Expert Review of Endocrinology & Metabolism

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Management of hyponatremia: causes, clinical

aspects, differential diagnosis and treatment

Alessandro Peri

To cite this article: Alessandro Peri (2018): Management of hyponatremia: causes, clinical
aspects, differential diagnosis and treatment, Expert Review of Endocrinology & Metabolism, DOI:
10.1080/17446651.2019.1556095

To link to this article: https://doi.org/10.1080/17446651.2019.1556095

Accepted author version posted online: 11

Dec 2018.
Published online: 31 Dec 2018.

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EXPERT REVIEW OF ENDOCRINOLOGY & METABOLISM
https://doi.org/10.1080/17446651.2019.1556095

REVIEW

Management of hyponatremia: causes, clinical aspects, differential diagnosis and

treatment
Alessandro Peri
Sodium Unit, Endocrinology, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, Careggi University
Hospital, Florence, Italy

ABSTRACT ARTICLE HISTORY

Introduction: Hyponatremia is the most frequent electrolyte disorder in hospitalised patients. Acute Received 5 September 2018
and severe hyponatremia may be a life-threatening situation. However, also mild and chronic hypona- Accepted 3 December 2018
tremia may negatively affect the health status (i.e. gait disturbances, attention deficits, falls and KEYWORDS
fractures, and bone loss) and may increase the risk of death. Therefore, it is of paramount importance Hyponatremia; sodium;
for clinicians to have an in-depth knowledge on this topic, in order to appropriately manage patients saline solution; SIAD;
affected by hyponatremia. vaptans
Areas covered: This review will cover different areas related to this electrolyte disorder. Because many
pathologic conditions may be associated with hyponatremia, thorough investigations have to be
performed in order to establish the underlying etiology. To establish the cause of hyponatremia is of
great importance, because an appropriate therapeutic strategy is strictly dependent on a correct
diagnosis. A description of the different available therapeutic approaches for the correction of hypona-
tremia, including vaptans, will follow.
Expert commentary: Undoubtedly, the studies that have been published in recent years and the
introduction of vaptans in clinical practice have contributed to increase the awareness on hyponatremia
among clinicians. Nevertheless, additional studies are needed in order to clarify some partially uncov-
ered areas.

1. Introduction the authors’ interpretation, aggravation and deterioration of

1.1. Epidemiology
Epidemiologic data collected from the general population
indicated that the prevalence of hyponatremia is around
6–7% and that there is a progressive increase with aging
[1,2]. In hospitalized patients, hyponatremia occurs more fre-
quently. The analysis of the data from almost 100,000 patients
admitted to two hospitals in Boston (U.S.) over a period of
three years revealed that in 19.7% of cases a serum [Na+]
<135 mEq/L was reported during hospitalization. A total of
14.5% of patients were hyponatremic on admission. In the
majority of cases, hyponatremia was mild (i.e. serum [Na+]
between 130 and 135 mEq/L), but in 2.5% of cases it was
moderate (i.e. serum [Na+] 120–129 mEq/L) or severe (i.e.
serum [Na+] <120 mEq/L) [3]. In a prospective cohort study,
which analyzed 2907 patients admitted over a period of
3 months at a University Hospital in The Netherlands, hypona-
tremia (serum [Na+] ≤135 mEq/L) was found in 30% of almost
3000 patients in which serum [Na+] was measured. Severe
hyponatremia (defined as [Na+] <125 mEq/L) was present in
2.6% of patients. The average serum [Na+] on admission in
the group of severe hospital-acquired hyponatremia was
133 mEq/L, indicating that mild hyponatremia was already
existing on admission at least in some patients. According to
hyponatremia was facilitated by factors introduced in the
hospital rather than a de novo development of hyponatremia.
The incidence of hyponatremia was significantly higher in
internal medicine, surgery, and intensive care departments as
compared to all other departments [4]. A recent epidemiologic
report of hyponatremia, which included more than 150,000
patients over a 5-year period in a teaching hospital in China,
indicated a prevalence of 17.5% for serum [Na+] <135 mEq/L.
In 13% of cases, hyponatremia was mild ([Na+] ≥130 mEq/L), in
4.2% of cases was moderate ([Na+] 120–129 mEq/L), and in
0.3% of cases was severe ([Na+] <120 mEq/L) [5].
It has to be considered that possible confounders may
affect the reliability of the reported prevalence of hypona-
tremia in hospitalized patients. First, serum [Na+] is subject
to analytical variations and a deviation of 3–4 mEq/L
between two samples collected from the same patient at
the same time may occur [6]. Second, some studies do not
specify whether pseudohyponatremia has been excluded
or whether serum [Na+] has been corrected for hypergly-
cemia [3–5]
2. Etiopathogenesis
Hyponatremia can be divided into two main categories
based on serum osmolality: hypotonic and non-hypotonic.

