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Hepatology Research 2016
Review Article
Diuretic usage for protection against end-organ damage in
liver cirrhosis and heart failure
Takefumi Mori,1,2,3 Yusuke Ohsaki,2,3 Ikuko Oba-Yabana1,2,3 and Sadayoshi Ito1
1
Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine,
Sendai, Japan, 2Division of Integrative Renal Replacement Therapy, Tohoku University Graduate School of Medicine
and 3Division of Nephrology and Endocrinology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
Volume overload is common in liver cirrhosis, heart failure, and
chronic kidney disease, being an independent risk factor for
mortality. Loop diuretics have been widely used for treating vol-
ume overload in these patients. However, there is a tendency to
increase the dose of loop diuretics partly because of diuresis re-
sistance. Neurohormonal factors are also enhanced in these pa-
tients, which play a role in volume overload and organ ischemia.
Loop diuretics cannot improve neurohormonal factors and could
result in end-organ damage. The water diuretic tolvaptan has
been approved for use for volume overload in heart failure and
liver cirrhosis. Despite causing similar increases in urine volume,
its characteristics differ from those of loop diuretics. Renal blood
flow is maintained with tolvaptan but decreased with furose-
mide in heart failure patients. Neurohormonal factors and blood
pressure are not markedly altered by tolvaptan administration. It
INTRODUCTION
V OLUME OVERLOAD IS common in patients with liver
cirrhosis, heart failure and chronic kidney disease, and
is an independent risk for mortality.1,2 Patients with ascites
accompanying liver cirrhosis have been shown to have
higher mortality.3 Progression to renal failure often occurs
in patients with liver cirrhosis, which can result in
mortality.4 Thus, volume overload is treated by diuretics
with various characteristics, as shown in Figure 1. Loop
diuretics are the major class of drugs used for controlling
Correspondence: Takefumi Mori, Division of Nephrology, Endocrinology, and
Vascular Medicine, Tohoku University Graduate School of Medicine, 1–1
Seiryo-machi, Aoba-ku, Sendai 980–8574, Japan. Email: tmori@med.
tohoku.ac.jp
Received 3 January 2016; revision 9 March 2016; accepted 10 March 2016.
Conflict of interest: T.M. is a consultant at a clinical trial by Otsuka Phar-
maceutical and has received honoraria for lectures and research
funding from Otsuka Pharmaceutical. The Division of Integrative Re-
nal Replacement Therapy is financially supported by Terumo, JMS,
Kyowa Hakko Kirin, and Otsuka Pharmaceutical.
© 2016 The Japan Society of Hepatology
doi: 10.1111/hepr.12700
is expected that these mechanisms of tolvaptan can protect
against worsening renal function by volume overload diseases
compared with loop diuretics. It has also been reported that
some patients do not respond well to tolvaptan. Loop diuretics
and tolvaptan share the same mechanism with regard to de-
creasing renal interstitial osmolality, which plays a fundamental
role in water diuresis. Thus, a high dose of loop diuretics could
result in resistance to tolvaptan, so tolvaptan should be adminis-
tered before increasing the loop diuretic dose. Therefore, vol-
ume control without enhancing end-organ damage can be
achieved by adding tolvaptan to a tolerable dose of Na-sparing
diuretics.
Key words: renal congestion, renin angiotensin system,
vasopressin
volume overload in these diseases. Despite their beneficial
diuretic effects, loop diuretics can induce renal dysfunction
and hyponatremia. Hyponatremia is also a risk for mortal-
ity in liver cirrhosis, heart failure, and renal failure.2
Resistance to furosemide frequently develops in cases of
liver cirrhosis by several mechanisms, such as reduced re-
nal flow and hypoalbuminemia,5 necessitating a high dose
of furosemide. In addition, furosemide can induce hepatic
encephalopathy with an increase in serum ammonia.6
The levels of renin–angiotensin system components,
vasopressin and catecholamine are increased in associa-
tion with the pathogenesis of liver cirrhosis.5 Although
tolvaptan increases urine volume similarly to furosemide,
these two diuretics differ in numerous characteristics. First,
tolvaptan is a water diuretic, but furosemide is an Na
diuretic, so Na excretion differs markedly between the
two.7 Second, it has been reported in heart failure patients
that renal blood flow is maintained after tolvaptan treat-
ment, but furosemide reduces it.8 In addition, vasocon-
strictive neurohormonal parameters such as the levels of
renin–angiotensin system components and vasopressin
1
2 T. Mori et al. Hepatology Research 2016

