JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 65, NO.

5, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER INC. http://dx.doi.org/10.1016/j.jacc.2014.12.010

THE PRESENT AND FUTURE

STATE-OF-THE-ART REVIEW

Hyponatremia in Acute Decompensated

Heart Failure
Depletion Versus Dilution

Frederik H. Verbrugge, MD,*y Paul Steels, MD,z Lars Grieten, PHD, MSC,*z Petra Nijst, MD,*y W.H. Wilson Tang, MD,x
Wilfried Mullens, MD, PHD*z

ABSTRACT

Hyponatremia frequently poses a therapeutic challenge in acute decompensated heart failure (ADHF). Treating physicians
should differentiate between depletional versus dilutional hyponatremia. The former is caused by diuretic agents, which
enhance sodium excretion, often with concomitant potassium/magnesium losses. This can be treated with isotonic saline,
whereas potassium/magnesium administration may be helpful if plasma concentrations are low. In contrast, as impaired
water excretion, rather than sodium deficiency, is the culprit in dilutional hyponatremia, isotonic saline administration
may further depress the serum sodium concentration. Because free water excretion is achieved by continuous sodium
reabsorption in distal nephron segments with low water permeability, diuretic agents that impair this mechanism (e.g.,
thiazide-type diuretic agents and mineralocorticoid receptor antagonists) should be avoided, and proximally acting
agents (e.g., acetazolamide and loop diuretic agents) are preferred. Vasopressin antagonists, which promote low water
permeability in the collecting ducts and, hence, free water excretion, remain under investigation for dilutional hypo-
natremia in ADHF. (J Am Coll Cardiol 2015;65:480–92) © 2015 by the American College of Cardiology Foundation.

H yponatremia, defined as a serum sodium

(Na þ) concentration <135 mEq/l, is the
most common electrolyte disorder in hos-
pitalized patients (1). Both admission and hospital-
acquired hyponatremia are associated
increased risk for adverse outcomes, including pro-
longed hospital stay, need for discharge to a short-
or long-term care facility, and all-cause mortality
(2). In a subanalysis from the OPTIMIZE-HF (Orga-
nized Program to Initiate Lifesaving Treatment in
Hospitalized Patients with Heart Failure) registry,
including 47,647 patients with acute decompensated
heart failure (ADHF), hyponatremia was present in
w20% upon admission (3). In addition, the incidence
of hospital-acquired hyponatremia during deconges-
tive treatment for ADHF is probably w15% to 25%
(4,5). Hyponatremia frequently poses an important
therapeutic challenge in ADHF because simple
with an administration of the depleted ion (as with other de-
ficiencies) cannot be easily performed, and there is
an obvious concern for harmful fluid overload. More-
over, the pathophysiology of hyponatremia in ADHF
is often dilutional, rather than depletional (6,7).
Importantly, ubiquitous use of powerful Na þ-wasting
diuretic agents in this context hampers differentia-
tion between the 2 conditions, each of which requires
a totally different approach. This review, therefore,
aims to provide, on the basis of the currently

From the *Department of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgium; yDoctoral School for Medicine and Life Sciences,
Hasselt University, Diepenbeek, Belgium; zBiomedical Research Institute, Faculty of Medicine and Life Sciences, Hasselt Uni-
versity, Diepenbeek, Belgium; and the xDepartment of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic,
Cleveland, Ohio. Dr. Verbrugge is supported by a PhD fellowship from the Research Foundation–Flanders. Drs. Verbrugge,
Grieten, Nijst, and Mullens are researchers for the Limburg Clinical Research Program UHasselt-ZOL-Jessa, supported by the
foundation Limburg Sterk Merk, Hasselt University, Ziekenhuis Oost-Limburg, and Jessa Hospital. Drs. Steels and Tang have
reported that they have no relationships relevant to the contents of this paper to disclose.
Listen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.
You can also listen to this issue’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.

Manuscript received July 30, 2014; revised manuscript received November 30, 2014, accepted December 2, 2014.
JACC VOL. 65, NO. 5, 2015 Verbrugge et al. 481
FEBRUARY 10, 2015:480–92 Hyponatremia in Decompensated Heart Failure

available evidence, a pathophysiology-based assess- interstitium—hence antidiuresis—through in- ABBREVIATIONS

ment and management strategy for the important creased hepatic urea production, improved AND ACRONYMS

clinical challenge of hyponatremia in ADHF. medullary urea reabsorption in the collecting

ADHF = acute decompensated
ducts, and reduced blood flow through the heart failure
PATHOPHYSIOLOGY OF vasa recta (Figure 1) (12,13). The vasa recta are
AVP = arginine vasopressin
HYPONATREMIA IN ADHF straight capillaries in the renal medulla with a
ENaC = epithelial sodium
hairpin loop. They receive a lower proportion channel
Table 1 provides a summary of the pathophysiology of of blood flow compared with the renal cortex, GFR = glomerular filtration
hyponatremia in ADHF. especially during antidiuresis. This is impor- rate

DILUTIONAL HYPONATREMIA. It is generally assumed tant, as high blood flow through the vasa recta MRA = mineralocorticoid
that hyponatremia in ADHF is more often a problem washes out the tonicity gradient from the receptor antagonist

of impaired water excretion than Naþ depletion (6,7). renal cortex toward the medulla, which is Naþ = sodium

