JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 65, NO. 5, 2015

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 deciency, 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 hyponatremia in ADHF. (J Am Coll Cardiol 2015;65:48092) 2015 by the American College of Cardiology Foundation.

yponatremia, dened as a serum sodium

of hospital-acquired hyponatremia during deconges-

(Na ) concentration <135 mEq/l, is the

tive treatment for ADHF is probably w15% to 25%

most common electrolyte disorder in hos-

(4,5). Hyponatremia frequently poses an important

pitalized patients (1). Both admission and hospital-

therapeutic

acquired

an

administration of the depleted ion (as with other de-

increased risk for adverse outcomes, including pro-

ciencies) cannot be easily performed, and there is

longed hospital stay, need for discharge to a short-

an obvious concern for harmful uid overload. More-

or long-term care facility, and all-cause mortality

over, the pathophysiology of hyponatremia in ADHF

(2). In a subanalysis from the OPTIMIZE-HF (Orga-

is often dilutional, rather than depletional (6,7).

nized Program to Initiate Lifesaving Treatment in

Importantly, ubiquitous use of powerful Na -wasting

Hospitalized Patients with Heart Failure) registry,

diuretic agents in this context hampers differentia-

including 47,647 patients with acute decompensated

tion between the 2 conditions, each of which requires

heart failure (ADHF), hyponatremia was present in

a totally different approach. This review, therefore,

w20% upon admission (3). In addition, the incidence

aims to provide, on the basis of the currently

hyponatremia

are

associated

with

challenge

in

ADHF

because

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 University, 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 FoundationFlanders. 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.
Manuscript received July 30, 2014; revised manuscript received November 30, 2014, accepted December 2, 2014.

simple

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481

Hyponatremia in Decompensated Heart Failure

available evidence, a pathophysiology-based assess-

interstitiumhence antidiuresisthrough 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

ducts, and reduced blood ow through the

PATHOPHYSIOLOGY OF

vasa recta (Figure 1) (12,13). The vasa recta are

HYPONATREMIA IN ADHF

straight capillaries in the renal medulla with a

hairpin loop. They receive a lower proportion

ADHF = acute decompensated

heart failure

AVP = arginine vasopressin

ENaC = epithelial sodium
channel

Table 1 provides a summary of the pathophysiology of

of blood ow compared with the renal cortex,

hyponatremia in ADHF.

GFR = glomerular ltration

especially during antidiuresis. This is impor-

rate

DILUTIONAL HYPONATREMIA. It is generally assumed

tant, as high blood ow 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 Na depletion (6,7).

renal cortex toward the medulla, which is

Na = 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 Henles loop

creased nonosmotic release of arginine vasopressin

promotion of prostaglandin synthesis in the collecting

(AVP) and insufcient tubular ow through diluting

ducts. This counteracts V 2 effects on aquaporin-2, thus

(distal) segments of the nephron. In many ways, this

stimulating water excretion (14). This latter effect may

is the opposite of the situation in diabetes insipidus,

explain why some heart failure patients demonstrate a

where decient AVP production and/or function

normal response to water loading, with production of

in the presence of normal tubular ow results in

adequately diluted urine, despite having elevated

very diluted urine, exaggerated water losses, and,

plasma AVP levels (15).

ultimately, in hypernatremia, unless compensation

Nonosmotic

occurs through increased water intake.

h e a r t f a i l u r e . Several studies have demonstrated

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

that AVP levels are generally elevated in heart failure

cyclic octapeptide (1,099 D) with a 3-amino acid tail,

(1618).

is a key regulator of water homeostasis. AVP is syn-

markedly up-regulated in a rat model of congestive

arginine

Moreover,

vasopressin

aquaporin-2

release

expression

in

was

thesized in large-diameter neurons in the supraoptic

heart failure (19), which would be expected to in-

and paraventricular nuclei of the anterior hypothal-

crease water permeability and reabsorption in the

amus. After axonal transport into nerve terminals

collecting ducts of the nephron. It is tempting to

within the posterior lobe of the pituitary, AVP is

speculate that both events are causally related and

released into the bloodstream in response to plasma

promoting excessive free water reabsorption, leading

hypertonicity (8). In healthy, normally hydrated

to hyponatremia in ADHF. Certainly, baroreceptor

persons,

low

activity, sympathetic overdrive, and angiotensin II,

(w1 pg/ml) because of its rapid degradation and

all stimulated by decreased effective circulatory

circulating

AVP

levels

are

very

excretion by the liver and kidneys (t 1/2 15 to 20 min)

(9). Consequently, hepatic dysfunction and renal
insufciency may contribute to increased plasma

T A B L E 1 Pathophysiology of Hyponatremia in

Acute Decompensated Heart Failure

levels of AVP in ADHF. AVP exerts its water-retaining

effects primarily through stimulation of high-afnity
V2 receptors in the collecting ducts of the nephron