Figure 1 Site of diuretic action in the nephron. Carbonic anhydride inhibitors, loop diuretics, thiazide diuretics, and aldoste-
rone blockers are commonly used for volume overload diseases such as liver cirrhosis, heart failure, and renal failure. Car-
bonic anhydride inhibitors act in proximal tubules, loop diuretics act in the thick ascending limb of Henle, thiazide acts
in the distal nephron, aldosterone blockers act in the late distal nephron and early collecting ducts, amilorides act in early
collecting ducts, and vasopressin V2 receptor blockers act in collecting ducts. The loop diuretic furosemide and the aldoste-
rone blocker spironolactone are major diuretics used for liver cirrhosis. Carbonic anhydride inhibitors, loop diuretics, and
thiazide diuretics are drugs that act from the luminal side of tubules. In contrast, aldosterone blockers and V2 receptor
blockers act from the basolateral side, which may have a beneficial role in liver cirrhosis. The V2 receptor blocker tolvaptan
is now used for volume control in heart failure and liver cirrhosis and acts at the most distal part of the nephron, namely,
the collecting ducts, which is tolerant to ischemic renal injury.

are not altered after tolvaptan treatment in heart failure.9
Blood pressure is also maintained at baseline levels with
tolvaptan compared with that with furosemide.9 Although
some patients do not respond to it, tolvaptan can increase
urine volume, even in those with chronic renal failure.10
These lines of evidence suggest that tolvaptan could play
a beneficial role in body fluid control in heart failure and
chronic renal failure without negatively affecting renal
function, instead improving renal congestion and the
cardio–renal connection.
However, in Japan, tolvaptan has not been approved
without cotreatment with Na-sparing diuretics. Patients
have to be hospitalized for a week when it is first pre-
scribed, so that the plasma Na concentration can be mon-
itored. Because of this burden, doctors tend to increase the
dose of furosemide first and then administer tolvaptan af-
ter a high dose of furosemide in cases in a diuretic-resistant
state. In this state, patients also become resistant to
tolvaptan and cannot benefit from its use. Thus, in this re-
view, we focus on the role of the renal circulation in the

© 2016 The Japan Society of Hepatology

Hepatology Research 2016 Diuretic usage in volume overload diseases 3

pathogenesis of liver cirrhosis and heart failure, and the
pathophysiological benefit of tolvaptan in these volume
overload diseases.
RENAL INJURY IN LIVER CIRRHOSIS AND HEART
FAILURE
Na excretion. Unfortunately, the precise mechanisms by
which these mechanisms reduce renal perfusion pressure
and renal flow remain to be elucidated.
Arterial underfilling, a common mechanism for liver cir-
rhosis and heart failure, could result in hypoxia in the kid-
ney, which is a common final pathway for renal injury.18
Kidney is normally hypoxic because of its unique vascular

