become hyponatraemic secondary to decreased solute
intake and excretion remains unproven. More com-
monly, a dry mouth secondary to use of medications with
anticholinergic activity could induce thirst in the elderly,
resulting in increased water intake that could cause
hyponatraemia. On the other hand, hypernatraemia can
also occur in the elderly secondary to a decreased thirst
drive and this perturbation, like hyponatraemia, has also
been shown to be associated with increased mortality.57
Thiazide diuretics are one of the most common
causes of hyponatraemia in the elderly. Of note, thi-
azides can cause both hypovolaemic and euvolaemic
types of hyponatraemia. In a large study of hypertensive
patients on a relatively low dose of thiazide in a primary
care setting, hyponatraemia was present in 18% of those
aged greater than 70years and only 4% of those aged
younger than 51years.58 Moreover, polypharmacy is
very common in the elderly population and an increas-
ing number of other medications are also recognized to
cause hyponatraemia (Box1).59
Hyponatraemia in heart failure
Hyponatraemia is common in patients with advanced
heart failure. One study reported that 38% of patients
admitted for acute decompensated heart failure had
hyponatraemia and that a further 28% developed
hyponatraemia during the hospital admission. 10
Hyponatraemia was associated with increased mortal-
ity and hospital readmission. The authors found that
the significant relationship between decreased sodium
and increased mortality began with a serum sodium
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Box 1 | Drugs associated with hyponatraemia*
Vasopressin analogues
Desmopressin
Oxytocin
Drugs that potentiate the renal action of vasopressin
Chlorpropamide
Cyclophosphamide
Nonsteroidal anti-inflammatory drugs
Acetaminophen
Drugs that enhance vasopressin release
Chlorpropamide
Clofibrate
Carbamazepine/oxcarbazepine
Vincristine
Nicotine
Narcotics
Antipsychotics/antidepressants
Ifosfamide
Drugs that cause hyponatraemia by unknown
mechanisms
Haloperidol
Fluphenazine
Amitriptyline
Thioridazine
Fluoxetine
Methamphetamine
MDMA (ecstasy)
Sertraline
*Not including diuretics. Abbreviation: MDMA,
3,4-methylenedioxymethamphetamine. Permission obtained from
Wolters Kluwer Health Berl, T. & Schrier, R. Disorders of water
metabolism. In Renal and Electrolyte Disorders 6th edn (ed.
Schrier, R.) (Philadelphia, Lippincott Williams & Wilkins, 2003).59
concentration of less than 138mmol/l and that the more
severe the hyponatraemia, the higher the mortality.
Hyponatraemia was also associated with an increased
length of hospital stay. As 30% of patients with acute
decompensated heart failure are readmitted within
60days,60 hyponatraemia could be a marker indicating
that a patient needs a more careful follow-up and perhaps
alterations in their therapy (for example, changes in
doses of reninangiotensinaldosterone system [RAAS]
blockers, blockers, and/or diuretics).
The long-term effect of hyponatraemia was analysed in
a large group of patients undergoing cardiac cathetheri-
zation who had a left ventricular ejection fraction of less
than 40% and grade II or III heart failure according to
the New York Heart Association Classification.26 Patients
were followed for an average of 4.5years. In this long-
term study, the presence of hyponatraemia was inde-
pendently associated with increased all-cause mortality,
cardiovascular mortality and rehospitalization. Another
study reported that on multivariate analysis, heart failure
patients with hyponatraemia had a poorer quality of life
than heart failure patients with a normal plasma sodium
concentration.61 Therefore, hyponatraemia is a serious
risk factor in chronic, as well as acute, heart failure.
The relationship between hyponatraemia, activation
of the neurohumoral axis and survival in patients with
advanced heart failure is also affected by decreased renal
function. This association of decreased renal function
REVIEWS
Cirrhosis
Heart failure
Cardiac output Primary systemic arterial vasodilation
Arterial underfilling
Arterial basoreceptors unloaded
Sympathetic tone Nonosmotic vasopressin stimulation RAAS stimulation
Hyponatraemia
Figure 1 | The pivotal role of vasopressin in the pathophysiology of hyponatraemia.
Stimulation of the sympathetic nervous system and the RAAS increases proximal
sodium and water reabsorption and thus decreases fluid delivery to the distal
diluting segment, but the primary defect in the pathophysiology of hyponatraemia is
the inability to dilute the urine. Urine dilution is primarily mediated by suppression
of vasopressin. Abbreviation: RAAS, reninangiotensinaldosterone system.
