European Journal of Internal Medicine 17 (2006) 8 – 19

www.elsevier.com/locate/ejim

Review article

Management of cirrhotic ascites: Physiological basis of diuretic action

Mitchell H. Rosner a,*, Rohit Gupta a, David Ellison b, Mark D. Okusa a
a
Division of Nephrology, University of Virginia School of Medicine, Box 133 Health Science Center, Charlottsville, VA 22908-0001, USA
b
Division of Nephrology, Hypertension and Clinical Pharmacology, Oregon Health Sciences University, Suite 262,
3314 S.W. US Veterans Hospital Rd., Portland, OR 97201, USA

Received 30 April 2005; received in revised form 24 July 2005; accepted 25 August 2005

Abstract

Ascites is a significant complication of cirrhosis that occurs in approximately 50% of patients. The mortality rate is high in patients with
cirrhosis and ascites. Conventional interventions rest with dietary sodium restriction, diuretic use, large-volume paracentesis,
peritoneovenous shunts and transjugular intrahepatic portosystemic shunts. The mainstay of therapy, however, is the judicious use of
diuretics. This article reviews the physiological basis of diuretic use in patients with cirrhosis and ascites, as well as recent concepts on the
pathogenesis of ascites formation. Through a better understanding of the pathophysiology of ascites formation and the mechanism of action
of diuretics, improved extracellular fluid balance can be achieved in these patients.
D 2005 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Keywords: Diuretics; Cirrhosis; Ascites; Diuretic resistance

Contents

1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2. Pathophysiology of ascites formation in cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.1. Portal hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.2. Renal sodium retention and impairment of water excretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
3. Mechanism of diuretic action. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
3.1. Normal renal sodium chloride handling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
3.2. Loop diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3.3. Distal convoluted tubule diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
3.4. Cortical collection tubule diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
4. Pharmacokinetics and pharmacodynamics of diuretics in cirrrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
5. Treatment of cirrhotic ascites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
5.1. Sodium restriction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
5.2. Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
5.3. Diuretic resistance in cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
5.4. Albumin infusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
5.5. Large-volume paracentesis, peritoneovenous shunts and transplantation . . . . . . . . . . . . . . . . . . . . . . . . . 15
6. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

* Corresponding author. Tel.: +1 434 924 2187; fax: +1 434 924 5848.
E-mail address: mhr9r@virginia.edu (M.H. Rosner).

