Acute Kidney Injury in Cirrhosis

Guadalupe Garcia-Tsao,1 Chirag R. Parikh,2 and Antonella Viola1,3

Acute renal failure (ARF), recently renamed acute kidney injury (AKI), is a relatively frequent problem, occurring in approximately 20% of hospitalized patients with cirrhosis.
Although serum creatinine may underestimate the degree of renal dysfunction in cirrhosis,
measures to diagnose and treat AKI should be made in patients in whom serum creatinine
rises abruptly by 0.3 mg/dL or more (>26.4 mol/L) or increases by 150% or more (1.5fold) from baseline. The most common causes of ARF (the term is used interchangeably with
AKI) in cirrhosis are prerenal azotemia (volume-responsive prerenal AKI), acute tubular
necrosis, and hepatorenal syndrome (HRS), a functional type of prerenal AKI exclusive of
cirrhosis that does not respond to volume repletion. Because of the progressive vasodilatory
state of cirrhosis that leads to relative hypovolemia and decreased renal blood ow, patients
with decompensated cirrhosis are very susceptible to developing AKI with events associated
with a decrease in effective arterial blood volume. HRS can occur spontaneously but is more
frequently precipitated by events that worsen vasodilatation, such as spontaneous bacterial
peritonitis. Conclusion: Specic therapies of AKI depend on the most likely cause and
mechanism. Vasoconstrictors are useful bridging therapies in HRS. Ultimately, liver transplantation is indicated in otherwise reasonable candidates in whom AKI does not resolve
with specic therapy. (HEPATOLOGY 2008;48:2064-2077.)
he development of acute kidney injury (AKI) in
patients with cirrhosis is an ominous event. In a
systematic review of 118 studies evaluating predictors of survival in cirrhosis, parameters of liver dysfunction (Child-Pugh score and its components) and
parameters of renal dysfunction (creatinine and blood
urea nitrogen/azotemia) were both powerful predictors of
death in decompensated cirrhosis.1 Higher serum creatinine (SCr) consistently portends worse survival. In fact,
SCr is one of three variables that form part of the model of

end-stage liver disease (MELD) score that is a good predictor of 3-month mortality and is currently used in determining priority for orthotopic liver transplantation
(OLT).2 Pretransplantation creatinine was recently found
to be the most powerful predictor of survival post-OLT.3
Therefore, identifying and treating the cause of renal dysfunction in cirrhosis is essential.
This review of AKI in cirrhosis expands several recent
reviews on hepatorenal syndrome (HRS)4-6 by covering
causes of acute renal failure (ARF) other than HRS and
expands recent reviews of ARF in cirrhosis.7,8

Abbreviations: AKI, acute kidney injury; ARF, acute renal failure; ATN, acute
tubular necrosis; FENa, fractional excretion of sodium; GFR, glomerular ltration
rate; HRS, hepatorenal syndrome; MAP, mean arterial pressure; MELD, model of
end-stage liver disease; OLT, orthotopic liver transplantation; RCT, randomized
controlled trials; SBP, spontaneous bacterial peritonitis; SCr, serum creatinine;
SLKT, simultaneous liver and kidney transplant; TIPS, transjugular intrahepatic
portosystemic shunt; UNa, urinary sodium.
From the 1Section of Digestives Diseases, Yale University School of Medicine,
New Haven, CT, and VA-Connecticut Healthcare System, West Haven, CT; the
2Section of Nephrology, Yale University School of Medicine, New Haven, CT and
VA-Connecticut Healthcare System, West Haven, CT; and the 3Department of
Clinical Medicine, University of Bologna, Italy.
Received July 3, 2008; accepted August 25, 2008.
Address reprint requests to: Guadalupe Garcia-Tsao, Yale University School of
Medicine, Section of Digestive Diseases, One Gilbert Street, TAC, room # S241B,
New Haven, CT 06510. E-mail: guadalupe.garcia-tsao@yale.edu; fax:
203-785-7273.
Copyright 2008 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.22605
Potential conict of interest: Nothing to report.

Denition

2064

In response to the need for a common denition and

classication of ARF, the Acute Kidney Injury Network
recently developed and published a consensus denition
of acute kidney injury (AKI), a new term for ARF.9 AKI
is dened as an abrupt (arbitrarily set at 48 hours) reduction in kidney function manifested by an absolute increase in SCr of 0.3 mg/dL or more (26.4 mol/L),
equivalent to a percentage increase in SCr 50% or more
(1.5-fold from baseline) or a urine output of less than 0.5
mL/kg per hour for more than 6 hours. The AKI denition has three stages that indicate the severity of renal
dysfunction and are based on SCr or urine output (Table
1). The urine output criterion was included based on the
predictive importance of this measure but with the awareness that urine output may not be measured routinely and

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2065

Table 1. Classication/Staging System for Acute Kidney Injury (AKI)9

Stage

1
2
3*

Serum Creatinine Criteria

Urine Output Criteria

Increase in serum creatinine of more than or equal to 0.3 mg/dL ( 26.4 mol/L) or increase to more than
or equal to 150% to 200% (1.5-fold to 2-fold) from baseline
Increase in serum creatinine to more than 200% to 300% (2-fold to 3-fold) from baseline

Less than 0.5 mL/kg per hour for

more than 6 hours
Less than 0.5 mL/kg per hour for
more than 12 hours
Less than 0.3 mL/kg per hour for
24 hours or anuria for 12
hours

Increase in serum creatinine to more than 300% (3-fold) from baseline (or serum creatinine of more than
or equal to 4.0 mg/dL [354 mol/L] with an acute increase of at least 0.5 mg/dL [44 mol/L])

*Any patient requiring renal replacement therapy is, by denition, at a stage 3.

accurately in nonintensive care unit settings. These criteria include both an absolute and a percentage change in
creatinine to accommodate variations related to age, sex,
and body mass index and to reduce the need for a baseline
creatinine but do require at least two creatinine values
within 48 hours.