with increased mortality in heart failure patients occurs
with an increase in serum creatinine as small as
27mol/l.62 Of interest, a rise in blood urea nitrogen cor-
relates even better with mortality than does increased
serum creatinine in patients with hyponatraemia.63 This
correlation with blood urea nitrogen may be due to the
effect of increased AVP increasing urea reabsorption in
the renal collecting duct.63
Although substantial evidence is available to show that
hyponatraemia in patients with heart failure is associated
with a poor prognosis, less evidence exists to show that
correction of the hyponatraemia has beneficial effects.
Thus, hyponatraemia may be primarily a marker of
more severe disease in patients with heart failure. In this
regard, hyponatraemia is known to be associated with
an increased plasma concentration of plasma renin and
norepinephrine, which are also known risk factors for
increased mortality in heart failure.64
In 1981, a sensitive radioimmunoassay was first used
to measure levels of the antidiuretic hormone, AVP,
in the plasma of hyponatraemic patients with heart
failure.65 The results demonstrated that hypo-osmolar
plasma levels, which would maximally suppress plasma
AVP in healthy individuals, did not suppress plasma
AVP concentration in hyponatraemic patients with
heart failure. Subsequent studies have reported similar
findings of a nonosmotic stimulation of AVP in heart
failure.66,67 Experimental studies have demonstrated that
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2013 Macmillan Publishers Limited. All rights reserved
the osmotic regulation of AVP can be overridden by the
nonosmotic baroreceptor pathway.68
When cardiac output decreases, the arterial stretch
baroreceptors in the carotid sinus and aortic arch become
unloaded (Figure1).69 Thus, the normal tonic inhibitory
effect to the central nervous system via the vagus and
glossopharyngeal nerves is removed, with a resultant
increase in sympathetic efferent activity. This increased
sympathetic activity is associated with stimulation of
the RAAS and the nonosmotic release of AVP.70 The
resultant systemic and renal vasoconstriction, as well as
the sodium and water retention, attenuates the arterial
underfilling, but ultimately at the expense of the occur-
rence of hyponatraemia, pulmonary congestion and
diminished kidney function.
The prevalence of hyponatraemia in patients with
high-output cardiac failure, as occurs in beriberi and
thyrotoxicosis, has not been well studied. The initiating
event in this setting, as occurs in patients with a large
arterio-venous fistula, is a decrease in systemic vascu-
lar resistance.71 As with a decrease in cardiac output,
primary arterial vasodilatation leads to unloading of
the arterial baroreceptors, with subsequent activation
of the neurohumoral axis, including the sympathetic
nervous system and RAAS, as well as the nonosmotic
release of AVP (Figure1).70 Thus, hyponatraemia would
be expected to be associated with worse survival in both
low-output and high-output cardiac failure. Evidence
also exists to show that hyponatraemia is associated with
increased mortality in patients with primary pulmonary
hypertension and pulmonary embolism.72,73 In addition,
preoperative hyponatraemia predicts an unfavourable
outcome after cardiac surgery.74
The recent availability of vasopressin V2-receptor
antagonists has been used to acutely reverse hypo
natraemia in patients with advanced cardiac failure.75
However, prospective studies are needed in patients with
heart failure before and after correction of hyponatraemia
to assess the effects on cognitive function, which is often
impaired in these patients.76 In the EVEREST study,
which investigated the safety of the V2-receptor antago-
nist tolvaptan in patients with heart failure, only 7.7%
of patients had hyponatraemia. This 9.9-month-long
randomized study demonstrated the safety of tolvaptan
in patients with heart failure, and showed a decrease in
body weight and improved dyspnoea in the first week of
therapy,77 but no effect on survival.27
Hyponatraemia in cirrhosis
The pathophysiology of hyponatraemia in patients with
cirrhosis is very similar to that observed in patients
with high-output heart failure. The portal hypertension
that occurs in patients with cirrhosis leads to primary
splanchnic arterial vasodilatation, which is the main
cause of the decreased systemic vascular resistance in
these patients.78,79 Several vasodilators have been pro-
posed as mediators of the splanchnic vasodilatation
in cirrhosis, but the most convincing results implicate
increased inducible and endothelial nitric oxide synthase
leading to nitric-oxide-mediated arterial vasodilatation.80

