Bailliere's Clinical Gastroenterology
�
Vol. 14, No. 6, pp. 945ą957, 2000
doi:10.1053/bega.2000.0140, available online at http://www.idealibrary.com on
5
Diagnosis and treatment of hepatorenal
syndrome
Pere Gine�s* MD
Associate Professor of Medicine
Liver Unit, Institut de Malalties Digestives, Hospital Cl��nic, IDIBAPS, University of Barcelona, Catalunya,
Spain
Hepatorenal syndrome (HRS) is a common complication of advanced cirrhosis characterized
not only by renal failure due to a marked vasoconstriction of the renal circulation but also by
marked alterations in systemic haemodynamics and activity of endogenous vasoactive systems.
The pathogenesis of HRS is not completely known but it is probably the result of an extreme
under�lling of the arterial circulation secondary to an arterial vasodilation located in the
splanchnic circulation. Besides the renal circulation all other extrasplanchnic vascular beds
appears to be vasoconstricted. The diagnosis of HRS is currently based on the exclusion of
non-functional causes of renal failure. Prognosis of patients with HRS is very poor. Liver
transplantation is the best option in selected patients, but is seldom applicable due to the
short survival expectancy of most patients with HRS, particularly those with the progressive
type (type I HRS). Therapies introduced during the last few years, such as transjugular
intrahepatic portosystemic shunts or, particularly, vasoconstrictor drugs with preferential
e�ect on the splanchnic circulation (V1 receptor agonists) are very e�ective in improving renal
function and reverting HRS. However, the impact of the improvement of renal function on
the natural course of HRS is unknown. Finally, the development of HRS after spontaneous
bacterial peritonitis can be e�ectively prevented by the administration of albumin together
with antibiotic therapy.
Key words: cirrhosis; ascites; renal failure; oedema; portal hypertension.
Patients with cirrhosis and ascites often develop a particular form of renal failure
known as hepatorenal syndrome (HRS), which is due to a marked vasoconstriction of
the renal circulation.1 This disorder is of functional origin because kidneys are normal
under histological examination and renal failure is reversible after liver transplantation.
Besides changes in renal function, patients with HRS also show remarkable abnorm-
alities in the systemic arterial circulation and activity of endogenous vasoconstrictor
systems, which probably play a major role in the development of renal failure. In
recent years, important advances have been made in the pathogenesis, diagnosis, and
management of patients with HRS (Table 1). The aim of this chapter is to provide an
updated review of HRS in cirrhosis.
*Address for correspondence: Liver Unit, Institut de Malalties Digestives, Hospital Cl��nic, IDIBAPS,
Villarroel, 170, 08036 Barcelona, Catalunya, Spain.
c
1521ą6918/00/060945�13 $35.00/00 *
2000 Harcourt Publishers Ltd.
946 P. Gine� s
Table 1. Landmarks in hepatorenal syndrome.
1860 First description
1950ą1960 Clinical characterization. Description of association with circulatory dysfunction
1960ą1970 Recognition of renal vasoconstriction
1970ą1980 Investigation of renal vasoactive factors
1988 Arterial vasodilation theory
1996 De�nition and diagnostic criteria
1990ą2000 Introduction of splanchnic vasoconstrictor drugs in clinical practice
DEFINITION
The new de�nition of HRS which emphasizes the changes occurring in both the renal
and extrarenal circulations is as follows: `Hepatorenal syndrome is a clinical condition
that occurs in patients with advanced chronic liver disease, liver failure, and portal
hypertension characterized by impaired renal function and marked abnormalities in
the arterial circulation and activity of the endogenous vasoactive systems. In the kidney
there is marked renal vasoconstriction that results in low glomerular �ltration rate
(GFR), whereas in the extrarenal circulation there is predominance of arterial vaso-
dilation, which results in reduction of total systemic vascular resistance and arterial
hypotension'.1 Although HRS occurs predominantly in advanced cirrhosis, it may also
develop in other chronic liver diseases associated with severe liver failure and portal
hypertension, such as alcoholic hepatitis, or in acute liver failure.2
PATHOGENESIS
The pathophysiological hallmark of HRS is a vasoconstriction of the renal circula-
tion.3ą5 The mechanism of this vasoconstriction is incompletely understood and
possibly multifactorial involving changes in systemic haemodynamics, increased
pressure in the portal venous system, activation of vasoconstrictor factors and
suppression of vasodilator factors acting on the renal circulation (Table 2). A detailed
analysis of these alterations and their possible role in the pathogenesis of renal
vasoconstriction is outside the scope of this article and may be found in recent
reviews.6,7 The theory that better explains the relationship between changes in the
renal circulation, activation of vasoconstrictor mechanisms and presence of marked
disturbances in systemic haemodynamics is the arterial vasodilation theory.8ą10 This
theory proposes that renal hypoperfusion represents the extreme manifestation of
under�lling of the arterial circulation secondary to a marked vasodilation of the
splanchnic vascular bed (Figure 1). This arterial under�lling would result in a progres-
sive baroreceptor-mediated activation of vasoconstrictor systems (i.e. the reniną
angiotensin and sympathetic nervous systems) that would eventually cause vaso-
constriction not only in the renal circulation but also in other vascular beds (lower and
upper limbs, cerebral circulation; see later). The splanchnic area would escape the
e�ect of vasoconstrictors and an intense vasodilation would persist because of a
markedly enhanced local production of vasodilator factors. Most of the available data
suggest that the most important factor responsible for splanchnic vasodilation in
cirrhosis is nitric oxide, although other factors such as prostaglandins and vasodilator
peptides may also play a role.11 In early phases following the development of portal
Hepatorenal syndrome 947
Table 2. Vasoactive factors potentially
involved in the regulation of renal
perfusion in cirrhosis and in the patho-
genesis of hepatorenal syndrome.