Mechanism of Action

Dilutional hyponatremia

(Figure 1) (9). V2 stimulation increases both the syn-

Increased sensitivity of osmotic AVP

Baroreceptor activation/angiotensin II
release / Lower osmo-checkpoint*

thesis and availability of aquaporin-2 channels on the

Increased nonosmotic AVP release

luminal side of these collecting ducts, which other-

Impaired AVP degradation

Liver and/or kidney dysfunction

wise have low water permeability (10). The hypertonic

Increased thirst

Baroreceptor activation/angiotensin II

Decreased distal nephron ow

Impaired glomerular ltration/Increased

proximal tubular reabsorption

environment of the renal interstitium subsequently

provides a strong impetus for water reabsorption,

Baroreceptor activation/angiotensin II

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

sensitive to small changes in plasma AVP levels, which

Exaggerated natriuresis

Diuretics, osmotic diuresis

are difcult to detect, even by modern assays (11). At

Sodium shift toward the intracellular

compartment

Potassium and/or magnesium

deciency

higher concentrations, the low-afnity V1a receptor,

which is expressed in the liver, collection ducts,
and vasa recta of the nephron, is stimulated (Figure 1).
This further enhances hypertonicity in the renal

*This is the level of plasma osmolality that is pursued by the homeostatic mechanisms of the
body.
AVP arginine vasopressin.

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Hyponatremia in Decompensated Heart Failure

resulting in baroreceptor activation and angiotensin

F I G U R E 1 Effects of AVP in the Nephron

II stimulation, may cause plasma levels many times

Distal tubules

higher than necessary to produce maximal anti-

Collecting ducts

Macula densa

diuresis (50 to 100 pg/ml) (22). Importantly, at these

high levels, AVP has potent V 1a -mediated vasocon-

INTERLOBAR
ARTERY

strictor effects that may contribute to hemodynamic

LOW WATER PERMEABILITY

Insufcient tubular ow through diluting segments

V
A
S
A

TAL

of the distal nephron. Healthy kidneys are able

H2O

to dilute urine to an osmolality as low as 30 to 60

mOsm/l, w5- to 10-fold lower than serum osmolality

H2O
H2O

BLOOD FLOW
H2O

V1a: VASOCONSTRICTION

Urea
UT-A1 transporter
Aquaporine-2 (AP2)
Stimulated
Inhibited

R
E
C
T
A

deterioration in ADHF (23).

AP2 EXPRESSION
V2
V1a

(24). However, micropuncture studies have demonstrated that tubular uid osmolality is quite similar
(w150 mOsm/l) at the level of the macula densa during antidiuresis versus water diuresis (25). Thus,

UREA REABSORPTION
INCREASED HEPATIC UREA
V1a: PRODUCTION
INCREASED UT-A1 TRANSPORTER

urine dilution depends heavily on the tubular function of more distal parts of the nephron (i.e., distal
convoluted tubules and collecting ducts). Free water
excretion is achieved by these segments through

OSMOTIC GRADIENT

continued solute reabsorption, primarily through the

thiazide-sensitive Na/chloride cotransporter and
aldosterone-sensitive

V2-receptor effects: The primary effect of AVP on water homeostasis is mediated through
stimulation of high-afnity V2 receptors, already with small increases in plasma levels (9).
V2-receptor stimulation in collecting duct cells results in increased production of AP2

epithelial

sodium

channels

(ENaCs), in the presence of low water permeability

(24,26). Importantly, less sodium is reabsorbed by

channels and facilitates recruitment of these channels on the luminal membrane, which

ENaCs in conditions of low tubular ow, irrespective

otherwise has low water permeability (10). Subsequently, water reabsorption is promoted

of aldosterone levels (27). Consequently, if more so-

as the renal interstitium is hypertonic and the basolateral membrane of collecting duct

dium is retained in the tubular lumen, free water

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

excretion is restricted. The ability of the kidneys to

excrete free water is, therefore, directly dependent

medullary part of the collecting ducts through UT-A1 transporters.

on: 1) the amount of tubular uid offered to the distal

V1a-receptor effects: At high plasma levels, AVP further stimulates hypertonicity in the

nephron; and 2) the relatively low water permeability

renal interstitium, and hence water reabsorption, through activation of the low-afnity V1a

of this segment, which can only be overcome

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

by insertion of aquaporin-2 channels through AVP

stimulation. For instance, a healthy person with a
ltration

causes vasoconstriction in the vasa recta, preventing wash-out of solutes from the renal

glomerular

medulla (12,13). On the other hand, V1a receptor stimulation in collecting duct cells also

(125 ml/min), of which 10% reaches the distal convo-

promotes prostaglandin synthesis. Prostaglandins counteract the effects of V2 by impeding

luted tubules and with total AVP suppression, would

AP2 recruitment in these collecting duct cells (14). This somewhat preserves the diluting

be able to drink w18 l (10% of 180 l) over the course of

capacity of the distal nephron, even when AVP levels are high because of neurohumoral
activation and nonosmotic AVP release. AP2 aquaporin-2; AVP arginine vasopressin;
TAL thick ascending limb of Henles loop.