As in those with high-output cardiac failure, arterial
baroreceptors are unloaded in patients with cirrhosis,
which results in compensatory activation of the neuro-
humoral axis, including the sympathetic nervous system
and the RAAS, as well as nonosmotic AVP stimulation
(Figure1).70 Again, the availability of a sensitive radio-
immunoassay implicated the nonosmotic AVP release
in patients with hyponatraemia, cirrhosis and impaired
water excretion.81 Hyponatraemia, high plasma nor-
epinephrine concentration and increased renin activity
have been associated with increased mortality in patients
with cirrhosis.78 Hyponatraemia rarely occurs in patients
with cirrhosis in the absence of ascites. In a 2002 study
involving patients with cirrhosis, survival was decreased
in patients who had spontaneous hyponatraemia (com-
pared with survival in normonatraemic controls with cir-
rhosis), but not in those who had hyponatraemia with
precipitating factors.82
The presence of hyponatraemia in patients with cir-
rhosis has been shown to predict the development of
hepatorenal syndrome.83 Hyponatraemia has also been
associated with hepatic encephalopathy and neurologi-
cal disturbances in patients with cirrhosis.84 A study
published in 2012 used the Medical Outcomes Study
Short-Form 36 (SF36) questionnaire to determine
factors associated with health-related quality of life in
523 patients with cirrhosis and ascites.33 Multivariate
analysis showed hyponatraemia to be a strong predictor
of impaired mental and physical component scores on
the SF36 survey.33
These findings indicate that, as in cardiac failure,
hyponatraemia is a strong predictor of morbidity and
mortality in patients with advanced cirrhosis. Several
studies have shown that vasopressin V2-receptor antag-
onists increase serum sodium concentration in patients
with cirrhosis.85,86 In a subanalysis of the SALT study, the
effect of correcting the hyponatraemia in cirrhosis was
assessed in the physical and mental component of the
SF12.87 The results demonstrated that correction of the
low serum sodium concentration improved the mental
component of this quality-of-life survey. However, no
data exist on the effect of long-term reversal of hypo
natraemia on morbidity and mortality in patients with
cirrhosis. Hyponatraemia has been shown to be associ-
ated with worse outcomes following liver transplantation
in some,88,89 but not all, studies.90
Hyponatraemia in chronic kidney disease
Patients with chronic kidney disease (CKD) are more
susceptible to developing hyponatraemia than are
healthy individuals by virtue of their diminished ability
to maintain water homeostasis in the face of decreas-
ing kidney function. A 2012 study that included 655,493
patients with predialysis CKD (mean estimated glomeru-
lar filtration rate 50.214.1ml/min/1.73m2) revealed
that 13.6% of patients were hyponatraemic at baseline
and 26% had at least one episode of hyponatraemia
during a median follow-up of 5.5years.41 A Ushaped
relationship was demonstrated, with both decreased and
increased serum sodium concentrations being associated
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REVIEWS
with increased all-cause mortality. Moreover, these
associations were linearly proportional to the severity
of the underlying serum sodium abnormality and were
independent of comorbid conditions, including heart
failure, liver cirrhosis and cancer. Development of hypo
natraemia during follow-up had a stronger association
with mortality than having hyponatraemia at baseline,
but the stage of CKD did not affect the mortality risk
associated with hyponatraemia.
A study in patients with end-stage renal disease
(ESRD) showed that predialysis hyponatraemia was
present in 29.3% of patients and was associated with
increased all-cause mortality. 42 Each 4mmol/l incre-
ment in baseline predialysis serum sodium concentra-
tion was associated with a decrease in the risk of all-cause
mortality (hazard ratio 0.84, 95% CI 0.780.90). The
association of hyponatraemia with mortality remained
after adjusting for mode of haemodialysis, ultrafiltration
volume, and presence of severe volume overload and/or
heart failure. It remains to be proven whether this close
relationship between hyponatraemia and mortality in
patients with CKD and ESRD can be reversed by avoiding
or correcting hyponatraemia.
Hyponatraemia in patients with SIADH
The diagnosis of SIADH is in large part a diagnosis of
exclusion. In a patient presenting with hyponatraemia,
a diagnosis of hypervolaemic hyponatraemia as occurs
with oedematous disorders, such as advanced cardiac
failure and cirrhosis, and with acute kidney injury or
advanced CKD, must be eliminated. In addition, hypo-
volaemic hyponatraemia must be excluded, such as
occurs in patients with gastrointestinal losses, diuretics,
primary adrenal insufficiency, salt-losing nephropathy,
solute diuresis with diabetes-related glucosuria, or
bicarbonaturia with metabolic alkalosis.
After the exclusion of hypervolaemic and hypo
volaemic hyponatraemia, euvolaemic hyponatraemia
can be considered; this category is the one in which
SIADH resides. However, euvolaemic hyponatraemia
can also have other causes; for example, advanced hypo
thyroidism or myxoedema.91 Nonosmotic plasma AVP
concentrations are elevated in experimental advanced
hypothyroidism, and the hyponatraemia is reversed
by thyroid replacement.92 A study in humans, however,
indicates that newly diagnosed hypothyroidism is rarely
associated with clinically significant hyponatraemia.93
Glucocorticoid deficiency, as occurs in patients with
hypopituitarism, may also be associated with hypo
natraemia and elevated plasma concentrations of AVP.
Physiological doses of glucocorticoid hormone have
been shown to reverse the hyponatraemia occurring in
patients with glucocorticoid deficiency.94
SIADH has several major aetiologies including
tumours, central nervous system disorders, pulmonary
disorders and drugs. After tumours, central nervous
system disorders are the second most common cause
of SIADH. Any diffuse disorder of the central nervous
system and traumatic brain injury can be associated with
SIADH.95 Hyponatraemia with brain trauma is often
REVIEWS
associated with increased intracranial pressure.96 Acute
psychotic exacerbation has also been reported to cause
