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BRIEF REVIEW www.jasn.


Diagnosis and Treatment of Hyponatremia: Compilation

of the Guidelines
Ewout J. Hoorn and Robert Zietse
Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The

Hyponatremia is a common water balance disorder that often poses a diagnostic or approach to hyponatremia, two sets of
therapeutic challenge. Therefore, guidelines were developed by professional orga- guidelines have been developed, one by
nizations, one from within the United States (2013) and one from within Europe professional organizations from within
(2014). This review discusses the diagnosis and treatment of hyponatremia, com- the United States (“United States guide-
paring the two guidelines and highlighting recent developments. Diagnostically, the line”) and one from within Europe (“Eu-
initial step is to differentiate hypotonic from nonhypotonic hyponatremia. Hypo- ropean guideline,” in which the authors
tonic hyponatremia is further differentiated on the basis of urine osmolality, urine of this review participated).6–9 The pro-
sodium level, and volume status. Recently identified parameters, including fractional fessional organizations involved in the
uric acid excretion and plasma copeptin concentration, may further improve the United States guideline were Tufts Uni-
diagnostic approach. The treatment for hyponatremia is chosen on the basis of versity Office of Continuing Education
duration and symptoms. For acute or severely symptomatic hyponatremia, both and In 2 MedEd; the initiative was
guidelines adopted the approach of giving a bolus of hypertonic saline. Although also supported by an unrestricted edu-
fluid restriction remains the first-line treatment for most forms of chronic hypona- cational grant from Otsuka America
tremia, therapy to increase renal free water excretion is often necessary. Vasopres- Pharmaceutical.9 The professional orga-
sin receptor antagonists, urea, and loop diuretics serve this purpose, but received nizations involved in the European
different recommendations in the two guidelines. Such discrepancies may relate to guideline were the European Renal As-
different interpretations of the limited evidence or differences in guideline meth- sociation–European Dialysis and Trans-
odology. Nevertheless, the development of guidelines has been important in ad- plantation Association, the European
vancing this evolving field. Society of Endocrinology, and the Euro-
pean Society of Intensive Care Medi-
J Am Soc Nephrol 28: 1340–1349, 2017. doi:
cine. 6–8 The United States guideline
refrained from using a quality-of-evidence
scoring system due to the limited evi-
dence. Instead, the guideline was on
Hyponatremia (serum sodium [S Na ] studies, because “the” patient with hypo- the basis of expert panel recommenda-
,136 mmol/L) is a common water bal- natremia does not exist. Instead, the un- tions, which relied on a critical evalua-
ance disorder that often poses a diagnos- derlying disease that is complicated by tion of relevant literature by the panel
tic or therapeutic challenge.1 This may hyponatremia usually characterizes pa- members. The European guideline
explain why management of hyponatre- tients with hyponatremia.4,5 The most did perform systematic reviews of the
mia is still suboptimal, as also recently common causes of hyponatremia are available evidence using the Grading of
illustrated by a hyponatremia registry.2 the syndrome of inappropriate antidiu-
Hyponatremia is not a disease but resis (SIAD), diuretic use, polydipsia,
rather a pathophysiologic process indi- adrenal insufficiency, hypovolemia,
Published online ahead of print. Publication date
cating disturbed water homeostasis. 3 heart failure, and liver cirrhosis (the lat- available at
Therefore, hyponatremia should be fur- ter two are often collectively referred to
ther classified in order to provide direc- as “hypervolemic hyponatremia”). Al- Correspondence: Dr. Ewout J. Hoorn, Erasmus
Medical Center, Internal Medicine – Nephrology,
tions for diagnosis and treatment (Table though recent years have seen several Room D-438, PO Box 2040, 3000 CA, Rotterdam,
1). These classifications illustrate that developments in the diagnosis and treat- The Netherlands. Email:
hyponatremia is a very heterogeneous ment of hyponatremia, the evidence base Copyright © 2017 by the American Society of
disorder. This has complicated clinical is still limited. To capture the current Nephrology

