426 Medicine Update 74 Hepatorenal Syndrome: Clinical Considerations

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426

Medicine Update

74

Hepatorenal Syndrome:

Clinical Considerations

V

IVEK

 A S

ARASWAT

, R

AVI

 R

ATHI

BACKGROUND

The hepatorenal syndrome (HRS) is a life-threatening

form of functional renal failure associated with

advanced liver disease. Its management poses one of

the most challenging problems in clinical medicine.

There are more reviews than original articles on HRS,

reflecting the difficulty in investigating this syndrome.

Clinical studies likely to generate data for an evidence

based approach to the management of HRS are difficult,

considering the gravity of the condition and multiple

problems of advanced liver failure that usually coexist

in the patient afflicted with HRS. Furthermore, no

experimental model has been developed for HRS. Many

aspects of HRS are therefore still poorly understood. The

aim of this article is to review the definition, diagnosis,

pathogenesis and rational basis of current therapy in

HRS.

EPIDEMIOLOGY

HRS occurs in about 4% of patients admitted with

decompensated cirrhosis. The cumulative probability of

developing HRS in decompensated cirrhosis is 18% at

one year, increasing to 39% at five years

5

. Retrospective

studies indicate that HRS is present in ~17% of patients

admitted to hospital with ascites and in >50% of

cirrhotics dying from liver failure.

DEFINITION

The term ‘hepatorenal syndrome’ was first coined

by surgeons in the 1930s to describe renal failure

occurring after biliary surgery or hepatic trauma in

patients with previously normal renal function

1

. Interest

in this condition was revived after the pioneering study

of Hecker and Sherlock in 1956 which showed that renal

failure in cirrhosis follows a progressive course may

appear in close temporal relationship with complications

such as gastrointestinal hemorrhage or bacterial

infections and has a poor prognosis

2

. During the 1960s

American nephrologists popularized this term for

describing an unusual form of renal failure seen in liver

cirrhosis. In Europe, however, the terms ‘functional renal

failure’ or ‘renal failure of cirrhosis’ were preferred by

most hepatologists. In 1978, the first consensus confe-

rence to define HRS and propose diagnostic criteria, was

organized in Sassari, Italy

3

. The International Ascites

Club (IAC), founded in Florence, Italy, in 1990, has taken

sustained interest in evolving definitions and consensus

in this difficult and contentious area. In the light of new

developments in the field of HRS research, it proposed

a revised definition and diagnostic criteria for HRS, after

a consensus conference in Chicago in 1994 that were

published in 1996

4

 and are currently followed.

To quote the IAC verbatim:

“Hepatorenal syndrome is a syndrome that occurs in

patients with chronic liver disease, portal hypertension and

advanced hepatic failure. It is characterized by impaired

renal function, marked abnormalities in arterial circulation

and activity of endogenous vasoactive systems. In the kidney,

there is marked renal vasoconstriction that results in low GFR.

In the extrarenal circulation there is predominance of arte-

riolar vasodilation, that results in reduction of total

systemic vascular resistance and arterial hypotension. A

similar syndrome may also occur in the setting of acute liver

failure.”

Put more simply, HRS is a complication seen in the

setting of portal hypertension and advanced liver failure

that is characterized by functional renal failure due to

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Hepatorenal Syndrome: Clinical Considerations

427

renal vasoconstriciton in the absence of underlying renal

pathology.

DIAGNOSIS

HRS is diagnosed when renal failure develops in the

presence of liver disease in an appropriate setting and

after exclusion of pre-renal factors, intrinsic renal

diseases and complications that could result in an

intrinsic renal disease viz. acute renal failure due to

acute tubular necrosis (ATN). HRS is a diagnosis of

exclusion since no specific diagnostic tests are available

to distinguish between HRS and other causes of renal

failure occurring in cirrhosis and is based on certain

major and minor criteria described in Table 1. There has

been some confusion in literature regarding the role of

sepsis, SBP, gastrointestinal hemorrhage and other

complications in the causation of HRS. Earlier

definitions emphasized the exclusion of these factors

before diagnosing HRS on the basis that these factors

commonly cause intrinsic renal failure due to ATN.