SIADH,97 possibly via the activation of stimulatory path-
ways or the removal of inhibitory neural pathways to the
magnocellular neurons from osmoreceptors in the ante-
rior hypothalamus or from cardiovascular and emetic
centres in the brainstem. When the cause of the SIADH is
not clear, computer tomography or magnetic resonance
imaging of both the lungs and the central nervous system
should be performed. As already noted, however, SIADH
in the elderly is idiopathic in up to 40% of cases, perhaps
secondary to cerebral atherosclerosis and/or impaired
autonomic neural function.
Pulmonary disorders are a relatively common cause
of SIADH and can be associated with acute pneu-
monia, pulmonary or miliary tuberculosis, chronic
obstructive lung diseases, cystic fibrosis and any type of
respiratory failure, perhaps involving hypoxia and hyper
capnia.40,98101 Mechanical ventilation may also worsen
SIADH in patients with pulmonary diseases.102
Drug-induced hyponatraemia is also a common cause
of hyponatraemia, over and above the hypovolaemic
hyponatraemia associated with diuretic use. As noted
earlier, a list of drugs that can cause SIADH is shown
(Box1).59 Psychopharmacological treatment may be
associated with drug-induced hyponatraemia and rates
are especially high with carbamazepine, oxcarbazepine
and selective serotonin reuptake inhibitors (SSRIs).103
SSRI medications cause SIADH in up to 30% of elderly
patients.104 SSRIs have been suggested to have a direct
tubular effect that leads to enhanced water reabsorp-
tion.105 All SSRIs, serotoninnorepinephrine reuptake
inhibitors (for example, venlafaxine) and anticonvulsants
(for example, levetiracetam) can be associated with
hyponatraemia. Severe hyponatraemia can also occur
with the recreational drug ecstasy (3,4-methylenedi-
oxymethamphetamine), which also has serotoninergic
activity.106 Patients with acquired immunodeficiency
syndrome (AIDS) may have hyponatraemia that fulfils
the criteria of SIADH.107
A subanalysis of the patients with SIADH from the
SALT study was undertaken to evaluate the safety and
efficacy of the V2-receptor antagonist, tolvaptan, in this
subgroup. The results demonstrated that the increased
serum sodium concentration with use of tolvaptan was
associated with significant improvements in the physical
component of the SF12 Health Survey in patients with
SIADH. Improvements seen in the mental component
of the SF12 survey were not statistically significant.108
In patients with SIADH, the hyponatraemia must be
associated with hypo-osmolality and a less-than-maximal
urinary dilution. A less-than-maximal urinary dilution in
general has been determined to be a urinary osmolality
greater than 100mOsm/kg H2O in the presence of hypo-
osmolality. Plasma AVP concentration assessed by sensi-
tive radioimmunoassay is not suppressed in those with
SIADH in spite of the hypo-osmolality that would lead
to maximal suppression of AVP in healthy individuals.
However, in about 10% of hyponatraemic patients, who
otherwise fulfil the diagnostic criteria for SIADH, plasma
42 | JANUARY 2013 | VOLUME 9  www.nature.com/nrneph
2013 Macmillan Publishers Limited. All rights reserved
AVP concentrations are not detectable. One explanation
for this occurrence is that physiological levels of plasma
AVP may not be detectable by the current sensitivity of
the radioimmunoassay. This lack of sensitivity has been
demonstrated in experimental studies in which a small
AVP infusion caused an antidiuresis, but plasma concen-
trations could not be detected by radioimmunoassay.1
Another explanation is that a mutation of the vaso-
pressin V2 receptor has activated the receptor in the
absence of AVP, the so-called nephrogenic syndrome of
inappropriate antidiuresis (NSIAD).109
A diagnostic algorithm for the treatment of patients
with hypotonic hyponatraemia is shown (Figure2).
Before using this approach, isotonic hyponatraemia
due to hyperparaproteinaemia, -globulin administra-
tion, use of contrast media and hyperlipidaemia needs
to be excluded. In addition, hypertonic hyponatraemia
caused by hyperglycaemia, mannitol, sorbitol or a posi-
tive anion gap need to be excluded. Thus, the diagnostic
workup of a patient with hyponatraemia should include a
measurement of plasma osmolality.
The pitfalls of this algorithm should be acknowledged.
For example, the urinary sodium concentration is not
of value if the patient is receiving diuretics. Secondly,
even after a careful history and physical examina-
tion is performed, the hypovolaemic and euvolaemic
hyponatraemic states may be difficult to distinguish.110
Patients with hypervolaemic causes generally have
oedema, severe disease and impaired kidney function.
Patients with hyponatraemia associated with primary
polydipsia usually have a urine osmolality that is less
that 100mOsm/kg. However, as discussed, hypo
natraemia can be associated with low solute intake and
beer potamania may have a urinary osmolality less than
100mOsm/kg. With the increase in total body water,
serum uric acid, urea and creatinine levels tend to be
lower than normal in patients with SIADH.111 Uric acid
excretion is increased in most patients with SIADH, and
may therefore be of diagnostic value in hyponatraemic
patients who are receiving diuretics.112 Serum copeptin,
a stable glycopeptide derived from the same precursor
peptide as arginine vasopressin in equimolar amounts,
has been measured in patients with hyponatraemia and
may exclude primary polydipsia.113
Normal saline infusion (0.51l over 12h) can differen-
tiate hypovolaemic from euvolaemic hyponatraemia. In
patients with SIADH, the sodium load will be excreted
without improvement in the hyponatraemia. However,
in patients with hypovolaemic hyponatraemia, volume
expansion with saline should increase the serum sodium
concentration.114 Among patients with SIADH with a
urinary osmolality lower than 500mOsm/kg, normal
saline infusion may cause a water diuresis and an
increase in serum sodium concentration.111
A prospective study in 121 consecutive patients with
hyponatraemia compared the diagnostic accuracy at
24h between inexperienced physicians using a diag-
nostic algorithm (such as the one presented in Figure2)
and senior intensive care physicians not using the algo-
rithm.115 After the availability of a complete work-up,
 REVIEWS