0953-6205/$ - see front matter D 2005 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejim.2005.08.003
 M.H. Rosner et al. / European Journal of Internal Medicine 17 (2006) 8 – 19
1. Introduction
Patients with cirrhosis and portal hypertension typically
develop altered extracellular volume regulation with renal
sodium and water retention. This eventually leads to the
development of ascites, which is the most common of the
major complications of cirrhosis [1]. The mainstay of the
management of ascites is the use of diuretics, which reverses
the renal sodium and water retention in an attempt to
normalize extracellular volume. Optimal diuretic manage-
ment requires an understanding of both the pathophysiology
of ascites formation and the pharmacology of diuretic
agents.
2. Pathophysiology of ascites formation in cirrhosis
The development of ascites in patients with cirrhosis
involves two major factors: portal hypertension and renal
sodium and water retention [2 –5]. Other factors of variable
importance include systemic hemodynamic abnormalities
and the interplay of numerous endocrine and paracrine
effector mechanisms.
2.1. Portal hypertension
Diseases that lead to cirrhosis lead to post-sinusoidal
vascular obstruction secondary to deposition of collagen in
the liver with distortion of the hepatic architecture [6,7].
This results in marked hypertension within the hepatic
sinusoids with the eventual development of portal hyper-
tension. Portal hypertension is required for the development
of cirrhotic ascites [8– 11]. Although the threshold pressure
before ascites develops is not known, Gines et al.
demonstrated that only 4 of 99 patients with ascites had a
portal pressures below 12 mm Hg, as measured by hepatic
venous wedge pressure [12].
The hepatic sinusoids, unlike other capillary beds, are
extremely permeable to plasma proteins [13]. This high
degree of vascular permeability means that fluid movement
across the sinusoids is almost entirely dictated by hydro-
static pressure. Thus, the obstruction to hepatic sinusoidal
and venous outflow results in the formation of increased
amounts of lymphatic fluid. The capacity of the lymphatic
system to return this fluid to the systemic circulation is
limited and, once overwhelmed, ascites ultimately results.
Given this proposed mechanism, one might expect the
protein concentration of ascitic fluid to be high. In fact, in
cases of ascites due to cirrhosis, the protein concentration is
low (< 2.5 g/dl) and the serum to ascites albumin gradient is
high (> 1.1 g/dl) [14]. These findings may be attributed to
several factors: (i) as liver disease progresses, there is
worsening of synthetic function; (ii) renal sodium and water
retention leads to dilution of serum albumin levels; and (iii)
the hepatic sinusoids eventually undergo anatomic changes
secondary to the effects of prolonged hypertension that lead
9
to decreased permeability to albumin (‘‘capillarization’’)
[15]. Another factor that contributes to the development of
low protein ascitic fluid is the development of hypertension
in the splanchnic circulation with transudation of protein-
poor fluid across these capillaries, which retain normal
permeability to plasma proteins [16].
2.2. Renal sodium retention and impairment of water
excretion
In addition to portal hypertension, renal sodium and
water retention must occur for ascites to develop [17 – 23].
Renal sodium retention is driven by high levels of renin –
angiotensin – aldosterone and increased sympathetic nervous
system activity, which together act to increase both proximal
and distal tubule sodium reabsorption [19].
In fact, renal sodium retention has been shown to precede
ascites formation in several animal models and it is the
earliest renal abnormality seen in cirrhotics [17 – 23].
Usually, sodium retention occurs in the setting of a normal
glomerular filtration rate (GFR) [23]. The stimulus for avid
renal sodium and water retention has been the subject of
much debate. Three separate theories (classical underfill
theory, overfilling theory and vasodilation theory) have been
proposed to explain renal sodium and water retention.
Initially, it was assumed that ascites formation led to a
decrease in plasma volume and cardiac output through the
loss of fluid into the peritoneal cavity [2,24]. This led to
secondary activation of renal sodium retention (classical
underfill theory) through the activation of pathways such as
the renin – angiotensin –aldosterone system [2,24]. Arguing
against this theory is the finding that renal sodium retention
occurs before the development of ascites [17 –23]. Further-
more, it has been difficult to demonstrate a decrease in
cardiac output in cirrhotic patients. In fact, cardiac output is
usually elevated in cirrhotic patients, in part secondary to
decreased afterload from systemic arterial vasodilation [24].
These discrepant findings have led to an alternative theory
in which hepatic venous outflow obstruction signals renal
sodium retention independent of changes in intravascular
volume (overfill mechanism) [25]. This theory postulates a
‘‘hepatorenal reflex’’ in which venous obstruction and
hypertension leads to activation of an intrahepatic sensory
system (including osmoreceptors and baroreceptors). This
signaling pathway then directly leads to renal sodium
retention, possibly through effects of the sympathetic
nervous system to increase renin levels [25 – 27]. The
expansion of the plasma volume through renal sodium and
water retention eventually leads to a change in Starling
forces in the hepatoportal circulation and to the formation of
ascites. Once ascites is present, plasma volume does begin
to contract, irrespective of whether the mechanism is due to
underfilling or overfilling. At this stage, renal sodium
retention occurs by similar mechanisms in either theory.
Finally, the vasodilation theory proposes that the onset of
urinary sodium retention prior to the development of ascites
10 M.H. Rosner et al. / European Journal of Internal Medicine 17 (2006) 8 – 19
is due to peripheral arteriolar dilation and a decrease in
effective circulating volume (ECV) [28]. The theory
proposes that, early in the pathogenesis of ascites, count-
er-regulatory hormones (renin, aldosterone, catecholamine
and antidiuretic hormone) are increased in an attempt to
restore ECV through sodium retention [29 – 32]. Initially,
sodium retention is able to restore hemodynamic balance,
but as liver failure progresses there is progressive vasodi-
lation. Vasodilation leads to persistently decreased ECV and
subsequent elevation of counter-regulatory hormones with
persistent sodium retention [33 – 36]. Eventually, this
pathway leads to ascites formation. The primary site of
reduced vascular resistance is the splanchnic circulation and
accumulating evidence implicates elevated levels of nitric