Two key events driving increased water retention needed to concentrate the urine. Finally, TAL = thick ascending

and progression of hyponatremia in ADHF are in- another effect of V1a receptor stimulation is limb of Henle’s loop

creased nonosmotic release of arginine vasopressin
(AVP) and insufficient tubular flow through diluting
(distal) segments of the nephron. In many ways, this
is the opposite of the situation in diabetes insipidus,
where deficient AVP production and/or function
in the presence of normal tubular flow results in
very diluted urine, exaggerated water losses, and,
ultimately, in hypernatremia, unless compensation
occurs through increased water intake.
A V P a n d r e g u l a t i o n o f p l a s m a o s m o l a l i t y . AVP, a
cyclic octapeptide (1,099 D) with a 3-amino acid tail,
is a key regulator of water homeostasis. AVP is syn-
thesized in large-diameter neurons in the supraoptic
and paraventricular nuclei of the anterior hypothal-
amus. After axonal transport into nerve terminals
within the posterior lobe of the pituitary, AVP is
released into the bloodstream in response to plasma
hypertonicity (8). In healthy, normally hydrated
persons, circulating AVP levels are very low
(w1 pg/ml) because of its rapid degradation and
excretion by the liver and kidneys (t 1/2 ¼ 15 to 20 min)
(9). Consequently, hepatic dysfunction and renal
insufficiency may contribute to increased plasma
levels of AVP in ADHF. AVP exerts its water-retaining
effects primarily through stimulation of high-affinity
V2 receptors in the collecting ducts of the nephron
(Figure 1) (9). V2 stimulation increases both the syn-
thesis and availability of aquaporin-2 channels on the
promotion of prostaglandin synthesis in the collecting
ducts. This counteracts V 2 effects on aquaporin-2, thus
stimulating water excretion (14). This latter effect may
explain why some heart failure patients demonstrate a
normal response to water loading, with production of
adequately diluted urine, despite having elevated
plasma AVP levels (15).
Nonosmotic arginine vasopressin release in
h e a r t f a i l u r e . Several studies have demonstrated
that AVP levels are generally elevated in heart failure
(16–18). Moreover, aquaporin-2 expression was
markedly up-regulated in a rat model of congestive
heart failure (19), which would be expected to in-
crease water permeability and reabsorption in the
collecting ducts of the nephron. It is tempting to
speculate that both events are causally related and
promoting excessive free water reabsorption, leading
to hyponatremia in ADHF. Certainly, baroreceptor
activity, sympathetic overdrive, and angiotensin II,
all stimulated by decreased effective circulatory
T A B L E 1 Pathophysiology of Hyponatremia in
Acute Decompensated Heart Failure
Mechanism of Action
Dilutional hyponatremia
Increased sensitivity of osmotic AVP Baroreceptor activation/angiotensin II
release / Lower osmo-checkpoint*
Increased nonosmotic AVP release Baroreceptor activation/angiotensin II

luminal side of these collecting ducts, which other- Impaired AVP degradation Liver and/or kidney dysfunction
Increased thirst Baroreceptor activation/angiotensin II
wise have low water permeability (10). The hypertonic
Decreased distal nephron flow Impaired glomerular filtration/Increased
environment of the renal interstitium subsequently proximal tubular reabsorption
provides a strong impetus for water reabsorption, Depletional hyponatremia
resulting in decreased water excretion and, conse- Low sodium intake Salt-restricted diet