Hyponatraemia

Sodium and water deficit Water excess Sodium and water excess

Hypovolaemia Euvolaemia Hypervolaemia

Total body water Total body water Total body water
Total body sodium Normal total body sodium Total body sodium

Renal losses Extrarenal losses Glucocorticoid deficiency Nephrotic syndrome Acute kidney injury
Diuretic excess Vomiting Hypothyroidism Cardiac failure Chronic renal failure
Mineralocorticoid Diarrhoea Pain Cirrhosis
deficiency Third-space burns Psychiatric disorders
Salt-losing nephritis Pancreatitis Drugs
Bicarbonaturia Traumatized muscle SIADH
Renal tubular acidosis
Ketonuria
Osmotic diuresis
(glucose, urea, mannitol)

Urinary sodium Urinary sodium Urinary sodium Urinary sodium Urinary sodium
concentration concentration concentration concentration concentration
>30 mmol/l <20 mmol/l >30 mmol/l <20 mmol/l >30 mmol/l

Isotonic saline Water restriction Sodium and water restriction

Normonatraemia

Figure 2 | Diagnostic and therapeutic approach to the hypovolaemic, euvolaemic, and hypervolaemic patient with
hyponatraemia. Urinary sodium concentrations in between 20mmol/l and 30mmol/l represent a grey zone. Abbreviation:
SIADH, syndrome of inappropriate secretion of antidiuretic hormone. Permission obtained from American Society of
Nephrology Schrier, R.W. J. Am. Soc. Nephrol. 17, 18201832 (2006).1

the results were compared to a reference standard of an
experienced endocrinologist with expertise in hypo
natraemia. The inexperienced physicians using the
algorithm had an overall agreement with the reference
standard of 86%, whereas the senior intensive care phy-
sicians not using the algorithm only had a 48% agree-
ment with the reference standard. So, although such
algorithms do have limitations in guiding the diagnos-
tic approach to hyponatraemia, they do seem to be of
considerable assistance to the practicing physician.
Hyponatraemia in strenuous exercise
Another cause of acute hyponatraemia is endurance
exercise such as marathons, ultra-marathons and tri-
athlons.116118 Among nonelite marathon runners, the
reported incidence of hyponatraemia has varied from
3% to 13%.4346 Hyponatraemia has been shown to cor-
relate with increased weight gain during the race.117
Hyponatraemia in this setting can be associated with
severe symptoms of cerebral oedema, convulsions, and
even death.119 Evidence exists to indicate that the non
osmotic release of AVP occurs during marathons.120 This
finding was demonstrated by directly measuring levels
of AVP or copeptin120,121 in hyponatraemic marathon
runners. Consumption of water in excess of insensible
losses (such as sweating and hyperventilation), in the
presence of the nonosmotic stimulation of vasopressin,
explains why weight gain during the marathon runs
correlates with hyponatraemia.43 In addition to exces-
sive water intake and weight gain during the race, other
risk factors for exercise-related hyponatraemia are female
gender, a body mass index (BMI) of less than 20kg/m2,
and a slow race time.43
Hyponatraemia-induced encephalopathy due to
strenuous exercise has been found to be associated with
noncardiogenic pulmonary oedema. The noncardiogenic
pulmonary oedema is a result of increased intracranial
pressure, and resolution of brain oedema resolves the
pulmonary oedema.122 The condition can be successfully
treated with hypertonic saline.122
Hyponatraemia in cancer patients
Hyponatraemia is one of the most common electro-
lyte disorders associated with tumour-related condi-
tions.123 Approximately 14% of cases of hyponatraemia
in medical inpatients is associated with an underlying
tumour-related condition.124 Such hyponatraemia usually
accompanies, but can also precede, the diagnosis of the
tumour.38 Hyponatraemia in patients with tumours may
also be related to medical125 or surgical treatment.126