Vasoconstrictors
Angiotensin II
Norepinephrine
Neuropeptide Y
Endothelin
Adenosine
Cysteinyl leukotrienes
F2-isoprostanes
Vasodilators
Prostaglandins
Nitric oxide
Natriuretic peptides
Kallikreinąkinin system
Cirrhosis
Portal hypertension
Splanchnic vasodilation
Reduced effective arterial blood volume
Stimulation of vasoconstrictor systems
Renal vasoconstriction
Hepatorenal syndrome
Figure 1. Proposed pathogenesis of hepatorenal syndrome in cirrhosis according to the arterial vasodilation
theory.
hypertension, renal perfusion would be maintained within normal or near-normal
levels despite the overactivity of vasoconstrictor systems by an increased synthesis/
activity of renal vasodilator factors. However, in later phases of the disease renal
perfusion would not be maintained because of the extreme arterial under�lling
causing maximal activation of vasoconstriction systems and/or decreased activity of
renal vasodilator factors, and HRS would develop. The observation that the admini-
stration of drugs causing vasoconstriction of the splanchnic circulation is associated
with the suppression in the activity of endogenous vasoconstrictor systems and
marked improvement of GFR is a strong argument supporting the arterial vasodilation
theory.12ą14
948 P. Gine� s
An alternative theory proposes that renal vasoconstriction in HRS is the result of a
direct relationship between the liver and the kidney and bears no pathogenic
relationship with the disturbances in systemic haemodynamics. The link between the
liver and the kidney would be either a vasodilator factor, the synthesis of which would
be reduced as a consequence of liver failure, or a hepatorenal reŻex causing renal
vasoconstriction.15ą17 Evidence supporting the sequence of events proposed by this
theory in human cirrhosis is weak.
CLINICAL AND LABORATORY FINDINGS
Hepatorenal syndrome is a common complication of patients with cirrhosis, with a
reported incidence of about 10% among hospitalized patients with ascites. The clinical
manifestations include a combination of signs and symptoms related to renal, liver and
circulatory failure.
Renal failure may have a rapid or insidious onset (see later) and is usually associated
with marked sodium and water retention which result in ascites and oedema and
dilutional hyponatraemia, respectively.1,6,7 HRS may occur in two di�erent clinical
patterns, according to the intensity and form of onset of renal failure (Table 3). The
dominant clinical features of type I HRS are those of severe renal failure with oliguria
or anuria and increased serum levels of urea and creatinine. Despite an important
reduction of GFR in these patients, serum creatinine levels are commonly lower than
values observed in patients with acute renal failure of similar intensity with respect to
the reduction in GFR, but without liver disease.6 This is probably due to the lower
endogenous production of creatinine secondary to reduced muscle mass in patients
with cirrhosis compared with patients without liver disease. This type of HRS is
frequently seen in patients with alcoholic cirrhosis, especially when associated with
alcoholic hepatitis, but it occurs in non-alcoholic cirrhosis as well. Type I HRS is
associated with a very low survival expectancy, the median survival time being of only
2 weeks.18 Type II HRS is characterized by less severe and stable reduction of GFR that
does not meet the criteria proposed for type I. Patients are usually in a better clinical
condition than those with type I HRS and their survival expectancy is longer. The
dominant clinical feature of these patients is diuretic-resistant ascites due to the
combination of intense sodium retention, reduced GFR, and marked stimulation of
antinatriuretic systems.1 Severe spontaneous hyperkalaemia is an uncommon feature of
HRS. However, marked hyperkalaemia may occur if patients are treated with
aldosterone antagonists, specially patients with type I HRS. Severe metabolic acidosis
and pulmonary oedema, which are frequent complications of acute renal failure of
patients without liver disease, are uncommon �ndings in patients with HRS.
Because HRS is a form of functional renal failure, the characteristics of urine are
those of pre-renal azotemia, with oliguria, low urine sodium concentration, and
Table 3. Clinical types of hepatorenal syndrome.