quently, less diuresis. Importantly, this system is very Exaggerated nonurinary sodium losses Diarrhea, ascites
Exaggerated natriuresis Diuretics, osmotic diuresis
sensitive to small changes in plasma AVP levels, which
Sodium shift toward the intracellular Potassium and/or magnesium
are difficult to detect, even by modern assays (11). At compartment deficiency
higher concentrations, the low-affinity V1a receptor,
which is expressed in the liver, collection ducts, *This is the level of plasma osmolality that is pursued by the homeostatic mechanisms of the
body.
and vasa recta of the nephron, is stimulated (Figure 1). AVP ¼ arginine vasopressin.
This further enhances hypertonicity in the renal
482 Verbrugge et al.
Hyponatremia in Decompensated Heart Failure
F I G U R E 1 Effects of AVP in the Nephron
Distal tubules
Collecting ducts
Macula densa INTERLOBAR
ARTERY
LOW WATER PERMEABILITY
V Insufficient tubular flow through diluting segments
A H2O
S
TAL A
H2O
H2O
AP2 EXPRESSION
BLOOD FLOW V2
V1a: VASOCONSTRICTION H2O V1a
R
E ing antidiuresis versus water diuresis (25). Thus,
C UREA REABSORPTION
Urea T INCREASED HEPATIC UREA
UT-A1 transporter A V1a: PRODUCTION
Aquaporine-2 (AP2) INCREASED UT-A1 TRANSPORTER
Stimulated
Inhibited
OSMOTIC GRADIENT
V2-receptor effects: The primary effect of AVP on water homeostasis is mediated through
stimulation of high-affinity V2 receptors, already with small increases in plasma levels (9).
V2-receptor stimulation in collecting duct cells results in increased production of AP2
channels and facilitates recruitment of these channels on the luminal membrane, which
otherwise has low water permeability (10). Subsequently, water reabsorption is promoted
as the renal interstitium is hypertonic and the basolateral membrane of collecting duct
cells is highly permeable to water. Hypertonicity in the renal interstitium is accomplished
through solute reabsorption in parts of the nephron that have relatively low water
permeability, that is, sodium and chloride transport in the TAL and urea reabsorption in the
medullary part of the collecting ducts through UT-A1 transporters.
V1a-receptor effects: At high plasma levels, AVP further stimulates hypertonicity in the
renal interstitium, and hence water reabsorption, through activation of the low-affinity V1a
receptor. First, this promotes both hepatic urea production and UT-A1 transport in the
medullary part of the collecting ducts, resulting in higher urea concentrations and a
stronger osmotic gradient in the renal interstitium. Furthermore, V1a receptor stimulation
causes vasoconstriction in the vasa recta, preventing wash-out of solutes from the renal
medulla (12,13). On the other hand, V1a receptor stimulation in collecting duct cells also
promotes prostaglandin synthesis. Prostaglandins counteract the effects of V2 by impeding
AP2 recruitment in these collecting duct cells (14). This somewhat preserves the diluting
capacity of the distal nephron, even when AVP levels are high because of neurohumoral
activation and nonosmotic AVP release. AP2 ¼ aquaporin-2; AVP ¼ arginine vasopressin;
TAL ¼ thick ascending limb of Henle’s loop.
volume in ADHF, fuel nonosmotic AVP release, as well
as thirst and thus free water intake (20). Importantly,
they also increase the sensitivity of osmotic AVP
release (Figure 2A). Indeed, compared with healthy
volunteers, ADHF patients show a more pronounced
increase in plasma AVP levels with osmotic loading
(21). In contrast to this osmotic AVP release, which
increases linearly and with very small changes in
serum osmolality, nonosmotic AVP release is expo-
nential (Figure 2B). Thus, isotonic plasma volume
reductions of 5% to 10% will have little effect on AVP
secretion, whereas reductions of 20% to 30%,
JACC VOL. 65, NO. 5, 2015
FEBRUARY 10, 2015:480–92
resulting in baroreceptor activation and angiotensin
II stimulation, may cause plasma levels many times
higher than necessary to produce maximal anti-
diuresis (50 to 100 pg/ml) (22). Importantly, at these
high levels, AVP has potent V 1a -mediated vasocon-
strictor effects that may contribute to hemodynamic
deterioration in ADHF (23).
of the distal nephron. Healthy kidneys are able
to dilute urine to an osmolality as low as 30 to 60
mOsm/l, w5- to 10-fold lower than serum osmolality
(24). However, micropuncture studies have demon-
strated that tubular fluid osmolality is quite similar
(w150 mOsm/l) at the level of the macula densa dur-
urine dilution depends heavily on the tubular func-
tion of more distal parts of the nephron (i.e., distal
convoluted tubules and collecting ducts). Free water
excretion is achieved by these segments through
continued solute reabsorption, primarily through the
thiazide-sensitive Naþ/chloride cotransporter and
aldosterone-sensitive epithelial sodium channels
(ENaCs), in the presence of low water permeability
(24,26). Importantly, less sodium is reabsorbed by
ENaCs in conditions of low tubular flow, irrespective
of aldosterone levels (27). Consequently, if more so-
dium is retained in the tubular lumen, free water
excretion is restricted. The ability of the kidneys to
excrete free water is, therefore, directly dependent
on: 1) the amount of tubular fluid offered to the distal
nephron; and 2) the relatively low water permeability
of this segment, which can only be overcome
by insertion of aquaporin-2 channels through AVP
stimulation. For instance, a healthy person with a
glomerular filtration rate (GFR) of 180 l/day
(125 ml/min), of which 10% reaches the distal convo-
luted tubules and with total AVP suppression, would
be able to drink w18 l (10% of 180 l) over the course of
a day without developing hyponatremia (Figure 3A).
Yet, with the GFR lowered to 43.2 l/day (30 ml/min),
and only 5% distal tubular flow because of increased
proximal reabsorption in ADHF, maximal water
intake without hyponatremia development would
be decreased tremendously to 2.16 l/day (5%
of 43.2 l/day) (28,29). The latter is even an over-
estimate, as it presumes that water permeability in
the distal nephron is as low as with total AVP sup-
pression, which is clearly not the case in ADHF
(Figure 3B). An intriguing study by Bell et al. (30)
further supports the concept of decreased distal
nephron flow in AHDF. In this study, free water
excretion was increased in ADHF patients with
hyponatremia after infusion of 5% mannitol, an os-
motic diuretic that enhances tubular flow through the
JACC VOL. 65, NO. 5, 2015
FEBRUARY 10, 2015:480–92
F I G U R E 2 Determinants of AVP Plasma Levels
A Osmotic AVP Release
Angiotensin II
baroreceptor activity
Plasma AVP (pg/ml)
12
Normal
8 patients adhere scrupulously to the salt-restricted
4 group called these diets into question, demonstrating
260 270 280 290 300 310
Plasma Osmolality (mOsm/l)
B Osmotic Versus Non-osmotic AVP release
50
Plasma AVP (pg/ml)
Osmotic Non-osmotic
40
30
20
10
0 try) receiving them (41). Moreover, 70% continue to
5 10 15 20
% Plasma osmolality increase
% Iso-osmotic plasma volume decrease
(A) Osmotic AVP release: AVP is near total suppression in normal
circumstances, but increases linearly with plasma osmolality (9).
Neurohumoral activation through angiotensin II and baroreceptor
activity increases the amount of AVP release for any given plasma
osmolality (20). In addition, it moves the set-point of total AVP
suppression to a lower plasma osmolality, hence promoting hy-
potonicity. (B) Osmotic versus nonosmotic AVP release: osmotic
AVP release is very sensitive and increases linearly, already with
very small changes in plasma osmolality (blue curve) (9). Non-
osmotic AVP release makes little contribution to overall AVP
plasma levels until a 10% to 15% decrease in isotonic plasma
volume, after which AVP release increases markedly, resulting in
plasma levels many times higher than needed to achieve maximal
antidiuresis (red curve) (22). Abbreviations as in Figure 1.
nephron. Mannitol exerts its diuretic effect through
solvent drag and water retention in the tubular
lumen, thereby also increasing distal delivery. Similar
findings have been demonstrated in patients with
cirrhosis, where the effective circulatory volume and
renal perfusion are also impaired (31). However, it
remains possible that correction of hyponatremia
with mannitol in ADHF and cirrhosis is partly due to
increased intravascular volume after infusion, sup-
pressing baroreceptor tonus and, hence, nonosmotic
AVP release (32).
DEPLETIONAL HYPONATREMIA. Because increased
Naþ avidity characterizes heart failure from the very
Verbrugge et al. 483
Hyponatremia in Decompensated Heart Failure
beginning and is exacerbated by unrestrained
neurohumoral up-regulation, Na þ depletion is rela-
tively rare in ADHF not treated with diuretic agents
(33,34). Still, osmotic diuresis because of hypergly-
cemia in the case of severe uncontrolled diabetes,
gastrointestinal losses, and third-space losses may all
contribute to a negative Na þ balance, especially if
diets recommended by the guidelines (35–37). One
that heart failure patients adhering to such diets
experienced increased hospitalizations and a higher
mortality rate (38–40). However, it should be noted
that these patients also received a high dose of
diuretic agents (125 to 500 mg furosemide equivalents
twice daily), increasing the risk of a negative Na þ
balance. Indeed, the combination of very low dietary
sodium intake and exaggerated losses might lead
to progressive depletion of whole-body sodium stores.
L o o p d i u r e t i c - i n d u c e d h y p o n a t r e m i a . The use
of powerful Na þ-wasting loop diuretic agents is
nearly ubiquitous in ADHF, with 88% of patients in
ADHERE (Acute Decompensated Heart Failure Regis-
receive daily maintenance therapy with loop diuretic
agents, although many are probably not persistently
volume-overloaded. Loop diuretic agents block the
Na þ/potassium/chloride cotransporter in the thick
ascending limb of Henle’s loop (TAL). Na þ and chlo-
ride transport in the TAL, which has a relatively low
water permeability, makes a crucial contribution to
the hypertonicity of the renal interstitium, in addition
to the other important factor, medullary urea trans-
port in the collecting ducts (42,43). This hypertonicity,
washed out by blood flow through the vasa recta with
inhibition of TAL transport by loop diuretic agents, is
the major driver of water reabsorption in the distal
nephron. Because of this interference of loop diuretic
agents with the renal capacity to concentrate urine,
less free water is reabsorbed, resulting in production
of hypotonic urine and, therefore, relative protection
against hyponatremia (Figure 4A) (44). However, in
conditions of profound volume depletion with strong
neurohumoral activation and compromised renal
blood flow, loop diuretic agents will fail to elicit
meaningful water diuresis. Eventually, GFR and distal
nephron flow will become depressed in the presence
of strongly up-regulated AVP, creating the necessary
environment for hyponatremia development (29).
O t h e r d i u r e t i c a g e n t s a n d h y p o n a t r e m i a . Miner-
alocorticoid receptor antagonists (MRAs) are a
cornerstone in the treatment of heart failure with
reduced ejection fraction and are promising in
selected patients with preserved ejection fraction
484 Verbrugge et al. JACC VOL. 65, NO. 5, 2015

