Diagnosis and management

of ascites and hepatorenal

syndrome (acute kidney
injury) in cirrhosis
Kevin Moore
Abstract
The development of ascites and/or the hepatorenal syndrome in liver
disease signies the beginning of the end of liver function (decompensa-
tion). These patients need careful medical management to reverse these
abnormalities, and identify any precipitating cause such as sepsis or
complication such as spontaneous bacterial peritonitis. Once ascites
develops, all patients should be considered for liver transplantation
since the long-term prognosis is poor. Patients should start modest salt
restriction, and spironolactone as the rst-line diuretic drug. Patients
with alcoholic liver disease need to stop drinking.
The development of hepatorenal syndrome is due to a combination of
vasodilatation causing a lowering of blood pressure, activation of the
sympathetic nervous system, impairment of cardiac function, and
increased synthesis of vasoactive mediators. Patients developing hepa-
torenal syndrome should be managed with volume expansion, terlipres-
sin, and a low threshold for intravenous antibiotics.
Keywords acute kidney injury in cirrhosis; AKI; hepatorenal syndrome;
paracentesis; renal failure in/and cirrhosis; spontaneous bacterial
peritonitis; transjugular intra-hepatic portosystemic shunt (TIPS)
Introduction and pathophysiology
Fifty percent (50%) of patients with compensated cirrhosis
develop ascites within 10 years of the onset of cirrhosis. Ascites
occurs only in patients with chronic liver disease and portal
hypertension. It results from sodium and water retention that
follows activation of arterial and cardiopulmonary volume
receptors, and homeostatic activation of the sympathetic nervous
system and the renineangiotensinealdosterone system,
secondary to arterial splanchnic vasodilatation and decreased
effective arterial blood volume (see Figure 1). Expansion of the
extracellular uid in the presence of portal hypertension
enhances formation of hepatic lymph, extravasation of peritoneal
uid and formation of ascites and oedema. The European Asso-
ciation for the Study of the Liver (EASL) has recently published
more extensive clinical guidelines than are presented here.
1
The development of ascites is associated with a poor prognosis
in patients with cirrhosis, since these patients may develop spon-
taneous bacterial peritonitis (SBP) or the hepatorenal syndrome
(HRS), with an increased risk of variceal bleeding or sepsis.
The probability of survival at 2 and 5 years after the appear-
ance of ascites in patients with cirrhosis is estimated to be about
65%, and 35% respectively
1
and the development of ascites has
a marked impact on quality of life. However, prognosis is
considerably better in patients with alcoholic cirrhosis if they
stop drinking alcohol. Low serum sodium concentration is the
most powerful predictor of mortality, and about 50% of patients
presenting with ascites have a serum sodium concentration less
than 135 mmol/litre.
2
Thus, patients with ascites should always
be considered for referral for liver transplantation.
While the majority of cases (75%) of patients who present
with ascites have underlying cirrhosis and portal hypertension,
the remaining 25% have alternative causes (see Box 1).
Diagnosis of ascites
A full history, physical examination, abdominal ultrasound,
measurement of liver and renal function, and serum and urine
electrolytes, as well as an analysis of the ascitic uid should be
undertaken in all patients. Patients should be asked about risk
factors for liver diseases, and a history of cancer, tuberculosis and
heart failure. The presence of jaundice, spider naevi, palmar
erythema, hepatomegaly and/or splenomegaly suggests under-
lying cirrhosis as a cause of ascites. An abdominal ultrasound is
needed to conrm the presence of ascites and a nodular looking
liver, and to screen for hepatocellular carcinoma (or other malig-
nancy) and portal vein thrombosis; it may even reveal dilated
hepatic veins that may suggest a cardiac cause, or thrombosis of
the hepatic veins (BuddeChiari syndrome). Portal vein throm-
bosis in the absence of cirrhosis does not cause ascites unless there
is a major insult such as gastrointestinal (GI) bleeding.
A diagnostic paracentesis with an appropriate ascitic uid
analysis is essential in all patients investigated for ascites, before
any therapy, to rule out spontaneous bacterial peritonitis (SBP)
and look for other causes of ascites. When the diagnosis of
cirrhosis is not clinically evident, ascites due to portal hyper-
tension can be differentiated from ascites due to other causes by
Whats new?