1340 ISSN : 1046-6673/2805-1340 J Am Soc Nephrol 28: 1340–1349, 2017 BRIEF REVIEW

Table 1. Classifications of hyponatremia

Limitations of
Classification Criteria
Clinical Utility
Moderate (125–129 mmol/L) Absolute SNa concentration Symptoms do not always
versus severe/profounda correlate with degree of hyponatremia
(,125 mmol/L)
Acute versus chronic Time of development (cutoff 48 h) Time of development not always known
Symptomatic versus asymptomatic Presence of symptoms Many symptoms aspecific; chronic
hyponatremia may be symptomatic
Hypotonic, isotonic, or hypertonic Measured serum osmolality Ineffective osmoles (e.g., urea, ethanol)
are also measured
Hypovolemic, euvolemic, hypervolemic Clinical assessment of Clinical assessment of volume status
volume status has low sensitivity and specificity
SNa,125 mmol/L is defined as “severe hyponatremia” by the United States guideline, and as “profound hyponatremia” by the European guideline.7,9

Recommendations Assessment Develop- or protein.16 The United States guide- less able to reabsorb sodium.7,22 In ad-
ment and Evaluation scoring system. line subsequently divided hypotonic dition, advanced CKD usually impairs
Both guideline committees were interdis- hyponatremia into hypovolemic, euvo- water excretion, complicating the eval-
ciplinary, and the European guideline was lemic, and hypervolemic hyponatre- uation of the role of vasopressin in water
endorsed by the European societies of ne- mia. 9 Although this represents the balance.23 These considerations prompted
phrology, endocrinology, and intensive most traditional and commonly used the European guideline committee
care.6–8 This brief review will compare approach to hypotonic hyponatremia, to propose an algorithm that prioritizes
the two guidelines to discuss the diagnosis it deserves scrutiny. Hypovolemic and UOsm and UNa over volume status (Fig-
and treatment of hyponatremia, while euvolemic hyponatremia are notori- ure 1). It also incorporates the limita-
also highlighting recent developments. ously difficult to differentiate on the ba- tions of UNa. In addition, it recommends
Because of the breadth of both guidelines, sis of physical examination,17 whereas early identification of acute or symp-
this review will focus on the salient fea- hypervolemic hyponatremia is usually tomatic hyponatremia to identify pa-
tures. To place both guidelines in perspec- clinically obvious (presence of edema tients in whom immediate treatment is
tive we will integrate in our discussion the or ascites). Two studies that analyzed indicated. Two additional diagnostic
pertinent comments published after their the diagnostic performance of the clin- tests for hyponatremia merit discussion,
release.10–13 ical assessment of volume status in pa- including a trial of volume expansion
tients with hyponatremia reported low and the fractional uric acid excretion
sensitivity (50%–80%) and specificity (FE UA ). A trial of volume expansion
DIFFERENTIAL DIAGNOSIS OF (30%–50%).18,19 Previously, we showed with isotonic saline can be used to diag-
HYPONATREMIA that clinicians often misclassify hypona- nose hypovolemic hyponatremia. 18
tremia when using algorithms that start Although a rise in SNa in response to iso-
Although the United States guideline did with clinical assessment of volume sta- tonic saline would be consistent with
not present a diagnostic algorithm, the tus.20 Similarly, physicians in training hypovolemic hyponatremia, another
classifications of hyponatremia on the had a better diagnostic performance possibility would be that the stimulus
basis of tonicity and volume status than senior physicians when using an for vasopressin release in a patient with
were discussed.9 The initial differentia- algorithm in which urine osmolality SIAD abated. Such stimuli are often
tion in hypotonic and nonhypotonic (UOsm) and urine sodium (UNa) con- nonspecific and transient, including
hyponatremia is important, because centration are prioritized over assess- pain or nausea. 14,24 In addition, S Na
management is different.14 Nonhypo- ment of volume status.21 Because the has been shown to improve upon saline
tonic hyponatremia is usually caused by kidneys will respond to hypovolemia infusion in patients with SIAD with
hyperglycemia, but may also be caused or a low effective arterial blood volume U Osm ,500 mOsm/kg. 25 Conversely,
by the administration of mannitol or with sodium retention, UNa,30 mmol/L isotonic saline may sometimes worsen
hypertonic radiocontrast.7 In these set- can be used to identify both hypovole- hyponatremia, a phenomenon called
tings, management is usually conserva- mic and hypervolemic hyponatremia. “desalination.” 26 In response to the
tive, although a decrease in extracellular Three caveats, however, should be em- United States guideline, Gross raised
tonicity may occur during treatment.15 phasized: (1) UNa will also be low in pa- the issue of how to deal with mixed
Nonhypotonic hyponatremia can also be tients consuming a low sodium diet forms of hyponatremia, for example
caused by pseudohyponatremia, a labora- (rare in the western populations), (2) SIAD and hypovolemia.10 Indeed, we
tory artifact that may occur with high con- the (recent) use of diuretics will increase previously showed that patients often
centrations of triglycerides, cholesterol, UNa, and (3) patients with CKD may be have two to three possible causes for