R ENAL DYSFUNCTION COMMONLY occurs in liver

cirrhosis and heart failure, and renal disease causes
deterioration of liver and heart function.11,12 This vicious
cycle via the hepato–renal or cardio–renal connection is
one of the major concerns in liver disease or heart failure,
respectively, and could play an important role in the prog-
nosis of these diseases. There are a number of mechanisms
involved in the hepato–renal and cardio–renal connections,
the pathways of which may be shared or differ. Enhanced
vasoconstrictive neurohormones are the shared pathways,
such as the renin–angiotensin system components, vaso-
pressin and catecholamine. These vasoconstrictive neuro-
hormones are enhanced by arterial underfilling in both
liver cirrhosis and heart failure.13,14 Inappropriate increases
in these neurohormones result in renal ischemia, Na reten-
tion and the further induction of volume overload.
In addition to underfilling, overflow and peripheral arte-
rial vasodilation are also known to be involved in volume
overload and ascites formation and are mechanisms
somewhat specific to liver cirrhosis.15,16 These mecha-
nisms have been reviewed elsewhere and will not be
discussed in detail here.17 However, underfilling, overflow,
and peripheral arterial vasodilation share common mech-
anisms and result in the reduction of renal blood flow and
and tubular anatomy; it actively creates a hypoxic environ-
ment by a countercurrent mechanism, as summarized in
Figure 2.19–21 Specifically, in this mechanism, oxygen dif-
fuses from arteries to veins that run parallel to each other.
Thus, oxygen pressure is as low as 10–20 mmHg at the tip
of the papilla.22 Tubules in the papilla, such as collecting
ducts and the thin limb of Henle, do not require oxygen
because they do not actively transport Na. However, those
in the outer medulla require oxygen because of active
Na transport by the furosemide-sensitive Na–K–2Cl
cotransporter, which is located on the luminal side of the
thick ascending limb of Henle. Na–K–2Cl cotransporter
activity is dependent on Na–K ATPase on the basolateral
side of the tubules pumping Na out of the cell membrane.
Oxygen-consuming mitochondrial ATP production is re-
quired for the Na–K ATPase pump. Thus, the outer me-
dulla is the region where oxygen is consumed, but is
normally hypoxic. Although total renal blood flow is
20% to 25% of cardiac output, medullary blood flow is ap-
proximately 10% or less of total renal blood flow.23 As
such, small changes in renal medullary blood flow could
further induce hypoxia in the outer medulla. Therefore,
tubulointerstitial injury in the outer medulla could be ob-
served in animal models of ischemic renal diseases that

Figure 2 Kidney is a hypoxic organ. The

blood flow of the renal medulla is as little
as 10% of total renal flow. In addition, as
the circulation of the renal medulla is not
well autoregulated, reduction of blood
pressure could result in renal medullary is-
chemia. The tip of the medulla is generally
hypoxic by the diffusion of oxygen from
adjacent arteries to veins in the medulla,
which is called the countercurrent mecha-
nism. Tubules and collecting ducts in the
inner medulla are tolerant to hypoxia,
whereas the thick ascending limb of Henle
and proximal tubules are susceptible to it.
Thus, ischemic renal injury occurring in hy-
pertension and diabetes is observed in the
outer medulla. In this regard, a response
to tolvaptan, which acts in the collecting
ducts, could occur in patients with ischemic
renal injury.