However, lately, it has been recognized that these very

same factors have a critical role in precipitating HRS

type 1 or contributing to the progression of HRS type 2

to type 1. Thus, one of the most common causes of acute

renal failure in cirrhotics is the development of

spontaneous bacterial peritonitis (SBP), with up to 30%

of patients with SBP developing renal failure, which is

often HRS type 1. This change is due to the realization

that, while these factors of themselves, if severe enough,

can precipitate intrinsic renal failure due to ATN, in

cirrhotics with liver failure, where HRS physiology is

already operating, lesser degrees of severity of these

complications can trigger intense renal vasoconstriction

and precipitate HRS type 1.

Renal Failure

The diagnosis of HRS is only made when serum

creatinine rises above 1.5 mg/dl. Low GFR is defined

by serum creatinine >1.5 mg/dl without diuretic therapy

for at least 5 days, though it is realized that serum

creatinine levels do not provide a precise estimation of

GFR in cirrhosis. Serum creatinine levels are lower than

expected due to low endogenous production of

creatinine, related to the reduced muscle mass that

frequently occurs in advanced cirrhosis and the presence

of liver disease. However, other measures of GFR also

have limitations and are more cumbersome. Thus,

endogenous creatinine clearance, though slightly better,

may overestimate GFR by up to 50% and is difficult to

perform since it depends on accurate, timed 24-hour

urine collection, which is often unsatisfactory in oliguric

patients. Inulin clearance for estimation of GFR is

expensive and cumbersome, and is not used clinically.

Thus, despite limitations, serum creatinine concentration

is currently used to estimate GFR in cirrhosis.

Urinary Electrolytes

Most patients with HRS have urine sodium below

10 mEq/L and urine osmolality higher than plasma

osmolality because of avid sodium retention with

preserved tubular function. Nevertheless, a minority of

patients may have higher urine sodium and low urine

osmolality similar to values found in acute tubular

necrosis, often due to the use of diuretics for oliguria.

Conversely, some cirrhotic patients with acute tubular

necrosis may have low urine sodium and high urine

osmolality. For these reasons, urinary indices are not

considered major criteria for the diagnosis of HRS.

Volume Depletion

Factors that may predispose to pre-renal failure such

as gastrointestinal fluid losses due to vomiting or

diarrhea, or renal fluid losses due to excessive diuretic

therapy are common in cirrhotic patients and should be

sought meticulously. When azotemia is pre-renal, renal

function improves after the intravenous administration

of fluids (i.e. 1,500 ml of isotonic saline), whereas no

improvement occurs in patients with HRS. Though

Table 1: Diagnostic criteria for HRS (IAC, 1996)

4

Major criteria

•

Chronic or acute liver disease with advanced hepatic failure and

portal hypertension

•

Low glomerular filtration rate (serum creatinine > 1.5 mg/dL or

24-h creatinine clearance < 40 mL/min)

•

No sustained improvement in renal function following diuretic

withdrawal and plasma volume expansion with 1.5 L isotonic

saline

•

Proteinuria < 500 mg/dL and no ultrasonographic evidence of

obstructive uropathy or parenchymal disease

•

Absence of shock, ongoing bacterial infection, current or recent

treatment with nephrotoxic drugs, excessive gastrointestinal or

renal fluid losses

Minor criteria

•

Urine volume < 500 mL/day

•

Urine sodium < 10 mmol/day

•

Urine osmolality greater than plasma osmolality

•

Urine red blood cells < 50 per high power field

•

Serum sodium concentration < 130 mmol/L

•

Only major criteria are required for diagnosis

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428

Medicine Update

resistance to volume expansion is a key factor in

diagnosing HRS, caution must be exercised while

mounting a 1.5 L fluid challenge in an oliguric patient

which might push the patient into pulmonary edema if

there is existing or impending fluid overload. Though

monitoring the central venous pressure (CVP) is helpful,

its limitations must be recognized as CVP may be

factitiously low due to peripheral vasodilatation. A

careful clinical evaluation of the state of hydration is

required, including assessment for fluid balances in the

preceding 3-5 day period or since the development of

oliguria. In the non-oliguric patient who has been on

diuretic therapy and develops renal failure, lack of

improvement in renal function following diuretic

withdrawal and plasma expansion is highly suggestive

of HRS.

Intrinsic Renal Disease

Other causes of renal failure in cirrhosis such as acute

tubular necrosis, drug-induced nephrotoxicity, renal

failure due to radio-contrast agents, and glomerulo-

nephritis in patients with hepatitis B or C should be

excluded before the diagnosis of HRS is made.

Insignificant proteinuria, normal urine sediment and a

normal renal ultrasound are required to rule out intrinsic

renal disease before diagnosing HRS. Proteinuria (>500

mg/day) and/or ultrasonographic abnormalities in the

kidneys indicate organic renal disease or obstructive

uropathy.