Type I. Rapid and progressive impairment of renal function as de�ned by a doubling of the initial serum
creatinine to a level higher than 2.5 mg/dl or a 50% reduction of the initial 24-hour creatinine
clearance to a level lower than 20 ml/minute in less than 2 weeks
Type II. Impairment in renal function (serum creatinine 41.5 mg/dl) that does not meet the criteria
of type I
Hepatorenal syndrome 949
increased urine osmolality and urine-to-plasma osmolality ratio.1,3,6,7 Nevertheless,
there are non-oliguric forms of the syndrome and in some cases urine sodium
concentration is not extremely reduced. As discussed later, urinary indices are not
considered essential at present for the diagnosis of HRS.1
Circulatory failure in patients with HRS is characterized by high cardiac output,
arterial hypotension (most patients have a mean arterial pressure in the range 60ą
80 mmHg), and low total systemic vascular resistance (Table 4).1,3,5 This pattern of
renal vasoconstriction and systemic vasodilation is very characteristic of HRS although
not exclusive because it may be observed in renal failure associated with conditions
other than cirrhosis, such as sepsis. Another important haemodynamic feature of HRS
is that the reduction in total systemic vascular resistance and arterial pressure occurs
in the setting of a markedly increased activity of vasoconstrictor systems (i.e. the
reninąangiotensin system and the sympathetic nervous system), which suggests that
the decrease in systemic vascular resistance and arterial pressure would be even
greater if these systems were not activated.1,6,7 Most importantly, the activation of
these vasoconstrictor systems provides a pathophysiological link between the disturb-
ances in systemic haemodynamics and renal vasoconstriction. Traditionally, arterial
vasodilation in patients with HRS had been considered to occur in all arterial vascular
beds other than the renal circulation. However, recent data indicate that this is not the
case. Studies assessing blood Żow and vascular resistance by duplex Doppler ultra-
sonography have found that blood Żow to the upper and lower limbs, either in
absolute terms or as fraction of the cardiac output, is reduced in patients with HRS
compared with values found in patients with cirrhosis and ascites without renal failure
or healthy controls.19,20 Moreover, in patients with cirrhosis a direct correlation exists
between GFR and brachial or femoral artery blood Żow, indicating that the upper and
lower limb vascular beds change in parallel with the renal circulation. Likewise, the
resistance to blood Żow in the cerebral circulation, as assessed by Doppler resistive
index in the mean cerebral artery, is also increased in patients with HRS.21 The
�ndings of increased vascular resistance in the brain and upper and lower limbs, leave
the splanchnic area as the only vascular bed responsible for arterial vasodilation and
reduced total systemic vascular resistance in patients with HRS. As will be discussed
later, this �nding has important implications in the management of patients with HRS.
Finally, the third type of clinical manifestation of HRS is related to the existence of
liver failure. Most patients show �ndings of advanced liver insu�ciency, particularly
jaundice, coagulopathy, poor nutritional status and encephalopathy, although some
patients with HRS may show only moderate liver failure. In general, patients with type
I HRS have more advanced liver disease compared with patients with type II HRS.
Table 4. Haemodynamic �ndings in hepatorenal syndrome.
Increased cardiac output
Arterial hypotension
Reduced total systemic vascular resistance
Increased total blood volume
Increased activity of vasoconstrictor systems
Increased portal pressure
Portosystemic shunting
Reduced splanchnic vascular resistance
Increased renal vascular resistance
Increased brachial and femoral artery resistance
Increased cerebral vascular resistance
950 P. Gine� s
PRECIPITATING FACTORS
In some patients, HRS develops without any identi�able precipitating factor, whereas
in others it occurs in close chronological relationship with bacterial infections, part-
icularly spontaneous bacterial peritonitis (SBP).1,3,6,7 Approximately one-third of
patients with SBP develop an impairment of renal function in the absence of shock and
despite treatment with non-nephrotoxic antibiotics.22 The impairment in renal
function is of functional origin and occurs in the setting of a further decrease in
e�ective arterial blood volume, as indicated by a marked activation of vasoconstrictor
systems, and increased serum and ascitic Żuid levels of cytokines.23 In approximately
one-third of patients developing renal failure after SBP, the impairment in renal
function is reversible after resolution of infection. However, in the remaining patients
the impairment in renal function is not reversible after the resolution of the infection
and meets the criteria of HRS (type I in most cases). Patients who develop type I HRS
after SBP have an in-hospital mortality close to 100%.
Although uncommon, HRS has been reported after therapeutic paracentesis
without plasma expansion.24 This is one of the reasons that supports the administration
of intravenous albumin when large-volume paracentesis is performed.25
Gastrointestinal bleeding has been classically considered as a precipitating factor of
HRS.3 However, the development of renal failure after gastrointestinal bleeding is
uncommon in patients with cirrhosis (approximately 10%), and it occurs commonly in
patients who have developed hypovolaemic shock, in most cases associated with
ischaemic hepatitis, which suggests that renal failure in this setting is probably related
to the development of acute tubular necrosis (ATN) and is not of functional origin
(P Gine� s, unpublished observations). Diuretic treatment has also been classically
described as a precipitating factor of HRS, but there is no clear evidence to support
such pathogenic relationship.