J Am Soc Nephrol 28: 1340–1349, 2017 Hyponatremia 1341


cerebral salt wasting, but normalizes in

SIAD only during treatment.32 Of note,
however, is that even in neurosurgical
patients with hyponatremia, cerebral
salt wasting is rare and has remained
an enigmatic and not widely accepted
clinical entity.33,34


Arginine vasopressin (the antidiuretic

hormone) plays a central role in the path-
ogenesis of hyponatremia. In one study,
nonosmotic secretion of vasopressin was
detected in 97% of patients with hypo-
natremia.35 Because hypotonicity nor-
mally suppresses vasopressin, the
reasons for nonosmotic vasopressin
release should be considered.36 “Appro-
priate” vasopressin release is due to hy-
povolemia or low effective arterial blood
volume, both of which activate barore-
ceptors to cause vasopressin release.
Although one might expect thiazide-
induced hyponatremia to be due to
hypovolemia secondary to saliuresis,
this is not the case.37 Instead, the path-
ogenesis appears to be a combination of
polydipsia and impaired urea-mediated
water excretion.37,38 “Inappropriate” va-
sopressin release is usually caused by the
effect of an underlying disease or drugs
on central osmoreceptors; alternatively,
vasopressin can be produced ectopically
(e.g., in small cell lung cancer or olfac-
tory neuroblastoma).3,39,40 In addition,
hypocortisolism increases vasopressin
Figure 1. Diagnostic algorithm for hyponatremia. Based on the European guideline.7 ECF, release, because corticotropin-releasing
extracellular fluid. hormone normally suppresses vasopres-
sin.41 Although rare, secondary and even
hyponatremia (although it was unclear of interest because it formally tested the primary adrenal insufficiency may
if and to which extent each cause con- diagnostic performance of several pa- mimic SIAD and can be missed without
tributed).27 In addition to a trial of vol- rameters using receiver operating appropriate testing.42–44 Although the
ume repletion, an alternative approach curves. More recently, a larger study kidney usually limits the degree of hypo-
to mixed pathogenesis would be to com- confirmed that FE UA .12% had the natremia in SIAD (“vasopressin es-
bine hypertonic saline with desmopres- best sensitivity and specificity for cape”45), it can also cause antidiuresis
sin.28,29 Although the literature on this SIAD.31 In absolute terms, however, the independent of vasopressin.46,47 A spe-
approach is limited, it offers a rational performance of FEUA was still moderate, cific example is gain-of-function muta-
approach to prevent a rapid rise in SNa and UNa.30 mmol/L and FEUrea.55% tions of the vasopressin type 2 receptor
that may occur once hypovolemia has had better sensitivity and specificity for causing hereditary hyponatremia
been corrected. Fenske et al. found that SIAD, respectively. We frequently ana- (“nephrogenic SIAD”). 48 Despite the
FEUA.12% had the highest sensitivity lyze FEUA in patients with hyponatremia, pathogenetic role of vasopressin in hy-
and specificity to diagnose SIAD with but mainly use it as supporting informa- ponatremia, plasma vasopressin is rarely
or without diuretic use.30 This study is tion. FEUA is high in both SIAD and measured in clinical practice. This has