Other criteria 

include absence of clinical conditions

that predispose to the development of acute renal failure

(i.e. volume depletion, shock, bacterial infections, or

nephrotoxic drugs). Shock, before the development of

renal failure in a cirrhotic patient, precludes the

diagnosis of HRS, and usually indicates that renal failure

is due to ATN. In the presence of significant bacterial

infections, the diagnosis of HRS should only be made if

renal failure persists after complete resolution of the

infection.

TYPES OF HRS

Two patterns of HRS are observed in clinical practice

and have been defined by the International Ascites

Club.

4

Type 1 hepatorenal syndrome 

is an acute form of HRS

in which renal failure occurs spontaneously in patients

with severe liver disease and is rapidly progressive. It

is characterized by rapid reduction, within two weeks,

and marked reduction of renal function, as defined by

doubling of the initial serum creatinine to a level greater

than 2.5 mg/dl or a 50% reduction in initial 24 hour

creatinine clearance to <20 ml/min. The development

of type 1 HRS signifies very poor prognosis with 80%

mortality within two weeks. Rarely, renal function may

recover spontaneously following dramatic improvement

in liver function. HRS type 1 may occur in the setting of

acute liver failure, alcoholic hepatitis, or following acute

decompensation on a background of cirrhosis, so-called

acute-on-chronic liver failure (ACLF). These patients are

usually deeply jaundiced and have significant

coagulopathy. Death often results from a combination

of hepatic and renal failure or variceal bleeding.

Type 2 hepatorenal syndrome 

usually occurs in patients

with diuretic resistant ascites and is often considered

synonymous with refractory ascites (RA). Renal failure

has a slow course and may deteriorate over months. It

is associated with a poor prognosis, although survival

is longer than in patients with type 1 HRS. A variable

proportion evolves to HRS type 1, usually in the setting

of acute complications.

PATHOPHYSIOLOGY

The pathophysiologic hallmark of HRS is severe

vasoconstriction of the renal circulation. Pathogenesis

of this vasoconstriction involves a complex interaction

between increased portal pressure, changes in the

systemic arterial circulation, activation of vasoconstrictor

factors and suppression of vasodilator factors acting on

the renal circulation. The theory that best explains the

relationship among changes in the renal circulation,

activation of vasoconstrictor mechanisms, and presence

of marked disturbances in systemic hemodynamics is

the arterial vasodilatation theory. This theory proposes that

renal hypoperfusion and vasoconstriction represent an

extreme expression of arterial underfilling secondary to

a marked vasodilatation of the splanchnic vascular bed.

The first step in the development of HRS is the

development of intense splanchnic arterial vasodilata-

tion, mediated by increased production of local

vasodilator substances, mainly nitric oxide. This is due

to advanced liver failure, which may be of rapid onset,

as in alcoholic hepatitis superimposed on alcoholic

cirrhosis or in other forms of ACLF and in ALF, and

may be exacerbated by complications such as infections

(SBP) and gastrointestinal hemorrhage. This intense

splanchnic vasodilatation results in systemic arterial

underfilling, that may clinically manifest as arterial

hypotension, and leads to a baroreceptor-mediated

activation of powerful endogenous vasoconstrictor and

antinatriuretic systems, notably the renin-angiotensin-

aldosterone system (RAAS), the sympathetic nervous

system (SNS), and arginine vasopressin (AVP). This

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Hepatorenal Syndrome: Clinical Considerations

429

compensation results in sodium and water retention as

well as vasoconstriction not only in the renal circulation

but also in other vascular beds.

In the early stages of cirrhosis, renal blood flow may

be kept within normal limits due to the effect of local

vasodilators such as prostaglandins, nitric oxide, and

natriuretic peptides that antagonize the renal vascular

effect of systemic vasoconstrictors and maintain renal

perfusion and glomerular filtration rate (GFR). The renal

production of prostaglandins and circulating levels of

natriuretic peptides are increased from the early stages

of the disease, even in patients with cirrhosis and ascites

without HRS. However, with disease progression

intense splanchnic vasodilatation results in extreme

arterial underfilling causing maximal activation of

vasoconstrictor systems and decreased activity of renal

vasodilators, leading to severe renal vasoconstriction

and reduction in GFR. At this critical point HRS 1 ensues.