CONTACT Alessandro Peri alessandro.peri@unifi.it Sodium Unit, Endocrinology, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’,
University of Florence, Careggi University Hospital, Viale Pieraccini, 6 50139, Florence, Italy
© 2018 Informa UK Limited, trading as Taylor & Francis Group
2 A. PERI
Non-hypotonic hyponatremia includes both hypertonic and
isotonic hyponatremia. The former may be a consequence of
water shift from cell cytoplasm into the extracellular fluid
(ECF), which may occur, for instance, in the presence of
hyperglycemia. Each increase of serum glucose levels of
100 mg/dL above 100 mg/dL results in a serum [Na+] reduc-
tion of about 1.7 mEql/L [7]. Isotonic hyponatremia may be
the consequence of the retention of large volumes of iso-
tonic, sodium-free fluids, in the extracellular space. This con-
dition may be caused by the absorption of irrigants, glycine,
sorbitol, or mannitol, which are contained in flushing solu-
tions used during invasive procedures, such as transurethral
resection of the prostate or hysteroscopy. It has to be taken
into account that a reduced serum [Na+] may be a laboratory
artifact, which can occur in the presence of severe hypertri-
glyceridemia or paraproteinemia. This possibility, named
pseudohyponatremia, should be ruled out, in order to avoid
inappropriate management.
The large majority of cases of hyponatremia occurring in
clinical practice fall into the category of hypotonic (dilutional)
hyponatremia. It has to be said that hyponatremia is the result of
a relative excess of water, due to excessive water intake or to
renal retention, in the presence of reduced, normal, or even
increased body sodium stores [8]. An excessive intake of water
is observed in primary polydipsia. In the presence of normally
functioning kidneys, which are able to eliminate up to 800/
1000 mL of fluid per hour, the load of water can be eliminated
through urine output and hyponatremia rarely occurs. However,
serum [Na+] may decrease when suboptimal kidney function
does not allow to effectively eliminate the excess of water.
Hyponatremia, which can be sometimes life-threatening, more
frequently occurs when an excess of water is introduced in
a limited period of time. This situation is perfectly described by
the terms ‘water intoxication’ or ‘water poisoning’. Based on ECF
assessment, hypotonic hyponatremia has been classically
divided into three categories: hypovolemic, hypervolemic, nor-
movolemic [8]. These terms, although largely used, are not com-
pletely appropriate, because volume assessment should also
include the interstitial fluids and the ad hoc term should there-
fore refer to the total ECF, instead of volemia. To make a practical
example, hypervolemic hyponatremia addresses, for instance,
hyponatremia associated to heart failure. However, in heart fail-
ure, volemia is not increased, yet the effective circulating volume
is reduced, whereas the total ECF is increased. Therefore, it would
be more appropriate to substitute the terms hypovolemic, euvo-
lemic, hypervolemic hyponatremia with reduced, normal,
increased ECF (Table 1).
Table 1. Main features of hypotonic hyponatremia.
Hyponatremia with increased ECF
Total body water ↑↑
Total body sodium ↑ ↔
ECF ↑↑
Edema Present
Causes Congestive heart failure, cirrhosis, nephrotic
syndrome, acute or chronic renal failure
ECF = extra cellular fluid.
Hyponatremia with reduced ECF may be due to renal solute
loss (e.g. diuretic therapy, cerebral salt wasting (CSW) syn-
drome, mineralocorticoid deficiency, salt wasting nephropa-
thy) or to extra-renal solute loss (e.g. vomiting, diarrhea,
pancreatitis, third space burns).
Hyponatremia with increased ECF, beyond congestive heart
failure, may be associated to cirrhosis, nephrotic syndrome,
renal failure (acute or chronic).
Hyponatremia with normal ECF is represented in most
cases by the syndrome of inappropriate secretion of antidiure-
tic hormone (SIADH). SIADH is estimated to be the cause of
chronic hyponatremia in at least 50% of cases. It may be
underdiagnosed because of inappropriate diagnostic investi-
gation. Comments regarding the pitfalls in the diagnosis of
SIADH will follow in the specific section. In SIADH, ‘inappropri-
ate’ means that vasopressin secretion is not caused by plasma
hyperosmolality or by arterial hypotension or hypovolemia.
This syndrome has been also renamed syndrome of inap-
propriate antidiuresis (SIAD), following the description of
infants with clinical and laboratory features consistent with
the presence of SIADH, but with undetectable vasopressin
levels. Gain-of-function mutations of the vasopressin type 2
(V2) receptor gene have been identified in these patients [9].
Therefore, the V2 receptor is constitutively activated and
causes water reabsorption via the activation of aquaporin-2
in the collecting duct cells. Plasma hypotonicity inhibits ADH
secretion. It is the opinion of the author that the acronym
SIAD should be therefore more appropriately used.
Many clinical conditions may cause SIAD and among them
tumors, which can ectopically secrete vasopressin, central ner-
vous system disorders, and pulmonary diseases (Table 2).
A number of drugs can induce SIAD, by increasing the secretion
of vasopressin (i.e. tricyclic antidepressants, selective serototin
reuptake inhibitors, phenotiazines, carbamazepine, vinca alka-
loids, alkylating agents, opiates) and/or potentiating its effect
(i.e. carbamazepine, chlorpropamide, alkylating agents, nonster-
oidal anti-inflammatory drugs). Some drugs may have an uncer-
tain or mixed effect (i.e. amiodarone).
Although in SIAD impaired renal water excretion occurs,
thus causing a slight increase in total body water, the devel-
opment of edema is prevented by the distribution of water in
both intra- and extracellular compartments of the body [8]. In
addition, the increased secretion of natriuretic peptides
promotes sodium urinary excretion [10]. Another cause of
normovolemic hyponatremia is secondary hypocortisolism
[11,12]. Here, the main cause of hyponatremia appears to be
the increased production of vasopressin, secondary to the loss
Hyponatremia with
normal ECF Hyponatremia with reduced ECF
↑ ↓
↓↓
↔/↑ ↓
Absent Absent
SIAD, hypocortisolism, Renal solute loss: Diuretic therapy, cerebral salt wasting
(hypothyroidism) syndrome, Addison’s disease, salt wasting nephropathy
Extrarenal solute loss: Vomiting, diarrhea, pancreatitis, third
space burns