rate

(GFR)

of

180

l/day

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 ow because of increased
proximal reabsorption in ADHF, maximal water

volume in ADHF, fuel nonosmotic AVP release, as well

intake without hyponatremia development would

as thirst and thus free water intake (20). Importantly,

be

they also increase the sensitivity of osmotic AVP

of 43.2 l/day) (28,29). The latter is even an over-

release (Figure 2A). Indeed, compared with healthy

estimate, as it presumes that water permeability in

volunteers, ADHF patients show a more pronounced

the distal nephron is as low as with total AVP sup-

increase in plasma AVP levels with osmotic loading

pression, which is clearly not the case in ADHF

(21). In contrast to this osmotic AVP release, which

(Figure 3B). An intriguing study by Bell et al. (30)

increases linearly and with very small changes in

further supports the concept of decreased distal

serum osmolality, nonosmotic AVP release is expo-

nephron ow in AHDF. In this study, free water

nential (Figure 2B). Thus, isotonic plasma volume

excretion was increased in ADHF patients with

reductions of 5% to 10% will have little effect on AVP

hyponatremia after infusion of 5% mannitol, an os-

secretion, whereas reductions of 20% to 30%,

motic diuretic that enhances tubular ow through the

decreased

tremendously

to

2.16

l/day

(5%

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Hyponatremia in Decompensated Heart Failure

beginning

F I G U R E 2 Determinants of AVP Plasma Levels

Plasma AVP (pg/ml)

and

is

exacerbated

by

unrestrained

neurohumoral up-regulation, Na depletion is relatively rare in ADHF not treated with diuretic agents

Osmotic AVP Release

Angiotensin II
baroreceptor activity

12

(33,34). Still, osmotic diuresis because of hyperglycemia in the case of severe uncontrolled diabetes,
gastrointestinal losses, and third-space losses may all

Normal

contribute to a negative Na balance, especially if

patients adhere scrupulously to the salt-restricted
diets recommended by the guidelines (3537). One
group called these diets into question, demonstrating

that heart failure patients adhering to such diets

experienced increased hospitalizations and a higher
260

Plasma AVP (pg/ml)

270
280
290
300
Plasma Osmolality (mOsm/l)

310

mortality rate (3840). However, it should be noted

that these patients also received a high dose of
diuretic agents (125 to 500 mg furosemide equivalents

Osmotic Versus Non-osmotic AVP release

50

Osmotic

Non-osmotic

40

twice daily), increasing the risk of a negative Na

balance. Indeed, the combination of very low dietary
sodium intake and exaggerated losses might lead
to progressive depletion of whole-body sodium stores.

30

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

20

of powerful Na -wasting loop diuretic agents is

nearly ubiquitous in ADHF, with 88% of patients in

10

ADHERE (Acute Decompensated Heart Failure Regis-

0
5

10

15

20

% Plasma osmolality increase

% Iso-osmotic plasma volume decrease

try) receiving them (41). Moreover, 70% continue to

receive daily maintenance therapy with loop diuretic
agents, although many are probably not persistently
volume-overloaded. Loop diuretic agents block the

(A) Osmotic AVP release: AVP is near total suppression in normal

Na /potassium/chloride cotransporter in the thick

circumstances, but increases linearly with plasma osmolality (9).

ascending limb of Henles loop (TAL). Na and chlo-

Neurohumoral activation through angiotensin II and baroreceptor

ride transport in the TAL, which has a relatively low

activity increases the amount of AVP release for any given plasma

water permeability, makes a crucial contribution to

osmolality (20). In addition, it moves the set-point of total AVP

suppression to a lower plasma osmolality, hence promoting hy-

the hypertonicity of the renal interstitium, in addition

potonicity. (B) Osmotic versus nonosmotic AVP release: osmotic

to the other important factor, medullary urea trans-

AVP release is very sensitive and increases linearly, already with

port in the collecting ducts (42,43). This hypertonicity,

very small changes in plasma osmolality (blue curve) (9). Non-

washed out by blood ow through the vasa recta with

osmotic AVP release makes little contribution to overall AVP

inhibition of TAL transport by loop diuretic agents, is

plasma levels until a 10% to 15% decrease in isotonic plasma

volume, after which AVP release increases markedly, resulting in

the major driver of water reabsorption in the distal

plasma levels many times higher than needed to achieve maximal

nephron. Because of this interference of loop diuretic

antidiuresis (red curve) (22). Abbreviations as in Figure 1.