In some cases a precipitating cause of circulatory

dysfunction such as spontaneous bacterial peritonitis

(SBP) leads to worsening of renal vasoconstriction. Once

vasoconstriction develops, intrarenal mechanisms

perpetuate HRS due to the development of intrarenal

vicious cycles in which hypoperfusion leads to an

imbalance in intrarenal vasoactive systems that in turn

causes more vasoconstriction.

DIFFERENTIAL DIAGNOSIS

This includes all the various causes of acute renal

failure in patients with cirrhosis or advanced liver

failure.

Prerenal

• Gastrointestinal, renal fluid losses

• Hemorrhage

• Shock

• Sepsis

• Congestive heart failure

• Medications: NSAIDs, radiocontrast agents

Intrinsic Renal

• Tubular necrosis

• Ischemia: all causes of prerenal azotemia

• Toxins: aminoglycosides, radiocontrast agents

• Interstitial nephritis

• Immuno-allergic (drugs)

• Infection

• Glomerulonephritis

• Infection

Postrenal

• Obstruction of urinary outflow tract.

Prerenal failure must be differentiated from intrinsic

renal failure. HRS, by definition a form of functional

renal failure, is an extreme example of prerenal failure,

where the renal failure is not corrected by volume

restitution. It shows all the lab characteristics of prerenal

failure and is diagnosed by excluding other causes of

prerenal failure in cirrhosis such as overzealous use of

diuretics, other drugs (ACD inhibitors, NSAIDs),

diarrhea, vomiting and other forms of GI fluid losses.

Often, this is best done by fluid challenge.

Table 2: Difference between prerenal vs. intrinsic renal failure

Index

Prerenal

Renal

causes

causes

Urinary sodium concentration (mmol/L)

< 20

> 40

Fractional excretion of sodium (%)

< 1

> 1

Ratio of urinary to plasma creatinine

> 40

< 20

Ratio of urinary to plasma osmolality

> 1.5

< 1.1

PROGNOSIS

HRS carries the worst prognosis of all the

complications of cirrhosis. Without treatment, the

median survival time of patients with type 1 HRS is <2

wk and practically all patients die within 8–10 wk after

the onset of renal failure

6

. On the other hand, patients

with type 2 HRS have a longer median survival time of

approximately 6 months.

Fig. 1: Pathophysiology of hepatorenal syndrome

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430

Medicine Update

MANAGEMENT

Type 1 HRS develops in the setting of advanced liver

disease in most cases but in some others it occurs in the

setting of acute liver failure. In both situations, patients

are very sick and unstable and require hospitalization,

preferably in an intensive care unit. A crucial aspect of

further management is a quick assessment of the

patient’s candidacy for liver transplantation. If the

patient is a candidate for liver transplantation, the focus

of further management is to optimize his condition for

the surgery, in as short a time as possible, in order to

obtain the best possible outcome after transplantation.

To improve renal function the aggressive use of

splanchnic vasoconstrictor therapy and other supportive

measures such as TIPS, MARS and Prometheus is best

justified in this setting.

General Measures

Continuous monitoring of vital signs, fluid intake,

daily weights, blood chemistries, and urinary output

should be performed. Central venous access with CVP

measurement is helpful in assessing volume status,

particularly when intravenous fluid challenge is

administered to rule out prerenal failure. Although

useful, this measure may not be necessary in all cases.

In patients with dilutional hyponatremia, fluid

restriction to 1 L/day is recommended. Diuretics must

be stopped as they can cause worsening renal failure

and, in the case of spironolactone, severe hyperkalemia.

In patients with tense ascites, large volume paracentesis

with albumin infusion (6-8 g/L tapped) may aid in

providing symptomatic relief. However, it is not known

whether large amounts of ascites can be safely tapped

in type 1 HRS without causing further deterioration of

renal function. Since most patients have ascites,

diagnostic paracentesis must be performed to rule out

SBP.

Specific Interventions

Available therapies for type 1 HRS include the use

of splanchnic vasoconstrictors and transjugular

intrahepatic portosystemic shunts (TIPS). Patients with

type 2 HRS are less sick and for the most part have

refractory ascites that can be managed with large volume

paracentesis and albumin infusion. Suitable candidates

need to be evaluated for liver transplantation. Limited

data suggest that these patients also respond well to

vasoconstrictors and TIPS.