Types of Acute Kidney Injury

Traditionally, three types of ARF/AKI are identied:
(1) prerenal azotemia, which results from renal hypoperfusion without a glomerular or tubular lesion; (2) intrinsic
renal failure, which results from tubular cell necrosis
(ischemic or toxic), glomerulonephritis, or interstitial nephritis; and (3) post-renal failure, which results from urinary tract obstruction causing hydronephrosis. Patients
with cirrhosis can develop all types of AKI,8 but they can
additionally develop HRS, a type of prerenal AKI that is
not responsive to volume expansion and is seen exclusively in patients with severe liver dysfunction
HRS is a unique potentially reversible form of ARF
secondary to renal vasoconstriction10 that results from
extreme vasodilatation.11,12 It is therefore a functional disorder, not associated with structural kidney damage. The
1-year and 5-year probabilities of developing HRS in patients with ascites are approximately 20% and 40%, respectively13 and are highest in patients with more marked
sodium and water retention and marked activation of vasoconstrictive systems.13,14
HRS is divided into two types (1 and 2) based on
prognosis and clinical characteristics. Survival of patients
with HRS-1 is shorter than that of patients with HRS-2
(median survival 1.0 versus 6.7 months).15
HRS-1 is characterized by an abrupt deterioration in
renal function that occurs mostly in an inpatient setting
and often develops after a precipitating event, particularly
spontaneous bacterial peritonitis (SBP).4,16 HRS-2 is
characterized by a steady or slowly progressive course that
occurs mostly in an outpatient setting in patients with
refractory ascites.17 Because this more chronic form of
HRS does not meet criteria for AKI, it is not considered in

this review. The term HRS will refer to HRS-1, unless

otherwise specied.

Prevalence
AKI occurs in approximately 19% of hospitalized patients with cirrhosis,18-22 and the most common cause is
prerenal AKI, accounting for approximately 68% of the
cases19,23,24 (Fig. 1). AKI is mostly secondary to infection,19,24 hypovolemia (gastrointestinal hemorrhage, aggressive diuresis, or diarrhea), use of vasodilators, and
other factors that cause renal vasoconstriction such as
nonsteroidal anti-inammatory drugs or intravenous
contrast agents. HRS, which is not volume-responsive,
constitutes approximately 25% of the cases of prerenal
ARF; that is, it accounts for only approximately 17% of
cases of ARF in hospitalized patients with cirrhosis19,23,24
(Fig. 1).
Acute tubular necrosis (ATN) is more common than
HRS as a cause of AKI, accounting for about a third of the
cases (Fig. 1). It is mainly caused by an ischemic insult to
the renal tubules as a result of a hypotensive event after
bleeding or severe sepsis. However, the use of aminoglycosides, which are directly toxic to renal tubules, was
found to be the most important predictor of ARF in cirrhosis in a study performed in U.S. veterans.18
Postrenal causes of AKI in cirrhosis are rare and represent less than 1% of the cases.23 Similarly, chronic kidney
injury also appears to be a rare diagnosis in hospitalized
patients,19 although a small study has recently shown that
immune-complex glomerulonephritis is quite common
in patients with end-stage hepatitis Cinduced cirrhosis.25 A recent review has suggested that an additional
subtype of HRS should include patients with chronic kidney injury who develop superimposed AKI.6
Mechanisms. ARF/AKI is common in cirrhosis for
several reasons. Patients with cirrhosis are prone to intravascular volume depletion secondary to gastrointestinal
bleeding, diuretic use, and lactulose-induced diarrhea.
Moreover, these patients are often exposed to nephrotoxic
agents such as nonsteroidal anti-inammatory drugs,

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GARCIA-TSAO, PARIKH AND VIOLA

HEPATOLOGY, December 2008

Fig. 1. Prevalence and types of acute renal

failure (ARF)/acute kidney injury (AKI) in hospitalized patients with cirrhosis. Percentages and
numbers were obtained by adding up patients in
the references cited. ATN, acute tubular necrosis;
GMN, glomerulonephritis; HRS, hepatorenal syndrome. *Infections precipitated this type of AKI in
51% of the cases.19,24

contrast agents, and aminoglycosides, to which they are

particularly susceptible.18,26 Perhaps most importantly,
because of the hyperdynamic circulatory state of cirrhosis,
renal blood ow in patients with cirrhosis (particularly in
those with more severe liver disease) is very susceptible to
events associated with a further decrease in effective arterial blood volume.
As recently reviewed,12 the hyperdynamic circulation
in cirrhosis is a progressive vasodilatory syndrome that
was rst recognized clinically in patients with cirrhosis by
observing that they frequently had warm extremities,

cutaneous vascular spiders, wide pulse pressure, and capillary pulsations in the nail beds.27 Progressive vasodilatation (both splanchnic and systemic) is a key factor in the
pathogenesis of many of the complications of cirrhosis,
prominently in the kidney.12 Splanchnic and systemic
vasodilatation in cirrhosis is a consequence of portal hypertension and is attributable mostly to nitric oxide overproduction, although other molecules also participate in
this complex process.12 As shown in Fig. 2, vasodilatation
leads to a decreased effective arterial blood volume (relative hypovolemia) and activation of neurohumoral sysCIRRHOSIS

Portal (sinusoidal) hypertension

Fig. 2. Hyperdynamic circulation in the pathophysiology of hepatorenal syndrome (HRS). Ascites, hyponatremia, and HRS in cirrhosis have a
common pathophysiology. The main abnormality
is splanchnic and systemic vasodilatation that
leads to a decreased effective arterial blood volume (relative hypovolemia) and activation of neurohumoral systems (RAAS, renin-angiotensinaldosterone system; SNS, sympathetic nervous
system; ADH, nonosmotic release of antidiuretic
hormone). Relative hypovolemia initially leads to
sodium and water retention (with ascites formation), increase in intravascular volume, and increased cardiac output. With progression of
cirrhosis, vasodilatation worsens and activated
vasoconstrictive systems lead to renal vasoconstriction. Additionally, the increased cardiac output is now insufcient to maintain perfusion
pressure (high-output heart failure) and further
contributes to a decrease in renal blood ow and
renal failure.