Hyponatremia in Decompensated Heart Failure FEBRUARY 10, 2015:480–92

F I G U R E 3 Maximal Free Water Excretion in Healthy Subjects Versus Patients With Heart Failure and an Impaired GFR

A Healthy person
MAXIMAL WATER DIURESIS

Glomerulus Distal Tubules

GFR = 125 ml/min Macula Densa
(low water permeability)
= 180 l/day 18 l/day
285 - 295 mOsm/l 150 mOsm/l

300 mOsm/l
O Collecting ducts
S (low water permeability)
M
O
V T
A
S I AVP suppressed:
Proximal Tubules
65% reabsorption A C LOW WATER PERMEABILITY
=117 l/day CONTINUED SOLUTE
285 - 295 mOsm/l REABSORPTION
G
R R
TAL E A
25% reabsorption C D
= 45 l/day T I
A E
N
500 mOsm/l T
HIGH BLOOD FLOW WASHOUT LOW GRADIENT

MAXIMAL
FREE WATER EXCRETION
~ 18l/day

B Heart failure patient

Urine: 30-60 mOsm/l

MAXIMAL WATER DIURESIS

Glomerulus Macula Densa Distal Tubules

GFR = 30 ml/min 2.16 l/day (low water permeability)
= 43.2 l/day 150 mOsm/l
285 - 295 mOsm/l

300 mOsm/l
O
Collecting ducts
S (low water permeability)
M
O
V T
A I
Proximal Tubules
70% reabsorption S C AVP not suppressed:
HIGH WATER PERMEABILITY
=30.24 l/day A STRONG OSMOTIC GRADIENT
285 - 295 mOsm/l
G
R CONTINUED WATER
TAL
R A REABSORPTION
25% reabsorption E D
= 10.8 l/day C I
T E
A N
700 mOsm/l T
VASOCONSTRICTION
NO WASHOUT HIGH GRADIENT
LOW BLOOD FLOW

MAXIMAL
FREE WATER EXCRETION
<1 l/day

Urine: 100-150 mOsm/l

(A) Through glomerular filtration, a healthy person forms 180 l of tubular fluid each day. As the proximal tubules, thin descending limb, and
ascending limb of Henle’s loop all have high water permeability, reabsorption in these nephron segments is isotonic, and tonicity of the tubular
fluid remains at 285 to 295 mOsm/l, equal to plasma. In contrast, the TAL has low water permeability. Thus, solutes in general and sodium/
chloride in particular are reabsorbed without water, contributing to the hypertonicity of the renal interstitium. Consequently, osmolality is
relatively stable (w150 mOsm/l) in the tubular lumen at the level of the macula densa, at which point 90% of reabsorption has occurred, with
10%, or 18 l, remaining on a daily basis (25). In the case of total AVP suppression, the distal nephron has very low water permeability, while
sodium and chloride are continuously reabsorbed; therefore, urine can be diluted up to 30 to 60 mOsm/l. Consequently, almost 18 l of free water
excretion can be achieved, which is the maximum a person can drink without developing plasma hypotonicity and hyponatremia. (B) Maximal free
water excretion in a patient with heart failure and a GFR of 30 ml/min is considerably lower. In this case, 43.2 l of tubular fluid is formed each day.
As proximal tubular reabsorption increases in heart failure, only 5% or 2.16 l of tubular fluid remains at the level of the macula densa, again with
an osmolality of w150 mOsm/l (25). As AVP is typically increased in heart failure and the minimal medullar tonicity is greater because of poor
flow through the vasa recta, the osmotic gradient for water reabsorption is increased in the presence of a more leaky distal nephron. Thus, water
is continuously reabsorbed, limiting maximal free water excretion to <1 l. This realistic example illustrates how difficult it can be for a patient to
prevent hyponatremia progression with fluid restriction only. GFR ¼ glomerular filtration rate; other abbreviations as in Figure 1.
JACC VOL. 65, NO. 5, 2015 Verbrugge et al. 485
FEBRUARY 10, 2015:480–92 Hyponatremia in Decompensated Heart Failure

F I G U R E 4 Effects of Diuretics on the Kidney’s Concentrating and Diluting Capacity

A Effect of loop Diuretics

MAXIMAL MAXIMAL WITH
on the Concentrating Capacity of the Kidneys ANTIDIURESIS LOOP DIURETICS

O O
300 mOsm/l
S S 300 mOsm/l
M M
O O
T T
I I
C C
LOOP DIURETICS

G G
R R
DISTAL CONVOLUTED TUBES
A A
& COLLECTING DUCTS D D
Na/Cl Co-transporter
CONTINUED SODIUM REABSORPTION
WATER REABSORPTION
I I
Na/K/2CI Co-transporter
Impaired osmotic gradient
E E
ENaC
N N
T T
1200 mOsm/l 800 mOsm/l