Table 2. Causes of SIAD.
Tumors ● Pulmonary/mediastinal
● Nonchest (i.e. duodenal carcinoma, pancreatic car-
cinoma, ureteral/prostate carcinoma, leukemia,
lymphoma, nasopharyngeal carcinoma)
Central nervous ● Mass lesions (tumors, brain abscesses, subdural
system disorders hematoma)
● Inflammatory diseases (i.e. encephalitis, meningitis,
herpes virus infection, sarcoidosis, multiple
sclerosis)
● Degenerative/demyelinative diseases
● Miscellaneous (i.e. subarachnoid hemorrhage, head
trauma, pituitary stalk section, Guillan-Barrè syn-
drome, hydrocephalus)
Drug induced ● Stimulated vasopressin release
● Direct renal effects and/or potentiation of vaso-
pressin antidiuretic effects
● Mixed or uncertain actions
Pulmonary diseases ● Infections (e.g. tuberculosis, acute bacterial and
viral pneumonia)
● Mechanical/ventilatory (i.e. acute respiratory failure,
positive pressure ventilation)
Other ● AIDS
● Prolonged strenuous exercise (e.g. marathon, hot-
weather hiking)
● Idiopathic
SIAD: syndrome of inappropriate antidiuresis.
of the tonic inhibitory effect on vasopressin secretion by
endogenous cortisol [13]. However, other associated factors
(i.e. nausea and hypoglycemia) may play a similar role [12].
Furthermore, hypocortisolism causes up-regulation of aqua-
porin-2 water channels, thus increasing water retention [14].
Hypothyroidism is another reported cause of normovolemic
hyponatremia. Here, increased vasopressin secretion may be
induced by the decreased cardiac output, which reduces effec-
tive arterial blood volume [15]. However, the role of hypothyr-
oidism in the pathogenesis of hyponatremia should be
considered minor, if any. A study reported that the distribution
of serum [Na+] in patients with or without hypothyroidism was
virtually the same [16]. Accordingly, it has been calculated that
for each 10 mU/L increase of thyroid-stimulating hormone
(TSH) a 0.14 mEq/L reduction of serum [Na+] is expected.
3. Clinical aspects
Hyponatremia causes water entry into the cells due to the
hypotonic state [8]. Symptoms are mostly related to cell enlar-
gement in the central nervous system and their severity is
dependent on serum [Na+] and particularly on the rate of its
reduction. In fact, if the ECF suddenly becomes hypotonic
relative to the intracellular fluid, water is drawn into the cells
by osmosis, and this can cause cerebral edema. However, in
the following days, an adaptative mechanism occurs: brain
cells extrude osmoles, first potassium and sodium salts and
then organic osmoles, thus establishing a new osmotic equili-
brium across the plasma membrane and reducing the edema
as water moves out of the cells. Thus, very severe symptoms,
such as stupor, coma, convulsions, respiratory arrest are
usually associated with acute (e.g. duration ≤48 h), life-
threatening hyponatremia. Less dramatic symptoms, such as
EXPERT REVIEW OF ENDOCRINOLOGY & METABOLISM 3
headache, irritability, nausea/vomiting, mental slowing, confu-
sion, disorientation are more likely present in chronic hypona-
tremia (e.g. duration >48 h). Accordingly, it has been shown
that the presence of stupor or coma is a strong indicator of
acute hyponatremia (100% of cases), whereas this presenta-
tion rarely occurs in chronic hyponatremia (6% of cases) [17].
Hyponatremic encephalopathy occurs more frequently in
menstruant females and prepubertal individuals of either gen-
der. Hypoxia is a major factor that leads to brain damage in
patients with hyponatremia. Hypoxia alters the homeostasis of
brain ion transport, which contributes to brain adaptation to
increased cell water. Other risk factors for hyponatremic ence-
phaolopathy are the postoperative state, acute water intoxica-
tion, the presence of an underlying central nervous system
disease [18].
In recent years it has become progressively clear that mild,
chronic hyponatremia is not asymptomatic, as traditionally
thought. It has been demonstrated, for instance, that slightly
reduced serum [Na+] is associated with an increased risk of
falls, unsteadiness and attention deficits [19], and bone frac-
tures [20,21]. Furthermore, there is evidence suggesting that
hyponatremia is associated with loss of bone density. This has