SPLANCHNIC / SYSTEMIC
VASODILATATION

Increased
cardiac output

Decreased effective arterial blood volume

Activation of neurohumoral systems

(RAAS, SNS, ADH)

Sodium and water

retention
Ascites and
hyponatremia

Renal vasoconstriction
Decreased renal blood flow

HRS

High-output
heart failure

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GARCIA-TSAO, PARIKH AND VIOLA

Rapid fluid loss (GI

bleed, diarrhea)

Hypovolemia

2067

Bacterial infection
(SIRS/Sepsis)
Decreased
effective arterial
blood volume

Further
vasodilatation*

Activation of VCS

Renal vasoconstriction

Fig. 3. Mechanisms for the development of

acute renal failure (ARF)/acute kidney injury (AKI)
in cirrhosis. GI, gastrointestinal; SIRS,systemic inammatory response syndrome; VCS, vasoconstrictive systems (include renin-angiotensinaldosterone and sympathetic nervous system).
*Worsening of the vasodilatation already present
in the patient with cirrhosis

ARF/AKI
Hypovolemic
shock

tems such as the renin-angiotensin-aldosterone system;

sympathetic nervous system; and non-osmotic release of
antidiuretic hormone). Relative hypovolemia initially
leads to sodium and water retention (with ascites formation), increased intravascular volume, and increased cardiac output. With progression of cirrhosis, vasodilatation
worsens and activated vasoconstrictive systems lead to renal vasoconstriction and decreased renal blood ow11,28
(Fig. 2). Additionally, as in other forms of high cardiac
output syndrome, the heart response becomes insufcient
to maintain perfusion pressure (high-output heart failure)
and further contributes to a decrease in renal blood ow
and renal failure12,29 (Fig. 2). It has been proposed that
the sympathetic nervous system causes a rightward shift in
the renal autoregulatory curve that makes renal blood
ow critically dependent on renal perfusion pressure and
that this further contributes to the development of renal
failure.30
Although the spontaneous development of renal failure in a patient with cirrhosis and hyperdynamic circulation indicates the presence of HRS, this syndrome often
presents after a precipitating event.4 In the setting of hyperdynamic circulation, rapid uid loss (from gastrointestinal bleeding or diarrhea) or sepsis/systemic inammatory
response syndrome-related vasodilation leads to a further decrease in effective arterial blood volume, renal vasoconstriction, and prerenal AKI (Fig. 3).
This is further complicated by the fact that these same
events, through the development of circulatory shock, can
lead to intrinsic renal failure from renal tubular necrosis.
Intense renal vasoconstriction, as seen in HRS, can in turn
lead to tubular ischemia and necrosis as demonstrated by

Renal tubular injury

Septic shock

electron microscopy31 or by urine markers of acute tubular necrosis32,33 (Fig. 3).

Diagnosis
SCr is the most established, simple, and inexpensive
parameter of glomerular ltration rate (GFR) and is the
primary method of detection of all forms of renal failure. However, it has several limitations. First, SCr is
not helpful in distinguishing among various causes of
renal injury. Second, SCr lags behind renal injury and
is therefore a delayed marker of decreased renal function.34 Third, signicant renal disease can exist with
minimal or no changes in SCr because of renal reserve,
enhanced tubular creatinine secretion, or other factors.35,36 Lastly, SCr is greatly inuenced by numerous
nonrenal factors such as body weight, race, age, sex,
total body volume, drugs, muscle metabolism, and protein intake.35 Although the simplied modication of
diet in renal disease formula provides a robust estimate of GFR relative to SCr corrected by age, race, and
sex in chronic kidney disease when SCr is at a steady
state, it is not useful in AKI when SCr is not in equilibrium. In cirrhosis, SCr may be an even poorer reection of kidney function because of a reduced muscle
mass, particularly in patients with severe liver disease.
In this setting, the release of creatinine is considerably
reduced, and therefore, patients may have a normal
SCr in the setting of a very low GFR. Additionally,
severe hyperbilirubinema gives a falsely low value of
SCr if the chemical rather than enzymatic method is
used for measurement.37

2068

GARCIA-TSAO, PARIKH AND VIOLA

Table 2. HRS New Diagnostic Criteria17

Cirrhosis with ascites
Serum creatinine 1.5 mg/dL (133 mol/L)
HRS-1 doubling of the initial serum creatinine concentrations to a
level greater than 2.5 mg/dL (226 mol/L) in less than 2 weeks
No improvement in serum creatinine (decrease to 1.5 mg/dL or less)
after at least 2 days of diuretic withdrawal and expansion of plasma
volume with albumin (1 g/kg body weight/day up to a maximum of
100 g/day)
Absence of shock
No current or recent treatment with nephrotoxic drugs or vasodilators
Absence of parenchymal kidney disease as indicated by proteinuria
500 mg/day, microhematuria (50 red blood cells per highpower eld), or abnormal renal ultrasonography

As recently reviewed,38 other methods of renal function assessment also have limitations and do not correlate
well with GFR. Newer serum markers such as cystatin C
are promising; however, they require further validation
using gold standard measures of GFR such as iodothalamate or inulin clearance. Therefore, and despite its
limitations; SCr remains the key biomarker in the diagnosis of ARF in cirrhosis.

Diagnosis of HRS
HRS type 1 has been dened by consensus as a doubling of SCr to a level greater than 2.5 mg/dL (226
mol/L) in less than 2 weeks.16,17 Per the AKI consensus
criteria, this level of renal failure would correspond to a
stage 2 (that is, a greater than twofold to threefold increase
in SCr from baseline)9 (Table 1).
The diagnosis of HRS has been dened in two International Ascites Club consensus conferences in 199616
and in 2005 (Table 2).17 The new denition of HRS: (1)
excludes creatinine clearance because it is more complicated to perform and does not increase the accuracy of
renal function estimation; (2) includes renal failure in the
setting of ongoing bacterial infection (but in the absence
of septic shock), indicating that the diagnosis can be established before completing antibiotic therapy; (3) determines that plasma volume expansion should be
performed with intravenous albumin rather than saline
solution; and (4) excludes minor diagnostic criteria (urinary indices) because these criteria have poor sensitivity
and specicity.
Although HRS is a diagnosis of exclusion, certain patient characteristics are more or less typical of HRS. The
presence of ascites is a prerequisite for the diagnosis of
HRS because the same mechanisms that lead to ascites
formation lead to HRS11 (Fig. 2). Other features that are
characteristic of patients with HRS can be gathered from
Table 3, which summarizes baseline characteristics of 509
patients with HRS that met International Ascites Club

HEPATOLOGY, December 2008

criteria for HRS (only 5% of whom had HRS-2) and that

specied, at a minimum, age, Child-Pugh class or score,
and mean arterial pressure (MAP).14,15,23,33,39-48 Patients
with HRS have advanced liver disease, as evidenced by the
median Child-Pugh score in these patients being 11.2,
and their low MAP (median, 74 mmHg), and low serum
sodium (median, 127 mEq/L), ndings that are consistent with the presence of vasodilatation (low MAP), sodium retention (ascites), water retention (dilutional
hyponatremia), and renal vasoconstriction (HRS) (Fig.
2). If these ndings are absent, the diagnosis of HRS is
unlikely. Of note, SCr levels in HRS are approximately
3.6 mg/dL and rarely exceed 6 mg/dL, and urine output is
usually approximately 600 mL/day (Table 3).