oxide (NO) as an important mediator of this effect [37]. In
humans with cirrhosis, vascular production for NO is
increased [38]. Correction of NO production leads to
correction of vasodilation and hyperdynamic circulation
[37]. NO synthase (NOS) catalyzes the conversion of l-
arginine to NO and l-citrulline. Thus far, three NOS
isoforms have been identified: NOS 1 (neuronal NOS),
initially characterized in the brain; NOS 2 (inducible NOS)
characterized in macrophages, hepatocytes, vascular smooth
muscle, endothelial cells and mesangial cells; and NOS 3
(endothelial NOS), identified in endothelial cells as well as
skeletal and cardiac muscle [39]. There is evidence that all
three isoforms may contribute to the overproduction of NO
in experimental cirrhosis [40,41]. Spontaneous bacterial
peritonitis leads to increased NO production and further
deterioration of systemic hemodynamic and renal function
[42].
Other factors may further decrease the ECV, such as
hypoalbuminemia, reduced cardiac preload and gastrointes-
tinal bleeding. Supportive evidence for this theory includes
observations that central and arterial volumes are reduced in
cirrhotics [28,34,43] and that, in some patients, total body
immersion (which is equivalent to infusing volume) results
in a natriuresis and restoration of normal renal salt and water
handling [44 –47].
Later in the course of cirrhosis, there is also impairment
in renal water excretion in addition to sodium retention. The
pathogenesis for this defect in renal water handling is
multifactorial and includes high levels of antidiuretic
hormone, reduced synthesis of renal prostaglandins and
decreased delivery of filtrate to the diluting segments of the
kidney [48,49]. In addition, since their discovery, the
aquaporin water channels have received significant interest
in the pathogenesis of the water defect in cirrhosis [50]. In
milder forms of cirrhosis, aquaporin 2 expression has been
found to be either increased or decreased or unchanged. In a
model of late cirrhosis induced by carbon tetrachloride and
characterized by sodium retention edema and ascites, there
is evidence for increased trafficking of aquaporin 2 to the
apical membrane and increased expression of aquaporin 1
and 3 [50]. Once this defect in renal water excretion occurs,
mortality increases dramatically. In fact, the capacity to
excrete a water load is one of the most sensitive prognostic
factors in cirrhotic patients with ascites [51].
In all of the proposed mechanisms that lead to the
formation of ascites, a common theme is renal retention of
sodium and water. Therefore, effective treatment of ascites
requires the use of diuretic agents that interfere with this
process.
3. Mechanism of diuretic action
3.1. Normal renal sodium chloride handling
Under normal circumstances, approximately 99.2% of
the filtered sodium chloride (NaCl) is reabsorbed by kidney
tubules. Sodium (Na) and chloride (Cl) and water reabsorp-
tion by the nephron is mediated by the ouabain-sensitive Na/
K ATPase expressed at the basolateral cell membrane of all
Na-transporting epithelial cells along the nephron. This
energy-requiring pump maintains large ion gradients across
the plasma membrane, with the intracellular Na concentra-
tion maintained low and the intracellular potassium (K)
concentration maintained high. Because the pump is
electrogenic, renal epithelial cells have a voltage gradient
across the plasma membrane: negative on the inside and
positive on the outside.
The combination of the low intracellular Na concentra-
tion and the plasma membrane voltage generates a large
electrochemical gradient favoring Na entry from the lumen.
Specific diuretic-sensitive Na transport pathways are
expressed at the apical (luminal) surface of cells along
the nephron, permitting vectorial transport of Na from
lumen to blood. Along the proximal tubule, where
approximately 50 –60% of filtered Na is reabsorbed, an
isoform of the Na/H exchanger is expressed at the apical
membrane [52]. Along the thick ascending limb, where
approximately 20 –25% of filtered Na is reabsorbed, an
isoform of the Na – K –2Cl cotransporter is expressed at the
apical membrane [53 –55]. Along the distal convoluted
tubule, where approximately 5% of filtered Na is reab-
sorbed, the thiazide-sensitive Na – Cl cotransporter is
expressed [56,57]. Along the connecting tubule and cortical
collecting duct, where approximately 3% of filtered Na is
reabsorbed, the amiloride-sensitive epithelial Na channel is
expressed [58]. These apical Na transport pathways form
the targets for diuretic action.
All diuretics, with the exception of agents that block the
mineralocorticoid receptor, must reach the tubule fluid
compartment to be effective since their actions depend
upon blockade of transport proteins expressed on the
luminal side of the cell membrane. Thus, the concentration
of diuretics in the urine depends upon the serum concen-
tration of the drug, as well as upon the glomerular filtration
rate (GFR) and rate of secretion by organic anion secretory
pathways in the proximal tubule [59]. In pathologic states,
where drug absorption and metabolism, volume of distri-
 M.H. Rosner et al. / European Journal of Internal Medicine 17 (2006) 8 – 19
bution, GFR and organic anion secretion may be perturbed,
the dose – response relationship of diuretic dose to sodium
excretion will be altered and thus require changes in the
dosing regimen to ensure natriuresis.
3.2. Loop diuretics
Loop diuretics (furosemide, bumetanide, torsemide and
ethacrynic acid) inhibit sodium and chloride transport along
the loop of Henle. Loop diuretics have the highest
natriuretic and chloriuretic potency of any class of diuretics;
they can increase Na and Cl excretion up to 25% of the
filtered load. The predominant effect of loop diuretic drugs
is to inhibit the electroneutral Na – K –2Cl cotransporter at
the apical surface of thick ascending limb cells [60,61]. The
loop of Henle reabsorbs 20 –50% of the filtered Na and Cl
load [62,63].
Unlike what occurs with most other classes of diuretic
drugs, GFR and renal blood flow (RBF) tend to be
preserved during loop diuretic administration [64], although
GFR and RBF can decline if extracellular fluid volume
contraction is severe. Loop diuretics reduce renal vascular
resistance and increase renal blood flow under experimental
conditions [65,66]. This effect is believed to be related to
the diuretic-induced production of vasodilatory prostaglan-
dins as well as to the blocking of the sensing mechanism
that activates the tubuloglomerular feedback (TGF) system
[67]. The TGF system involves NaCl transport across the
apical membrane of macula densa cells by the loop diuretic-
sensitive Na – K – 2Cl cotransporter decreasing GFR. Loop
diuretics can thus increase GFR by blocking Na – K –2Cl
cotransporter at the levels of the macula densa [67].