been demonstrated for instance in a rat model of SIAD [21].
Data from the Third National Health and Nutrition Examination
Survey (NHANES III) confirmed this finding. In particular, it was
demonstrated that hyponatremia is a significant predictor of
osteoporosis, independent of age, sex, body mass index, phy-
sical activity, serum vitamin D, and diuretic use [22]. A
recently published meta-analysis, we confirmed that hypona-
tremia is associated with a significantly increased risk of falls
(MH-OR = 2.14[1.71; 2.67]) and of fractures, particularly hip
fractures (MH-OR = 2.00[1.43; 2.81]) [23].
In patients, hyponatremia has been associated with an
increased risk of cognitive decline and dementia [24,25], with
more severe neuropsycological abnormalities in schizophrenia,
in which polydipsia-related hyponatremia is present in at least
20% of patients [26–28], and with motor deficits [29,30].
Furthermore, in a male rat model of SIAD, hyponatremia was
associated with the exacerbation of multiple manifestation of
senescence, such as reduction of bone mineral density, hypo-
gonadism, decreased body fat, skeletal muscle sarcopenia, and
cardiomyopathy [31].
Even more surprising is the fact that hyponatremia has
been associated with an increased risk of in-hospital mor-
tality. As an example, a large cohort study, which included
more than 50,000 adult hospitalizations at a University med-
ical center during an 8-year period, demonstrated that even
mild hyponatremia was a risk factor for increased in-hospital
mortality. In particular, it was calculated that the risk of
death was increased by 2.3% for each 1 mEq/L decline of
serum [Na+] [32]. A comprehensive meta-analysis, based on
the data retrieved from 81 studies for a total of 850,222
patients, of whom 17.4% were hyponatremic, confirmed
that hyponatremia was associated with an increased risk of
overall mortality (RR = 2.60[2.31–2.93]). Such a result was
obtained also when patients were grouped according to
different clinical conditions: myocardial infarction (RR =
2.83[2.23–3.58]), heart failure (RR = 2.47[2.09–2.92]), cirrhosis
4 A. PERI
(RR = 3.34[1.91–5.83]), pulmonary infections (RR = 2.49
[1.44–4.30]) [33]. Noteworthy, a mean difference of serum
[Na+] of just 4.8 mEq/L was found in subjects who died
compared to survivors (130.1 ± 5.6 vs. 134.9 ± 5.1 mEq/L).
Conversely, an additional meta-analysis demonstrated that
any improvement of hyponatremia was associated with
a reduced risk of overall mortality (RR = 0.57[0.40–0.81]).
The reduced mortality rate persisted after a follow-up of
12 months (RR = 0.55[0.36–0.84] [34]. The duration of the
trials was relatively short and there were not enough data
to analyze a longer follow-up. In addition, admittedly these
results cannot definitively clarify whether hyponatremia or
the lack of correction of this alteration are the cause of poor
outcomes or are simply markers of severity of associated co-
morbidities. Furthermore, it cannot be excluded that an
improvement of the underlying co-morbidities may both
improve serum [Na+] and mortality.
In view of the demonstrated clinical impact of hyponatre-
mia, it is not surprising that this condition has been asso-
ciated with an increased length of hospital stay and in-
hospital resource utilization and costs [35]. Hospital-acquired
hyponatremia was associated with higher costs of care in
patients with cancer [36], cirrhosis [37], and heart failure
[38]. Accordingly, a meta-analysis covering this topic showed
that, among almost 4 million patients, hyponatremia was
associated with a significantly longer duration of hospitaliza-
tion (OR = 3.30[2.90; 3.71] mean days; p < 0.000), particularly
in elderly male patients. Furthermore, patients with hypona-
tremia had a higher risk of readmission after the first hospi-
talization (OR = 1.32[1.18;1.48]; p < 0.000). Finally,
hyponatremia was associated with US $3000 higher hospital
costs/patient when compared to the cost of normonatremic
subjects [39]. Nevertheless, it has not be proven, so far, that
the correction of hyponatremia reduces the length of hospi-
tal stay and related costs.
4. Differential diagnosis
A correct diagnostic approach is of pivotal importance, in
order to start the appropriate treatment without any delay. It