Vasoconstrictor Therapy

The realization that the basic problem in HRS was

intense renal vasoconstriction resulted in initial efforts

towards achieving renal vasodilatation by various

pharmacologic interventions. However, the use of renal

vasodilators such as dopamine and prostaglandin and

analogues was abandoned due to lack of adequate data

confirming benefit and side effects. Other drugs such as

endothelin blockers (BQ 123) and N-acetylacysteine are

promising, but larger pilot studies followed by

controlled studies are needed to establish their role in

the therapy of HRS

7

.

Systemic vasoconstriction with plasma volume

expansion is currently the best medical therapy for HRS

type 1, as borne out by several uncontrolled studies

confirming benefit. The rationale for the apparently

paradoxical use of vasoconstrictors to reverse intense

renal vasoconstriction is that systemic infusion of

vasodilatation that is at the root of development of HRS,

removing the stimulus that reduces effective arterial

blood volume and perpetuates HRS. At the same time,

albumin infusions expand the effective arterial blood

volume and correct the severe apparent ‘underfilling’.

This approach effectively suppresses the powerful

compensatory response mediated by the RAAS, SNS,

AVP, etc. and reverses renal vasoconstriction, thus

improving renal function.

Vasoconstrictors used in HRS include vasopressin

analogues (ornipressin and terlipressin), somatostatin

analogues (octreotide), and alpha-adrenergic agonists

(midodrine and noradrenaline). Vasopressin analogues

have a marked vasoconstrictor effect on the splanchnic

circulation and have been used for several years in the

management of acute variceal bleeding in cirrhotic

patients. Ornipressin, although effective in HRS, caused

significant ischemic side effects and was abandoned. The

most studied vasopressin analogue in HRS is

Fig. 2: Survival of the patients with cirrhosis with

type 1 and type 2 HRS

6

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Hepatorenal Syndrome: Clinical Considerations

431

terlipressin. The administration of terlipressin and

albumin is associated with a significant improvement

of GFR and reduction of serum creatinine to below 1.5

mg/dl in approximately 60-75% of patients with type 1

HRS

8

. There is a low incidence of ischemic side effects

(<5%) as demonstrated by several studies that pool over

150 patients.

In most studies vasoconstrictors were given in

combination with albumin, which improved the efficacy

of treatment. Patients with Child-Pugh scores >13 and

those who do not receive albumin expansion did not

respond well to this treatment. Reversal of HRS occurred

over several days but despite improvement in GFR and

serum creatinine to normal or near-normal levels, GFR

remained below normal values in most patients who

responded. Recurrence after stopping treatment in

responders was uncommon (<15% of patients); for

recurrent HRS, a repeat course of terlipressin with

albumin was usually effective

9

. Administration of

midodrine, an oral 

α1 agonist, in association with

octreotide, which inhibits release of glucagon and other

vasodilator peptides, and albumin also improved renal

function in cirrhotic patients with HRS, although data

about this therapeutic approach are limited. A recent

study revealed that patients with HRS 1 treated

successfully with vasopressin analogues and albumin

before liver transplantation had post-transplantation

outcome and survival similar to that in patients

transplanted witout HRS

16

. This study supports the

concept that HRS should be treated aggressively before

liver transplantation because improvement in renal

function is associated with better outcome. Non-

transplant candidates also benefit from this therapy and

have reduced morbidity and mortality.

Transjugular Intrahepatic Portosystemic

Shunt (TIPS)

TIPS, the non-selective, non-surgical shunt, is a

method of portal decompression that reduces portal

pressure and returns some of the volume of blood

pooled in the splanchnic circulation to the systemic

circulation, thus expanding effective circulating arterial

blood volume. This suppresses RAAS and SNS activity

and ameliorates their vasoconstrictor effect on the renal

circulation. Small uncontrolled studies indicated that

TIPS may improve renal function and GFR as well as

reduce the activity of RAAS and SNS in cirrhotics with

type 1 HRS

10

. Improvement in renal function after TIPS

placement alone is generally slow with success in

approximately 60% of patients

11

. However, the effects

on renal function and the clinical course of patients after

TIPS insertion are variable: some have a delayed

response while others actually worsen. As with surgical

nonselective shunts, TIPS carries the risk of worsening

of hepatic encephalopathy (HE) and worsening of liver

failure. A problem with studies assessing TIPS for type

1 HRS has been the exclusion of those with Child-Pugh

score >12 due to the risk of worsening liver failure and/

or hepatic encephalopathy. Unfortunately, it is this

group that commonly develops type 1 HRS and needs

TIPS.