1342 Journal of the American Society of Nephrology J Am Soc Nephrol 28: 1340–1349, 2017 BRIEF REVIEW

low effective arterial blood volume.53,54

Because hypovolemic hyponatremia is
characterized by high plasma copeptin
and low UNa , the plasma copeptin to
UNa ratio may be especially useful to dif-
ferentiate it from SIAD. Although the
study by Fenske et al. did indeed dem-
onstrate this,52 the specificity of copep-
tin/UNa for SIAD in a more recent and
larger study was less high.31 An interest-
ing approach was the use of plasma
copeptin to differentiate SIAD sub-
types.55 Using hypertonic saline, SIAD
subtypes were defined on the basis of
their relationship between serum os-
molality and plasma copeptin (Figure
2). As expected, low plasma copeptin
levels are diagnostic for hyponatremia
due to polydipsia. 31,52 Arguably, the
need for a novel diagnostic marker for
this cause of hyponatremia is limited, as
it is usually obvious from the clinical
setting and the low UOsm. In addition
to plasma copeptin, two additional cir-
Figure 2. Copeptin-based classification of five subtypes of the syndrome of in- culating markers were recently evalu-
appropriate antidiuresis (SIAD). The shaded gray area and the black dashed line show ated in patients with hyponatremia,
the normal physiologic relationship between serum osmolality and plasma copeptin (as including apelin and midregional
surrogate marker for vasopressin). In SIAD type B this relationship is intact, but the proatrial natriuretic peptide (MR-
osmotic threshold for vasopressin release has decreased. In SIAD types A and C va- proANP). 56,57 Physiologically, apelin
sopressin release is no longer regulated by serum osmolality. In SIAD type D plasma and vasopressin are regulated in oppo-
copeptin levels are undetectable. In SIAD type E the normal relationship between serum site directions by volemic and osmotic
osmolality and copeptin has reversed. This phenomenon has been coined “barostat stimuli.56 Apelin not only inhibits vaso-
reset,” as it may indicate increased sensitivity of baroreceptors to increased vaso- pressin release centrally, but also coun-
pressin release. Percentages indicate how often each subtype was present in one study
teracts the antidiuretic effect in the
of 50 patients. Data on the basis of Fenske et al.55 and figure modified from Fenske
kidney.58 However, in patients with hy-
et al.116 with permission.
ponatremia due to SIAD or heart failure,
plasma apelin was insufficiently sup-
two reasons. First, UOsm accurately re- pressin, but also neurophysin and copep- pressed, possibly contributing to anti-
flects vasopressin activity, and, therefore, tin (also called C-terminal proarginine diuresis in these settings.56 Similar to
this more readily available parameter can vasopressin). 51 Because copeptin is plasma copeptin, MR-proANP levels
be used instead. Second, vasopressin is more stable, it can be measured more were higher in patients with hypovole-
difficult to measure reliably in nonexpert easily. Copeptin can therefore be used mic or hypervolemic hyponatremia
laboratories, because it binds to platelets, as a surrogate marker for vasopressin. than in patients with SIAD (although
it is unstable in isolated plasma, and com- Although both guidelines only briefly these levels were still higher than in
mercial assays are not very sensitive for discuss copeptin, emerging data healthy subjects).57 High MR-proANP
low concentrations.49 These limitations, justify a brief discussion on the diagnos- in hypovolemic hyponatremia is coun-
however, have largely been resolved tic utility of this novel marker. Fenske terintuitive, but may be explained by
by the development of an assay for et al. found that plasma copeptin levels lower GFR secondary to volume deple-
copeptin.50 were higher in patients with hypo- or tion.59 Although plasma copeptin, ape-
hypervolemic hyponatremia than in pa- lin, and MR-proANP increase insight
tients with SIAD.52 This was demon- into the pathophysiology of hyponatre-
COPEPTIN strated previously35 and likely reflects mia, the true diagnostic potential
an “osmoreceptor gain,” the phenome- of these parameters remains to be de-
Enzymatic cleavage of the vasopressin non in which angiotensin II amplifies termined. In addition, one single pa-
prohormone produces not only vaso- vasopressin release in the context of a rameter is unlikely to achieve optimal