NATURE REVIEWS | NEPHROLOGY VOLUME 9 | JANUARY 2013 | 43

2013 Macmillan Publishers Limited. All rights reserved
REVIEWS
The exact frequency of hyponatraemia in patients with
cancer is uncertain, primarily because of variations in
the populations evaluated and differences in the defi-
nitions of hyponatraemia.127 A serum sodium concen-
tration of 130mmol/l or less was used to analyse the
frequency of hyponatraemia in a prospective study per-
formed at a dedicated cancer hospital in Belgium. During
11months of observation, 3.7% of the 106 patients with
cancer had hyponatraemia, which is within the range
reported for general hospitals, intensive care wards, and
geriatric centres.38 However, in a large study of 3,357
cancer patients in whom a serum sodium concentra-
tion of less than 135mmol/l was used to define hypo
natraemia, 47% of the patients had hyponatraemia (23%
had hyponatraemia on admission and 24% developed
hyponatraemia during hospitalization).39 Hyponatraemia
in patients with cancer is associated with a poor prog-
nosis. After adjusting for several confounding factors,
including age, chemotherapy and serum creatinine
concentration, the presence of hyponatraemia (versus
normon atraemia) was associated with an increased
hospital stay and increased 90-day mortality.39
SIADH is the most common cause of hyponatraemia
in cancer patients, but anticancer treatment may also be
involved. The tumours most commonly associated with
SIADH are lung, breast and head and neck tumours.38
A paper published in 1957 reported the presence of
hyponatraemia in two patients with lung cancer; the
authors postulated that the tumours led to the inap-
propriate release of antidiuretic hormone.128 This sug-
gestion of SIADH in cancer patients was supported by
a paper published in 1978 in which researchers found
that plasma AVP was elevated in hyponatraemic patients
with bronchogenic carcinoma. 129 The vast majority
of the tumours that have been found to produce AVP
are small cell lung cancers and, much less commonly,
non-small-cell lung cancer.129 Studies have shown that
1015% of patients with small cell lung carcinoma have
hyponatraemia130,131 and that approximately 70% of these
patients have significant elevations of plasma AVP. 132
However, in one-third of patients with small cell lung
cancer and hyponatraemia, no evidence of ectopic AVP
production is found.
SIADH occurs in 3% of patients with head and neck
cancer.38,132 Head and neck lesions associated with the
development of SIADH are often located in the oral
cavity, and less often in the larynx, pharynx, maxillary
sinus or salivary glands.133 Other tumours that have been
more rarely associated with SIADH include olfactory
neuroblastoma, small cell neuroendocrine carcinomas,
adenoid cystic carcinoma, undifferentiated carcinoma
and sarcoma.134
Antineoplastic agents such as vincristine, vinblastine
and cyclophosphamide can induce hyponatraemia,125
possibly via a central mechanism of AVP release
caused by cytotoxicity of paraventricular and supra
optic neurons.127 However, direct tubular cisplatin tox-
icity causing salt-wasting and volume depletion has
been proposed as a cause of hyponatraemia.135 During
transurethral resection of prostate and transcervical
44 | JANUARY 2013 | VOLUME 9  www.nature.com/nrneph
2013 Macmillan Publishers Limited. All rights reserved
endometrial ablation,136138 irrigation with large volumes
of sorbitol, saline, or hypertonic glucose may contrib-
ute to hyponatraemia in the presence of nonosmotic
AVP release.
Postoperative hyponatraemia
Hyponatraemia is the most frequent electrolyte abnor-
mality observed in postoperative patients who are
receiving intravenous maintenance fluid therapy. Ayus
and colleagues analysed risk factors for postoperative
hyponatraemic encephalopathy. 139 They found that
the prevalence of hyponatraemia and hyponatraemic
encephalopathy was equal in male and female patients;
however, when hyponatraemic encephalopathy devel-
oped, young, menstruant women were about 25 times
more likely to die or have permanent brain damage
than either men or postmenopausal women. The patho
genesis of postoperative hyponatraemia is believed to be
caused by hypotonic infusions in patients with high AVP
concentrations related to surgery.
Several studies have addressed associations between
type of postsurgery fluid management and the risk of
developing hyponatraemia. 140142 The use of isotonic
saline has been considered preferable to use of hypotonic
fluids, as is the case with irrigation solutions.
Falls, osteoporosis and fractures
Hyponatraemia can be associated with impaired cogni-
tion, gait disturbances and falls. People over the age of
65years have at least one fall every year on average.47
The prevalence of falls is much greater in patients with
chronic asymptomatic hyponatraemia than in normo
natraemic patients, with an adjusted odds ratio as high as
67-fold greater in those with hyponatraemia (Table2).54
One-third of total-body sodium is stored in bone,
of which 40% is exchangeable with serum. In states of
chronic sodium depletion, sodium is mobilized from
the bone with resultant bone matrix resorption and
bone demineralization. 143,144 Severe chronic hypo
natraemia has been shown to cause a 30% decrease in
bone mineral density in animal models.145 Although
sodium-dependent activation of osteoclasts is not clearly
understood, low serum sodium concentration is associ-
ated with increases in osteoclastic activity and low bone
mineral density.145,146
Examination of data from NHANES III showed that
mild hyponatraemia (mean serum sodium concentra-
tion 133.0mmol/l) is associated with increased osteo
porosis (T-score 2.5).146 This analysis was adjusted for
age, sex, BMI, physical activity, diuretic use and serum
level of 25-hydroxyvitamin D. However, several studies
found that hyponatraemia was associated with fractures
independent of a low bone mineral density.48,147,148
An analysis of medical records of elderly patients
who experienced bone fractures following falls has
shown the prevalence of hyponatraemia to be between
9.1% and 13.0%,47,48 two to three times higher than in
matched controls without a history of bone fracture.
The authors suggested that the occurrence of falls and
fractures was caused by gait instability and attention