has to be remembered that blood and urine samples should
be taken at baseline, before treatment is initiated. This is an
essential and apparently obvious point, because the diagnos-
tic work-up cannot omit basal laboratory data, but it is not
rarely ignored by clinicians.
The etiopathogenesis of hyponatremia in any single case
should be investigated based on several parameters, which
include the clinical history of the patient, medications, co-
morbidities, clinical examination. Particular attention should
be dedicated to the evaluation of signs of volume depletion
or excess. The American recommendations for the diagnosis
and management of hyponatremia suggest that ‘…clinical
evaluation should include skin and mucous membranes
assessment, pulse rate, presence or not of orthostatic hypo-
tension’ [40]. However, there are rather frequent cases in
which volume assessment based on clinical judgment may
be difficult. As the European guidelines recall, ‘…the sensitiv-
ity and specificity of clinical assessments of volume status are
low, potentially leading to misclassification early in the
Table 3. Essential diagnostic criteria of SIAD.
● Hyponatremia (serum [Na+] <136 mEq/L)
● Plasma hypo-osmolality (<275 mOsm/Kg)
● Urine osmolality >100 mOsm/Kg
● Clinical normovolemia
● Increased urinary sodium excretion (>40 mEql/L with normal salt and water
intake)
● Absence of other potential causes of euvolaemic hypo-osmolality
● Exclude recent diuretic use, renal disease, hypocortisolism, (hypothyroidism)
SIAD: syndrome of inappropriate antidiuresis.
diagnostic tree’ [41]. Therefore, additional investigations,
such as the evaluation of central venous pressure (CVP), if
possible, may help in clarifying the assessment of volume
status. An estimate of the CVP may be obtained by ultrasound
methods, which include the evaluation of jugular vein dia-
meter and area, estimation of the height of the jugular vein,
measurement of inferior vena cava diameter and collapsibility
index [42]. CVP estimates may be also obtained by determin-
ing the height of the internal jugular venous waveforms rela-
tive to the sternal angle. CVP is considered elevated when the
height of the venous column is >3 cm above the sternal
angle [43].
Laboratory data should include serum and urine electro-
lytes, glycaemia, urea, creatinine, uric acid, serum and urine
osmolality, hematocrit, lipids, and proteins to exclude the
possible presence of pseudohyponatremia, serum cortisol. It
is the opinion of the author that the evaluation of TSH and fT4
may be optional, in view of the very low possibility that
hyponatremia is caused by hypothyroidism.
Altogether, these data should provide enough information
for a correct diagnosis. With regard to SIAD, there are essential
diagnostic criteria that should be fulfilled (Table 3).
There are controversial situations, in which it may be diffi-
cult to obtain evidence for a conclusive diagnosis. One of
these situations may be represented by the determination of
the differential diagnosis between SIAD and CSW syndrome.
CSW usually arises within a few days after a neurosurgical
procedure or a stroke or subaracnoid hemorrhage. Some fea-
tures of CSW are virtually identical to those of SIAD. In both
cases, hypotonic hyponatremia, inappropriate urinary osmol-
ality, and inappropriately high urinary sodium excretion are
present. A crucial difference, yet not always easily recognized
as discussed above, is represented by the fact that whereas in
SIAD ECF is normal in CSW it is reduced [40]. A short-term
infusion of isotonic saline solution, which is expected to cause
[Na+] increase in CSW but not in SIAD, may be of help in
establishing the correct diagnosis.
5. Treatment
The correction of hyponatremia should consider, when possi-
ble, the treatment of the underlying disease, which might
correct by itself the electrolyte disorder. For instance, thiazide
diuretics and SIAD-inducing drugs should be discontinued if
possible and hormone replacement therapy should be started
in patients with hypocortisolism.
It should be also kept in mind that the therapeutic strategy
should be guided by the presence and severity of symptoms
and not just by the reduction of serum [Na+].