Differential Diagnosis
Differentiation among the three main causes of AKI
may be difcult in patients with cirrhosis because the
clinical presentations do not match classical paradigms
and, as mentioned previously, factors that lead to prerenal
azotemia can precipitate HRS and can also precipitate
ATN (Fig. 3).
Tubular ability to reabsorb sodium and to concentrate
urine is preserved in prerenal azotemia and HRS but is
impaired in ATN. Prerenal azotemia and HRS are therefore classically described as sodium avid states with low
(20 mEq/L) urinary sodium (UNa), low (1%) fractional excretion of sodium (FENa), and elevated (500
mOsm/kg) urine osmolality. Conversely, patients with
ATN have high UNa (40 mEq/L), high FENa (2%),
and urine osmolality under 350 mOsm/kg. However, in
patients with HRS, particularly in those on a high dose of
diuretics, UNa is consistently greater than 10 mEq/L.49
Conversely, ATN that occurs in patients with sodium
avid states, such as cirrhosis, has been described as having
a FENa 1%.7,50 UNa and FENa are thus less useful in
patients with cirrhosis and have been eliminated as diagnostic criteria in HRS.17
Classic descriptions of prerenal azotemia and HRS describe a bland urine sediment, and bile-stained granular
and epithelial casts are described in ATN. However, these
casts may be seen as nonspecic ndings in patients with
advanced liver disease and jaundice.51,52 Conversely,
ATN has been described morphologically31 and by urine
biomarkers such as -2 microglobulin32 in HRS.33 Thus,
urine sediment may not be helpful either in the differential of ARF in cirrhosis.
Differentiation between prerenal azotemia and HRS
also may be difcult. By denition, prerenal azotemia
improves with volume expansion. However, assessment
of exact intravascular volume decit in a patient who is
already total body sodium overloaded is difcult; the rate

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2069

Table 3. Baseline Characteristics of 509 Patients with HRS in Different Series in the Literature that Specied, at a
Minimum, Age, Child-Pugh Score/Class, and MAP

First Author
Year

N
(n HRS-2)

Age
(years)

Sex
(% Male)

%
Alcoholic
Cirrhosis
(%alc hep)

Child-Pugh
Score

MAP
(mmHg)

Serum
Creatinine
mg/dL
(mol/L)

Serum
Sodium
(mEq/L)

Urine Output
(mL/day)

Angeli 99 (33)
5 (0)
62
40
1/4 (B/C)
76
5 (442)
130
680
study group
Angeli 99 (33)
8 (0)
61
37.5
1/7 (B/C)
79
3.6 (319)
128
479
controls
Gulberg 99
7 (0)
50
57
57
0/7 (B/C)
74
2 ( 177)
124
425
(39)
Mulkay 01
12 (0)
54
68
75 (42)
2/10 (B/C)
76
3.4 (301)
127
500
(40)
Moreau 02
99 (0)
56
71
90 (26)
Most C
78
2.9 (257)
127
(23)
Colle 02 (41)
18 (0)
47
72
89 (39)
13
75
3.2 (283)
127
655
Halimi 02 (42)
18 (2)
60
73
78 (22)
11
82
3.2 (283)
131
489
Duvoux 02
12 (0)
54
58
67
11
65
3.9 (345)
125
638
(43)
Solanki
12 (0)
51
75
9
76
2.9 (257)
627
03 (44)
Study group
Solanki 03
12 (0)
53
67
9
74
2.2 (195)
569
(44) Control
group
Kiser 05 (45)
19 (1)
52
68
11.5
61
4.5 (398)
128
Group 1
Kiser 05 (45)
16 (8)
47
63
11.2
71
3.6 (319)
133
Group 2
Kiser 05 (45)
8 (2)
51
50
11
61
3 (265)
132
Group 3
Alessandria 05
41 (0)
56
88
46
11
71
3.9 (345)
122
(15)
Ruiz del Arbol
12 (0)
12
70
4.3 (381)
124
05 (14)
Neri 08 (46)
26 (0)
59
38.5
11.5
11.5
72
2.8 (248)
126
571
Study group
Neri 08 (46)
26 (0)
60
42
15.4
11.2
68
2.9 (257)
126
620
Control
group
Sanyal 08 (47) 56 (0)
51
73
52 (36)
12
76
4 (354)
131
Study group
Sanyal 08 (47)
56 (0)
53
70
52 (36)
11
77
3.9 (345)
132
Control
group
Martin-Llahi 08
23 (6)
59
70
61
10
73
3.6 (319)
124
607
(48) Study
group
Martin-Llahi 08
23 (5)
55
56.5
83
11
68
4.1 (363)
129
596
(48) Control
group
Median (IQ
Total N 54 (5159) 68 (5772) 57 (4078) 11.2 (1112) 74 (6876) 3.6 (2.94.0) 127 (125131) 596 (489638)
range)*
509 (24)
319 (257354)

Urinary
Sodium
(mEq/day)

5
6.6
7
7
16
8
-

7 (612)

All values are expressed as mean values except for Mulkay (median values).
* Median (IQ range) of studies; MAP, mean arterial pressure; alc hep, alcoholic hepatitis; IQ, interquartile.

of uid administration is unspecied, and thus the rate of

response in SCr is highly variable and often incomplete.
The difculty in establishing an early diagnosis of HRS
leads to a signicant delay in the initiation of specic
therapy and is one of the barriers in the development of
new agents.

In noncirrhotic patients, urinary biomarkers such as

interleukin-18 have an accuracy of 95% in differentiating
ATN from other causes of renal dysfunction such as prerenal azotemia, urinary tract infection, and chronic kidney disease53 and are being investigated in patients with
cirrhosis.

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GARCIA-TSAO, PARIKH AND VIOLA

Treatment
Treatment of AKI in cirrhosis depends on its cause. Prerenal azotemia should be managed by treating/discontinuing
the precipitant and through volume repletion. ATN should
be treated using renal replacement therapy, particularly in
the presence of volume overload, hyperkalemia, or metabolic
acidosis not responding to medical therapy. Because of a lack
of clinical studies, there are no special recommendations for
dose, intensity, and duration of dialysis in patients with cirrhosis who develop ATN. Interestingly, a recent study has
demonstrated benet of terlipressin in a consecutive series of
patients with cirrhosis with ATN.54 It is likely that mesenteric/systemic vasoconstriction induced by terlipressin will
lead to renal vasodilatation with improvement of renal blood
ow to the damaged renal tubules. Therapy of the complications of AKI and dialysis therapy are beyond the scope of
this review. The remainder of this section deals with treatment of HRS.