J Am Soc Nephrol 28: 1340–1349, 2017 Hyponatremia 1343


Table 2. Comparison of the United States and European guidelines

Subject United States Guideline European Guideline
Acute or symptomatic Severe symptoms: Bolus 3% NaCl Severe symptoms: Bolus 3%
hyponatremia (100 ml over 10 min 3 3 as needed) NaCl (150 ml over 20 min 2–3
times as needed)
Moderate symptoms: Continuous Moderate symptoms: Bolus 3%
infusion 3% NaCl (0.5–2 ml/kg per h) NaCl (150 ml 3% over 20 min once)
Chronic hyponatremia
SIAD Fluid restriction (first line) Fluid restriction (first line)
Demeclocycline, urea, or vaptan (second line) Urea or loop diuretics + oral
NaCl (second line)
Do not recommend or recommend
against vaptana
Recommend against lithium
or demeclocycline
Hypovolemic hyponatremia Isotonic saline Isotonic saline or balanced
crystalloid solution
Hypervolemic hyponatremia Fluid restriction Fluid restriction
Vaptansb Recommend against vaptan
Correction rates Minimum: 4–8 mmol/L per d, No minimum
4–6 mmol/L per d (high risk of ODS)
Limits: 10–12 mmol/L per d, Limit: 10 mmol/L per d
8 mmol/L per d (high risk of ODS)
Management of overcorrection Baseline SNa$120 mmol/L: Start once limit is exceeded
probably unnecessary
Baseline SNa,120 mmol/L: Consult an expert to discuss
start relowering with electrolyte-free infusion containing electrolyte-free
water or desmopressin after water (10 ml/kg) with or without 2 mg
correction exceeds 6–8 mmol/L per d desmopressin iv
“Do not recommend” when SNa,130 mmol/L, “recommend against” when SNa,125 mmol/L.
In liver cirrhosis, restrict to patients where potential benefit outweighs risk of worsened liver function.9

discriminatory power. A relevant ques- Therefore, for each patient with profound have gradually become more conserva-
tion is whether a combination of diag- hyponatremia (SNa,125 mmol/L), it is tive (with recommended correction rates
nostic parameters might improve useful to consider whether cerebral as high as 20 mmol/L per day around
management. edema or ODS should be suspected.62,63 1990).65 A subject directly related to cor-
This automatically leads to the often rection rates is overcorrection. Both
heated debate on optimal correction guidelines recommend frequent moni-
GENERAL APPROACH TO rates in hyponatremia.64 Both guidelines toring of SNa during the active correction
TREATMENT reached consensus that the limit (not the phase (i.e., all treatments except fluid re-
goal) should be around 10 mmol/L per striction). An aspect that was overlooked
A cutoff of 48 hours is usually used to day for both acute and chronic hypona- by both guidelines is that the measure-
differentiate acute from chronic hypo- tremia (Table 2).7,9 Of note, the United ment of SNa may not offer the precision
natremia (Table 1). 7 This classification States guideline recommends a lower required for this monitoring. Tormey
is useful because acute and chronic hy- limit of 8 mmol/L per day if there is a et al. calculated the so-called “reference
ponatremia may be complicated by high risk of ODS (e.g., in patients with change value” for SNa using a common
different neurologic conditions. Acute hypokalemia, alcoholism, malnutrition, analyzer and demonstrated that only
hy ponatremia can cause cerebral or liver disease).9 In response to these changes in SNa $4 mmol/L were certain
edema when cells have insufficient recommendations, Adrogué and Madias to be real.12 If overcorrection is detected,
time to adapt to the hypotonic extra- proposed even more conservative limits both guidelines used different criteria for
cellular environment. In chronic hy- of 6–8 mmol/L per day regardless of du- when to relower SNa: when initial SNa was
ponatremia brain cell adaptation has ration or symptoms.11 Although we agree ,120 mmol/L (United States guideline)
occurred and, in this setting, an acute that this is likely to be both sufficient and or when limits are exceeded (European
increase in extracellular tonicity in- safe, the data to support this are still lim- guideline, Table 2). Both guidelines rec-
duced by treatment can cause osmotic ited. It is of interest to see how over the ommend hypotonic fluids or desmopres-
demyelination syndrome (ODS). 60,61 years the recommended correction rates sin for relowering SNa. A combination of