B Effect of THIAZIDE-TYPE Diuretics and MRA MAXIMAL MAXIMAL WITH

THIAZIDE-TYPE
on the Concentrating Capacity of the Kidneys ANTIDIURESIS
DIURETICS

O O
300 mOsm/l S S 300 mOsm/l

M M
THIAZIDE-TYPE
O O
DIURETICS T T
I I
C C

G G
R R
DISTAL CONVOLUTED TUBES
A A
& COLLECTING DUCTS
D D
Na/Cl Co-transporter
IMPAIRED SODIUM REABSORPTION
Thiazide-type diuretics & MRA I I
E
UNCHANGED WATER REABSORPTION
Na/K/2CI Co-transporter
E
ENaC
N N
MRA T T
1200 mOsm/l 1200 mOsm/l

(A) Loop diuretic agents block the sodium/chloride/potassium cotransporter in the TAL, interfering with the generation of hypertonicity in the
renal interstitium and decreasing the osmotic gradient that promotes water reabsorption. Loop diuretic agents have no effect on sodium or
chloride transport in the distal nephron, which has low water permeability, and they therefore do not interfere with the kidneys’ capacity to
produce hypotonic urine. (B) Thiazide-type diuretic agents block the sodium/chloride symporter, whereas MRAs inhibit ENaCs in the distal
nephron. As both make a negligible contribution to the hypertonicity achieved in the renal interstitium, thiazide-type diuretic agents and MRAs
do not interfere with the water reabsorption gradient. However, as sodium and chloride reabsorption in the relatively water-impermeable distal
nephron is the mechanism of urinary dilution, this process is impaired, resulting in a higher urinary tonicity and, hence, lower free water
excretion compared with loop diuretic agents. ENaC ¼ epithelial sodium channel; MRA ¼ mineralocorticoid receptor antagonists; other
abbreviations as in Figure 1.
486 Verbrugge et al.
Hyponatremia in Decompensated Heart Failure
(45,46). Together with thiazide-type diuretic agents,
often recommended as first-line therapy in case of
loop diuretic resistance, they interfere with sodium
reabsorption by ENaCs and Naþ/chloride cotrans-
porters, respectively, in the distal convoluted tubules
and collecting ducts (Figure 4B) (47). Thus, they
have a direct effect on the diluting tubular segments
of the kidneys and may cause hyponatremia, even
without pronounced hypovolemia, as they generate
less hypotonic urine (47–49). From a pathophysio-
logical perspective, it is, therefore, prudent to
avoid their use in any patient with hyponatremia—at
least temporarily, until serum sodium levels are
corrected—and to prefer a proximally working
diuretic (e.g., acetazolamide) in such cases with vol-
ume overload and diuretic resistance (29).
P o t a s s i u m a n d m a g n e s i u m d e p l e t i o n . Both loop-
and thiazide-type diuretic agents are a major cause of
potassium and magnesium wasting in ADHF. This may
have important implications, such as a higher risk of
arrhythmic death (50). In addition, potassium deple-
tion shifts Na þ towards the intracellular compartment
to preserve cellular volume homeostasis, which may
contribute to development of hyponatremia (51).
Indeed, intracellular Na þ concentrations are higher in
muscle cells of ADHF patients with hypokalemia (52).
Furthermore, magnesium is critical for functioning of
the Naþ/potassium ATPase that pumps Na þ out of
cells; thus, hypomagnesemia may also exacerbate
þ
extracellular Na depletion.
INITIAL APPROACH TO HYPONATREMIA IN
DECOMPENSATED HEART FAILURE
The Central Illustration presents a stepwise diagnostic
and therapeutic approach to hyponatremia in de-
compensated heart failure.
CONFIRM PLASMA HYPOTONICITY. In patients with
hyponatremia, the first step is generally to assess
whether plasma hypotonicity is present by measuring
the plasma osmolality (reference value: 285 to
295 mOsm/l). This may not be necessary when
hyponatremia is mild (serum Na þ concentration
130 to 134 mEq), asymptomatic, and easily corrected
by empiric treatment. Elevated triglyceride or
cholesterol levels, immunoglobulins, and monoclonal
gammopathies—through laboratory artifacts—may all
cause falsely low serum Na þ concentrations without
affecting plasma osmolality (53–55). Additionally,
the presence of effective osmoles raising serum
osmolality—most notably glucose in uncontrolled
diabetes and/or hyperosmolar radiocontrast media—
may result in hyponatremia with normal, or even
high, plasma tonicity (56,57). Indeed, the serum Na þ
JACC VOL. 65, NO. 5, 2015
FEBRUARY 10, 2015:480–92
concentration decreases by approximately 2.4 mEq/l
per 100 mg/dl increase in serum glucose (56). If these
underlying causes are managed appropriately, hypo-
natremia is probably not associated with worse
outcome (58).
AVOID AND TREAT DEPLETIONAL HYPONATREMIA.
In any patient with hypotonic hyponatremia, it is best
to avoid thiazide-type diuretic agents, MRAs, and
ENaC blockers (e.g., amiloride), as these medications
interfere directly with the kidneys’ capacity to pro-
duce hypotonic urine. However, it should be stressed
that this advice is purely on the basis of the patho-
physiological rationale, as high-quality evidence is
lacking. Further, potassium and magnesium stores
should be replenished if serum levels are low. We
propose aiming for serum potassium levels $4 mEq/l
and magnesium levels $1.7 mEq/l ($2 mg/dl) in ADHF
patients presenting with hyponatremia, but this cut-
off is arguably somewhat arbitrary.
DIFFERENTIATE BETWEEN DEPLETIONAL AND
DILUTIONAL HYPONATREMIA. In ADHF, clinicians
should differentiate between depletional hypo-
natremia, requiring the administration of saline,
versus dilutional hyponatremia, where free water
excretion should be promoted. Acute gastrointestinal
or third-space losses, clinical signs of hypovolemia,
and recent use of diuretic agents—especially at high
doses or in combination therapy—increase the likeli-
hood of depletional hyponatremia. In this case, pro-
duction of hypotonic urine is promoted by the
administration of isotonic saline, with subsequent
normalization of serum sodium levels. In contrast, it
would be impossible to correct dilutional hypona-
tremia with isotonic saline, as free water excretion is
compromised and hypotonic urine production is
impaired. One might consider a fluid challenge with 1
of isotonic saline over 24 h to differentiate between
these conditions, measuring the effect on serum so-
dium levels. However, this should be avoided in case
of clear fluid overload and/or severe hyponatremia
(serum sodium <125 mEq/l). Indeed, signs of volume
overload indicate a component of dilutional hypona-
tremia, in which case an improvement is unlikely,
and the risk of further deteriorating congestion is
substantial. Further worsening of hyponatremia
should certainly be avoided in patients with severe
hyponatremia. Alternatively, one could measure
urine osmolality, which should be adequately sup-
pressed (<100 mOsm/l) in patients with depletional
hyponatremia, but not in patients with dilutional
hyponatremia. If urine osmolality is >150 mOsm/l,
isotonic solutions should certainly be avoided, as
administration would result in further worsening of
JACC VOL. 65, NO. 5, 2015 Verbrugge et al. 487
FEBRUARY 10, 2015:480–92 Hyponatremia in Decompensated Heart Failure