DIAGNOSIS
The diagnosis of HRS is currently based on several diagnostic criteria (Table 5).1 The
value of serum creatinine required for the diagnosis of HRS is 1.5 mg/dl. Although this
value may seem low compared with values of serum creatinine in acute renal failure in
patients without liver disease, patients with cirrhosis with a serum creatinine above
1.5 mg/dl usually have a GFR below 30 ml/minute.6 In patients receiving diuretics,
creatinine measurement should be repeated after diuretic withdrawal because, in some
patients, creatinine may increase during diuretic therapy even in the absence of
excessive diuresis, causing volume depletion.
Because no speci�c laboratory tests are available for the diagnosis of HRS, and
patients with advanced cirrhosis may develop renal failure of other aetiologies (pre-
renal failure due to volume depletion, ATN, drug-induced nephrotoxicity and
glomerulonephritis), the most important step in the diagnosis of HRS is to rule out
renal failure secondary to volume depletion or organic renal causes.1 Gastrointestinal
Żuid losses, due to vomiting or diarrhoea, or renal Żuid losses, due to excessive diuresis,
should be looked for in all patients with cirrhosis presenting with renal failure. If renal
failure is secondary to volume depletion, renal function improves rapidly after volume
repletion and treatment of the precipitating factor. Shock is another common condition
in patients with cirrhosis that may lead to renal failure due to ATN. While hypovolaemic
shock related to gastrointestinal bleeding is easily recognized, the presence of septic
Hepatorenal syndrome 951
Table 5. Diagnostic criteria of hepatorenal syndrome.a
Major criteria
1. Low glomerular �ltration rate, as indicated by serum creatinine greater than 1.5 mg/dl or 24-hour
creatinine clearance lower than 40 ml/minute
2. Absence of shock, ongoing bacterial infection, Żuid losses and current treatment with nephrotoxic
drugs
3. No sustained improvement in renal function (decrease in serum creatinine to 1.5 mg/dl or less or
increase in creatinine clearance to 40 ml/minute or more) following diuretic withdrawal and
expansion of plasma volume with 1.5 l of a plasma expander
4. Proteinuria lower than 500 mg/day and no ultrasonographic evidence of obstructive uropathy or
parenchymal renal disease
Additional criteria
1. Urine volume lower than 500 ml/day
2. Urine sodium lower than 10 mEq/l
3. Urine osmolality greater than plasma osmolality
4. Urine red blood cells less than 50 per high-power �eld
5. Serum sodium concentration lower than 130 mEq/l
a
All major criteria must be present for the diagnosis of hepatorenal syndrome. Additional criteria are not
necessary for the diagnosis, but provide supportive evidence.
shock may be more di�cult to diagnose because of the paucity of symptoms of bacterial
infection in some patients with cirrhosis. Moreover, arterial hypotension due to the
infection may be erroneously attributed to the underlying liver disease. In some patients
with septic shock oliguria is the �rst sign of infection. These patients may be mis-
diagnosed as having HRS if signs of infection (cell blood count, examination of ascitic
Żuid) are not sought. On the other hand, as discussed before, patients with cirrhosis and
SBP may develop renal failure during the course of the infection, in the absence of septic
shock.22 Renal failure in these patients may either improve with the antibiotic therapy
or evolve into a true HRS, even after resolution of the infection has been achieved. The
administration of non-steroidal anti-inŻammatory drugs (NSAIDs) is another common
cause of acute renal failure in patients with cirrhosis and ascites, which is clinically
indistinguishable from a true HRS.26 Therefore, treatment with these drugs should
always be ruled out before the diagnosis of HRS is made. Similarly, patients with
cirrhosis are also at high risk of developing renal failure due to ATN when treated with
aminoglycosides.26 Because of this high risk of nephrotoxicity and the existence of other
e�ective antibiotics (i.e. third-generation cephalosporins) treatment with aminoglyco-
sides should be avoided in patients with chronic liver disease. Finally, patients with
cirrhosis may also develop renal failure due to glomerulonephritis. In these cases,
proteinuria and/or haematuria are almost constant and provide a clue for the diagnosis,
which may be con�rmed by renal biopsy in selected cases.
TREATMENT
Many therapeutic methods have been used in patients with HRS in an attempt to
improve renal failure and increase survival.3,6,27 Unfortunately, most of these methods
have no, or only minor, bene�cial e�ects, except for liver transplantation, the admini-
stration of vasopressin analogues and transjugular intrahepatic portosystemic shunts
(Figure 2).