agents with the renal capacity to concentrate urine,

less free water is reabsorbed, resulting in production
of hypotonic urine and, therefore, relative protection

nephron. Mannitol exerts its diuretic effect through

against hyponatremia (Figure 4A) (44). However, in

solvent drag and water retention in the tubular

conditions of profound volume depletion with strong

lumen, thereby also increasing distal delivery. Similar

neurohumoral activation and compromised renal

ndings have been demonstrated in patients with

blood ow, loop diuretic agents will fail to elicit

cirrhosis, where the effective circulatory volume and

meaningful water diuresis. Eventually, GFR and distal

renal perfusion are also impaired (31). However, it

nephron ow will become depressed in the presence

remains possible that correction of hyponatremia

of strongly up-regulated AVP, creating the necessary

with mannitol in ADHF and cirrhosis is partly due to

environment for hyponatremia development (29).

increased intravascular volume after infusion, sup-

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-

pressing baroreceptor tonus and, hence, nonosmotic

alocorticoid

AVP release (32).

cornerstone in the treatment of heart failure with

DEPLETIONAL HYPONATREMIA. Because increased

reduced ejection fraction and are promising in

Na avidity characterizes heart failure from the very

selected patients with preserved ejection fraction

receptor

antagonists

(MRAs)

are

483

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Hyponatremia in Decompensated Heart Failure

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

Healthy person
MAXIMAL WATER DIURESIS
Glomerulus
GFR = 125 ml/min
= 180 l/day
285 - 295 mOsm/l

Distal Tubules
(low water permeability)

Macula Densa
18 l/day
150 mOsm/l

300 mOsm/l

Proximal Tubules
65% reabsorption
=117 l/day
285 - 295 mOsm/l

TAL
25% reabsorption
= 45 l/day

O
S
M
O
T
I
C

V
A
S
A
R
E
C
T
A
500 mOsm/l
HIGH BLOOD FLOW

WASHOUT

G
R
A
D
I
E
N
T

Collecting ducts
(low water permeability)

AVP suppressed:
LOW WATER PERMEABILITY
CONTINUED SOLUTE
REABSORPTION

LOW GRADIENT

MAXIMAL
FREE WATER EXCRETION
~ 18l/day

Urine: 30-60 mOsm/l

Heart failure patient
MAXIMAL WATER DIURESIS
Glomerulus
GFR = 30 ml/min
= 43.2 l/day
285 - 295 mOsm/l

Macula Densa
2.16 l/day
150 mOsm/l

Distal Tubules
(low water permeability)

300 mOsm/l

Proximal Tubules
70% reabsorption
=30.24 l/day
285 - 295 mOsm/l

TAL
25% reabsorption
= 10.8 l/day

V
A
S
A
R
E
C
T
A
700 mOsm/l
VASOCONSTRICTION
LOW BLOOD FLOW

NO WASHOUT

O
S
M
O
T
I
C
G
R
A
D
I
E
N
T

Collecting ducts
(low water permeability)

AVP not suppressed:

HIGH WATER PERMEABILITY
STRONG OSMOTIC GRADIENT
CONTINUED WATER
REABSORPTION

HIGH GRADIENT

MAXIMAL
FREE WATER EXCRETION
<1 l/day
Urine: 100-150 mOsm/l

(A) Through glomerular ltration, a healthy person forms 180 l of tubular uid each day. As the proximal tubules, thin descending limb, and
ascending limb of Henles loop all have high water permeability, reabsorption in these nephron segments is isotonic, and tonicity of the tubular
uid 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 uid is formed each day.
As proximal tubular reabsorption increases in heart failure, only 5% or 2.16 l of tubular uid 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
ow 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 difcult it can be for a patient to
prevent hyponatremia progression with uid restriction only. GFR glomerular ltration rate; other abbreviations as in Figure 1.

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Hyponatremia in Decompensated Heart Failure

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

A Effect of loop Diuretics

MAXIMAL
ANTIDIURESIS

on the Concentrating Capacity of the Kidneys

300 mOsm/l

MAXIMAL WITH
LOOP DIURETICS

O
S
M
O
T
I
C

O
S
M
O
T
I
C

G
R
A
D
I
E
N
T

G
R
A
D
I
E
N
T

300 mOsm/l

LOOP DIURETICS

DISTAL CONVOLUTED TUBES

& COLLECTING DUCTS
Na/Cl Co-transporter

CONTINUED SODIUM REABSORPTION

WATER REABSORPTION
Impaired osmotic gradient

Na/K/2CI Co-transporter
ENaC

1200 mOsm/l

B Effect of THIAZIDE-TYPE Diuretics and MRA

on the Concentrating Capacity of the Kidneys

MAXIMAL
ANTIDIURESIS

MAXIMAL WITH
THIAZIDE-TYPE
DIURETICS

O
S
M
O
T
I
C

O
S
M
O
T
I
C

G
R
A
D
I
E
N
T

G
R
A
D
I
E
N
T

300 mOsm/l

THIAZIDE-TYPE
DIURETICS

DISTAL CONVOLUTED TUBES

& COLLECTING DUCTS

Na/Cl Co-transporter

800 mOsm/l

IMPAIRED SODIUM REABSORPTION

Thiazide-type diuretics & MRA
UNCHANGED WATER REABSORPTION

Na/K/2CI Co-transporter
ENaC
MRA
1200 mOsm/l

300 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 epithelial sodium channel; MRA mineralocorticoid receptor antagonists; other
abbreviations as in Figure 1.