The three loop diuretics that are used most commonly –
furosemide, bumetanide and torsemide –are absorbed quick-
ly after oral administration, reaching peak concentrations
within 0.5 –2 h. Furosemide absorption is slower than its
elimination in normal subjects; thus, the time to reach peak
serum level is slower for furosemide than for bumetanide
and torsemide. This phenomenon is called Fabsorption-
limited kinetics_ [68]. The bioavailability of loop diuretics
varies from 50% to 90%; when furosemide dosing is
switched from intravenous to oral, the dose may need to
be increased to compensate for its poor bioavailability [68].
The half-lives of the loop diuretics vary, but all are relatively
short, ranging from approximately 1 h for bumetanide to 3 –
4 h for torsemide. Loop diuretics are organic anions that
circulate tightly bound to albumin (> 95%); thus, their
volume of distribution is limited, except during extreme
hypoproteinemia [69]. This can be an important issue in
patients with cirrhosis where the volume of distribution is
significantly higher owing to significant hypoalbuminemia.
Torsemide and bumetanide are eliminated both by hepatic
processes and through renal excretion. The differences in
metabolic rate mean that the half-life of furosemide is
altered by renal failure, whereas this is not true for torsemide
and bumetanide. Furthermore, in patients with significant
11
liver disease, the concentrations of torsemide and bumeta-
nide that actually reach the urine are increased owing to the
decreased hepatic metabolism [70 – 72].
3.3. Distal convoluted tubule diuretics
Thiazide diuretics primarily block the Na – Cl cotrans-
porter expressed at the apical membrane of the distal
convoluted tubule [73 –76]. Thiazide diuretics are organic
anions that circulate in a highly protein-bound state. As with
loop diuretics, the amount reaching the tubule fluid by
filtration across the glomerular basement membrane is
small; the predominant route of entry into tubule fluid is
by secretion via the organic anion secretory pathway in the
proximal tubule. Thiazide diuretics are rapidly absorbed
across the gut, reaching peak concentrations within 1.5– 4
h [68]. The amount of administered drug that reaches the
urine varies greatly [68], as does the half-life. The clinical
effects of the differences in half-life are unclear, except in
the incidence of hypokalemia, which is much more common
in patients taking longer-acting drugs such as chlorthalidone
[77,78].
Thiazide diuretics are not commonly used as single
agents in the treatment of cirrhotic ascites, largely because
the increase in fractional excretion of sodium induced by
these agents tends to be less than 5%.
3.4. Cortical collection tubule diuretics
Diuretic drugs that act primarily in the cortical collecting
tubule (potassium-sparing diuretics) include aldosterone
antagonists (spironolactone, eplerenone), triamterene and
amiloride. Of these drugs, aldosterone antagonists such as
spironolactone represent the ones used most often in treating
edema associated with ascites. The site of action of
spironolactone is the cortical collecting duct and the
connecting tubule, where they interfere with sodium
reabsorption and, indirectly, potassium secretion. The
collecting tubule is composed of two cell types that have
entirely separate functions. Principal cells (collecting duct
cells) are responsible for the transport of sodium, potassium
and water, whereas intercalated cells are primarily respon-
sible for the secretion of hydrogen or bicarbonate ions. The
apical membrane of principal cells expresses separate
channels that permit selective conductive transport of
sodium and potassium (Fig. 1). The mechanism by which
sodium reabsorption occurs is through conductive sodium
channels [79]. The low intracellular sodium concentration as
a result of the basolateral Na,K-ATPase generates a favorable
electrochemical gradient for sodium entry through sodium
channels. Because sodium channels are present only in the
apical membrane of principal cells, sodium conductance
depolarizes the apical membrane, resulting in an asymmetric
voltage profile across the cell. This effect produces a lumen-
negative transepithelial potential difference. The lumen-
negative potential difference, together with a high intracel-
12 M.H. Rosner et al. / European Journal of Internal Medicine 17 (2006) 8 – 19
(ENaC)
Na+
Inhibited by K+
sparing diuretics
+ +
(ROMK)
K+
Lumen
electronegative
Fig. 1. Principal cell. Aldosterone acts to increase sodium reabsorption in exchange for potassium and hydrogen ions. This site is where spironolactone acts to
inhibit sodium reabsorption.
lular to lumen potassium concentration gradient, provides
the driving force for potassium secretion [80 –86].
Although generally considered a weak diuretic, spirono-
lactone is effective for the treatment of ascites and edema in
patients with cirrhosis [84]. Antagonizing the secondary
hyperaldosteronism has been the mainstay of diuretic
therapy in the treatment of cirrhosis [88,89]. In the kidney,
spironolactone and its metabolites enter target cells from the
peritubular side (unlike the other classes of diuretics), bind
to cytosolic mineralocorticoid receptors and act as compet-
itive inhibitors of the endogenous hormone [90 – 93]. It is
thought that spironolactone acts to block the translocation of
mineralocorticoid receptors to the nucleus and thus facilitate
proteolysis of the mineralocorticoid receptor [94].
Spironolactone induces a mild increase in sodium
excretion (1 – 2%) and a decrease in potassium and
hydrogen ion excretion [95,96]. Its effect depends on the
presence of aldosterone. Spironolactone is ineffective in
experimental adrenalectomized animals [96] and in patients
with Addison’s disease [97] or patients on a high-salt diet.
Spironolactone is poorly soluble in aqueous fluids.
Bioavailability of an oral dose is approximately 90%.
Spironolactone and its metabolites are extensively bound
to plasma protein (98%). The onset of action is extremely
slow, with peak response sometimes occurring 48 h or more
after the first dose; effects gradually wane over a period of
48 –72 h. In cirrhotic patients, pharmacokinetic studies
indicate that the half-lives of spironolactone and its
metabolites are significantly increased (up to four times
longer than in normal subjects) [98].
Spironolactone is especially appropriate for the treatment
of cirrhosis with ascites, a condition invariably associated
with secondary hyperaldosteronism. In comparison to loop
or thiazide diuretics, spironolactone is equivalent or more
effective in inducing a natriuresis [84]. Furthermore, a
Na+
ATP
+ K+
Mineralocorticoid
receptor ALDOSTERONE
combination of a loop diuretic and spironolactone can be
used to boost natriuresis when the diuretic effect of