© 2016 The Japan Society of Hepatology

4 T. Mori et al.
reduce medullary blood flow, such as hypertension, diabe-
tes, and ischemic acute kidney injury.
Renal circulation plays an important role in the patho-
genesis of both liver cirrhosis and heart failure. Total renal
blood flow and cortical blood flow are well autoregulated
by changes in renal arterial perfusion pressure.24,25 How-
ever, using laser Doppler flowmetry, it has been shown
in anesthetized rats that renal medullary blood flow is
not well autoregulated and a decrease in renal perfusion
pressure results in a reduction of renal medullary blood
flow.25 Arterial underfilling and reduced renal blood flow
could further result in a reduction of renal medullary
blood flow, which could enhance ischemia in the outer
medulla.
Renal medullary blood flow participates in the regula-
tion of Na metabolism and volume control.23,26 It has also
been reported in rat models that a reduction of renal med-
ullary blood flow by 10–30% increases Na retention in the
renal tubules.26 A reduction of renal blood flow in cases of
liver cirrhosis and heart failure results in increases of Na re-
tention and volume overload. In addition, enhanced activ-
ity of the renin–angiotensin system could produce reactive
oxygen species in the renal medulla and further reduce
blood flow and increase Na retention in the tubules.27 It
has been shown that high salt intake in Dahl salt-sensitive
rats, a model of heart failure, induces volume-dependent
hypertensive heart failure and renal injury.28 An increase
of reactive oxygen species as well as a decrease of nitric ox-
ide was observed in response to angiotensin II in the outer
medulla.29 This leads to a reduction of medullary blood
flow and increased Na retention and renal injury.27,30–32
Although reduced medullary blood flow in liver cirrhosis
is also expected to be involved in enhanced Na retention
and renal injury, the mechanism involved has not been
well established and requires further investigation. How-
ever, it has been reported that Na reabsorption was en-
hanced in the medullary thick ascending limb in a rat
model of liver cirrhosis.33
Renal congestion has been considered as one of the
mechanisms responsible for the cardio–renal connection
and the mechanism regulating renal blood flow and Na re-
tention. As shown in Figure 3(a), renal interstitial fluid
flows from the medulla to the cortex.34 Water reabsorption
from the collecting ducts is one of the features upstream of
this interstitial flow. As the kidney is covered with a cap-
sule, an increase in renal venous pressure by vena cava
pressure increases renal interstitial pressure (Fig. 3b).35
This increase in renal interstitial pressure compresses renal
capillaries such as the vasa recta and tubules, which could
result in reductions of medullary blood flow and glomeru-
lar filtration, respectively. A reduction of renal medullary
© 2016 The Japan Society of Hepatology
Hepatology Research 2016
blood flow increases sodium reabsorption from the tu-
bules and increases body fluid, which could result in
sustained hypertension.21,27
Renal congestion could also play an important role in
the pathogenesis of liver cirrhosis. As this shunt floods into
the renal vein, renal venous pressure is expected to increase
in accordance with portal hypertension. Because of arterial
underfilling and a lower renal perfusion pressure, a higher
relative renal interstitial pressure could compress the
peritubular capillaries and the vasa recta, potentially re-
ducing renal medullary blood flow and causing ischemia.
However, renal congestion in liver cirrhosis has not been
well characterized and requires further investigation.
LOOP DIURETIC RESISTANCE IN LIVER
CIRRHOSIS AND HEART FAILURE
T HE LOOP DIURETIC furosemide binds to albumin in
the blood and is delivered to the renal circulation.36
When the furosemide–albumin complex reaches the
peritubular capillaries of proximal tubules, furosemide is
transported to the tubular lumen by organic anion trans-
porters (Fig. 4).37 During this transport, the albumin disas-
sociates, leaving furosemide in its free form. This free
furosemide blocks the Na–K–2Cl cotransporter at the thick
ascending limb of Henle. As shown in Figure 4, furosemide
resistance can occur when the delivery of furosemide to the
Na–K–2Cl cotransporter is disturbed, such as in renal hypo-
perfusion, hypoalbuminuria, and renal dysfunction, as
commonly observed in liver cirrhosis and heart failure.38
Hypoperfusion by arterial underfilling in cases of heart
failure and liver cirrhosis could reduce renal flow, causing
reduced delivery of the furosemide–albumin complex. Hy-
poalbuminemia due to a reduced nutritional status, in-
flammation, and liver cirrhosis could inhibit the binding
of furosemide to albumin. Hypokalemia due to hyperal-
dosteronism could induce renal tubulointerstitial injury
in the outer medulla, where the active site of the
furosemide-sensitive Na–K–2Cl cotransporter is located.
In albuminuria cases, such as in nephrotic syndrome and
diabetic nephropathy, furosemide resistance may also be
evident because of free furosemide binding again to albu-
min in the tubules, thereby also inhibiting the effect of fu-
rosemide. Drugs that inhibit organic anion transporters
could also inhibit the effects of furosemide.
Alternatively, furosemide may increase the levels of
vasopressor neurohormones such as renin–angiotensin
system components, vasopressin and catecholamine.
In addition, metabolic dysfunction such as ammonia
accumulation and electrolyte disorders, including
hyponatremia and hypokalemia, can occur. As
Hepatology Research 2016 Diuretic usage in volume overload diseases 5

Figure 3 Mechanism of renal congestion. Illustration of the tubules and blood vessels in the outer medulla. The thick ascending limb of
Henle located on the left side and the adjacent collecting ducts are located on the right. (a) Steady state. Interstitial fluid flows from the
medulla to the cortex and floods into the cortical vein. Upstream of this interstitial fluid flow, water absorption from collecting ducts
occurs. (b) Renal congestion. Renal interstitial pressure increases by an increase of venous pressure. Increased interstitial pressure results
in the compression of tubules and vessels, reducing the glomerular filtration rate and renal blood flow, respectively. NKCC2, Na–K–2Cl;
TAL, thick ascending limb of Henle.