1344 Journal of the American Society of Nephrology J Am Soc Nephrol 28: 1340–1349, 2017 BRIEF REVIEW

hypotonic fluids and desmopressin may mild-to-moderate symptoms (Table TREATMENT OF CHRONIC
be required for treating overcorrection 2).9 The European guideline based its HYPONATREMIA
in hypovolemic hyponatremia, because recommendations primarily on the
a persistent water diuresis may ensue presence and severity of symptoms Except for hypovolemic hyponatremia,
after correction of hypovolemia.66 Ex- rather than on duration.7 Both guide- the treatment of chronic hyponatremia
perimental data indicate improved lines recommend hypertonic saline relies on reducing free water intake
outcomes with reinduction of hypona- (typically 3% NaCl) for acute or symp- and/or increasing renal free water excre-
tremia after rapid overcorrection. 67 tomatic hyponatremia. 7,9 Hypertonic tion (Table 2). Fluid restriction (,1 L/d)
Another point that merits discussion saline is an effective and potentially is often the cornerstone of the therapy
is the consistent association of hypona- life-saving treatment for cerebral edema for chronic hyponatremia.24 The urine
tremia with worse outcomes.63,68 This due to hyponatremia, as the high extra- to serum electrolyte ratio ([UNa + urine
may indicate that hyponatremia has cellular sodium concentration immedi- potassium concentration]/S Na ) indi-
adverse effects beyond the classic neu- ately removes water from the intracellular cates if the patient is in an antidiuretic
rologic symptoms.69,70 However, in the space. In patients with hypervolemic hy- or aquaretic phase, and can also help
absence of randomized intervention ponatremia, hypertonic saline may be estimate the degree of fluid restriction
studies indicating that correction of combined with loop diuretics.9 The re- required to increase S Na . 3,11,24,82 For
hyponatremia improves outcomes, it re- quired volume of hypertonic saline to patients with a ratio.1 (indicating con-
mains unclear whether these associations reach a predefined increase in SNa can centrated urine), ,500 ml fluid/d is rec-
are causal.5 be estimated using the Adrogué–Madias ommended, which is difficult to adhere
or Barsoum–Levine formulae.77,78 Al- to. Winzeler et al. recently showed that
though predictions with these formulae in patients with SIAD fluid restriction is
TREATMENT OF ACUTE are fairly accurate,66 a switch toward effective in 59% of patients.83 Predictors
HYPONATREMIA giving hypertonic saline as fixed bolus of nonresponse were a UNa$130 mmol/L
has occurred in recent years.79 No stud- and UOsm$500 mOsm/kg.83 This im-
Several settings predispose to acute hy- ies have systematically tested this ap- plies that in patients with chronic hypo-
ponatremia, especially if combined with proach, but there are a number of natremia pharmacologic therapy is
increased free water intake.71 Among appealing aspects. First, especially in pa- often required to increase renal free wa-
others, these include the postoperative tients with cerebral edema, it is desirable ter excretion. This can be achieved by