952 P. Gine� s
Liver transplantation
Cirrhosis
TIPS Portal hypertension
Splanchnic vasodilation
Ornipressin
+
albumin
Reduced effective arterial blood volume
Vasoconstrictor
Stimulation of vasoconstrictor systems
antagonists
Renal vasoconstriction
Vasodilators
Hepatorenal syndrome
Figure 2. Proposed pathogenesis of hepatorenal syndrome in cirrhosis according to the arterial vasodilation
theory with potential therapeutic interventions.
LIVER TRANSPLANTATION
Because HRS is a functional disorder due to an advanced liver disease, liver trans-
plantation is theoretically the ideal treatment for patients with HRS as it allows the
cure of both the diseased liver and the associated renal failure. The long-term outcome
of patients with cirrhosis and HRS treated by liver transplantation is usually good, the
probability of survival being 60% after 3 years of transplantation. This survival is only
slightly reduced compared with that of 70ą80% for transplanted patients without HRS
and markedly increased compared with the survival of non-transplanted patients with
HRS, which is close to 0% after 3 years.28,29 Nevertheless, the presence of HRS is
associated with an increased morbidity and early mortality compared with patients
transplanted without HRS.
The main problem regarding liver transplantation for patients with HRS is that,
because of the poor prognosis of HRS and the prolonged waiting times in most
transplant centres, a signi�cant proportion of patients with HRS, particularly those
with type I HRS, die before transplantation can be done. Therefore, there is a need for
e�ective therapies to increase survival of these patients until transplantation can be
performed. An alternative, but not exclusive, approach to this problem is to indicate
liver transplantation before the development of HRS. Several predictive factors for the
development of HRS in patients with cirrhosis and ascites have been identi�ed
(Table 6).18 Patients showing some of these predictive factors should be evaluated for
liver transplantation before the development of HRS. Of note, the severity of liver
dysfunction, as assessed by the ChildąPugh classi�cation has no predictive value for the
development of HRS in patients with cirrhosis and ascites.18
PHARMACOLOGICAL TREATMENT
The administration of vasoconstrictors represents the most promising pharmacological
approach to therapy of HRS.12ą14 The rationale behind the use of these drugs in
Hepatorenal syndrome 953
Table 6. Predictive factors of development of hepatorenal
syndrome in patients with cirrhosis and ascites.
Slightly increased BUN and/or serum creatinine levels
Dilutional hyponatraemia
Reduced free water excretion after water load
Low urinary sodium excretion
Arterial hypotension
High plasma renin activity
High plasma norepinephrine concentration
Previous episodes of ascites
Absence of hepatomegaly
Poor nutritional status
Moderately increased renal vascular resistive index
patients with HRS is to improve renal perfusion by increasing systemic vascular
resistance and suppressing the activity of endogenous vasoconstrictors (Figure 2).
Because arterial vasodilation in HRS is exclusively located in the splanchnic circulation,
the ideal vasoconstrictor for patients with HRS would be a drug with a selective action
in the splanchnic arteries without e�ect on the extrasplanchnic circulation. Although
such an ideal drug is not available at present, the family of drugs that are closer to the
ful�lment of these requirements are the agonists of the vasopressin V1 receptors
(analogues of vasopressin with a predominant action on the V1 receptors and less
e�ect on the V2 receptors). Alpha-adrenergic agonists (i.e. norepinephrine, meta-
raminol) and agonists of the angiotensin AT1 receptors have been used without
signi�cant clinical bene�ts.27 By contrast, the administration of V1 receptor agonists,
such as ornipressin or terlipressin, is associated with suppression of the activity of
endogenous vasoconstrictor systems and marked improvement of renal perfusion and
GFR and normalization of serum creatinine levels in most patients (Figure 3).12ą14
Although information about the use of V1 agonists in patients with HRS is still very
limited and based only on a few phase II studies conducted in small series of patients,
the following preliminary conclusions can be drawn while awaiting for results of large
randomized trials. 1. These drugs should be given for prolonged periods, usually 5ą15
days, because the improvement in renal function occurs slowly. Therapy should be
aimed at reducing serum creatinine below 1.5 mg/dl; when this goal has been
achieved, HRS usually does not recur after discontinuation of therapy. 2. The e�ective
doses of these drugs have not been de�ned precisely and may vary from patient to
patient; ornipressin has been given in continuous intravenous infusion at doses ranging
from 1 to 6 IU/hour while terlipressin has been used as intravenous boluses from 0.5
to 2 mg/4 hours. At present, it seems advisable to start with low doses (i.e. ornipressin
1ą2 IU/hour or terlipressin 0.5ą1 mg/4 hours) and increase the doses in a stepwise
manner (i.e. every 2ą3 days) in cases showing no response to therapy. 3. In some
studies a concomitant administration of albumin has been used to improve e�ective
arterial blood volume further; whether or not this manoeuvre increases the bene�cial
e�ects of these drugs on renal function is not known. 4. The incidence of important
ischaemic side-e�ects requiring the withdrawal of the drug is high, especially with
ornipressin; the incidence of ischaemic complications seems low in patients treated
with terlipressin, which has a better safety pro�le than ornipressin, but this requires
con�rmation in larger studies. The risk of ischaemic complications should be weighed
against the lack of alternative pharmacological therapies for HRS. 5. The potential
bene�cial impact of the improvement of renal function on survival of patients with
954 P. Gine� s
8
5
4
3
2
1
3
0 7 10 15
Days
Figure 3. Individual values of serum creatinine in nine patients treated with terlipressin and intravenous
albumin. Reproduced from Uriz et al (2000, Journal of Hepatology) with permission.