Liver Transplantation (OLT)

OLT is the only denitive therapy for HRS, because it is
the only therapy associated with improvement in survival.
However, it is important to reverse HRS because improving
renal function pretransplantation is associated with improved posttransplantation outcomes.55-59 It has been shown
that renal insufciency, including HRS, has a negative impact on OLT outcomes, with a higher mortality and higher
posttransplantation end-stage renal disease.3,55-58 Patients
who are transplanted with HRS have more complications
and a higher in-hospital mortality rate than those undergoing transplantation without HRS.56 Conversely, the outcome of OLT in patients with HRS treated with vasopressin
analogs before transplantation is similar to that of patients
undergoing transplantation without HRS.60
With the implementation of the MELD score in the
allocation of organs in the United States, the presence of
HRS increases the possibility of obtaining an organ for
transplantation. However, although survival in HRS-2
(the more benign, chronic type of HRS) correlates with
the MELD score, all patients with HRS-1 have a very
poor outcome,15 suggesting that the development of
HRS-1 per se should indicate a high priority for transplantation, independent of MELD.
Simultaneous liver and kidney transplant (SLKT) is
increasingly considered in patients with renal dysfunction
undergoing OLT.59 There is specic concern that some
patients who undergo SLKT may have reversible renal
failure. There is also concern that liver grafts are placed
prematurely in those with end-stage renal disease. Thus,
to assure allocation of transplants only to those truly in
need, the transplant community met in March 2006 to

HEPATOLOGY, December 2008

review post-MELD data on the impact of renal function

on liver waitlist and transplant outcomes and the results of
SLKT.61 This consensus conference resulted in an evaluation algorithm that has the goal of conrming the presence of kidney disease with structural damage (preferably
on biopsy) that would merit an SLKT. In the setting of
chronic kidney disease, a measured creatinine clearance
(or preferentially an iothalamate clearance) of 30 cc/
minute or less was considered the appropriate threshold
for SLKT.62 HRS alone should not be a reason for SLKT;
however, this is now being considered in patients with
HRS who become dialysis dependent and in whom there
is no recovery after 6 to 8 weeks of dialysis (the usual
recovery time for ATN).61 The need for dialysis should
theoretically be prevented by early treatment of HRS with
the bridging therapies outlined below, particularly the
use of vasoconstrictive therapy.

Vasoconstrictors Plus Albumin

Because the main pathogenic mechanism in HRS is
splanchnic and systemic vasodilatation (Fig. 2), vasoconstrictors should ameliorate vasodilatation and improve effective arterial blood volume, renal vasoconstriction, and renal
ow. Vasoconstrictors have been used in conjunction with
intravenous albumin with the intention of increasing effective blood volume. Because albumin dialysis is associated
with an increase in MAP attributable to the ability of albumin to bind vasodilators, it is conceivable that an improvement of renal function in patients with HRS treated with
vasoconstrictors and albumin is attributable to the additive
effects of both compounds in producing vasoconstriction.
The need for albumin has only been examined in a nonrandomized small study that showed that treatment with terlipressin and albumin was associated with a signicant
decrease in SCr and an increase in MAP, changes that were
not observed in a nonconcurrent group of patients treated
with terlipressin alone.63
Vasoconstrictors used in the treatment of HRS in small
numbers of patients for periods greater than 3 days are
associated with increases in MAP, GFR, and serum sodium and decreases in SCr and plasma renin activity (Table 4). Terlipressin is the preferred vasopressin analog
because of a lower incidence of side effects and because its
administration does not require continuous intravenous
infusion.23,40-42,44,46-48,63,64
Noradrenaline, in continuous infusion, has also been
shown to ameliorate the hemodynamic/renal abnormalities in HRS,43 as has the combination of midodrine plus
octreotide, which has the advantage of oral/subcutaneous
administration.33,65,66 However, octreotide alone is no
more effective than placebo67 and did not improve SCr.45
It is therefore uncertain whether the effectiveness of the

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Table 4. Changes in Mean Arterial Pressure, Parameters of Renal Function and Plasma Renin Activity in Prospective Proofof-Concept Studies of Vasoconstrictors Albumin Administered for More Than 3 Days

Author (Year)

Vaso-constrictor

Guevara98 (69)

Or

Gulberg99 (39)

Or

Angeli99 (33)

OM

Uriz01 (64)

Mulkay01 (40)

12

Ortega02 (63)

13

Duvoux02 (43)

12

MAP (mmHg)

69 383
120%
74 389
120%
76 397
128%
68 380
118%
76 387
114.5%
70 379
113%
65 373
112%

Serum
Creatinine
(mg/dL)

Serum
Sodium
(mEq/L)

3 30.7
2 77%
2 3? *

122 3131
17%
124 3?*

5 31.8
2 64%
3.9 31.5
2 61.5%
3.4 31.6
2 53%
3.6 31.5
2 58%
3.9 31.6
2 59%

130 3139
17%
122 3131
17%
127 3135
16%
123 3131
16.5%
125 3131
15%

Glomerular
Filtration
Rate
(cc/min)

Urine
Output
(cc/day)

Urine Sodium
(mEq/L)

9 341
1356%
14.6 336.9
1153%
10.4 346.1
1343%
8 324
1200%
11 333
1200%
10 330
1200%
15 343
1187%

450 31383
1207%
425 3911
1112%
680 31540
1126.5%
710 31115
157%
500 31160
1132%
571 31057
185%
638 31982
1211%

2 37
1250%
7 330
1329%
5 346
1820%
3 37
1133%
7 338
1443%
3 39
1200%
8 352
1550%

Plasma Renin
Activity
(ng/mL/h)

19 30.8
2 96%
17 34
2 77%
23 33.5
2 85%
20 34
2 80%
565 3164
2 71%

All values are expressed as mean values except for Mulkay (median values). Changes in bold lettering were statistically signicant.
Or, ornipressin,; OM, octreotide plus midodrine; T, terlipressin; N, noradrenaline.
*In responders, serum creatinine 4.6 31.3 (2 72%) and serum sodium 124 3134 (18%).
Calculated by MDRD.
ng/L.