CENTRAL I LLU ST RAT ION Approach to Hyponatremia in Decompensated Heart Failure

DEFINITION

Hyponatremia: Serum sodium (Na+) ≤135 mEq/L

Assess plasma osmolality (can be skipped in cases of mild hyponatremia that is easily corrected with initiation of therapy)

Pseudohyponatremia Hypotonic hyponatremia

(Plasma osmolality ≥285 mOsm/L) (Plasma osmolality <285 mOsm/L)
Falsely low serum Na+ concentrations caused by laboratory artefacts (elevated
triglyceride/cholesterol levels, immunoglobulins and monoclonal gammopathies)
Increased plasma osmolality caused by hyperglycemia, hyperosmolar
radio-contrast media, use of mannitol, ethanol, methanol, ethylene glycol

Differentiate between
Na+ deficit (depletional) Water Excess (dilutional)
DIAGNOSIS

hyponatremia conditions

Depletional hyponatremia Dilutional hyponatremia

• Negative Na+ balance • Impaired water excretion
• Potassium (K+) and magnesium (Mg++) depletion • Excessive water reabsorption

Clinical presentation: Clinical presentation:

• Hypovolemia • Hypervolemia (Edema, ascites, pleural effusion)

Caused by: Caused by:

• Use of powerful Na+-wasting loop diuretics • Non-osmotic release of arginine vasopressin (AVP)
• Use of thiazide-type or combinational diuretics • Insufficient tubular flow through diluting segments
• Salt-restricted diets recommended by the guidelines of the distal nephron
• Acute gastro-intestinal or third-space losses

Urinary analysis: Urinary analysis:

• Urinary osmolality adequately suppressed (<100 mOsm/L) • Urinary osmolality inadequately suppressed (≥100 mOsm/L)
• Urinary sodium depleted (<50 mEq/L)

For both depletional and dilutional hyponatremia

• Stop distally working diuretics (thiazide-type, amiloride, mineralocorticoid receptor antagonists)
GENERAL RECOMMENDATIONS

• Correction of K+ and Mg++ deficiencies (aiming for serum K+ levels ≥4 mEq/L and Mg++ levels ≥1.7 mEq/L)

Depletional hyponatremia Dilutional hyponatremia

• Administer saline. One liter of infusate is expected • Limit water intake
to change the serum sodium concentration with: • Promote free water excretion
(Na+)infusate + (K+)infusate – (Na+)serum - AVP
- Improve distal nephron flow (loop diuretics with
(TBW + 1)
or without hypertonic saline, acetazolamide,
TBW = α x body weight (kg); α = 0.6 in children and non-elderly men, renin-angiotensin system blockers, inotropes
0.5 in non-elderly women and elderly men, 0.45 in elderly women and vasodilator therapy)

Verbrugge, F.H. et al. J Am Coll Cardiol. 2015; 65(5):480–92.

A flowchart with a stepwise diagnostic approach to hyponatremia in decompensated heart failure is presented. Therapeutic options are
proposed according to the underlying pathophysiological culprit. AVP ¼ arginine vasopressin.
488 Verbrugge et al.
Hyponatremia in Decompensated Heart Failure
hyponatremia. Finally, very low urinary Na þ and/or
chloride concentrations (<50 mEq/l) are a relatively
strong argument for electrolyte depletion.
TREATMENT OF DEPLETIONAL
HYPONATREMIA
As with other deficiencies, pure depletional hypo-
natremia is easily treated by administration of saline.
Hypertonic saline will correct hyponatremia faster and
with a lower water load than isotonic saline, which
might be preferred in patients who are already nor-
movolemic on clinical examination. However, if no
severe hyponatremia symptoms are present, it is rec-
þ zation of hyponatremia at hospital discharge was not
ommended to correct the serum Na concentration
slowly, at a maximal rate of 5 mEq/l per day. If hypo-
natremia is profound (<125 mEq/l), correction up to
10 mEq/l per day is acceptable (59). At any time,
þ interpretation is that only durable hyponatremia
increasing the serum Na concentration >10 mEq/l in
24 h should be avoided because of the risk of central
pontine myelinolysis (60). Importantly, replenishment
of potassium and magnesium stores through adminis-
tration of supplements contributes to hyponatremia
correction, and this should be taken into account when
determining the correction rate (52,61). Although
certainly not a substitute for frequent monitoring, the
þ be lowered, or AVP effects should be antagonized.
change in serum Na concentration with 1 l of infusate
might be approximated by the following formula:
 þ    