period, exercise, and the use of 3,4- to achieve a rapid partial correction in treatment with loop diuretics, urea, vaso-
methylenedioxymethamphetamine SNa. Second, a fixed bolus omits the need pressin receptor antagonists (“vaptans”),
(“Ecstasy”), haloperidol, thiazide di- for calculations in a patient with an or demeclocycline. The two guidelines
uretics, desmopressin, oxytocin, or in- acute problem, limiting potential calcu- diverge in their recommendations re-
travenous cyclophosphamide. 71–74 A lation errors. Third, bolus therapy limits garding pharmacologic therapy for
specific situation is the use of irrigants the risk of overcorrection, which does SIAD and hypervolemic hyponatremia
(glycine, sorbitol, mannitol) during occur commonly with a continuous in- (Table 2). This was the case especially
transurethral or hysteroscopic proce- fusion of hypertonic saline.80 On the for vaptans, which will therefore be dis-
dures. Although absorption of the irri- basis of these considerations, both cussed in more detail below.
gants glycine and sorbitol may cause guidelines recommend bolus therapy,
hypotonic hyponatremia, the degree of albeit with slightly different specifica- Vaptans
hypotonicity and therefore the risk tions (Table 2).7,9 Recently, Ayus and Vaptans block vasopressin type 2 recep-
of cerebral edema depends on the type colleagues reported their experience tors in collecting duct principal cells and
of irrigant and the time course in osmo- using a different protocol (500 ml 3% therefore induce aquaresis (for compre-
lar shifts.75,76 In contrast, mannitol cau- NaCl over 6 hours) in 64 patients with hensive review, see Berl,84 Hoorn and
ses hypertonic hyponatremia without a hyponatremic encephalopathy (SNa,130 Zietse, 85 Lehrich et al., 86 Rozen-Zvi
risk for cerebral edema. In daily practice, mmol/L and neurologic symptoms).81 On et al.,87 and Greenberg and Verbalis88).
the distinction between acute and average, this protocol increased SNa with Several vaptans were developed, includ-
chronic hyponatremia is difficult, be- 12 and 14 mmol/L in the first 24–48 ing tolvaptan, satavaptan, lixivaptan,
cause the time in which hyponatremia hours, and improved symptoms without and conivaptan (which also targets vaso-
developed is usually unknown. The evidence of ODS.81 However, the severity pressin type 1a receptors). On the basis
United States and European guidelines of hyponatremia (SNa frequently ,110 of their mechanism of action, vaptans
approached this challenge differently. mmol/L) and the duration of symptoms are a logical and targeted therapy for hy-
The United States guideline adhered to suggest that some of these patients had ponatremic patients with excess vasopres-
acute versus chronic hyponatremia, but chronic hyponatremia. If so, these correc- sin. Indeed, several large clinical trials
did subdivide acute hyponatremia on tion rates would exceed currently recom- have shown that vaptans are clearly effec-
the basis of the presence of severe or mended limits (Table 2). tive in increasing SNa in patients with