spironolactone alone is inadequate.
The utility of spironolactone is limited by its side effect
profile, which is, in part, due to the fact that spironolactone
binds to other steroid receptors in addition to the mineral-
ocorticoid receptor [107]. Thus, patients may suffer from
gynecomastia, impotence, menstrual irregularities and hir-
sutism, which are due to progestational and antiandrogenic
effects of spironolactone [108]. This has led to the search for
agents that can selectively block the aldosterone receptor.
Eplerenone is the first such selective aldosterone antagonist,
acting to competitively antagonize aldosterone binding at
the mineralocorticoid receptor [109,110]. Eplerenone was
derived from spironolactone by substitution of the 17[a]-
thioacetyl group of spironolactone with a carbomethoxy
group and the addition of a 9[a],11[a]-epoxy bridge [110].
These substitutions remove the progestational and antian-
drogenic effects while maintaining blockade of the aldoste-
rone receptor. Eplerenone is approximately 50 –75% as
potent as spironolactone [110]. Its bioavailability
approaches 98%. It is hepatically metabolized to inactive
metabolites with a half-life of 4 –6 h (longer in the presence
of liver disease) [110].
4. Pharmacokinetics and pharmacodynamics of diuretics
in cirrrhosis
The pharmacokinetics and pharmacodynamics of loop
diuretics in cirrhotic patients are altered and lead to
important considerations in the dosing of these agents. In
the setting of normal renal function, there is no limitation to
the delivery of the diuretic to the urinary site of action
[105,106]. However, the natriuretic response to a given dose
 M.H. Rosner et al. / European Journal of Internal Medicine 17 (2006) 8 – 19
of loop diuretic in cirrhotics is altered as compared to
normal subjects. The maximal response to a given dose of
loop diuretic is shifted downward (change in pharmacody-
namics) and thus limits the total amount of sodium excretion
that can be obtained. In the extreme case, this natriuretic
effect is severely reduced (diuretic resistance, see below).
The mechanism for this change in pharmacodynamics is
unknown. Possibilities include: (1) increased proximal
tubule reabsorption of sodium, in part secondary to
increased levels of angiotensin II and other counter-
regulatory hormones, with diminished delivery of sodium
to the loop of Henle [111,112]; (2) increased distal tubular
reabsorption of sodium (under the influence of aldosterone),
which limits the final natriuretic response to loop diuretics
[113,114]; and/or (3) a change in the dynamics of the
interaction between the diuretic and the Na/K/2Cl trans-
porter [115 – 119]. In order to combat the decreased
natriuresis to a maximal dose of diuretic, the drug must be
given more frequently to afford negative sodium balance.
Increasing the dose of the diuretic will have little effect on
natriuresis as the fractional excretion of sodium is usually
maximal on the usual doses of loop diuretics. This important
clinical fact is often overlooked in the management of
cirrhotic ascites.
A further complicating factor is the common occurrence
of hypoproteinemia in patients with cirrhosis. Given the
high affinity of loop diuretics and spironolactone for serum
proteins, this hypoproteinemia leads to an increase in the
volume of distribution of these drugs and lowers effective
serum concentrations [115 – 121]. Whether this effect leads
to a diminished delivery of diuretic to the urine is doubtful.
In fact, renal clearance of loop diuretics in cirrhotic patients
with normal renal function is identical or even greater than
normal patients. For example, furosemide clearance aver-
ages 95 –125 ml/min in healthy subjects and 100 –120 ml/
min in patients with cirrhosis [115– 121]. Drugs such as
torsemide and bumetanide, which undergo significant
hepatic metabolism, tend to have even higher renal
clearances in cirrhotic patients. Thus, in the face of normal
or supra-normal renal clearances of loop diuretics, pharma-
codynamic alterations must explain the altered dose –
natriuretic response of these agents in cirrhotic patients.
5. Treatment of cirrhotic ascites
Treatment of cirrhotic ascites relies on maximizing
sodium excretion with the use of diuretic agents and
minimizing sodium intake through dietary restriction.
Through these maneuvers, the aim is to allow sodium
excretion to exceed sodium intake. Once this occurs,
extracellular volume will contract and ascites will slowly
improve. Total body immersion, as mentioned earlier, is one
way to maximize intravascular volume to result in a
physiological natriuresis. However, this is usually imprac-
tical and thus other strategies will often need to be deployed.
13
5.1. Sodium restriction
All patients with cirrhotic ascites should be counseled on
dietary sodium restriction. The goal should be a 2 g (88
meq)/day sodium diet [122,123]. On this diet, extracellular
volume contraction will occur if urinary losses exceed 78
meq/day (accounting for approximately 10 meq/day sodium
loss through extra-renal pathways). Compliance should be
assessed with a 24-h urine collection for both sodium and
creatinine (to ensure a complete collection). The creatinine
excretion per 24 h in cirrhotics averages 15– 20 mg/kg/day
in men and 10 –15 mg/kg/day in women [122]. Lower total
creatinine values in the 24-h collection suggest an incom-
plete collection of urine. Non-adherence to dietary sodium
restriction should also be suspected if a patient fails to lose
weight despite an adequate 24-h urinary sodium excretion
(> 78 meq/day).
Additional benefit can be obtained through limitation of
physical activity. Bed rest will lead to additional natriuresis,
in part due to shifting of fluid from the splanchnic
circulation to the central circulation with recumbency
[124]. Furthermore, renin and aldosterone levels fall when
supine [125]. For many patients, strict dietary sodium
restriction and limitation of physical activity are difficult
goals. Thus, diuretics must be utilized to allow for
contraction of the extracellular volume. For those patients
with a low level of baseline urinary sodium excretion,
diuretic therapy will be required.
5.2. Diuretics
In the vast majority of patients, mobilization of ascites
requires diuretic therapy. Generally, the aim is to slowly
decrease extravascular volume and to avoid intravascular
volume depletion. This goal can sometimes be difficult
since ascites and edema fluid is compartmentalized outside
of the intravascular volume [126]. Diuretic therapy will
initially lead to loss of intravascular volume with subse-
quent ‘‘buffering’’ of this loss of fluid by mobilization of
ascitic and edema fluid. If the loss of intravascular volume is
too great or too rapid, ‘‘buffering’’ of intravascular volume
cannot occur at such a rapid rate and hypotension and renal