furosemide is short-acting, it does not cause the excre-
tion of Na for over 24 h; instead, rebound of the absorp-
tion of Na can be observed after the effect of furosemide
has dissipated. In addition, furosemide increases ammo-
nium production in the kidney, so careful attention
should be paid in cirrhosis patients with a high blood
ammonia level.6
DISCOVERY OF WATER DIURETICS
W ATER DIURETICS WERE largely developed by
Manning and colleagues in the 1960s and 1970s
as peptide analogs of vasopressin.39 The development of
vasopressin V2 receptor agonists and antagonists made a
major contribution to establishing the pathophysiological

© 2016 The Japan Society of Hepatology

6 T. Mori et al.
mechanism behind water diuresis and renal physiological
function using animals and cells. However, concerns were
raised about the half-life, bioavailability, species differ-
ence, and specificity of peptide vasopressin antagonists.
Yamamura et al. were the first to establish a non-peptide
water diuretic, OPC-31 260 (mozavaptan).40 In a dog
model of heart failure, an increase in serum Na level and
a decrease in plasma atrial natriuretic peptide were ob-
served when OPC-31 260 was given. Despite these results,
OPC-31 260 also shows species differences in water diure-
sis, so in Japan it was not approved for use in heart failure
and only approved for the syndrome of inappropriate
antidiuretic hormone secretion in cancer cases. OPC-
41 061 (tolvaptan) was also established by Yamamura
et al., showing higher bioavailability.7 As shown in
Figure 1, tolvaptan acts in the most distal portion of the
nephron, in contrast to other available diuretics.
ROLE OF TOLVAPTAN IN THE HEPATO–RENAL
CONNECTION AND CARDIO–RENAL
CONNECTION
T HE NON-PEPTIDE V2 receptor antagonist tolvaptan, a
water diuretic, has been shown to be efficacious and
safe, and was first approved for use in heart failure,41 then
in liver cirrhosis42 and recently in autosomal dominant
polycystic kidney disease43 in Japan. The benefits of
tolvaptan have been well documented in heart failure pa-
tients and in animal models. In a study in which heart
© 2016 The Japan Society of Hepatology
Hepatology Research 2016
Figure 4 Mechanism of furosemide
resistance. Illustration of furosemide
action and mechanism of furosemide
resistance. Furosemide binds to albumin
in the blood and is delivered to the renal
circulation. Furosemide is transported
through organic anion transporters
(OAT-1 and OAT-4) into the tubular
lumen. Albumin is detached when
furosemide is transported through OATs.
Free furosemide is delivered to Na–K–2Cl
(NKCC2) cotransporters and inhibits Na
reabsorption. Thus, mechanisms 1–8 are
the common mechanisms of furosemide
resistance. GFR, glomerular filtration rate;
NSAIDs, non-steroidal anti-inflammatory
drugs.
failure patients were treated with a placebo or tolvaptan
and then switched over to furosemide, renal flow was
decreased during furosemide treatment and was not
decreased, but instead increased, by tolvaptan.8 The results
in the QUEST study9 also showed its beneficial role for
body fluid control in heart failure cases without altering
the activity of plasma vasopressin and renin, which are
usually upregulated by furosemide. Blood pressure was
also maintained in the tolvaptan group.
The role of tolvaptan in Dahl salt-sensitive rats, a
model of cardio–renal failure, was also determined.
Cardio–renal injury was observed in such rats fed a
high-salt diet. The oral administration of tolvaptan
reduced cardio–renal injury without altering blood pres-
sure, heart rate, or electrolyte parameters. Neurohor-
monal parameters such as plasma renin activity and
serum aldosterone and plasma vasopressin concentra-
tions were unchanged. A significant reduction of renin
mRNA expression was observed in heart and renal tissues
isolated from rats in the tolvaptan treatment group com-
pared with that in the control high-salt-fed group, sug-
gesting that the tissue renin–angiotensin system is
inhibited by tolvaptan. Interestingly, the expression of
V2 receptor mRNA was also observed. These lines of evi-
dence suggest that tolvaptan could play a beneficial role
in body fluid control without altering renal function in
heart failure by improving the renal circulation.
Tolvaptan is expected to reduce renal congestion by sev-
eral pathways (Fig. 5). First, reduction of the systematic
Hepatology Research 2016 Diuretic usage in volume overload diseases 7