In severely symptomatic hyponatremia prompt infusion of
3% NaCl saline solution should be started, independent of ECF.
In such a scenario, the primary objective is to obtain a rapid
increase of serum [Na+]. Saline solution should be infused as
boluses of 100/150 ml intravenously over 10–20 min and
repeated twice or until a target of 5 mEq/L increase in serum
[Na+] is obtained [40,41]. Hypertonic saline may be adminis-
tered also as a continuous infusion. The formula proposed by
Adrogué and Madias can be used to calculate the rate of
infusion [8]. An initial 4–6 mEq/L increase is considered suffi-
cient to reduce the risk of brain herniation and neurological
damage from cerebral ischemia and it can be a safe cut-off for
first day’s increase. An easy to remember ‘rule of sixes’ has been
proposed to indicate that ‘six a day makes sense for safety; so
six in six hours for severe symptoms and stop’ [40]. In true acute
hyponatremia the rate of correction does not represent
a critical issue. However, if there is uncertainty whether hypo-
natremia is acute or chronic, it is judicious to follow the sug-
gested limits for correction. In fact, in chronic hyponatremia the
risk of osmotic demyelination syndrome (ODS) is increased,
because effective osmoles have been eliminated previously by
the cells, as the consequence of the hypotonic state. This risk is
particularly high in some instances, such as in patients with
a [Na+] <105 mEq/L, with concomitant hypokalemia, with
a story of alcohol abuse, cirrhosis, malnutrition [40,44].
Therefore, whereas in the absence of risk factors for ODS
a limit of 10–12 mEq/L in 24 h or of 18 mEql/L in 48 h appears
to be appropriate, in high-risk patients a correction >8 mEq/L in
24 h may justify [Na+] relowering to a goal of 4–6 mEq/L
increase [40]. This objective can be obtained by desmopressin
administration (2–4 mcg every 8 h parenterally), or by replacing
water orally or as 5% dextrose in water intravenously.
In the absence of severe symptoms related to hyponatremia,
or when they are no longer present, the therapeutic strategy
differs between patients with reduced ECF or normal/increased
ECF. In the first case, isotonic saline (0.9% NaCl) infusion is
recommended, whereas in the other conditions fluid restriction
represents the first-line therapy [31,32]. In SIAD, fluid restriction
can be associated with a high sodium-diet (10 g/day orally),
unless contraindicated. However, the efficacy of fluid restriction
is questionable for various reasons. In fact, it usually corrects
hyponatremia by only 1–2 mEq/L/day, even when severe
(<500 ml/day) [45]. Furthermore, it has to be considered that
fluid restriction may be poorly tolerated because of increased
thirst, with subsequent poor compliance, especially if extended
for a prolonged time. Finally, it has to be remembered that fluid
restriction may not work at all. This occurs when the patient is
not able to excrete free water. Free water clearance by the
kidney can be predicted using the urine/serum electrolyte
ratio [46]. If the U/ S ratio is ≥1, the free water clearance is
negative, and no excretion of free water is expected.
Urea is considered a possible alternative to fluid restriction.
This option is based on the principle that the intake of osmotic
solutes can enhance the clearance of water. Disadvantages of
oral urea intake are poor palatability and the development of
azotemia at high doses. In addition, some cases of overly rapid
correction have been reported [40,41].
Loop diuretics have proven effective in the treatment of
SIAD, because they increase free water excretion rates. In
EXPERT REVIEW OF ENDOCRINOLOGY & METABOLISM 5
patients considered at risk for the development of pulmonary
edema during treatment with hypertonic saline, treatment
with loop diuretics can help in avoiding excessive volume
expansion.
The use of demeclocycline or lithium, which corrects hypo-
natremia by inducing diabetes insipidus, is considered subop-
timal for several reasons, including variable efficacy, slow
responses, and toxic effects [47].
6. Treatment 2.0: vaptans
The development of nonpeptide vasopressin receptor antago-
nists, the so-called vaptans, initiated almost a decade ago
a new era in the treatment of hyponatremia. Vaptans block
vasopressin binding to V2 receptors expressed in renal collect-
ing duct cells, thus inhibiting the synthesis and transport of
aquaporin-2 water channel proteins into the apical membrane
of these cells. Free water reabsorption is prevented and urine
volume is increased (Figure 1) [48]. Therefore, vaptans ulti-
mately cause serum [Na+] increase by inducing aquaresis.
The first successful use of a nonpeptide V2 receptor antagonist
in humans was reported in 1993 [49].
Currently, only one selective V2 receptor antagonist, namely
tolvaptan, is available on the market in Europe and in the U.S. for
the treatment of hyponatremia. In the U.S., tolvaptan (oral
tablets) was approved by the Food and Drug Administration
(FDA) on May 29 2009, for the ‘treatment of clinically significant
hypervolemic and euvolemic hyponatremia', whereas in Europe
it was approved by the European Medicines Agency (EMA) on
August 9 2009, with the indication ‘treatment of adult patients
with hyponatremia secondary to SIADH'. At variance with tolvap-
tan, conivaptan has also affinity for the V1a receptor and it has
been approved by the FDA on December 29 2005, for i.v.
administration in ‘hospitalized patients with euvolemic and
hypervolemic hyponatremia’ [50,51]. Other V2 receptor antago-
nists, such as satavaptan and lixivaptan, have been shown to
increase serum [Na+] in patients with euvolemic or hypervolemic