insufficiency can result. The maximal rate of this fluid loss
is approximately 500 ml/day in patients without peripheral
edema and 800 –1000 ml/day in patients with peripheral
edema [126,127].
The two major classes used in patients with cirrhosis are
loop diuretics and aldosterone antagonists. Spironolactone is
the most commonly used agent in these patients. Starting
doses begin at 50 mg/day and can be increased to doses as
high as 400 mg/day. At the higher doses, side effects,
especially painful gynecomastia, are more common and
often limit the maximal doses to 100 mg/day. The
usefulness of spironolactone relates to several features of
both the drug and the disease state. Spironolactone is unique
among diuretic agents in that it does not require tubular
14 M.H. Rosner et al. / European Journal of Internal Medicine 17 (2006) 8 – 19
secretion to cause natriuresis [98]. Other diuretics require
tubular secretion and thus are dependent upon intact renal
blood flow. Furthermore, in cirrhotic patients, there is
typically an accumulation of bile salts that can compete
with the tubular secretion of diuretic agents [106]. As a
result of these factors, spironolactone retains its efficacy in
cirrhotic patients. In a head-to-head trial of single agent
diuretic therapy in the treatment of ascites, spironolactone
proved more efficacious than furosemide [128,129]. There
is generally a 2-week interval before the onset of the full
diuretic action of spironolactone [98].
Spironolactone is a potassium-sparing diuretic that may
be important in the prevention of hypokalemia-induced
hepatic encephalopathy. Hypokalemia is a potent stimulus
for renal ammonia synthesis as well as decreased
gastrointestinal motility with increased gastrointestinal
absorption of nitrogen. Thus, spironolactone may protect
patients from worsening hepatic encephalopathy, which
can occur with diuretic-induced hypokalemia. Antiandro-
genic side effects may limit therapy with spironolactone. In
this case, either eplerenone or potassium canrenoate (a
metabolite of a spironolactone) may be acceptable sub-
stitutes [145].
In the majority of patients with significant ascites, loop
diuretics will be required. Furosemide at a starting dose of
40 mg once or twice daily is usually a reasonable starting
dose. Other loop diuretics, such as bumetanide or torsemide,
can also be used and may offer slightly increased efficacy
owing to higher drug concentrations of these hepatically
metabolized agents. As stated above, the altered pharmaco-
kinetics and pharmacodynamics of loop diuretics require
that these drugs be given more frequently, rather than at
higher dosages, to affect a sustained natriuresis.
5.3. Diuretic resistance in cirrhosis
Diuretic resistance in patients with cirrhosis has been
variably defined but clinically is manifested by the failure
to lose weight or ascitic volume despite high dosages of
loop diuretics and sodium restriction [1]. Often times,
these patients will manifest metabolic side effects of
diuretic agents such as hyponatremia, renal failure,
worsening metabolic alkalosis, gynecomastia, muscle
cramps and encephalopathy. These side effects will
necessarily limit the dose of diuretic used. A functional
definition of diuretic resistance is based upon the failure to
increase 24-h urine sodium excretion to greater than 78
meq/day despite high-dose diuretics. This amount of
sodium excretion is chosen since a 2-g sodium diet is
equivalent to 88 meq of sodium and insensible sodium
losses approximate 10 meq/day. Thus, to affect any degree
of weight loss, urinary sodium loss must at a minimum be
greater than 78 meq/day.
Diuretic resistance has several potential etiologies
including high dietary sodium intake, poor intestinal
absorption of the diuretic, decreased GFR and decreased
renal blood flow with resulting decreased drug entry in the
tubule lumen, proteinuria with decreased concentration of
free diuretic in the tubule lumen, and increased proximal
and distal sodium reabsorption. Unfortunately, after max-
imal dosages of loop diuretics and concomitant distal
acting diuretics show no effect, the options are limited.
Many patients will have difficulty limiting their sodium
intake to less than 78 meq/day, but every effort to achieve
this goal must be made. At this point, most patients require
frequent paracentesis to control ascites. Assuming no
urinary sodium losses and a diet restricted to 88 meq
sodium/day, most patients can be kept free from tense
ascites with the removal of 8 l of ascites every 2 weeks
[1,130]. More rapid accumulation is often indicative of
dietary sodium indiscretion. Other treatment options for
diuretic resistance include peritoneovenous shunting, trans-
jugular intrahepatic portosystemic shunting (TIPS) and
liver transplantation.
5.4. Albumin infusions
Albumin infusions, either alone or in conjunction with
loop diuretics, have been attempted to alleviate cirrhotic
ascites in the setting of diuretic resistance. Much of the
experimental evidence supporting this approach comes
from the study of diuretic use in patients with the
nephrotic syndrome and hypoalbuminemia [131 – 134].
There are several reasons why one might expect albumin
infusions to increase the response to loop diuretics. Since
loop diuretics are bound to albumin, the concomitant
administration of these agents allows for a smaller volume
of distribution of the diuretic and allows more diuretic to
reach the proximal tubule secretory site. This effect is
likely to be significant when the serum albumin falls to
less than 2.0 g/dl since, at this level, the unbound fraction
of furosemide begins to increase markedly [135]. Albumin
may also bind other free organic anions, such as bile acids,
that compete for the secretory site. Other effects of
albumin may include increasing the plasma volume with
secondary effects to increase renal blood flow and decrease
the sodium-conserving counter-regulatory hormones, such
as angiotensin II and aldosterone [136]. In analbuminemic
rats, the combination of albumin and furosemide infusion
resulted in a significant diuresis over furosemide alone
[120]. The reason for this was that a greater amount of
furosemide reached the proximal tubule secretory site
secondary to a decrease in the volume of distribution of
the drug. These same authors also demonstrated the same
effect in severely hypoalbuminemic patients with urine
volume increasing from 50 ml/h to 150 ml/h in several, but
not all, patients [120]. In a recent study, specific to patients
with cirrhosis, the mixture of albumin and furosemide in
patients with Child-Pugh Class B or C cirrhosis had no
effect on urinary sodium excretion [137]. Furthermore,
albumin did not alter the pharmacokinetics or pharmaco-
dynamics of furosemide. The authors concluded that
 M.H. Rosner et al. / European Journal of Internal Medicine 17 (2006) 8 – 19 15