C
In patients with hepatorenal syndrome (HRS), cardiac output is
inadequate to maintain normal blood pressure and this may be
secondary to cirrhotic cardiomyopathy
C
The most common trigger for the development of type 1 HRS is
bacterial infection
C
Renal function and survival in HRS can be improved by phar-
macological therapy
Kevin Moore BSc MB BS PhD FRCP is Professor of Hepatology at the UCL
Institute of Hepatology, Royal Free Campus, University College London
Medical School, UK. His interests include the role of oxidative stress
and vascular function in liver disease, with an emphasis on complica-
tions of portal hypertension. Clinically Professor Moore practises as
a Hepatologist, but is also accredited (on the specialist register) for
Clinical Pharmacology and Therapeutics and General Internal Medicine
(GIM). He is co-author of the Oxford Handbook of Acute Medicine.
Conicts of interest: I have been an advisor to Servier, Norgine, Cum-
berland Pharmaceuticals.
MANAGEMENT PROBLEMS IN LIVER DISEASE
MEDICINE 39:10 612 2011 Published by Elsevier Ltd.
means of the serum:ascites albumin gradient (SAAG). This is
calculated by subtracting the ascitic albumin concentration from
the serum albumin. An SAAG of 11 g/litre or more identies
portal hypertension as the cause with 97% accuracy.
The ascitic uid should be inoculated into a blood culture bottle
and a plain plastic tube or EDTA tube for examination by micros-
copy. Anascitic polymorphonuclear leucocyte count over 250/mm
3
is diagnostic of SBP, inthe absence of abdominal surgicallytreatable
sources of infection. Coulter counter counts of white blood cells
(WBCs) may be unreliable. Ascitic uid amylase activity should be
measured. A clinical suspicion of alternative causes of ascites,
suggestedbylymphocytosis or SAAGunder 11g/litre, justies other
tests, such as cytology, polymerase chain reation (PCR) and culture
for mycobacteria.
Management of ascites
Mild or moderate ascites: patients with mild or moderate ascites
can generally be treated as outpatients. They should be advised
to reduce their sodium intake with a no-added-salt diet, and to
avoid foods with a high salt content (e.g. prepared meals).
Patients with moderate ascites will usually benet from spi-
ronolactone to increase urinary sodium excretion. Loop diuretics
should be avoided unless ascites is difcult to treat.
Spironolactone dosage should start at 100 mg/day and be
increased (in 100 mg increments) every 7e10 days to
a maximum of 400 mg/day if there is no response (no loss of
ascites as assessed by weight, and no change in urine sodium
concentration, see below). In patients who do not respond to
aldosterone antagonists (<2 kg weight loss/week until clinical
resolution of ascites), or in patients who develop hyperkalemia,
furosemide should be added, starting at 40 mg/day and
increasing by 40-mg increments to a maximum of 160 mg/day.
Monitoring e during the rst 4 weeks of diuretic therapy,
serum urea and electrolytes should be measured weekly. Patients
with avid sodium retention excrete virtually no sodium and may
benet from a more rapid escalation of diuretic therapy with
weekly monitoring of renal function. Thus, measuring urinary
Compensated
cirrhosis
Sinusoidal portal hypertension
Splanchnic arteriolar vasodilation
Decreased effective arterial blood volume
High-pressure baroreceptor-mediated
stimulation of renin-angiotensin-aldosterone
and sympathetic nervous systems
and vasospressin
Sodium and
water retention
Adequate to normalize
circulatory homeostasis
Inadequate to normalize
circulatory homeostasis
Increase in
plasma volume
Moderate Severe
Decompensated
cirrhosis
The development of portal hypertension leads to system vasodilatation of the splanchnic vascular bed, decreased effective arterial volume, leading to activation of
the sympathetic nervous system and renion-angiotensin system, and subsequently increased sodium and water retention.
Return of plasma renin,
aldosterone, noradrenaline
and vasopressin levels to
normal values
Plasma renin, aldosterone,
noradrenaline and vasopressin
levels remain at high values
Continuous renal sodium
and water retention
Ascites formation
Return of renal sodium and
water excretion to normal
Pathogenesis of salt and water retention in cirrhosis
Figure 1 From Schrier RW et al
3
, with kind permission of John Wiley & Sons.