Table 2 | Risk of falls in patients with asymptomatic hyponatraemia
Group n Individuals
Asymptomatic chronic hyponatraemia 122
Normonatraemic controls 244
*Adjusted for age, sex, and covariates. Permission obtained from Excerpta Medica Inc. Renneborg, B. et al. Am. J. Med. 119, 71.e171.e8 (2006).54
deficits.47 Underlying causes of hyponatraemia were not
studied. However, up to 24.2% of these hyponatraemic
patients in one study were taking SSRIs, 48 which can
induce hyponatraemia and cause impaired sensorium
and mobility deficits.149
Moreover, experimental chronic hyponatraemia has
been found to be associated with sarcopenia. 150 The
presence of sarcopenia could predispose to falls by
decreasing muscle mass and strength, particularly in
elderly individuals.
The prospective Rotterdam study investigated the
association of hyponatraemia with the risk of falls in
5,208 patients aged greater than 55years. In total, 7.7%
of individuals included in the study had hyponatraemia.
The presence of hyponatraemia was associated with
an increased risk of recent falls. Moreover, baseline
hyponatraemia was associated with an increased inci-
dence of nonvertebral fractures over 67years of follow-
up.148,151 No relationship, however, was found between
serum sodium concentration and bone mineral density.
Although emerging evidence has revealed a close cor-
relation between hyponatraemia and the risk of falls
and fractures, no data are available to show whether
correction of hyponatraemia decreases this risk.
Available therapies for hyponatraemia
The treatment of hyponatraemia is dependent on several
factors. These factors include the symptoms present, the
duration of hyponatraemia, and the diagnostic category
(namely hypovolaemic, hypervolaemic or euvolaemic
hyponatraemia).1,152 In hyponatraemic patients with
severe symptoms including obtundation, coma, sei-
zures, and respiratory arrest, the treatment of choice
is 3% hypertonic saline (513mmol/l) to decrease brain
oedema and avoid brainstem herniation and cardio
respiratory arrest. Although not evidence-based, a prac-
tical approach is a 100ml bolus of 3% sodium chloride
to be repeated within 30min if no clinical improvement
occurs.153 This approach will increase serum sodium
concentration by 24mmol/l and thereby attenuate
the brain oedema. In rare cases, however, this amount
of hypertonic saline may be insufficient. Concomitant
furosemide use could increase serum sodium concen-
tration even more. In patients with transtentorial brain
herniation secondary to hyponatraemia, researchers have
reported the more rapid (>5mmol/l per hour) correction
of serum sodium using 23.4% saline (3060ml bolus).154
In most cases, such severe symptomatology occurs
when acute hyponatraemia has developed over less than
2448h, when brain adaptation has not yet occurred.
Patients with moderate neurological symptoms due to
NATURE REVIEWS | NEPHROLOGY VOLUME 9 | JANUARY 2013 | 45
REVIEWS
Odds ratio Adjusted odds ratio*
with falls (%)
21.3 9.45 (95% CI 2.6434.09); 67.43 (95% CI 7.48607.42);
P<0.001 P<0.001
5.35 1.00 1.00
hyponatraemia may present with confusion, disorienta-
tion, nausea and alerted mental status. This scenario can
occur with either acute or chronic hyponatraemia. Such
moderate symptoms may progress to more severe neuro
logical abnormalities and therefore should probably
also be treated with hypertonic saline. This approach,
however, should be used with caution so as to avoid too
rapid a correction of hyponatraemia. In patients with
either severe or moderate symptoms, fluid restriction
should be instituted and the patient followed carefully
in hospital.
Minimal symptoms of hyponatraemia include head-
ache, inability to concentrate, irritability, altered mood
and depression. Patients with these symptoms generally
have more chronic hyponatraemia and can be treated
with fluid restriction. The degree of fluid restriction
depends on the patients urine output. For example, if
a patients daily urine output is 1,200ml, their daily oral
fluid intake should be restricted to 750ml. The water
in food generally equates to the amount of insensible
loss. Such fluid restriction will generally increase the
patients serum sodium concentration by 12mmol per
day. The higher the urinary-to-plasma osmolality ratio,
the less effective fluid restriction becomes, and long-term
compliance, particularly outside the hospital, is poor.
Although some patients with mild hyponatraemia can be
managed by fluid restriction alone, this strategy is insuf-
ficient in some cases. In elderly females with chronic
hyponatraemic encephalopathy, normal saline infusion
was reported to be associated with much better outcomes
than was fluid restriction alone.155
Administration of demeclocycline can result in a vas-
opressin-resistant diabetes insipidus and enable more
liberal fluid intake. However, owing to drug accumula-
tion and toxic effects, demeclocycline is contraindicated
in patients with either heart failure or cirrhosis.156 Oral
urea (1530g per day in divided doses) has been used
to treat hyponatraemia; this agent works by causing
a solute diuresis (that is, increased solute-free water
excretion). The main criticism associated with urea is
its bitter taste.157 Because of its poor palatability, oral
urea should be given with orange juice. In the inten-
sive care unit setting, urea (0.51g/kg per day) can be
given via gastric tube.158 Soupart etal. have reported that
urea has a similar efficacy and tolerance compared to
vasopressin-receptor antagonists in the long-term treat-
ment of patients with SIADH.159 A loop diuretic admin-
istered together with increased sodium intake can also
enhance solute-free water excretion.160 The US FDA has
not approved demeclocycline, urea or furosemide and
sodium chloride to treat hyponatraemia.
2013 Macmillan Publishers Limited. All rights reserved
REVIEWS
As most hyponatraemia is primarily mediated by the
nonosmotic release of AVP,161 the most direct treatment
would be the use of a vasopressin-receptor blocker.
Conivaptan was the first FDA-approved AVP-receptor
blocker. 162 Conivaptan is given only by the intra
venous route (20mg bolus, then continuous infusion
2040mg/24h) over up to 4days in hospital. Although
the drug is both a V1a and a V2 vasopressin-receptor
blocker, the mechanism of the solute-free water diu-
resis (aquaresis) is via the blockade of V2 receptors
in the collecting duct. Tolvaptan is an orally active,
selective V2-receptor blocker that must be started in
hospital for safety reasons, but has been shown to be
effective and safe for as long as 3years.163 Both conivap-
tan and tolvaptan are FDA approved for the treat-
ment of hypervolaemic hyponatraemia (for example,
in patients with heart failure or cirrhosis) and euvol-
aemic hyponatraemia (for example, in patients with
SIADH). Tolvaptan has been approved by the European