Na INFUSATE þ Kþ INFUSATE  Naþ SERUM ðTBW þ 1Þ
with TBW ¼ a  body weight (kg), and a ¼ 0.6 in chil-
dren and nonelderly men, 0.5 in nonelderly women
and elderly men, and 0.45 in elderly women (62). Take
for example a female patient, 50 years of age and
weighing 62 kg, presents with a serum Naþ concen-
tration of 130 mEq/l and a serum K þ of 3.5 mEq/l. This is
presumably because of depletion, as she is on a high
maintenance dose of furosemide (120 mg twice daily)
and has no overt signs of volume overload. Infusion of
1 normal saline ([Naþ] ¼ 154 mEq/l) with addition of
40 mEq K þ supplements would be expected to raise
the serum Naþ concentration by 2 mEq/l ([154 mEq/l þ
40 mEq/l  130 mEq/l]/[(0.5  62) þ 1]). However,
without K þ supplements, the increase would only be
0.75 mEq/l ([154 mEq/l  130 mEq/l]/[(0.5  62) þ 1]).
TREATMENT OF HYPOTONIC
DILUTIONAL HYPONATREMIA
Acute treatment of hypotonic dilutional hypo-
natremia is focused on promoting free water excretion
to restore normal serum sodium levels. However, for
long-term treatment success, it is important to subse-
quently prevent a positive free water balance. This
JACC VOL. 65, NO. 5, 2015
FEBRUARY 10, 2015:480–92
may be important, as the question whether hypona-
tremia in ADHF reflects a therapeutic target or is
merely a marker of advanced disease has not been
fully established. Indeed, studies looking at the
prognostic effect of hyponatremia correction have
yielded conflicting results (63,64). Madan et al. (63)
demonstrated in a cohort of 322 ADHF patients with
hyponatremia that long-term changes in serum Naþ
concentration (assessed 60 to 270 days after hospital
discharge) are significant predictors of mortality, with
improving hyponatremia associated with better
outcome. In contrast, after correction for disease
severity markers, Lee et al. (64) found that normali-
associated with improved survival (64). Obviously,
confounding by different treatment strategies in both
studies cannot be excluded, but a conservative
correction is potentially associated with improved
outcome in ADHF. To achieve this, good heart failure
management is often fundamental.
ACUTE TREATMENT OF DILUTIONAL HYPONATREMIA.
To promote free water excretion in a patient with
ADHF and hypotonic dilutional hyponatremia, distal
nephron flow should be increased, AVP levels should
Loop diuretic agents with or without hypertonic
s a l i n e . The powerful inhibitory effect of loop
diuretic agents on Naþ transport in the TAL increases
the amount of tubular fluid presented to the distal
nephron. Loop diuretic agents also reduce hyperto-
nicity of the renal interstitium, further facilitating
water excretion (Figure 4A) (44). Because loop
diuretic agents are cheap and readily available, they
remain the first-line therapy in ADHF with dilutional
hyponatremia and volume overload. The addition of
hypertonic saline to improve loop diuretic efficacy in
ADHF is a controversial issue. Although counterin-
tuitive from a pathophysiological point of view, some
small studies have suggested more efficient decon-
gestion and better renal preservation when loop
diuretic agents are combined with hypertonic saline
(Table 2) (65–70). Importantly, decreases in plasma
renin activity, inflammatory markers, and even
natriuretic peptide levels have been demonstrated
with hypertonic saline administration in ADHF
patients who receive loop diuretic agents (71,72). Still,
it remains difficult to draw any firm conclusions,
because the use of high doses of loop diuretic agents
that might have induced these alterations might
have confounded these improvements with sodium
loading. As serum Na þ levels are more easily cor-
rected, patients with hyponatremia might benefit
more from the addition of hypertonic saline to loop
JACC VOL. 65, NO. 5, 2015 Verbrugge et al. 489
FEBRUARY 10, 2015:480–92 Hyponatremia in Decompensated Heart Failure

diuretic agents; however, this remains highly

T A B L E 2 Studies on Hypertonic Saline in Patients With Acute Decompensated
speculative. Heart Failure
A c e t a z o l a m i d e . Alternatively, combinational diu-
First Author (Ref. #) n Treatment Outcome
retic treatment with loop diuretic agents and acet-
þ Paterna et al. (65) 60 IV furosemide 500–1,000 mg Increase in diuresis, natriuresis,
azolamide ensures minimal tubular Na reabsorption
with vs. without 150 ml and serum sodium levels;
proximal from the macula densa and maximal flow 1.4%–4.6% hypertonic decrease in serum creatinine;
saline BID and shorter hospitalization
through the distal nephron (29). For this reason, if
time with hypertonic saline
combination therapy is needed to overcome loop Licata et al. (66) 107 IV furosemide 500–1,000 mg Increase in diuresis, natriuresis,
diuretic resistance in ADHF, acetazolamide should be with vs. without 150 ml and serum sodium levels;
1.4%–4.6% hypertonic decrease in serum creatinine;
preferred over thiazide-type diuretic agents, MRAs, or saline BID and improved survival with
ENaC blockers. hypertonic saline