volume by water diuresis could reduce the pressure in both
the vena cava and the renal vein. Second, renal interstitial
fluid is reduced by a decrease in water reabsorption from
the collecting ducts. A reduction of renal congestion also
occurs with loop diuretics, so they show similar advan-
tages in this regard. However, large differences in renal cir-
culation were observed between loop diuretics and
tolvaptan in heart failure cases. These findings suggest the
beneficial role of tolvaptan in heart failure by improving
the cardio–renal connection and the vicious cycle
associated with renal congestion. The beneficial role of
tolvaptan for the renal circulation has not been well deter-
mined in liver cirrhosis. However, as reduced renal flow is
also expected to occur through arterial underfilling and re-
nal congestion in liver cirrhosis, tolvaptan should play a
beneficial role in the pathogenesis of the hepato–renal
connection in this disease.44–46 Hyponatremia is also com-
monly observed in liver cirrhosis and heart failure, which
is also a risk for mortality.2 Tolvaptan could improve
hyponatremia by the excretion of free water, which is also

Figure 5 Beneficial role of tolvaptan in renal congestion. Illustration of tolvaptan action in renal congestion. (a) Renal congestion as
described in Figure 3(b). (b) Tolvaptan treatment. Tolvaptan could improve renal congestion by the reduction of venous pressure with
volume control, thereby reducing interstitial pressure. However, tolvaptan could also reduce upstream interstitial flow by inhibiting wa-
ter retention, resulting in a reduction of interstitial pressure. TAL, thick ascending limb of Henle.