albumin/furosemide combinations offered no improvement
over furosemide alone.
5.5. Large-volume paracentesis, peritoneovenous shunts
and transplantation
Despite aggressive attempts to diurese patients with
ascites, some patients will remain diuretic-resistant. These
patients require large-volume paracentesis to affect a
negative sodium balance [1,138]. This procedure is safe,
effective and has been extensively reviewed. When
compared to diuretics, large-volume paracentesis leads to
a more rapid mobilization of ascites; however, efficacy and
long-term mortality are similar [139]. The use of large-
volume paracentesis necessitates the use of diuretics as
maintenance therapy in order to prevent re-accumulation
of ascites [140]. Other options for patients who are
diuretic-resistant include peritoneovenous shunting of
ascitic fluid into the vascular space [141], transjugular
intrahepatic portosystemic shunts (TIPS) [142] and trans-
plantation. TIPS were initially utilized to control variceal
bleeding but are also very effective in mobilizing ascitic
fluid through a diuretic effect [143,144]. Interestingly, this
diuretic effect may not be seen for several weeks
following the procedure. Ultimately, the natural course of
cirrhosis is one of inexorable decline, and the treatment of
choice for patients with continued decline is hepatic
transplantation.

ASCITES-
Unresponsive to sodium restriction (2 grams per day)