combination octreotide/midodrine is attributable to

midodrine alone or to the combination. Experimental
studies showing that octreotide potentiates the effect of
vasoconstrictors68 would suggest the latter.
Clinical outcomes of 12 uncontrolled studies including 258 patients with HRS are summarized in Table
5.23,33,39-43,45,63-65,69 Complete response (mostly dened
as a decrease in SCr to 1.5 mg/dL) was observed in 60%
(156/258) overall, and in 65% (110/169) of patients who
received terlipressin.23,40-42,63,64 Interestingly, HRS recurred in only a minority of responders (22% or 16/72)
once therapy was discontinued. Median survival is approximately 41 days (compared with 14 days in a group of
untreated patients.13).
Five randomized controlled trials (RCTs) of terlipressin in HRS compared with albumin alone46,48 or with a
placebo44,47,70 have been published. The study by Hadengue et al70 was a proof-of-concept crossover study that
showed that terlipressin (but not placebo) was associated
with an increase in GFR. All other studies investigated
clinical outcomes (Table 6) and, except for the study by
Sanyal et al.,47 they were all open-label studies. In all of
them, HRS reversal was higher in the terlipressin group
(54/117 or 46%) compared with the control group (13/
117 or 11%). In the only placebo-controlled, doubleblind multicenter trial that included the largest number of
patients,47 HRS reversal occurred in 34% of the patients,
a rate signicantly greater than that of placebo-treated
patients (13%) but lower than that reported in uncontrolled studies. The low rate of recurrence of HRS in

treated patients is conrmed in these studies (2/29 or

7%). Both controlled and uncontrolled studies agree that
survival is signicantly better in terlipressin responders.23,45,47,48 Additional information from recent RCTs46
conrms that terlipressin plus albumin has a benecial
effect in the treatment of HRS. Because survival was not
improved in the two largest RCTs,47,48 liver transplantation is still the therapy of choice for HRS, but terlipressin
appears to be the bridging therapy of choice.
Specics such as the optimal time for initiation of vasoconstrictive therapy, dose and duration, failure criteria,
and the inuence and dose of albumin remain to be determined. Vasoconstrictor therapy has been used at different doses and with different side effects (Table 7);
patients that receive higher doses appear to have a higher
rate of adverse events.71
Terlipressin needs to be compared with other vasoconstrictors (Table 7). Two recent small, open-label RCTs
comparing noradrenaline with terlipressin showed that
neither HRS reversal nor the rate of side effects was different between groups.72,73 This is interesting from a
pathophysiological perspective because noradrenaline
does not induce splanchnic vasoconstriction, suggesting
that the main effect is peripheral vasoconstriction.

Transjugular Intrahepatic Portosystemic

Shunt
Three small prospective but uncontrolled studies have
assessed the role of transjugular intrahepatic portosys-

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HEPATOLOGY, December 2008

Table 5. Clinical Outcomes of Therapy with Vasoconstrictors (Plus IV Albumin) in Uncontrolled Studies
Complete
Response
n (%)

Days to CR
(median
value and
range)

HRS Recurrence:
n/responders
(%)

Median Survival
(days)

7 (415)

2/6 (33)

60

4 (57)

14 (827)

2/4 (50)

90

MO
T
T
T
T

5 (100)
7 (78)
11 (92)
10 (77)
58 (58)

20 (520)
6 (615)
(212)
7 (414)
NA

0/5 (0)
0/7 (0)
4/9 (44)
1/10 (10)
NA

NA
39
42
40*
21

11 (61)

NA

7/11 (64)

24

13 (72)

NA

NA

NA

10 (83)

7 (510)

0/10 (0)

60

MO

10 (71)

16

0/10 (0)

NA

VO

8 (42)

NA

NA

O
V

0 (0)
3 (38)

7.5
6

NA
NA

NA
NA

N
(n HRS-2)

Denition of Complete
Response (CR)

Guevara 98
(69)
Gulberg 99 (39)

8 (?)

2sCr1.5 mg/dL

Or

6 (75)

7 (0)

Or

Angeli 99 (33)
Uriz 01 (64)
Mulkay 01 (40)
Ortega 02 (63)
Moreau 02 (23)

5 (0)
9 (3)
12 (0)
13 (4)
99 (0)

Colle 02 (41)

18 (0)

Halimi 02 (42)

18 (0)

Duvoux 02 (43)

12 (0)

Wong 04 (65)

14 (0)

Kiser 05 (45)

19 (1)

2-fold 1CrCl to a
value 40 mL/min
2sCr 2 mg/dL
2sCr1.5 mg/dL
2sCr2 mg/dL
2sCr 1.5 mg/dL
2sCr1.5 mg/dL or
of at least 20% from
BL
2sCr1.5 mg/dL or
of at least 20% from
BL
2sCr at least of 30%
from BL
2sCr 1.5 mg/dL or
1CrCl to 40 mL/
min
2sCr1.5 mg/dL for
3 consecutive days
2sCr 1.5 mg/dL
without dialysis

Kiser 05(45)
Kiser 05 (45)

16 (8)
8 (2)

Author and Year

Vasoconstrictor

All prospective except for Moreau, Colle, Halimi, and Kiser (retrospective).
Or, ornipressin; MO, midodrine plus octreotide; T, terlipressin; N, noradrenaline; V, vasopressin; VO, vasopressin plus octreotide; sCr, serum creatinine; CrCl,
creatinine clearance; NA, not available; BL, baseline; CR, complete response.
*Median survival for whole series (N 21; 13 with albumin, 8 without albumin).
No mention of albumin administration.
Mean.

temic shunt (TIPS) in HRS,65,74,75 including one performed in ve patients whose renal function had
improved on octreotide/midodrine.65 These studies show
a decrease in SCr in most patients, even in a few with
organic renal failure,76 but slower than that obtained using terlipressin plus albumin. Recurrence of HRS is rare as

long as the shunt remains patent, but hepatic encephalopathy is a frequent complication. Post-TIPS resolution of
HRS appears to improve survival. Long-term success was
demonstrated in the study that explored sequential treatment with vasoconstrictors and albumin followed by
TIPS.65 Notably, a great majority of patients included in

Table 6. Clinical Outcomes of Therapy with Terlipressin (Plus Albumin) in Randomized Controlled Trials

Author Year

Solanki 03 (44)
Neri 08 (46)
Sanyal 08 (47)
Martin-Llahi
08 (48)

Denition of
Complete
Response (CR)

Improvement in
renal function
2sCr 1.5 mg/dL
2sCr 1.5 mg/dL
without dialysis
2sCr1.5 mg/dL

sCr, serum creatinine; NA, not available.