Causes of ascites
C
Cirrhosis and portal hypertension 75%
C
Malignancy 10%
C
Pancreatic ascites 2%
C
Tuberculous ascites 2%
C
Cardiac causes 3%
C
Miscellaneous 8%
Box 1
MANAGEMENT PROBLEMS IN LIVER DISEASE
MEDICINE 39:10 613 2011 Published by Elsevier Ltd.
sodium on a spot urine sample during treatment is a useful test;
those with a relatively high urine sodium concentration (>40
mmol/litre) are more likely to respond to diuretic therapy.
Following mobilization of ascites, the dose of diuretics should be
reduced to avoid diuretic-induced complications while preventing
clinically signicant ascites. Alcohol abstinence is crucial for the
control of ascites in patients with alcohol-related cirrhosis and can
lead to withdrawal of diuretics. The use of diuretics in cirrhotic
patients with ascites may be associated with several complications,
such as renal failure, hepatic encephalopathy, electrolyte and acid-
base disorders, gynaecomastia and muscle cramps.
The commonest complications of spironolactone use are
gynaecomastia, hyponatraemia and hyperkalaemia. In the UK, it
is common practice to stop diuretics temporarily in patients
whose serum sodium decreases to less than 125 mmol/litre
(although EASL guidelines state 120 mmol/litre). If there is
a signicant rise in serum creatinine, diuretics should be stopped
and rehydration initiated if necessary.
Severe ascites: large-volume paracentesis (LVP) combined with
the infusion of human albumin is the treatment of choice. It is more
effective than diuretics and shortens the duration of hospitaliza-
tion, as well as the frequency of hyponatraemia, renal impairment
and hepatic encephalopathy. There is no limit to the amount of
ascites that can be removed in a single session, and it should be
completed withina single tapwith removal of the drainage cannula
within 6 hours of initiation. Within the rst hour, there is a reduc-
tion of intra-abdominal pressure, an increase in cardiac output,
a modest reduction of right atrial pressure, a lowering of systemic
vascular resistance and a mild lowering of blood pressure.
Albumin (20%) is the most effective plasma expander to
prevent postparacentesis-related circulatory dysfunction. The
recommended amount of albumin to be infused during para-
centesis is 8 g for every litre tapped, and this should be given at
the conclusion of paracentesis rather than concurrently. If
fewer than 5 litres of ascites are removed, human albumin can be
safely replaced by an alternative plasma volume expander, such
as gelofusine (150 ml/litre of ascites removed). Spironolactone
(100 mg/day) should be started either before or following para-
centesis, if the patient is not already taking it.
Refractory ascites is dened as ascites that cannot be mobilized
or the early recurrence of which (i.e. after LVP) cannot be satis-
factorily prevented by medical therapy. Once ascites becomes
refractory to medical treatment, the median survival of patients is
about 6 months. Repeated LVP is an effective and safe therapy. A
recent study showed that patients with refractory ascites taking
b-blockers have a marked reduction in survival, so b-blockers
should be STOPPED in all patients with refractory ascites.
Drugs contraindicated in patients with ascites
Box 2 lists drugs that are contraindicated in patients with ascites.
Use of transjugular intra-hepatic portosystemic shunts (TIPS)
for ascites: insertion of a TIPS shunt decreases the portal pressure.
Within 4 weeks after TIPS insertion there is usually an improve-
ment of urinary sodium excretion and renal function. Complica-
tions include the development of hepatic encephalopathy, which
occurs in 30e50% of patients, shunt thrombosis and stenosis.
Spontaneous bacterial peritonitis
SBP occurs in about 2% of outpatients and about 10% of patients
admitted to hospital with cirrhosis and ascites; it has an overall
mortality of about 20e30%. In half of all episodes of SBP, the
condition is present at the time of hospital admission (Figure 2).
In 50% of patients, SBP is asymptomatic. Symptoms include:
abdominal pain
abdominal tenderness
vomiting
Gut flora
Bacteria in lymphatic system
Bacteraemia
Bacterascites
Opsonins Opsonins Opsonins
SBP CNNA Normal ascites
Bacteria in hepatic lymph
Pneumonia
Complement
UTI
Instrumentation
Pathophysiology of spontaneous
bacterial peritonitis (SBP)
Micro-organisms enter the blood stream and lymphatic system and
enter ascitic fluid through lymphatic drainage. If opsonic adctivity is
high, i.e the body is capable of eradicating the infection then infection
resolves. If the host defence is low (low ascitic total protein 15g/litre),
low complement or low ascitic immunoglobulins, then spontaneous
bacterial peritonitis develops.