hyponatremia, but they have never been marketed. In Japan,
mozavaptan is available since October 2006 for the treatment of
hyponatremia caused by paraneoplastic SIAD [51,52].
The efficacy and the safety of tolvaptan in patients with
euvolemic or hypervolemic hyponatremia was assessed in
two-multicenter, randomized, double-blind, placebo-con-
trolled trials, i.e. the Study of Ascending Levels of Sodium in
Hyponatremia 1 and 2 (SALT-1 and SALT-2) [53]. A subsequent
study (SALTWATER trial), which was an open-label extension of
the SALT-1 and SALT-2 trials, demonstrated the long-term
efficacy of tolvaptan in maintaining normal serum [Na+] after
initial correction [54].
According to the U.S. recommendations, the likely role of
vaptans in SIAD is in correcting ‘mild to moderate hypona-
tremia and asymptomatic severe hyponatremia’ [40].
Conversely, European guidelines do not recommend, yet
with a low quality of evidence (e.g. ‘the true effects might
be substantially different from the estimates of the effects’),
the use of tolvaptan in moderate hyponatremia [41]. The
authors’ concerns are related to the risk of overly rapid
correction of hyponatremia with vaptans and to the risk of
hepatotoxicity. However, it has to be said that the risk of
6 A. PERI
Figure 1. Mechanism of action of vaptans. AC = adenylate cyclase, cAMP = cyclic adenosine monophosphate, ATP = adenosine triphosphate, PKA = protein kinase
A, AQP-2 = aquaporin-2, P = phosphate.
overly rapid correction may be minimal, provided that tol-
vaptan is not used together with other active treatments for
hyponatremia, that serum [Na+] is frequently monitored
(every 4–6 h during initial dose titration) and that the use
of lower doses than those initially recommended is consid-
ered. With regard to the risk of hepatotoxicity, significant
increases (greater than 3 x Upper Limit of Normal) of serum
alanine aminotransferase and bilirubin were initially
reported in patients treated with tolvaptan for a different
indication, e.g. autosomal dominant polycystic kidney dis-
ease, and using much higher doses [55]. The elevations
gradually improved after discontinuation of tolvaptan. In
a subsequent post-authorization safety study of tolvaptan
in hyponatremia secondary to SIAD, cases of hepatic disor-
ders and elevated transaminases were observed. Therefore,
liver function tests must be readily performed in patients
taking tolvaptan who report symptoms suggestive of liver
injury (such as fatigue, anorexia, right upper abdominal
discomfort, dark urine, or jaundice). If liver injury is sus-
pected, tolvaptan must be discontinued, appropriate treat-
ment has to be instituted, and investigations have to be
performed to determine the probable cause. Tolvaptan can
be re-initiated only if it is demonstrated that the cause for
the observed liver injury is not related to treatment with
this drug. With that in mind, the opinion of the author,
shared by other European colleagues, is that tolvaptan can
be safely used for the correction of mild to moderate hypo-
natremia secondary to SIAD [56]. As a matter of fact, tol-
vaptan has been widely used in clinical practice also across
Europe since its commercialization.
The usual starting dose is 15 mg/day. However, in clinical
practice it has become evident that lower doses (e.g.
7.5 mg/day) may be effective to warrant a desired serum
[Na+] increase. For instance, a recent study performed at
a University Hospital in Northern Italy demonstrated that
both 7.5 mg and 15 mg were able to significantly increase
serum [Na+] after 24 h. However, an optimal correction,
defined as a ≤8 mEq/L increase in 24 h, was observed more
frequently in patients who had received 7.5 mg (45.4% vs.
25%). In addition, an excessive correction (>12 mEq/L in
24 h) was observed in 41.7% of cases in patients treated
with 15 mg of tolvaptan, yet in none of the patients treated
with 7.5 mg [57]. The daily dose can be increased if [Na+] rise
is less than 5 mEq/L in 24 h, up to a maximal daily dose of
60 mg. Treatment has to be initiated in a hospital setting,
because of the need of close monitoring during the titration
phase.
When administering vaptans, it has to be taken into
account that they are metabolized by cytochrome CYP3A4
and therefore co-administration of CYP3A4 inhibitors (i.e. keto-
conazole, macrolide antibiotics, diltiazem) or inducers (i.e.
rifampicin, barbiturates) may increase or reduce, respectively,
the effect on serum [Na+] increase [58]. Grapefruit, a potent
inhibitor of CYP3A4, may increase the bioavailability of vaptans
and therefore its ingestion should be avoided in patients who
are treated with these drugs [59]. Tolvaptan use has been
associated with increased serum digoxin concentrations and
therefore patients receiving both drugs should be evaluated
for excessive digoxin effects [60].
Although the efficacy of tolvaptan vs. other strategies for
the correction of hyponatremia has yet to be ascertained in
depth, it has been shown that in patients receiving this treat-
ment for hyponatremia serum [Na+] normalization occurred
more frequently than in patients receiving other treatments
[61]. These data were obtained from the Hyponatremia
Registry, designed in order to understand current practice in
a number of sites in the United States and in the European
Union. However, a direct head-to-head comparison of effec-
tiveness of different strategies would be needed, in order to
confirm this observation.
7. Conclusions
Hyponatremia is an electrolyte disorder, which can be often
encountered in clinical practice. It can cause a wide variety of
clinically relevant effects. A careful diagnostic work-up is