A V P a n t a g o n i s t s . AVP antagonists are the only Paterna et al. (71) 94 IV furosemide 500–1,000 mg Increase in diuresis and
with vs. without 150 ml natriuresis; decrease in BNP
medication class to directly promote free water 1.4%–4.6% hypertonic levels; shorter hospitalization
excretion by prevention of aquaporin-2 channel saline BID time; and lower 30-day
readmission rate with
availability in the collecting ducts of the nephron hypertonic saline
(73,74). Three oral V 2 receptor antagonists (tolvaptan, Parrinello et al. (67) 133 IV furosemide 250 mg plus Increase in diuresis, natriuresis,
150 ml 3% hypertonic and serum sodium levels;
satavaptan, and lixivaptan) have been tested for
saline BID vs. IV furosemide improved renal function; and
ADHF, with the former 2 shown to be efficacious in 250 mg BID plus low faster reduction of echo-
restoring serum Na þ levels in patients with volume sodium diet (<80 mmol) PCWP with hypertonic saline
Paterna et al. (68) 1,771 IV furosemide 250 mg plus Increase in diuresis, natriuresis,
overload and hyponatremia (75–78). Similar data are 150 ml 3% hypertonic and serum sodium levels;
available for conivaptan, an intravenous agent that saline BID vs. IV furosemide decrease in serum creatinine;
250 mg BID plus low shorter hospitalization time;
antagonizes both the V 2 and V 1a receptors (74,79,80). sodium diet (<80 mmol) lower readmission rate; and
Table 3 summarizes the currently available evidence improved survival with
hypertonic saline
on AVP antagonists in patients with ADHF and hypo-
Issa et al. (69) 34 100 ml 7.5% hypertonic saline Improved in glomerular and
natremia. Importantly, EVEREST (Efficacy of Vaso- BID vs. placebo for 3 days tubular biomarkers with
pressin Antagonism in Heart Failure Outcome Study hypertonic saline
Okuhara et al. (70) 44 500 ml 1.7% hypertonic saline Improved GFR and better diuresis
with Tolvaptan), including 4,133 patients with ADHF
vs. glucose 5% with 40 mg with hypertonic saline
but without hyponatremia as an inclusion criterion, furosemide
compared tolvaptan with placebo and was powered
BID ¼ twice daily; BNP ¼ B-type natriuretic peptide; GFR ¼ glomerular filtration rate; IV ¼ intravenous;
for clinical endpoint analysis (81). The overall trial did PCWP ¼ pulmonary capillary wedge pressure.
not show a significant reduction in all-cause mortality
or readmission rates, but, interestingly, a subanalysis
in patients presenting with pronounced hypona-
tremia (<130 mmol/l) suggested improved survival hyponatremia, less is known about their long-term
free from cardiovascular death or readmission (76,81). efficacy in providing a sustained correction of serum
This promising finding warrants further study in an Na þ levels. In EVEREST, serum Na þ concentration
adequately powered, randomized clinical trial. increased more with tolvaptan compared with pla-
LONG-TERM MANAGEMENT OF HYPOTONIC DILU- cebo during in-hospital stay (81). However, patients
TIONAL HYPONATREMIA. W a t e r r e s t r i c t i o n . Water also reported feeling thirsty significantly more
restriction is uniformly recommended by the guide- frequently, and the difference with serum Na þ levels
lines in ADHF patients with hyponatremia as it is in in the placebo group disappeared after instillation of
others with dilutional hypotonic hyponatremia (35– outpatient management, which suggests that patients
37,59). Whilst limiting free water intake certainly may have drank more to compensate for increased
aids to prevent a positive free water balance, few data water losses.
support its long-term efficacy, and adherence might Renin-angiotensin system blockers. Renin-angiotensin
be a problem. Indeed, thirst is a frequent, under- system blockers are known to increase renal blood
recognized, and distressing problem in heart failure, flow and decrease proximal tubular sodium reab-
and many patients may find it difficult to comply with sorption. Therefore, it is not surprising that they were
strict water restriction (<1 l) (82). Nevertheless, a among the first agents demonstrated to be effective in
recent study found that ADHF patients with mild hypotonic dilutional hyponatremia in heart failure
hyponatremia had improvements in quality of life (84,85). Up-titration of renin-angiotensin system
with such a strategy (83). blockers should always be promoted for this indica-
A V P a n t a g o n i s t s . Although AVP antagonists are tion if there are no contraindications, such as coex-
highly efficacious for short-term correction of isting renal dysfunction.
490 Verbrugge et al. JACC VOL. 65, NO. 5, 2015

Hyponatremia in Decompensated Heart Failure FEBRUARY 10, 2015:480–92

mortality, afterload reduction probably remains the

T A B L E 3 Studies on AVP Antagonists in Patients With Acute Decompensated Heart
Failure and Hyponatremia
best option to increase the effective circulatory vol-
ume; however, its use is limited by low arterial blood
First Author (Ref. #) n/N Treatment Outcome
pressure (86,87). Observational data have demon-
Gheorghiade et al. (77) 71/254 Tolvaptan 30, 45, or Normalization of serum
(subgroup 60 mg vs. placebo sodium after 24 h, strated that nitroprusside, titrated on arterial blood
analysis) greater decrease in body pressure and with conversion to oral hydralazine and
weight and edema,
increased urine output nitrates, is feasible and potentially associated with
with tolvaptan better outcomes in ADHF (88,89). Alternatively, ser-
Gheorghiade et al. (78) 51/319 Tolvaptan 30, 60, or Normalization of serum elaxin, a vasodilator agent under investigation, might
(subgroup 90 mg vs. placebo sodium with tolvaptan
analysis) be of particular interest because of its specific renal
Ghali et al. (79) 19/74 Conivaptan 40 or Normalization of serum vasodilator properties (90,91). The RELAX-AHF-EU
(subgroup 80 mg vs. placebo sodium with conivaptan
(Effect of Serelaxin Versus Standard of Care in Acute
analysis)
Zeltser et al. (80) 28/84 Conivaptan 40 or Increase in serum sodium Heart Failure Patients) trial is currently enrolling
(subgroup 80 mg vs. placebo concentration with ADHF patients and is powered for clinical endpoint
analysis) conivaptan
evaluation (92). Nevertheless, the specific effects of
Konstam et al. (81) 1,157/4,133 Tolvaptan 30 mg vs. No effect on mortality or
(subgroup placebo rehospitalization, both inotropes and vasodilator therapy on hypo-
analysis) significant increase in natremia remain insufficiently elucidated.
serum sodium with
tolvaptan
CONCLUSIONS
Aronson et al. (75) 90/118 Satavaptan 25 or 50 mg Increase in serum sodium
(subgroup vs. placebo concentration with
analysis) satavaptan The pathophysiology of hyponatremia in ADHF is
complex, and a 1-size-fits-all approach is therefore
likely to fail. Appropriate differentiation between
I n o t r o p e s a n d v a s o d i l a t o r t h e r a p y . Increasing the
dilutional and depletional hyponatremia is crucial
effective circulatory volume in heart failure is ex-
and depends on good history taking, clinical exami-
pected to result in less nonosmotic AVP release
nation, and correct interpretation of laboratory re-
and better renal blood flow, which, from a patho-
sults. A targeted, pathophysiology-based approach
physiological perspective, might help to correct dilu-
should help to treat this challenging condition effi-
tional hyponatremia. Because cardiac output in ADHF
ciently, thereby minimizing adverse events.
is rather insensitive to changes in cardiac pre-load—as
the Frank-Starling mechanism is depleted—improve-
ments can only be obtained through direct stimula- REPRINT REQUESTS AND CORRESPONDENCE: Dr.
tion of contractility with inotropes or reducing Wilfried Mullens, Department of Cardiology, Ziekenhuis
afterload with vasodilator therapy. As the former Oost-Limburg, Schiepse Bos 6, 3600 Genk, Belgium.
treatment strategy is associated with increased E-mail: wilfried.mullens@zol.be.

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KEY WORDS arginine vasopressin,
distal, diuretics, kidney tubules,
physiopathology, sodium