© 2016 The Japan Society of Hepatology

8 T. Mori et al. Hepatology Research 2016

a benefit of using this drug for body fluid control in liver of the tubules. Therefore, as long as renal blood flow is
cirrhosis and heart failure. maintained, it is not dependent on glomerular filtration.
Second, in contrast to furosemide, tolvaptan does not bind
VASOPRESSIN RECEPTORS IN THE REGULATION to albumin, so hypoalbuminemia does not develop and
OF RENAL CIRCULATION cause diuretic resistance when it is given. In addition, the
collecting ducts do not require oxygen, so it can be success-
A LTHOUGH THE BENEFICIAL role of tolvaptan has
been evaluated, the precise mechanism by which it
maintains renal function is not fully understood. There
fully administered irrespective of hypoxia.
Despite the beneficial role of tolvaptan in cases of liver
cirrhosis and heart failure, it has been reported that there
is good evidence that terlipressin plays a beneficial role
are patients who do not respond to it.10,51,52 For example,
in the renal circulation in hepato–renal syndrome.47
Imamura et al. suggested that those with baseline urinary
How could both the stimulation of vasopressin recep-
osmolality over 352 mOsm/kg and an increase in urinary
tors by vasopressin and the inhibition of V2 receptors
osmolality by 26% at 4–6 h after tolvaptan treatment in-
by tolvaptan increase renal blood flow? There are several
cluded a higher rate of responders in heart failure.52 This
hypotheses to explain this. The functional mechanisms
can be explained by renal interstitial osmolality, which is
associated with vasopressin receptors have been well in-
largely determined by urea transport in the collecting ducts
vestigated in rats.48,49 A low subpressor dose of vaso-
and Na reabsorption from the Na–K–2Cl cotransporter
pressin infused in the renal medulla did not change
and Na/K ATPase in the thick ascending limb of Henle.53
renal medullary blood flow.49 However, renal medul-
Urinary osmolality has a strong association with renal in-
lary infusion of a low dose of a NO synthase inhibitor,
terstitial osmolality.53 As shown in Figure 6(a), interstitial
L-NG-nitroarginine methyl ester, which does not reduce
osmolality is increased by Na reabsorption from the Na–
medullary blood flow itself, at the same subpressor dose
K–2Cl cotransporter in the thick ascending limb of Henle
as vasopressin, reduced medullary blood flow, indicat-
and urea transporter in the collecting duct by vasopressin.
ing that vasopressin induced NO production and
As aquaporin 2, a water channel, is stimulated by renal in-
inhibited the reduction of medullary blood flow by va-
terstitial osmolality, a reduction of renal interstitial osmo-
sopressin.49 Vasopressin induces NO in the inner med-
lality results in a reduction of aquaporin 2 activity and
ullary collecting ducts by a calcium-dependent
thereby inhibits water reabsorption.53 Tolvaptan inhibits
pathway.50 However, how vasopressin receptors are in-
urea transport in the collecting duct, reduces interstitial os-
volved in NO production in the renal medulla has yet
molality, and excretes free water (Fig. 6b). Furosemide
to be investigated. V1 receptor agonist reduced medul-
blocks the Na–K–2Cl cotransporter and decreases Na reab-
lary blood flow, but V2 receptor agonist did not have
sorption from the thick ascending limb, thereby reducing
such an effect, although it increased medullary blood
renal interstitial osmolality (Fig. 6c). In addition, it can in-
flow.48 Thus, a dose of terlipressin that does not mark-
hibit urea transport and further reduce renal interstitial os-
edly reduce medullary blood flow may actually increase
molality.54 Thus, furosemide can strongly reduce urinary
it through a V2-receptor-dependent pathway. In this
osmolality together with renal interstitial osmolality. In
context, the V2 receptor antagonist tolvaptan could be
this regard, furosemide and tolvaptan share a common
expected to reduce medullary blood flow through V2 re-
mechanism for water diuresis. If a low dose of furosemide
ceptor antagonism, but it actually does not reduce such
is given prior to tolvaptan, tolvaptan can further reduce in-
flow at all. This could in part be explained by the finding
terstitial osmolality and increase water diuresis (Fig. 6d).
that tolvaptan reduced the levels of both V1 and V2 re-
However, if a high dose of furosemide is given prior to
ceptor mRNA. However, there is little evidence of the
tolvaptan, resistance to tolvaptan is likely to develop by
role of renal vasopressin receptors in liver cirrhosis, so
maximum reduction of interstitial osmolality (Fig. 6e).54
further study of this issue is also required.
If patients receive a high dose of furosemide and show re-
duced urine osmolality, together with reduced renal inter-
RESPONSE TO TOLVAPTAN IN HEART FAILURE
stitial osmolality, it is unlikely that they will respond to
PATIENTS AND TOLVAPTAN RESISTANCE
tolvaptan. In addition, if tolvaptan fails to reduce urinary

A s described above, resistance to loop diuretics is often

observed in cases of liver cirrhosis and heart failure.
Tolvaptan has an advantage over loop diuretics in that
the diuretic response occurs by a different mechanism.
First, it blocks the V2 receptor from the basolateral side
osmolality, together with unchanged renal interstitial os-
molality, the patient is also unlikely to respond to
tolvaptan. These mechanisms have been explained in heart
failure patients, but little evidence on them has been ob-
tained for liver cirrhosis. Although similar mechanisms