*Terlipressin-responders only.
Three-month survival.
30% of patients had type 2 HRS.

Group

Terlipressin
Control
Terlipressin
Control
Terlipressin
Placebo
Terlipressin
Control

12
12
26
26
56
56
23
23

Complete
Response
n (%)

Days to Achieve
CR (median
and range)

HRS
Recurrence
(%)

Median
Survival
(days)

5 (42)
0 (0)
21 (81)
5 (19)
19 (34)
7 (13)
9 (39)
1 (4)

15?
NA
NA
6 (214)
3 (27)
11 (616)
NA

Some
NA
NA
1/19 (5)
1/7 (14)
1/10 (10)
NA

8.5
9.0
90*
15
24
31
27%
19%

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2073

Table 7. Vasoconstrictors in HRS: Doses Used and Adverse Events

Drug

Dose Range

Observed Adverse Events

Terlipressin
(23;4042;44;4648;63;64;70)

0.52.0 mg intravenously every 46 hours

Ornipressin (39;69)

26 U/h (continuous intravenous infusion)

Vasopressin (45)

0.010.8 U/min (continuous intravenous

infusion)
0.53.0 mg/h (continuous intravenous
infusion)
100200 g subcutaneously three times
a day
7.512.5 mg orally three times a day
25 g 3 25 g/h (continuous
intravenous infusion)
2.5 mg/day orally

GI: abdominal cramps associated with increased bowel movements,

diarrhea, nausea, vomiting, intestinal ischemia
Cardiac: arrhythmia (tachycardia, bradycardia, extrasystolia, AF),
chest pain, MI
Peripheral: livedo reticularis, nger ischemia, cutaneous necrosis at
the infusion site, scrotal necrosis, skin lymphangitis
Others: arterial hypertension, dyspnea, bronchospasm, respiratory
acidosis
Abdominal cramps, intestinal ischemia with or without bleeding,
tongue ischemia, cardiac arrhythmia
None reported

Noradrenaline (43;73)
Octreotide Midodrine (33;65)

Chest pain with or without ventricular hypokinesia

Diarrhea, tingling, goosebumps

GI, gastrointestinal; AF, atrial brillation; MI, myocardial infarction; AE, adverse events.

these three studies had alcoholic cirrhosis, many with active alcoholism, and therefore the improvement observed
could have resulted from improvement in an acute-onchronic process. Also, all three studies excluded patients
with a Child-Pugh score equal to or greater than 12.
Given the paucity of data, the efcacy of TIPS should
be further explored in RCTs.

Extracorporeal Albumin Dialysis

In a small RCT, the molecular adsorbent recirculating system, a modied dialysis method using an extracorporeal albumin-containing dialysate, was shown to
improve 30-day survival in eight patients with HRS
compared with ve patients treated with intermittent
venovenous hemoltration alone.77 Because extracorporeal albumin-containing dialysate incorporates a
standard dialysis machine or a continuous venovenous
hemoltration monitor and GFR was not measured,
the decrease in SCr observed in most patients could be
related to the dialysis process. However, clear benecial
effects on MAP and on hepatic encephalopathy were
observed. Extracorporeal albumin-containing dialysate
is still considered an experimental therapy, and its use
in patients with type 1 HRS cannot be recommended
outside of prospective studies.

Approach to the Patient with Cirrhosis and

ARF
We propose that, as per the recent AKI consensus (Table 1), a diagnosis of HRS (type 1) be considered when-

ever there is an increase in SCr of 0.3 mg/dL or more

(26.4 mol/L) or an increase of 150% or more (1.5fold) from baseline. Delaying therapy until higher SCr
levels are reached would not seem warranted because baseline SCr is a predictor of HRS reversal,47,48,65 and the
probability of HRS reversal decreases by 39% for each
1-mg/dL increase in baseline creatinine.78 Treatment for
HRS should therefore be initiated earlier, with only 1.5fold increases in creatinine (Fig. 4).
The setting in which AKI occurs is essential. In patients
in whom there is a clear history of septic or hypovolemic
shock, or in whom there is a recent history of nephrotoxin
administration , the most likely cause is ATN. In all other
patients, the rst step is to discontinue diuretics, lactulose
(because it is a frequent cause of diarrhea), vasodilators,
and any potential nephrotoxins. Secondly, intravascular
volume should be expanded with intravenous albumin at
a dose of 1 g/kg body weight up to a maximum of 100 g.17
This dose can be repeated in 12 hours if the SCr has not
normalized. A reduction in SCr indicates that AKI is attributable to prerenal azotemia. Intravenous albumin is
preferred over saline solution as a volume expander because sodium load is signicantly lower with albumin,
and it will not worsen uid retention, and because it will
not be associated with a dilutional decrease in SCr. Third,
and concurrently, investigations to rule out precipitants
of AKI should be undertaken, specically diagnostic paracentesis (to rule out SBP), blood and urine bacteriological
cultures, and chest x-ray (to rule out bacterial infections
other than SBP) and patients treated accordingly.

2074

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HEPATOLOGY, December 2008

Patient with cirrhosis and acute renal failure (abrupt

increase in creatinine by >1.5 fold from baseline)

Discontinue: diuretics, lactulose, vasodilators,

potential nephrotoxins
Investigate and initiate treatment (if present)
for infection, blood or fluid losses
Albumin IV (1 g/Kg of body weight QD or BID)

History of shock
(septic or hypovolemic),
nephrotoxins, contrast

Treat as ATN

Improvement in
creatinine

Continue
therapy

No
improvement
in creatinine

Granular or epithelial
casts in urine?
Urine biomarkers of
ATN?