HRS has not been assessed and requires investigation in large comparative studies. 6.
Because of limited information, treatment with V1 agonists should probably be
restricted at present to patients with type I HRS.
Another approach to the pharmacological treatment of HRS which has been
described recently consists of the administration of an orally-active alpha-adrenergic
agonist (midodrine) associated with octreotide and intravenous albumin.30 The aim of
this therapy is twofold: to suppress the activity of vasoconstrictor systems by increas-
ing total systemic vascular resistance with the vasoconstrictor and improving central
blood volume with albumin and reducing the release of splanchnic vasodilator factors
with octreotide. Although this therapeutic approach was associated with a marked
improvement of renal function in a small series of patients with HRS, its e�ectiveness
requires con�rmation in further studies.
TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT
Despite the existence of isolated reports of improvement of renal function in patients
with HRS after side-to-side or end-to-side portacaval shunts during the 1970s, these
procedures did not become an accepted therapy for HRS because of their high
morbidity and mortality.27 However, the recent introduction of a non-surgical method
Serum creatinine (mg/dL)
Hepatorenal syndrome 955
of portal decompression, the transjugular intrahepatic portosystemic shunt (TIPS), has
led to reconsideration of this therapeutic approach in the management of HRS. TIPS is
usually performed under analgesia and consists of the placement of a self-expandable
metal stent between an hepatic vein and the intrahepatic portion of the portal vein
using a transjugular approach. Because of its powerful e�ect in reducing portal
pressure, TIPS has become a therapy frequently used in high-risk patients bleeding
from oesophageal varices not responding to usual therapeutic measures and its use is
also being evaluated in the management of refractory ascites.31 The information about
the e�ect of TIPS in patients with HRS is still very limited but published studies
indicate that TIPS improves renal perfusion and GFR and reduces the activity of
vasoconstrictor systems.32,33 In patients with type II HRS, the improvement of renal
perfusion is associated with an increase in urinary sodium excretion and improved
renal response to diuretics. In patients with type I HRS, the use of TIPS is associated
with a moderate increase in renal blood Żow and GFR and a reduction in serum
creatinine levels in some, but not all, patients. As with vasoconstrictor drugs, it is not
known whether the improvement in renal function is associated with an increased
survival. Because the use of TIPS is frequently associated with signi�cant side-e�ects,
particularly hepatic encephalopathy and impairment of liver function, its role in the
management of HRS needs to be established by prospective controlled investigations.
OTHER THERAPEUTIC METHODS
Drugs with renal vasodilator activity have been used in patients with HRS in an
attempt to counteract the e�ect of vasoconstrictor factors on the renal circulation.
Dopamine was the �rst drug used owing to its renal vasodilatory e�ect when given in
subpressor doses. Although there are isolated reports of reversal of HRS after
dopamine administration, studies speci�cally assessing the e�ects of dopamine on renal
function in series of patients with HRS have shown no e�ects, or only minor e�ects, on
GFR.27 Despite its lack of e�cacy, dopamine is still commonly used in clinical practice
in patients with HRS. The second type of renal vasodilators used in patients with HRS
are prostaglandins and prostaglandin analogues.27 The rationale for the use of prosta-
glandins was the proposal that renal vasoconstriction in HRS could be due to a
reduced intrarenal synthesis of prostaglandins. Unfortunately, however, no bene�cial
e�ects on renal function have been observed after the intravenous or intra-arterial
administration of PGA1 or PGE2. The oral administration of misoprostol (a PGE1
analogue) was found to improve renal function in one study but this bene�cial e�ect
was not con�rmed in a subsequent investigation.27 The potential e�cacy of this drug
deserves further investigation but its use in clinical practice may be limited by the high
incidence of side-e�ects, especially diarrhoea.
Peritoneovenous shunting was widely used in the past in the management of
patients with cirrhosis and refractory ascites, which is commonly seen in association
with type II HRS. However, the use of this method has declined markedly because of
important side-e�ects and the existence of other therapeutic methods with a similar
e�cacy but fewer side-e�ects (i.e. therapeutic paracentesis associated with albumin). In
patients with type I HRS, peritoneovenous shunting prevents the progression of renal
failure but does not prolong survival compared with supportive therapy.34 For these
reasons, peritoneovenous shunting is not commonly used at present in the
management of patients with HRS.