Spironolactone
24-hour urine to 50-200 mg/day
monitor for sodium
restriction (should be
< 100 mmol/day) Inadequate diuresis/weight gain

Loop Diuretic
(Furosemide 40 mg/day)

Weight loss, ascites control,

Continued ascites, weight gain, 24
24-hour urine sodium > 88
hour urine sodium < 88 mmmol
mmol

Increase loop diuretic dose and

frequency of administration
Continue current diuretic
therapy
Monitor electrolytes, weight
Follow 24-hour urine
sodium to ensure Complications of diuretic
compliance with low- therapy (hypokalemia, metabolic
sodium diet alkalosis), inadequate diuresis
despite maximal dose diuretics

Therapeutic paracentesis
or
TIPS

Fig. 2. Algorithm for the treatment of edema and ascites in the cirrhotic patient.
16 M.H. Rosner et al. / European Journal of Internal Medicine 17 (2006) 8 – 19
6. Summary
The treatment of patients with cirrhosis and ascites is
challenging. Diuretic therapy is required for essentially all
of these patients and requires a thorough understanding of
the pharmacokinetics and pharmacodynamics of these
agents in this disease state. Treatment of ascites should
follow a logical, step-wise approach with sodium restriction
and sequential addition of diuretic agents to affect a negative
sodium balance (Fig. 2). Combinations of diuretic agents are
required to antagonize the neurohormonal activation that
tends to counteract natriuresis and can ultimately lead to
diuretic resistance. In those patients with diuretic resistance,
alternative therapies, such as paracentesis and TIPS, are
required. Liver transplantation for suitable candidates is the
ultimate solution to this difficult clinical problem.
Acknowledgement
This work was supported in part by funds from NIH
DK56223, DK58413, HL37942 and 2R01DK051496.
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