No granular or epithelial
casts in urine?
Central venous pressure
>10 cmH2O
Treat as HRS*

If SCr does not improve or continues to worsen despite

these measures, the differential diagnosis is between intrinsic renal failure (ATN), HRS, and postrenal failure.
Treatment of HRS can be initiated before completion of
antibiotic therapy in patients with bacterial infection
whose SCr does not improve despite a clear amelioration
in the signs of infection. Because assessment of volume
status may be uncertain, and to ensure that volume has
been adequately expanded, intravascular volume should
be assessed by measuring central venous pressure. A normal or increased central venous pressure indicates that the
cause of renal failure is not volume-related. To rule out
postrenal failure, a renal ultrasound should be obtained,
although this is a rare cause of AKI in cirrhosis (Fig. 1). To
rule out intrinsic renal failure, urinary sediment should be
analyzed. Finding granular or epithelial casts suggests
ATN but is not denitive. The differentiation between
ATN and HRS is the most difcult, and studies using
urine biomarkers of ATN are awaited. It has been suggested that the response to vasoconstrictors plus albumin
may be used to establish this differential.7

Approach to the Patient with HRS

Once the diagnosis of HRS is suspected, specic treatment with vasoconstrictors plus albumin should be initiated. Best evidence supports the use of terlipressin, which
should be started at a dose of 0.5 mg intravenously every
6 hours. If there is no early response (25% decrease in
creatinine levels) after 2 days of therapy, the dose can be
doubled every 2 days up to a maximum of 12 mg/day (in
other words, 2 mg intravenously every 4 hours). Starting

Fig. 4. Approach to the patient with cirrhosis

and acute renal failure. IV, intravenously; QD,
every day; BID, twice per day; ATN, acute tubular
necrosis; HRS, hepatorenal syndrome. *If compatible clinical characteristics, in other words,
ascites, low MAP, and hyponatremia (see text for
approach to patient with suspected HRS).

at lower doses will minimize potential severe adverse

events from this therapy.71
A more rational method to adjust the dose of vasoconstrictors is by monitoring MAP (an indirect indicator of
vasodilatation), a method that has been used for adjusting
the dose of midodrine plus octreotide,33 an alternative to
terlipressin in sites such as the United States, where terlipressin is not available. In this study, the doses of octreotide and midodrine were titrated to obtain an increase
in MAP of at least 15 mmHg; midodrine was administered orally at an initial dose of 7.5 mg three times daily
and, if necessary, increased to 12.5 mg three times daily;
octreotide was administered subcutaneously at an initial
dose of 100 g three times daily and, if necessary, increased to 200 g three times daily.33 Other alternatives
to terlipressin are vasopressin or noradrenaline. Noradrenaline is used as a continuous intravenous infusion at
an initial dose of 0.5 mg/hour, adjusted to achieve an
increase in MAP of at least 10 mm Hg or an increase in
4-hour urine output to more than 200 mL. If these goals
are not reached, the dose is increased every 4 hours in steps
of 0.5 mg/hour, up to the maximum dose of 3 mg/
hour.43,73 Vasopressin is also used as a continuous intravenous infusion, starting at a very low dose of 0.01 U/min
and titrating up to a dose of 0.5 U/min, depending on
changes in MAP and urine output as well as the presence
of ischemic side effects. In the study that assessed vasopressin for HRS, the mean vasopressin dose in the group
of responders was 0.23 0.19 U/min.45
Albumin is administered together with the vasoconstrictor. The maintenance dose, once the diagnosis of

HEPATOLOGY, Vol. 48, No. 6, 2008

GARCIA-TSAO, PARIKH AND VIOLA

2075

HRS is established and vasoconstrictors are initiated, is of

25 to 50 g/day. Albumin may be discontinued if serum
albumin concentration is greater than 45 g/L and should
be withdrawn in case of pulmonary edema. Because this
complication is uncommon, catheterization to monitor
central venous pressure is not mandatory, but careful
monitoring of the cardiopulmonary function is recommended.17
Treatment can be stopped if SCr does not decrease by
at least 50% after 7 days at the highest dose, or if there is
no reduction in creatinine after the rst 3 days. In patients
with early response, treatment should be extended until
reversal of HRS (decrease in creatinine below 1.5 mg/dL)
or for a maximum of 14 days.17 Vasoconstrictor therapy
should be restarted if HRS recurs after discontinuation of
therapy. Once creatinine normalizes, TIPS should be
considered, particularly if transplantation is not foreseeable in the near future and the patient has refractory ascites.65

On the other hand, a recent placebo-controlled RCT

that included hospitalized patients with low (1.5 g/L)
ascites protein who also had advanced liver failure or renal dysfunction (dened as SCr 1.2 mg/dL or blood
urea nitrogen 25 mg/dL, or serum sodium level 130
mEq/L) demonstrated that oral noroxacin was associated with a reduction in the 1-year probability of HRS
(28% versus 41%) and an improvement in survival at 3
but not 12 months.85 Noroxacin may act by ameliorating or preventing vasodilatation by preventing bacterial
translocation and overt infection.86 Notably, 79% of the
patients met renal dysfunction criteria at baseline, suggesting that patients with a more altered hemodynamic
status were those more likely to benet from antibiotics
and would probably benet from vasoconstrictors.
In both studies,82,85 the relation between prevention of
HRS and improved short-term survival is further proof
that renal failure is an important determinant of death in
patients with decompensated cirrhosis1 and that early
treatment or prevention are essential.

Prevention

References

Prophylaxis of AKI in cirrhosis consists of measures

that will prevent/treat volume depletion or vasodilatation.
Measures that prevent volume depletion include careful
use of diuretics with close weight and laboratory followup, preventing weight loss of more than 1 kg/day as well as
avoidance of diarrhea with the use of lactulose by adjusting its dose to obtain two to three semiformed bowel
movements/day. The use of albumin after large-volume
paracentesis (LVP) is a measure that can theoretically prevent the development of renal dysfunction by preventing
the development of postparacentesis circulatory dysfunction,79 an entity that has been shown to be secondary to
vasodilatation80 and is associated with development of
renal dysfunction and a higher mortality.81
Measures to prevent ATN include avoiding the use of
aminoglycosides and nonsteroidal anti-inammatory
drugs, particularly in patients with ascites, and aggressively treating hypovolemia/hypotension when it occurs.
It is uncertain whether HRS can really be prevented. It
has been suggested that in the setting of SBP, the administration of albumin prevents HRS. This is based on a
nonplacebo-controlled study in patients with SBP, in
which the intravenous administration of albumin decreased the risk of HRS by 66% compared with antibiotic
treatment alone.82 However, the benet of albumin is
observed mainly in patients with SCr greater than 1.0,
urea greater than 30 mg/dL, or a serum bilirubin greater
than 4 mg/dL,82-84 that is, patients who already have some
degree of renal dysfunction at the time of the diagnosis of
SBP.

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