956 P. Gine� s
Haemodialysis or peritoneal dialysis have been used in the management of patients
with HRS, and sporadic cases of improvement of renal function have been reported.27
Unfortunately, there are no controlled studies evaluating the e�ectiveness of dialysis in
HRS. Uncontrolled studies suggest that it is hardly e�ective because most patients die
during treatment and there is a high incidence of severe side-e�ects, including arterial
hypotension, coagulopathy and gastrointestinal bleeding. In some centres, haemodia-
lysis is used to treat patients with HRS awaiting liver transplantation. The e�ectiveness
of dialysis in this setting has not been appropriately studied. Continuous arterio-
venous or veno-venous haemo�ltration have also been used but their e�cacy also
remains to be determined.27
PREVENTION
Up to now, no e�ective methods for the prevention of HRS existed. However, recent
data indicate that the development of HRS in the setting of spontaneous bacterial
peritonitis can be e�ectively prevented by the administration of albumin (1.5 g/kg
intravenously at the diagnosis of infection and 1 g/kg intravenously 48 hours later)
together with antibiotic therapy.35 The incidence of HRS is markedly lower in patients
receiving albumin compared with that in patients not receiving albumin. Most
importantly, albumin administration also improves survival in these patients. The
bene�cial e�ect of albumin is probably related to its capacity to prevent the impair-
ment in the e�ective arterial blood volume and subsequent activation of vasocon-
strictor systems that occurs during the infection.
Acknowledgement
Studies reported in this chapter have been partly supported by a grant from the Fondo de
Investigacion Sanitaria (FIS 97/2073).
�
REFERENCES
* 1. Arroyo V, Gines P, Gerbes A et al. De�nition and diagnostic criteria of refractory ascites and hepatorenal
�
syndrome in cirrhosis. Hepatology 1996; 23: 164ą176.
2. Wilkinson SP, Blendis LM & Williams R. Frequency and type of renal and electrolyte disorders in
fulminant hepatic failure. British Medical Journal 1974; 1: 186ą189.
3. Papper S. Hepatorenal syndrome. In Epstein M (ed.) The Kidney in Liver Disease, 1st edn, pp 91ą112. New
York: Elsevier Biomedical, 1978.
4. Epstein M, Berck, Hollemberg NK et al. Renal failure in the patient with cirrhosis. The role of active
vasoconstriction. American Journal of Medicine 1970; 49: 175ą185.
5. Gines P & Rodes J. Clinical disorders of renal function in cirrhosis with ascites. In Arroyo V, Gine� s P,
� �
Rode� s J & Schrier RW (eds) Ascites and Renal Dysfunction in Liver Disease. Pathogenesis, Diagnosis and
Treatment, pp 36ą62. Malden: Blackwell Science, 1999.
6. Bataller R, Gine� s P, Guevara M & Arroyo V. Hepatorenal syndrome. Seminars in Liver Disease 1997; 17:
233ą248.
7. Moore K. The hepatorenal syndrome. Clinical Science 1997; 92: 433ą443.
* 8. Schrier RW, Arroyo V, Bernardi M et al. Peripheral arterial vasodilation hypothesis: a proposal for the
initiation of renal sodium and water retention in cirrhosis. Hepatology 1988; 8: 1151ą1157.
9. Schrier RW, Niederbeger M, Weigert A & Gine� s P. Peripheral arterial vasodilation: determinant of
functional spectrum of cirrhosis. Seminars in Liver Disease 1994; 14: 14ą22.
Hepatorenal syndrome 957
10. Gines P & Schrier RW. The arterial vasodilation hypothesis of ascites formation in cirrhosis. In Arroyo V,
�
Gines P, Rodes J & SchrierRW(eds) Ascites and Renal Dysfunction in Liver Disease. Pathogenesis, Diagnosis
� �
and Treatment, pp 411ą430. Malden: Blackwell Science, 1999.
*11. Martin PY, Gines P & Schrier RW. Role of nitric oxide as mediator of hemodynamic abnormalities and
�
sodium and water retention in cirrhosis. New England Journal of Medicine 1999; 339: 533ą541.
*12. Guevara M, Gines P, Ferna�ndez-Esparrach G et al. Reversibility of hepatorenal syndrome by prolonged
�
administration of ornipressin and plasma volume expansion. Hepatology 1998; 27: 35ą41.
*13. Gulberg V, Bilzer M & Gerbes AL. Long-term therapy and retreatment of hepatorenal syndrome type I
�
with ornipressin and dopamine. Hepatology 1999; 30: 870ą875.
*14. Uriz J, Gines P, Ca�rdenas A et al. Terlipressin plus albumin infusion: an e�ective and safe therapy of
�
hepatorenal syndrome. Journal of Hepatology 2000; 33: 43ą48.