Medicines Agency (EMA) for the treatment of SIADH
and by the Japanese Health Ministry for treating diuretic
resistance in heart failure. In hyponatraemic patients
starting these V2-receptor blockers, fluid should not
be restricted and the patients serum sodium concen-
tration should be monitored every 68h so as to avoid
an excessive increase in serum sodium concentration
(>12mmol/24h or >18mmol/48h). More rapid correc-
tion of chronic hyponatraemia can lead to the osmotic
demyelination syndrome secondary to brain dehydra-
tion and bloodbrain barrier disruption. The excess
correction of hyponatraemia occurring secondary to a
rapid water diuresis (for example, vaptan therapy) may
indicate the need for interventional treatment, such as
an increase in water intake and possibly administration
of desmopressin.
Acutely, hyponatraemia causes brain oedema, but after
approximately 4872h an adaptation occurs to attenu-
ate this oedema. This adaptation is associated with the
extrusion of cell potassium and organic osmolytes, such
as myoinositol, phosphocreatinine and amino acids (for
example, glutamine and taurine).164 After this adapta-
tion, a rapid correction of hyponatraemia of more than
1012mmol/l in 24h may lead to osmotic demyelina-
tion in the brain.165 This entity can be associated with
severe brain damage and even death. Osmotic demy-
elination has been reported to occur mostly in patients
who have an initial serum sodium level lower than
115120mmol/l.166 Risk factors for developing demy-
elination are concomitant liver diseases, hypoxia, hypo
kalaemia, malnutrition and a change in serum sodium of
more than 25mmol/l in the initial 48h of treatment.167 In
a rat model, urea treatment was shown to protect against
the negative consequences of rapid serum sodium cor-
rection.168 This effect is not mediated by a urea-induced
reverse osmotic shift, as observed in dialysis; it has been
observed in rats with renal failure in the absence of renal
replacement therapy.169 Moreover, hypoxia is known to
alter brain adaptation to a change in serum sodium,
and it can produce demyelinization even in the absence
of hyponatraemia.170 Much less information exists on
46 | JANUARY 2013 | VOLUME 9  www.nature.com/nrneph
2013 Macmillan Publishers Limited. All rights reserved
the adaptation and consequences of hyponatraemia in
the myocardium. However, experimental taurine defi-
ciency has been associated with heart failure. 171 This
finding may be relevant as, at least in the brain, chronic
hyponatraemia leads to the cellular depletion of taurine.
Moreover, interstitial oedema can cause myocardial
dysfunction.172,173 Experimental evidence also exists to
indicate that hypo-osmolality increases the contractile
response of vascular smooth muscle.174 This theoretically
could increase invivo cardiac afterload in patients with
heart failure and hyponatraemia.
A consensus exists, though remains to be proven, that
osmotic demyelination is more likely to occur in patients
with a baseline serum sodium concentration of less than
120mmol/l.165 The use of tolvaptan is FDA approved for
patients with serum sodium concentrations of less than
125mmol/l or patients with clinically related symptoms.
Few data exist, however, on the use of tolvaptan to treat
patients with serum sodium concentrations of less than
125mmol/l.85 Large swings in serum sodium concentra-
tion can occur in patients on dialysis. However, osmotic
demyelination rarely occurs in this setting, probably
because the increased intracellular urea may protect
against brain dehydration. Patients with a chronic serum
sodium concentration of less than 105mmol/l, liver
disease, malnutrition, alcoholism and hypokalaemia are
at increased risk of developing osmotic demyelination.
In these settings, serum sodium correction should not
exceed 8mmol in 24h.152
Although osmotic demyelination has not been
reported with use of V2-receptor antagonists (conivap-
tan and tolvaptan) in all published studies, including
use in more than 2,000 heart failure patients, Otsuka
recently issued a warning letter concerning the occur-
rence of neurological sequelae in some patients treated
with tolvaptan in whom the correction of serum sodium
exceeded the suggested rate.175
Adverse effects of vasopressin-receptor antagonists
include dry mouth, thirst and increased urination in
most patients. These agents may not be effective in
patients with advanced acute or chronic renal failure
such as those with serum creatinine concentrations
greater than 221mol/l. In addition, vasopressin-
receptor antagonists should not be used in patients with
hypovolaemic hyponatraemia, who should instead be
treated with isotonic saline. As Gross etal. have stated,176
the indications for use of vaptans need to be more firmly
established and comparisons are needed with other
therapies. Several unanswered questions remain relat-
ing to the use of vaptans to treat hyponatraemia. For
example, what symptoms of hyponatraemia should be
treated? Will there be an effect on quality of life and/or
mortality in various patient populations? Will the use of
vaptans decrease the length of hospital stays in patients
with hyponatraemia? And will these agents be proven to
be cost-effective?
Conclusions
Although the relationship between hyponatraemia
and increased morbidity and mortality is very strong
 REVIEWS

in some patient populations, the beneficial effects of Review criteria

treating hyponatraemia are less clear. Evidence on the
adverse effects of hyponatraemia on the central nervous
function is quite convincing, but it is yet to be proven
that correction of hyponatraemia will improve cogni-
tion and prevent falls in the elderly, or in patients with
advanced cardiac or liver disease. In addition, whether
correction of hyponatraemia can improve cardiac func-
tion in patients with heart failure is yet to be determined.
Prospective, randomized trials are needed to examine
whether hyponatraemia is just a marker of severe disease
or whether correction of hyponatraemia could improve
a patients quality of life.
The MEDLINE and PubMed databases were searched
for English-language articles published between January
1950 and January 2012, including articles published
online ahead of print. We also identified English-language
abstracts in cases where the manuscript was not published
in English. Search terms included hyponatraemia, serum
sodium, SIADH, sodium handling, vasopressin-
receptor antagonists and vaptans. In addition, we used
a manual search strategy where relevant review articles
were searched to identify studies that might have been
missed by our database screening. Studies that have not
yet been accepted for publication were excluded.

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Author contributions
The authors contributed equally to all aspects of this
manuscript.