Diagnosis and treatment of hepatorenal

syndrome

Pere GineÁs*

MD

Associate Professor of Medicine

Liver Unit, Institut de Malalties Digestives, Hospital ClõÂnic, 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.

1521±6918/00/060945‡13 $35.00/00

*

c 2000 Harcourt Publishers Ltd.

BaillieÁre's Clinical Gastroenterology

Vol. 14, No. 6, pp. 945±957, 2000

doi:10.1053/bega.2000.0140, available online at http://www.idealibrary.com on

5

*Address for correspondence: Liver Unit, Institut de Malalties Digestives, Hospital ClõÂnic, IDIBAPS,

Villarroel, 170, 08036 Barcelona, Catalunya, Spain.

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.

3±5

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.

8±10

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 renin±

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

Table 1. Landmarks in hepatorenal syndrome.

1860

First description

1950±1960

Clinical characterization. Description of association with circulatory dysfunction

1960±1970

Recognition of renal vasoconstriction

1970±1980

Investigation of renal vasoactive factors

1988

Arterial vasodilation theory

1996

De®nition and diagnostic criteria

1990±2000

Introduction of splanchnic vasoconstrictor drugs in clinical practice

946 P. GineÁs

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.

12±14

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

Kallikrein±kinin 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.

Hepatorenal syndrome 947

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 re¯ex causing renal

vasoconstriction.

15±17

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

948 P. GineÁs

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 60±

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

renin±angiotensin 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 ¯ow and vascular resistance by duplex Doppler ultra-

sonography have found that blood ¯ow 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 ¯ow, indicating that the upper and

lower limb vascular beds change in parallel with the renal circulation. Likewise, the

resistance to blood ¯ow 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

Hepatorenal syndrome 949

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 ¯uid 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 GineÁs, 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

¯uid losses, due to vomiting or diarrhoea, or renal ¯uid 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

950 P. GineÁs

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

¯uid) 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-in¯ammatory 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

).

Table 5. Diagnostic criteria of hepatorenal syndrome.

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, ¯uid 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.

a

Hepatorenal syndrome 951

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 70±80% 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 Child±Pugh 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.

12±14

The rationale behind the use of these drugs in

Cirrhosis

Portal hypertension

Splanchnic vasodilation

Reduced effective arterial blood volume

Stimulation of vasoconstrictor systems

Renal vasoconstriction

Hepatorenal syndrome

Liver transplantation

TIPS

Ornipressin

+

albumin

Vasoconstrictor

antagonists

Vasodilators

Figure 2. Proposed pathogenesis of hepatorenal syndrome in cirrhosis according to the arterial vasodilation

theory with potential therapeutic interventions.

952 P. GineÁs

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

).

12±14

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 5±15

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

1±2 IU/hour or terlipressin 0.5±1 mg/4 hours) and increase the doses in a stepwise

manner (i.e. every 2±3 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

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

Hepatorenal syndrome 953

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

0

3

7

10

15

Days

8

5

4

3

2

1

Serum creatinine (mg/dL)

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.

954 P. GineÁs

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 ¯ow 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.

Hepatorenal syndrome 955

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

InvestigacioÂn Sanitaria (FIS 97/2073).

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