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Hyponatremia in Decompensated Heart Failure

(45,46). Together with thiazide-type diuretic agents,

concentration decreases by approximately 2.4 mEq/l

often recommended as rst-line therapy in case of

per 100 mg/dl increase in serum glucose (56). If these

loop diuretic resistance, they interfere with sodium

underlying causes are managed appropriately, hypo-

reabsorption by ENaCs and Na/chloride cotrans-

natremia is probably not associated with worse

porters, respectively, in the distal convoluted tubules

outcome (58).

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 (4749). From a pathophysiological perspective, it is, therefore, prudent to
avoid their use in any patient with hyponatremiaat
least temporarily, until serum sodium levels are
correctedand

to

prefer

proximally

working

diuretic (e.g., acetazolamide) in such cases with volume overload and diuretic resistance (29).

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 produce hypotonic urine. However, it should be stressed
that this advice is purely on the basis of the pathophysiological 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

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 magnesium levels $1.7 mEq/l ($2 mg/dl) in ADHF

and thiazide-type diuretic agents are a major cause of

patients presenting with hyponatremia, but this cut-

potassium and magnesium wasting in ADHF. This may

off is arguably somewhat arbitrary.

have important implications, such as a higher risk of

arrhythmic death (50). In addition, potassium deple-

DIFFERENTIATE

tion shifts Na towards the intracellular compartment

DILUTIONAL HYPONATREMIA. In ADHF, clinicians

BETWEEN

to preserve cellular volume homeostasis, which may

should

contribute to development of hyponatremia (51).

natremia, requiring the administration of saline,

Indeed, intracellular Na concentrations are higher in

versus dilutional hyponatremia, where free water

muscle cells of ADHF patients with hypokalemia (52).

excretion should be promoted. Acute gastrointestinal

Furthermore, magnesium is critical for functioning of

or third-space losses, clinical signs of hypovolemia,

the Na/potassium ATPase that pumps Na out of

and recent use of diuretic agentsespecially at high

cells; thus, hypomagnesemia may also exacerbate

doses or in combination therapyincrease the likeli-

differentiate

DEPLETIONAL

between

depletional

AND

hypo-

hood of depletional hyponatremia. In this case, pro-

extracellular Na depletion.

duction of hypotonic urine is promoted by the

INITIAL APPROACH TO HYPONATREMIA IN

administration of isotonic saline, with subsequent

DECOMPENSATED HEART FAILURE

normalization of serum sodium levels. In contrast, it

would be impossible to correct dilutional hypona-

The Central Illustration presents a stepwise diagnostic

tremia with isotonic saline, as free water excretion is

and therapeutic approach to hyponatremia in de-

compromised and hypotonic urine production is

compensated heart failure.

impaired. One might consider a uid challenge with 1

CONFIRM PLASMA HYPOTONICITY. In patients with

of isotonic saline over 24 h to differentiate between

hyponatremia, the rst step is generally to assess

these conditions, measuring the effect on serum so-

whether plasma hypotonicity is present by measuring

dium levels. However, this should be avoided in case

the plasma osmolality (reference value: 285 to

of clear uid overload and/or severe hyponatremia

295 mOsm/l). This may not be necessary when

(serum sodium <125 mEq/l). Indeed, signs of volume

hyponatremia is mild (serum Na concentration

overload indicate a component of dilutional hypona-

130 to 134 mEq), asymptomatic, and easily corrected

tremia, in which case an improvement is unlikely,

by

or

and the risk of further deteriorating congestion is

cholesterol levels, immunoglobulins, and monoclonal

substantial. Further worsening of hyponatremia

gammopathiesthrough laboratory artifactsmay all

should certainly be avoided in patients with severe

cause falsely low serum Na concentrations without

hyponatremia. Alternatively, one could measure

affecting plasma osmolality (5355). Additionally,

urine osmolality, which should be adequately sup-

the presence of effective osmoles raising serum

pressed (<100 mOsm/l) in patients with depletional

osmolalitymost notably glucose in uncontrolled

hyponatremia, but not in patients with dilutional

diabetes and/or hyperosmolar radiocontrast media

hyponatremia. If urine osmolality is >150 mOsm/l,

may result in hyponatremia with normal, or even

isotonic solutions should certainly be avoided, as

high, plasma tonicity (56,57). Indeed, the serum Na

administration would result in further worsening of

empiric

treatment.

Elevated

triglyceride

Verbrugge et al.