essential in order to promptly initiate the most appropriate
treatment, aiming to correct hyponatremia and to avoid clin-
ical sequelae. In such a scenario, tolvaptan has proven to be
an effective and safe pharmacological option.
8. Expert commentary
Hyponatremia is an electrolyte alteration that is frequently
encountered in clinical practice. It is a biochemical sign, not
a disease. Therefore, a low serum [Na+] has to be appropriately
interpreted, in order to find the most likely etiology. This is of
paramount importance, because a correct treatment is strictly
dependent on a correct diagnosis.
It is well known that severe, acute hyponatremia may be
a life-threatening situation. However, less severely sympto-
matic hyponatremia, especially if chronic, may be not con-
sidered clinically relevant in clinical practice. One of the
most important achievement of the research in this field
in recent years is the demonstration that mild, chronic
hyponatremia is not asymptomatic, as traditionally thought.
In particular, it is has been demonstrated that slightly
reduced serum [Na+] is associated with an increased risk
of falls, unsteadiness and attention deficits, and bone frac-
tures. There is evidence suggesting also that hyponatremia
is associated with loss of bone density and that it can be
considered a predictor of osteoporosis.
Very interestingly, hyponatremia has been demonstrated to
be a negative prognostic factor in many different pathological
conditions. In the past few years it became evident that hypo-
natremia reduces the overall survival also in cancer patients,
thus strongly suggesting that also in this subset of patients
reduced serum [Na+] should not be neglected.
Basic research studies brilliantly showed that the effects of
hyponatremia at the cellular level are not limited to the entry
of water into the cells, as a consequence of the hypotonic
state in the extracellular compartment. Studies in which cells
were grown in the presence of reduced [Na+], yet in the
absence of a hypotonic state, demonstrated that additional
mechanisms, mainly related to oxidative stress that is elicited
by reduced [Na+], are able to induce cell damage. This is a new
area of research that should be further addressed in the next
future.
Overall, this new body of evidence increased the awareness
on hyponatremia among clinicians. As a matter of fact,
a number of studies addressing the correct management of
hyponatremia have been published in the last decade, and in
particular it is worth mentioning the European guidelines and
the U.S. recommendations, which extensively covered this
topic.
The increasing literature on hyponatremia is due, at least in
part, to the development of a new class of drugs, the vaso-
pressin receptor antagonists, namely vaptans, which are the
first example of drugs specifically targeted to correct serum
[Na+]. These drugs have proven to be effective and safe in
correcting hyponatremia and have been licensed for the treat-
ment of hyponatremia secondary to SIAD (U.S. and Europe)
and to hypervolemic hyponatremia (U.S.). Undoubtedly, the
introduction of these new molecules has been clinically rele-
vant, because vaptans offer a valid alternative to the
EXPERT REVIEW OF ENDOCRINOLOGY & METABOLISM 7
traditional therapeutic options. Not many studies aiming to
compare the efficacy of vaptans vs. traditional treatments for
the correction of hyponatremia have been designed, so far.
This is an area that should be more extensively covered in the
upcoming years, in order to make available to clinicians clear
indications on the most appropriate strategies in specific
circumstances.
Finally, besides the improved awareness of clinicians about
hyponatremia and its consequences, specific educational pro-
grams covering this topic, starting from medical schools, are of
pivotal importance and will certainly lead to better outcomes
for patients and for our health systems.
9. Five-year view
The literature addressing hyponatremia has grown in recent
years. Basic and clinical research provided a number of data,
which support the current interest for this topic. The next few
years are expected to clarify some aspects that have not been
completely elucidated yet (i.e. possible additional molecular
mechanisms through which hyponatremia leads to cell
damage, more effective strategies for assessing volume status,
most appropriate approaches in specific subsets of patients)
and mainly to provide additional studies that compare the
efficacy of vaptans vs. other therapeutic strategies.
Key issues
● Hyponatremia is the most frequent electrolyte disorder in
hospitalized patients and its prevalence increases with
aging.
● It may be of clinical relevance even when mild and chronic
and it has been associated with an increased risk of falls,
demineralization and bone fractures.
● Thus, hyponatremia represents a clinical, social and eco-
nomic burden.
● A thorough evaluation of the possible underlying causes is
of pivotal importance. This includes patients’ history, pre-
sent morbidities, medications, physical evaluation, bio-
chemical and imaging assessment.
● More causes of hyponatremia may be present in one
patient.
● Treatment must be guided by the etiology of hyponatremia
and by the severity of symptoms.
● Vaptans represent an effective and safe option for the
treatment of hyponatremia secondary to SIAD.
● Close monitoring should be performed during active treat-
ment for hyponatremia.
● Overly rapid correction should be avoided, especially in
chronic hyponatremia and in patients at high risk of ODS.
Acknowledgments
The author wishes to thank all the collaborators, who contributed to
basic research as well as to clinical research studies, and in particular
Susanna Benvenuti, Paola Luciani, Cristiana Deledda, Benedetta Fibbi,
Corinna Giuliani, Giada Marroncini, Gabriele Parenti, Giovanni Corona,
8 A. PERI
Dario Norello, Mario Maggi from the University of Florence, Italy, and
Joseph G Verbalis from Georgetown University (Washington DC, U.S.A.).
Funding
This paper was not funded.
Declaration of interest
A Peri is on the Otsuka Pharmaceutical advisory board for tolvaptan and
has received honoraria from Otsuka Pharmaceutical for speaking at
symposia.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
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