CNNA; culture-negative neutrocytic ascites
Figure 2
Drugs relatively contraindicated in ascites
C
Non-steroidal anti-inammatory drugs, including aspirin
C
Gentamicin
C
Amikacin
C
a-blockers
C
b-blockers
C
Angiotensin-converting enzyme inhibitors
C
Contrast media
C
Dipyridamole
Box 2
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MEDICINE 39:10 614 2011 Published by Elsevier Ltd.
diarrhoea
ileus
signs of systemic inammation, such as:
e hyper- or hypothermia
e chills
e altered WBC count
e tachycardia, and/or tachypnea
e worsening of liver function
e hepatic encephalopathy
e shock
e acute kidney injury
e gastrointestinal bleeding.
Management of SBP
1. Antibiotic therapy should be initiated immediately once the
diagnosis has been made, based on the ascitic neutrophil count
(>250/mm
3
). Intravenous cefotaxime (5 days) covers most
causative organisms and resolution of infection occurs in 80%.
Alternatively, amoxicillin/clavulanic acid or ciprooxacin,
given intravenously for 48 hours, then orally, is also effective.
2. Intravenous albumin (20%) should be given at a dose of 1.5
g/kg body weight within 6 hours of diagnosis, followed by 1
g/kg on day 3. Albumin infusion decreases the incidence of
type 1 hepatorenal syndrome and mortality from 30% to
10%, compared with antibiotics alone.
Prophylaxis against SBP: prophylactic antibiotics (e.g. cipro-
oxacin 500 mg daily) should be given to all patients with a low
ascitic protein (<15 g/litre) or previous SBP (the recurrence rate
is w70%). All patients who present with GI bleeding and ascites
should undergo an ascitic tap since 25e65% have bacterial
infection at presentation.
Hyponatraemia
The development of hyponatraemia (<130 mmol/litre) is asso-
ciated with a poor prognosis. The most common cause of
hyponatraemia in cirrhosis is excess water retention. Occasional
patients present with salt depletion, and need to be treated with
sodium chloride. An infusion of sodium chloride 0.9% (sodium
concentration 154 mmol/litre) increases serum sodium slowly
(by no more than 8 mmol/litre sodium/day) and relatively
safely; hypertonic saline should be avoided.
Patients with water overload (hypervolaemic hyponatraemia)
are more difcult to treat. Fluid restriction is helpful in pre-
venting a further decrease in serum sodium, although it is rarely
effective in improving serum sodium concentration. However,
a new family of drugs, the vaptans, improve solute-free water
excretion by antagonizing selectively the effects of vasopressin
(AVP) in renal tubular V2 receptors and are effective in the
treatment of hyponatraemia in cirrhosis. These are not yet
licensed in the UK for use in cirrhosis, but have been licensed
for the management of inappropriate antidiuretic hormone
secretion.
Hepatorenal syndrome
Hepatorenal syndrome (HRS) is the occurrence of renal failure in
a patient with advanced liver disease in the absence of an iden-
tiable cause. The prognosis remains poor, with a median
survival time of 1e3 months. The factors involved in the path-
ogenesis of HRS are shown in Box 3.
Acute kidney injury in cirrhosis includes all causes of acute
deterioration of renal function, as indicated by an increase in serum
creatinine of more than 50% from baseline, or a rise in serum
creatinine of 26.4 mmol/litre in less than 48 hours. Chronic renal
disease is dened as an estimated glomerular ltration rate (eGFR)
of <60 ml/minute, calculated using the modication of diet in renal
disease (MDRD6) formula, recognizing that this formula is not
perfect for cirrhoticpatients andwill includetype2HRS(seebelow).