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Approach to Hyponatremia in Decompensated Heart Failure

DEFINITION

CENTRAL I LLU ST RAT ION

Hyponatremia in Decompensated Heart Failure

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
(Plasma osmolality 285 mOsm/L)

Hypotonic hyponatremia
(Plasma osmolality <285 mOsm/L)

Falsely low serum Na+ concentrations caused by laboratory artefacts (elevated

triglyceride/cholesterol levels, immunoglobulins and monoclonal gammopathies)

GENERAL RECOMMENDATIONS

DIAGNOSIS

Increased plasma osmolality caused by hyperglycemia, hyperosmolar

radio-contrast media, use of mannitol, ethanol, methanol, ethylene glycol

Na+ deficit (depletional)

Differentiate between
hyponatremia conditions

Water Excess (dilutional)

Depletional hyponatremia
Negative Na+ balance
Potassium (K+) and magnesium (Mg++) depletion

Dilutional hyponatremia
Impaired water excretion
Excessive water reabsorption

Clinical presentation:
Hypovolemia

Clinical presentation:
Hypervolemia (Edema, ascites, pleural effusion)

Caused by:
Use of powerful Na+-wasting loop diuretics
Use of thiazide-type or combinational diuretics
Salt-restricted diets recommended by the guidelines
Acute gastro-intestinal or third-space losses

Caused by:
Non-osmotic release of arginine vasopressin (AVP)
Insufficient tubular flow through diluting segments
of the distal nephron

Urinary analysis:
Urinary osmolality adequately suppressed (<100 mOsm/L)
Urinary sodium depleted (<50 mEq/L)

Urinary analysis:
Urinary osmolality inadequately suppressed (100 mOsm/L)

For both depletional and dilutional hyponatremia

Stop distally working diuretics (thiazide-type, amiloride, mineralocorticoid receptor antagonists)
Correction of K+ and Mg++ deficiencies (aiming for serum K+ levels 4 mEq/L and Mg++ levels 1.7 mEq/L)

Depletional hyponatremia
Administer saline. One liter of infusate is expected
to change the serum sodium concentration with:
(Na+)infusate + (K+)infusate (Na+)serum
(TBW + 1)
TBW = x body weight (kg); = 0.6 in children and non-elderly men,
0.5 in non-elderly women and elderly men, 0.45 in elderly women

Dilutional hyponatremia
Limit water intake
Promote free water excretion
- AVP
- Improve distal nephron flow (loop diuretics with
or without hypertonic saline, acetazolamide,
renin-angiotensin system blockers, inotropes
and vasodilator therapy)

Verbrugge, F.H. et al. J Am Coll Cardiol. 2015; 65(5):48092.

A owchart with a stepwise diagnostic approach to hyponatremia in decompensated heart failure is presented. Therapeutic options are
proposed according to the underlying pathophysiological culprit. AVP arginine vasopressin.

487

488

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Hyponatremia in Decompensated Heart Failure

hyponatremia. Finally, very low urinary Na and/or

may be important, as the question whether hypona-

chloride concentrations (<50 mEq/l) are a relatively

tremia in ADHF reects a therapeutic target or is

strong argument for electrolyte depletion.

merely a marker of advanced disease has not been

fully established. Indeed, studies looking at the

TREATMENT OF DEPLETIONAL

prognostic effect of hyponatremia correction have

HYPONATREMIA

yielded conicting results (63,64). Madan et al. (63)

As with other deciencies, pure depletional hyponatremia 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 normovolemic on clinical examination. However, if no
severe hyponatremia symptoms are present, it is recommended to correct the serum Na

concentration

slowly, at a maximal rate of 5 mEq/l per day. If hyponatremia is profound (<125 mEq/l), correction up to
10 mEq/l per day is acceptable (59). At any time,

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 administration 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

change in serum Na concentration with 1 l of infusate

might be approximated by the following formula:
 
 




Na INFUSATE K INFUSATE  Na SERUM TBW 1

demonstrated in a cohort of 322 ADHF patients with

hyponatremia that long-term changes in serum Na
concentration (assessed 60 to 270 days after hospital
discharge) are signicant predictors of mortality, with
improving

hyponatremia

associated

with

better

outcome. In contrast, after correction for disease

severity markers, Lee et al. (64) found that normalization of hyponatremia at hospital discharge was not
associated with improved survival (64). Obviously,
confounding by different treatment strategies in both
studies cannot be excluded, but a conservative
interpretation is that only durable hyponatremia
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 ow should be increased, AVP levels should
be lowered, or AVP effects should be antagonized.
Loop diuretic agents with or without hypertonic
s a l i n e . The

powerful

inhibitory

effect

of

loop

diuretic agents on Na transport in the TAL increases

the amount of tubular uid presented to the distal

with TBW a  body weight (kg), and a 0.6 in chil-

nephron. Loop diuretic agents also reduce hyperto-

dren and nonelderly men, 0.5 in nonelderly women

nicity of the renal interstitium, further facilitating

and elderly men, and 0.45 in elderly women (62). Take

water excretion (Figure 4A) (44). Because loop

for example a female patient, 50 years of age and

diuretic agents are cheap and readily available, they

weighing 62 kg, presents with a serum Na concen-

remain the rst-line therapy in ADHF with dilutional

tration of 130 mEq/l and a serum K of 3.5 mEq/l. This is

hyponatremia and volume overload. The addition of

presumably because of depletion, as she is on a high

hypertonic saline to improve loop diuretic efcacy in

maintenance dose of furosemide (120 mg twice daily)