15. Alvestrand A & Bergstrom J. Glomerular hyper�ltration after protein ingestion, during glucagon
infusion, and in insulin-dependent diabetes is induced by a liver hormone: de�cient production of this
hormone in hepatic failure causes hepatorenal syndrome. Lancet 1984; i: 195ą197.
16. Sa�rstein R & Levitt MF. A hepatorenal depressor reŻex: a possible clue to the pathogenesis of the
hepatorenal syndrome. Hepatology 1991; 14: 734ą735.
17. Lang F, Gerok W & Ha� ussinger D. New clues to the pathophysiology of hepatorenal failure. Clinical
Investigation 1973; 71: 93ą97.
*18. Gines A, Escorsell A, Gines P et al. Incidence, predictive factors, and prognosis of hepatorenal syndrome
� �
in cirrhosis. Gastroenterology 1993; 105: 229ą236.
19. Ferna�ndez-Seara J, Prieto J, Quiroga J et al. Systemic and regional hemodynamics in patients with liver
cirrhosis and ascites with and without functional renal failure. Gastroenterology 1989; 97: 1304ą1312.
20. Maroto A, Gine� s P, Arroyo V et al. Brachial and femoral artery blood Żow in cirrhosis: relationship to
kidney dysfunction. Hepatology 1993; 17: 788ą793.
21. Guevara M, Bru C & Gines P. Increased cerebrovascular resistance in cirrhotic patients with ascites.
�
Hepatology 1998; 28: 39ą44.
*22. Follo A, Llovet JM, Navasa M et al. Renal impairment after spontaneous bacterial peritonitis in cirrhosis:
incidence, clinical course, predictive factors and prognosis. Hepatology 1994; 20: 1495ą1501.
23. Navasa M, Follo A, Filella X et al. Tumor necrosis factor and interleukin-6 in spontaneous bacterial
peritonitis in cirrhosis: relationship with the development of renal impairment and mortality. Hepatology
1998; 27: 1227ą1232.
24. Gines P, Tito LI, Arroyo V et al. Randomized comparative study of therapeutic paracentesis with and
� �
without intravenous albumin in cirrhosis. Gastroenterology 1988; 94: 1493ą1502.
25. Gines P, Arroyo V & Rodes J. Ascites, hepatorenal syndrome, and spontaneous bacterial peritonitis. In
� �
McDonald J, Burroughs AK & Feagan B (eds) Evidence-Based Gastroenterology and Hepatology, pp 427ą442.
London: BMJ Books, 1999.
26. Salerno F & Badalamenti S. Drug-induced renal failure in cirrhosis. In Arroyo V, Gines P, Rodes J &
� �
Schrier RW (eds) Ascites and Renal Dysfunction in Liver Disease. Pathogenesis, Diagnosis and Treatment
511ą521. Malden: Blackwell Science, 1999.
27. Arroyo V, Bataller R & Guevara M. Treatment of hepatorenal syndrome in cirrhosis. In Arroyo V, Gine� s
P, Rode� s J & Schrier RW(eds) Ascites and Renal Dysfunction in Liver Disease. Pathogenesis, Diagnosis and
Treatment, pp 492ą510. Malden: Blackwell Science, 1999.
28. Gonwa TA & Wilkinson AH. Liver transplantation and renal function: results in patients with and
without hepatorenal syndrome. In Epstein M (ed.) The Kidney in Liver Disease, 4th edn, pp 529ą542.
Philadelphia: Hanley & Belfus, 1996.
29. Rimola A, Navasa M & Grande L. Liver transplantation in cirrhotic patients with ascites. In Arroyo V,
Gines P, Rodes J & SchrierRW(eds) Ascites and Renal Dysfunction in Liver Disease. Pathogenesis, Diagnosis
� �
and Treatment, pp 522ą537. Malden: Blackwell Science, 1999.
*30. Angeli P, Volpin R, Gerunda G et al. Reversal of type 1 hepatorenal syndrome with the administration of
midodrine and octreotide. Hepatology 1999; 29: 1690ą1697.
31. Arroyo V & Gines P. TIPS and refractory ascites. Lessons from recent history of ascites therapy. Journal of
�
Hepatology 1996; 25: 221ą223.
32. Ochs A, Rossle M, Haag K et al. The transjugular intrahepatic portosystemic stent shunt procedure for
�
refractory ascites. New England Journal of Medicine 1995; 332: 1192ą1197.
33. Guevara M, Gines P, Bandi JC et al. Transjugular intrahepatic portosystemic shunt in hepatorenal
�
syndrome. E�ects of renal function and vasoactive systems. Hepatology 1998; 27: 35ą41.
34. Linas SL, Scha�er JW, Moore EE et al. Peritoneovenous shunt in the management of the hepatorenal
syndrome. Kidney International 1986; 30: 736ą740.
*35. Sort P, Navasa M, Arroyo V et al. E�ect of plasma volume expansion on renal impairment and mortality
in patients with cirrhosis and spontaneous bacterial peritonitis. New England Journal of Medicine 1999;
341: 403ą409.