Traditionally, HRS is divided into two types. Type 1 HRS is
a rapidly progressive acute renal failure that develops concur-
rently with evidence of deterioration of liver function (e.g.
worsening coagulopathy and a signicant elevation of serum
bilirubin). It commonly occurs in severe alcoholic hepatitis or in
patients with end-stage cirrhosis following a septic insult, such as
SBP, although in some patients it may occur in the absence of
any identiable triggering event. Conventionally, type 1 HRS is
diagnosed only when serum creatinine increases by more than
100% from baseline to over 220 mmol/litre. Type 2 HRS occurs in
patients with refractory ascites and there is a steady but
moderate degree of functional renal failure, often with avid
sodium retention. In type 2 HRS, renal function uctuates over
time; deterioration may be slow, or the patient may develop type
1 HRS following a precipitating event such as SBP.
In patients presenting with cirrhosis and ascites, the proba-
bility of developing HRS is 18% in the rst year, and about 40%
at 5 years. Risk factors include hyponatraemia, arterial hypo-
tension, and elevated plasma renin activity or noradrenaline
concentration. However, recent studies have conrmed that the
development of sepsis is the most important risk factor. In
patients with cirrhosis and acute impairment of renal function
associated with bacterial infections, MELD score, neutrophil
count, and lack of resolution of infection are predictive factors of
the occurrence of renal failure. Moreover, the presence of
Factors involved in the pathogenesis of hepatorenal
syndrome (HRS)
C
Development of splanchnic vasodilatation, which causes
a reduction in effective arterial blood volume and a decrease
in mean arterial pressure
C
Activation of the sympathetic nervous system and the
renineangiotensinealdosterone system, which causes renal
vasoconstriction and a shift in the renal autoregulatory curve,
making renal blood ow much more sensitive to changes in
mean arterial pressure
C
Impaired cardiac function due to the development of cirrhotic
cardiomyopathy. Although cardiac output is initially high in
patients with ascites, as cirrhosis advances cardiac function
becomes unable to compensate for the systemic vasodilata-
tion and blood pressure decreases
C
Increased synthesis of several vasoactive mediators that may
affect renal blood ow or glomerular microcirculatory hae-
modynamics, such as cysteinyl leukotrienes, thromboxane A
2
,
F
2
-isoprostanes and endothelin-1, although the role of these
factors in the pathogenesis of HRS remains unknown
Box 3
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MEDICINE 39:10 615 2011 Published by Elsevier Ltd.
a systemic inammatory response (SIRS) is an independent
predictive factor of mortality.
Management of hepatorenal syndrome: general measures
include careful monitoring of blood pressure and urine output,
daily liver and renal function tests, and assessment for the pres-
ence of bacterial infection (including ascitic, urine and blood
cultures), gastrointestinal bleeding and hepatic encephalopathy.
All patients should be given cautious volume expansion with
Hartmanns solution or 4.5% human albumin solution (1e2
litres), assuming the patient has no signs of uid overload, and
managed (ideally) in an intensive care or semi-intensive care unit.
Administration of terlipressin with intravenous 20% albumin
solution (1 g/kg on day 1, followed by 40 g/day thereafter)
improves renal function in patients with type 1 HRS. Treatment is
effective in about 35e40% of patients, and is associated with an
improved survival. Terlipressin should be started at a dose of 0.5
mg intravenously (IV) four times daily (2 mg/day) and the dose
increased if there is no reduction in serum creatinine, depending
on urine output and change in arterial pressure, up to a maximum
of 2 mg IV four times daily. Recent studies have suggested that
continuous intravenous infusion of terlipressin (suggested
regimen 3 mg/day) is more effective and has fewer adverse effects.
Terlipressin has less than 3% of the antidiuretic activity of vaso-
pressin, and a half-life of 24 minutes, so a continuous infusion will
lead to steady state concentrations within 2 hours.
Adverse effects of terlipressin: cardiovascular or ischaemic
complications occur in 9e22% of patients treated with bolus
injections of terlipressin, although most studies have excluded
patients with known ischaemic heart disease.
Both haemodialysis or continuous venovenous haemoltra-
tion have been used to treat patients with type 1 HRS. In
general, renal replacement therapy should be considered in all
patients presenting with type 1 HRS, and those in whom HRS is
potentially reversible. The survival of patients with HRS with
renal support is around 15e20%. Patients with other evidence
of organ failure, such as respiratory failure, have a worse
prognosis.
Liver transplantation is the treatment of choice for both type 1
and type 2 HRS, with survival rates of approximately 65% in type
1 HRS. However, with current waiting times for liver trans-
plantation, it is not readily available in the UK. A
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MANAGEMENT PROBLEMS IN LIVER DISEASE
MEDICINE 39:10 616 2011 Published by Elsevier Ltd.