ADHF is a controversial issue. Although counterin-

and has no overt signs of volume overload. Infusion of

tuitive from a pathophysiological point of view, some

1 normal saline ([Na] 154 mEq/l) with addition of

small studies have suggested more efcient decon-

40 mEq K supplements would be expected to raise

gestion and better renal preservation when loop

the serum Na concentration by 2 mEq/l ([154 mEq/l

diuretic agents are combined with hypertonic saline

40 mEq/l  130 mEq/l]/[(0.5  62) 1]). However,

(Table 2) (6570). Importantly, decreases in plasma

without K supplements, the increase would only be

renin activity, inammatory markers, and even

0.75 mEq/l ([154 mEq/l  130 mEq/l]/[(0.5  62) 1]).

natriuretic peptide levels have been demonstrated

with hypertonic saline administration in ADHF

TREATMENT OF HYPOTONIC

patients who receive loop diuretic agents (71,72). Still,

DILUTIONAL HYPONATREMIA

it remains difcult to draw any rm conclusions,

because the use of high doses of loop diuretic agents

Acute

treatment

of

hypotonic

dilutional

hypo-

that might have induced these alterations might

natremia is focused on promoting free water excretion

have confounded these improvements with sodium

to restore normal serum sodium levels. However, for

loading. As serum Na levels are more easily cor-

long-term treatment success, it is important to subse-

rected, patients with hyponatremia might benet

quently prevent a positive free water balance. This

more from the addition of hypertonic saline to loop

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diuretic

agents;

489

Hyponatremia in Decompensated Heart Failure

however,

this

remains

highly

speculative.
A c e t a z o l a m i d e . Alternatively, combinational diuretic treatment with loop diuretic agents and acet

azolamide ensures minimal tubular Na reabsorption

T A B L E 2 Studies on Hypertonic Saline in Patients With Acute Decompensated

Heart Failure
First Author (Ref. #)

Licata et al. (66)

107 IV furosemide 5001,000 mg

with vs. without 150 ml
1.4%4.6% hypertonic
saline BID

Increase in diuresis, natriuresis,

and serum sodium levels;
decrease in serum creatinine;
and improved survival with
hypertonic saline

Paterna et al. (71)

94 IV furosemide 5001,000 mg
with vs. without 150 ml
1.4%4.6% hypertonic
saline BID

Increase in diuresis and

natriuresis; decrease in BNP
levels; shorter hospitalization
time; and lower 30-day
readmission rate with
hypertonic saline

Parrinello et al. (67)

133 IV furosemide 250 mg plus

150 ml 3% hypertonic
saline BID vs. IV furosemide
250 mg BID plus low
sodium diet (<80 mmol)

Increase in diuresis, natriuresis,

and serum sodium levels;
improved renal function; and
faster reduction of echoPCWP with hypertonic saline

1,771 IV furosemide 250 mg plus

150 ml 3% hypertonic
saline BID vs. IV furosemide
250 mg BID plus low
sodium diet (<80 mmol)

Increase in diuresis, natriuresis,

and serum sodium levels;
decrease in serum creatinine;
shorter hospitalization time;
lower readmission rate; and
improved survival with
hypertonic saline

diuretic resistance in ADHF, acetazolamide should be

preferred over thiazide-type diuretic agents, MRAs, or

medication class to directly promote free water

excretion by prevention of aquaporin-2 channel
availability in the collecting ducts of the nephron
(73,74). Three oral V 2 receptor antagonists (tolvaptan,
satavaptan, and lixivaptan) have been tested for
ADHF, with the former 2 shown to be efcacious in
restoring serum Na levels in patients with volume
overload and hyponatremia (7578). Similar data are

Paterna et al. (68)

available for conivaptan, an intravenous agent that

antagonizes both the V 2 and V 1a receptors (74,79,80).
Table 3 summarizes the currently available evidence
on AVP antagonists in patients with ADHF and hyponatremia. Importantly, EVEREST (Efcacy of Vaso-

Issa et al. (69)

34 100 ml 7.5% hypertonic saline

BID vs. placebo for 3 days

Improved in glomerular and

tubular biomarkers with
hypertonic saline

Okuhara et al. (70)