© 2016 The Japan Society of Hepatology

Hepatology Research 2016 Diuretic usage in volume overload diseases 9

Figure 6 Role of interstitial osmolality (Osm) in the diuretic response. Illustration of the regulation of interstitial osmolality by vaso-
pressin and diuretics. The level of interstitial osmolality has a positive linear correlation with urinary osmolality, which explains why
urinary osmolality could predict responders and non-responders to tolvaptan. (a) Role of interstitial osmolality in the antidiuretic re-
sponse by vasopressin. Vasopressin stimulates Na reabsorption in the thick ascending limb of Henle (TAL) and urea transport in the
collecting ducts and increases interstitial osmolality. Interstitial osmolality stimulates water retention by aquaporin 2 and concentrates
the urine. (b) Changes in interstitial osmolality after tolvaptan treatment. Tolvaptan inhibits urea transporter by blockade of the V2 re-
ceptor. Reduction of interstitial osmolality inhibits water retention. (c) Changes in interstitial osmolality after furosemide treatment. Fu-
rosemide inhibits Na reabsorption and urea transport to the interstitium and reduces osmolality, thereby inducing Na and water
diuresis. (d) State of interstitial osmolality for responders to tolvaptan. When interstitial osmolality is maintained by low-dose furose-
mide, tolvaptan could further reduce urea transport and osmolality, thereby increasing water diuresis. (e) State of interstitial osmolality
for non-responders to tolvaptan. When interstitial osmolality is maximally reduced by high-dose furosemide, tolvaptan cannot further
reduce interstitial osmolality, so no response can be expected. NKCC2, Na–K–2Cl.

are expected to be observed in liver cirrhosis, this should
be confirmed by future clinical studies.
ROLE OF TOLVAPTAN IN CHRONIC RENAL
FAILURE
undergoing peritoneal dialysis.10 Tolvaptan was given
to 15 peritoneal dialysis patients at a dose of 15 mg daily.
A total of 11 patients responded, and their urine volume
was increased by more than 400 mL/day, together with a
reduction of urinary osmolality. Interestingly, urinary Na
excretion increased in responders. Although several

A LTHOUGH TOLVAPTAN IS approved for use in body

fluid control in heart failure and liver cirrhosis cases, it
has not yet been approved for use in renal failure. We pre-
viously determined the effectiveness of tolvaptan in pa-
tients with end-stage renal disease and heart failure
mechanisms could be responsible for the increase in Na
excretion and further investigation is required, the
improvement of renal congestion could be one of the
mechanisms explaining the increase in Na excretion by
tolvaptan. As an initial step in research on this issue, this

© 2016 The Japan Society of Hepatology

10 T. Mori et al.
study has shown the beneficial role of tolvaptan, even in
patients with end-stage renal disease.
CONCLUSION
T OLVAPTAN IS NOW widely used for hyponatremia in
heart failure and liver cirrhosis cases, but its potential
benefits in other volume overload diseases have not been
well investigated. As shown in Figure 7, we hypothesize that
renal congestion plays a major role in the pathogenesis of
heart failure and possibly in liver cirrhosis, explaining why
Na retention, volume overload, and renal injury are
commonly observed in heart failure and liver cirrhosis.
Tolvaptan could improve renal congestion through several
pathways, so it is expected to reduce volume without alter-
ing blood pressure and neurohormones or injuring organs.
The accumulation of evidence on the use of this diuretic is
required.
ACKNOWLEDGMENTS
W E THANK KENJI Koizumi MD, PhD, Shinichi Sato
MD, PhD, Satoshi Shimada MD, Emiko Sato PhD,
Naho Kurasawa, Mihoko Tsuchikawa, Eri Naganuma,
Chika Takahashi, and staff members of the Division of
© 2016 The Japan Society of Hepatology
Hepatology Research 2016
Figure 7 Tolvaptan hypothesis for the
pathogenesis of renal congestion. Illustra-
tion of the role of tolvaptan in the treat-
ment of renal congestion. Upper panel:
Renal congestion. Increase in central ve-
nous pressure (CVP) or portal vein pres-
sure could induce renal congestion,
which could increase renal interstitial hy-
drostatic pressure, resulting in renal ische-
mia and Na retention by the compression
of renal vessels and tubules. Lower panel:
Tolvaptan treatment. Treatment with
tolvaptan can improve renal congestion
by the reduction of interstitial hydrostatic
pressure and the compression of vessels
and tubules, thereby protecting against re-
nal injury and increased Na excretion.
Nephrology, Endocrinology, and Vascular Medicine,
Tohoku University Graduate School of Medicine, for their
advice and administrative and technical assistance. This
study was supported in part by Grants for Scientific Re-
search (25 293 193, 26 670 424, and 25 860 156) from
the Ministry of Education, Culture, Sports, Science and
Technology of Japan and the Japan Society for the Promo-
tion of Science.
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