J Am Soc Nephrol 28: 1340–1349, 2017 Hyponatremia 1345


hyponatremia due to SIAD, heart failure, Urea evaluated all available international guide-
or liver cirrhosis.89,90 Both guidelines Both guidelines suggest an interesting al- lines on hyponatremia and analyzed how
agree that there is no place for vaptans ternative to vaptans for chronic hypona- well they met the Appraisal of Guidelines
in patients with acute or severely symp- tremia due to SIAD, namely urea.102 Urea for Research and Evaluation criteria.114
tomatic hyponatremia, for which hyper- induces an osmotic diuresis, thereby in- They identified considerable variation in
tonic saline is the treatment of choice.7,9 creasing renal free water excretion. methodologic rigor in the development of
Still, it has been difficult to position vap- Decaux and colleagues pioneered the use guidelines, potentially explaining incon-
tans in the therapeutic arsenal of chronic of urea in the 1980s for SIAD, but also for sistencies in recommendations.114 Be-
hyponatremia. 11,84,91,92 The United other forms of hyponatremia.103–109 More cause hyponatremia is a heterogeneous
States guideline lists vaptans as one of recently, in 12 patients with SIAD, Soupart disorder rather than a clear-cut disease,
the pharmacologic options, if fluid re- et al. compared the treatment with not all patients can be covered by guide-
striction has failed (Table 2).9 The Eu- satavaptan to urea (both treatment periods lines. That said, which evidence does the
ropean guideline did not recommend 1 year).110 Interestingly, both therapies field need for the coming years? First, it
vaptans in moderate hyponatremia. 7 had a similar efficacy and side-effect pro- would be useful to evaluate if a combina-
The reason to do so was the absence of file. Although urea does not prevent over- tion of the traditional and newer diagnos-
evidence for improved hard outcomes correction, it may reduce the risk of the tic tests would improve not only diagnosis
with correction of SNa. Meanwhile, one associated brain damage. In a rat model but also outcomes. Second, the approach
meta-analysis has suggested improved of experimental SIAD, Gankam Kenge of giving a bolus of hypertonic saline
survival with correction of hyponatre- et al. compared the neurologic outcomes should be studied to address the optimal
mia,93 although bias is difficult to exclude after overcorrection (approximately volume, whether this should be on the
because no randomized controlled tri- 30 mmol/L per day) with hypertonic sa- basis of (ideal) body weight, and how of-
als are available. Furthermore, there is line, lixivaptan, or urea.111 Quite strikingly, ten it should be repeated to reach the de-
evidence for potential harm of vaptans, neurologic scores and survival were better sired increase in SNa.115 Third, the role of
including overcorrection, and liver tox- in the animals treated with urea. Histologic vaptans in the treatment of chronic hypo-
icity.7,87,94–96 Because ODS has mainly analysis showed that, in comparison to the natremia remains a logical focus. For ex-
been reported after overcorrection of two other treatments, urea reduced demy- ample, it would be important to analyze
profound hyponatremia, the European elination, microglial activation, and whether the copeptin-based subtypes of
guideline recommended against vap- changes in the blood-brain barrier, and in- SIAD respond differently to vaptans (Fig-
tans in this setting.7 Recently, Tzoulis creased astrocyte viability.111 Although ure 2). Finally, studies analyzing the effect
et al. reported “real-life experience” one should be careful to extrapolate these of a vaptan in comparison with another
with tolvaptan in 61 patients with resis- findings to humans, this may explain why active treatment (rather than placebo) on
tant hyponatremia due to SIAD.97 The patients with ESRD and hyponatremia do patient-relevant outcomes (rather than
average rise in SNa after 24 hours was not develop ODS after treatment with he- SNa) are warranted.
9.063.9 mmol/L. Excessive correction modialysis.112 One specific disadvantage
of hyponatremia (.12 mmol/L per of urea used to be its palatability. This
day) was observed in 23% of patients problem has been solved by developing a
(all with profound hyponatremia), al- formulation in which urea is combined ACKNOWLEDGMENTS
though none of them developed signs with sodium bicarbonate, citric acid, and
of ODS.97 ODS was reported in one pa- sucrose (see European guideline for pre- E.J.H. is supported by the Dutch Kidney
tient with heart failure in whom 15 mg scription7) and by the development of a Foundation (KSP-14OK19).
tolvaptan caused SNa to increase from commercially available urea powder drink
126 to 142 mmol/L in the first day and mix (Ure-Na by Nephcentric).
to further increase to 187 mmol/L in DISCLOSURES
subsequent days.94 On the other hand, None.
improvement of symptoms has been SUMMARY AND CONCLUSIONS
shown with the use of vaptans. This in-
cludes improvements in some neurocog- Our impression is that the development of
nitive symptoms,98 performance status in the United States and European guidelines 1. Adrogué HJ, Madias NE: The challenge of hy-
cancer patients,99 dyspnea in patients with has helped to standardize and improve the ponatremia. J Am Soc Nephrol 23: 1140–1148,
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with liver cirrhosis.101 Therefore, in our guidelines are more often in agreement 2. Greenberg A, Verbalis JG, Amin AN, Burst
VR, Chiodo JA 3rd , Chiong JR, Dasta JF,
view, an unresolved question with regard than in disagreement. The discrepancies
Friend KE, Hauptman PJ, Peri A, Sigal SH:
to the use of vaptans remains, of whether are likely related to the interpretation of Current treatment practice and outcomes.
symptomatic improvement outweighs the the limited evidence and the methodology Report of the hyponatremia registry. Kidney
risk of overcorrection, even if ODS is rare. used to draft the guidelines.113 Nagler et al. Int 88: 167–177, 2015

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