44 500 ml 1.7% hypertonic saline

vs. glucose 5% with 40 mg
furosemide

Improved GFR and better diuresis

with hypertonic saline

pressin Antagonism in Heart Failure Outcome Study

with Tolvaptan), including 4,133 patients with ADHF

Outcome

Increase in diuresis, natriuresis,

and serum sodium levels;
decrease in serum creatinine;
and shorter hospitalization
time with hypertonic saline

through the distal nephron (29). For this reason, if

ENaC blockers.
A V P a n t a g o n i s t s . AVP antagonists are the only

Treatment

60 IV furosemide 5001,000 mg
with vs. without 150 ml
1.4%4.6% hypertonic
saline BID

proximal from the macula densa and maximal ow

combination therapy is needed to overcome loop

Paterna et al. (65)

but without hyponatremia as an inclusion criterion,

compared tolvaptan with placebo and was powered
for clinical endpoint analysis (81). The overall trial did

BID twice daily; BNP B-type natriuretic peptide; GFR glomerular ltration rate; IV intravenous;
PCWP pulmonary capillary wedge pressure.

not show a signicant reduction in all-cause mortality

or readmission rates, but, interestingly, a subanalysis
in patients presenting with pronounced hyponatremia (<130 mmol/l) suggested improved survival

hyponatremia, less is known about their long-term

free from cardiovascular death or readmission (76,81).

efcacy in providing a sustained correction of serum

This promising nding warrants further study in an

Na levels. In EVEREST, serum Na 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

restriction is uniformly recommended by the guide-

frequently, and the difference with serum Na 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 efcacy, 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,

ow and decrease proximal tubular sodium reab-

and many patients may nd it difcult to comply with

sorption. Therefore, it is not surprising that they were

reported

feeling

thirsty

signicantly

more

strict water restriction (<1 l) (82). Nevertheless, a

among the rst 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

isting renal dysfunction.

efcacious

for

short-term

correction

of

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Hyponatremia in Decompensated Heart Failure

T A B L E 3 Studies on AVP Antagonists in Patients With Acute Decompensated Heart

Failure and Hyponatremia

mortality, afterload reduction probably remains the

best option to increase the effective circulatory volume; however, its use is limited by low arterial blood

First Author (Ref. #)

n/N

Gheorghiade et al. (77)

71/254
(subgroup
analysis)

Treatment

Outcome

Tolvaptan 30, 45, or

Normalization of serum
60 mg vs. placebo
sodium after 24 h,
greater decrease in body
weight and edema,
increased urine output
with tolvaptan

pressure (86,87). Observational data have demonstrated that nitroprusside, titrated on arterial blood
pressure and with conversion to oral hydralazine and
nitrates, is feasible and potentially associated with
better outcomes in ADHF (88,89). Alternatively, ser-

Gheorghiade et al. (78)

51/319
(subgroup
analysis)

Tolvaptan 30, 60, or

Normalization of serum
90 mg vs. placebo
sodium with tolvaptan

elaxin, a vasodilator agent under investigation, might

Ghali et al. (79)

19/74
(subgroup
analysis)

Conivaptan 40 or
Normalization of serum
80 mg vs. placebo
sodium with conivaptan

vasodilator properties (90,91). The RELAX-AHF-EU

Zeltser et al. (80)

28/84
(subgroup
analysis)

Conivaptan 40 or
Increase in serum sodium
80 mg vs. placebo
concentration with
conivaptan

1,157/4,133
(subgroup
analysis)

Tolvaptan 30 mg vs.
placebo

90/118
(subgroup
analysis)

Satavaptan 25 or 50 mg Increase in serum sodium

vs. placebo
concentration with
satavaptan

Konstam et al. (81)

Aronson et al. (75)

No effect on mortality or
rehospitalization,
signicant increase in
serum sodium with
tolvaptan

be of particular interest because of its specic renal

(Effect of Serelaxin Versus Standard of Care in Acute
Heart Failure Patients) trial is currently enrolling
ADHF patients and is powered for clinical endpoint
evaluation (92). Nevertheless, the specic effects of
both inotropes and vasodilator therapy on hyponatremia remain insufciently elucidated.

CONCLUSIONS
The pathophysiology of hyponatremia in ADHF is
complex, and a 1-size-ts-all approach is therefore

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
effective circulatory volume in heart failure is expected to result in less nonosmotic AVP release
and better renal blood ow, which, from a pathophysiological perspective, might help to correct dilutional hyponatremia. Because cardiac output in ADHF
is rather insensitive to changes in cardiac pre-loadas

likely to fail. Appropriate differentiation between

dilutional and depletional hyponatremia is crucial
and depends on good history taking, clinical examination, and correct interpretation of laboratory results. A targeted, pathophysiology-based approach
should help to treat this challenging condition efciently, thereby minimizing adverse events.

the Frank-Starling mechanism is depletedimprovements 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