In patients with type 2 HRS, TIPS improves renal

function and reduces ascites. However, experience from

a large series of cirrhotic patients undergoing TIPS for

refractory ascites indicates that those with hepatic

encephalopathy, liver failure, and severe coagulopathy

are prone to develop further complications. Although

uncontrolled studies suggest that TIPS improves

prognosis in patients with type 1 and 2 HRS, the impact

of this therapy on patient survival remains to be

assessed.

Dialysis

Small uncontrolled studies using hemodialysis and

peritoneal dialysis suggest that both are ineffective

mainly due to a high incidence of severe side effects,

including arterial hypotension, coagulopathy, gastro-

intestinal bleeding and increased mortality. In some

Table 3: Pharmacological management of hepatorenal syndrome

Drug and references

Dose range

Maximum

Potential  side-effects

duration of

therapy (days)

Terlipressin

0.5-2.0 mg every 4 hour as intravenous bolus

15

Peripheral, splanchnic, or cardiac ischemia

Norepinephrine

0.5-3.0 mg/hour intravenous infusion

15

Peripheral, splanchnic, or cardiac ischemia

Midodrine

7.5-12.5 mg every 8 hour by mouth

Indefinite?

Not reported

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Medicine Update

centers, hemodialysis is routinely used to treat patients

with HRS waiting for liver transplantation. However

the effectiveness of dialysis in this setting has not been

adequately studied. Continuous arterio-venous or veno-

venous hemofiltration have also been used but their

efficacy remians to be determined. Although hemo-

dialysis is not routinely recommended in HRS, it may

be a reasonable option in suitable liver transplant

candidates as a bridge to transplantation when there is

no response to vasoconstrictors or TIPS or in patients

who develop severe volume overload, metabolic

acidosis, or refractory hyperkalemia.

ALBUMIN DIALYSIS

Currently, three systems are available for albumin

dialysis.

1. MARS (Molecular Adsorbent Recirculating System).

MARS was designed by Stange and Mitzner from

Germany in 1993 by converting the albumin circuit

into a closed circuit and recirculating a fixed volume

of dialysate

12

. The system consists of three

compartments: a blood circuit, an albumin circuit,

and a renal circuit (hemofiltration/hemodialysis).

Blood flows through a hollow fiber dialysis module,

where it is dialyzed across an albumin-impregnated

high-flux polysulfone dialysis membrane; 600 ml of

20% human albumin in the albumin circuit acts as

the dialysate, and is passed through the dialysate

compartment of the blood dialyzer. Albumin-bound

toxins in the plasma pass on to the mebrane-

impregnated albumin. These toxins are subsequently

picked up by the albumin dialysate, which, in turn,

is regenerated by hemofiltration/hemodialysis.

Substances with a molecular weight of more than

50 kDa such as essential hormones bound to carrier

proteins, growth factors, and albumin are not

removed from the perfused plasma because of

the pore size of the MARS membrane. A recent

randomized-controlled trial evaluated 13 patients

with acute-on-chronic renal failure (ACLF) and

type 1 HRS who were treated with either MARS

(n=8) or standard medical therapy including

hemodiafiltration (n=5)

18

. The mortality rate was

100% in the group receiving hemodiafiltration at day

7 compared with 62.5% in the MARS group at day 7

and 75% at day 30, respectively (p< 0.01). Mean

survival was longer in the MARS group and was

accompanied by significant decrease in serum

bilirubin and creatinine and rise in serum sodium

and prothrombin activity. At the end of treatment,

mean arterial pressure (MAP) was significantly

higher in the MARS group. Although increase in

urine output was not significant in the MARS group,

4 of the 8 patients showed an increase compared with

none in the control group.

2. Prometheus. First described in 1999, Prometheus acts

on the principle of fractioned plasma separation and

adsorption, i.e. fractionation of the plasma with the

subsequent detoxification of the native albumin by

adsorption. It uses an albumin-permeable membrane

with a pore size cut-off of 250 kDa. Albumin crosses

the membrane and passes through special adsorbers

that remove toxins. The cleansed albumin is returned

to the plasma. Recently, the results of Prometheus

treatment in 11 patients with ACLF and accompany-

ing renal failure have been published

19

. Improve-

ment was noted in serum levels of conjugated

bilirubin, bile acids, ammonia, cholinesterase,

creatinine, urea, and blood pH. Another study

compared alternating treatments with MARS and

Prometheus in five patients with ACLF. Reduction

ratios of both bilirubin and urea were more with

Prometheus. Their safety profiles were found to be

comparable. More data from prospective controlled

trials are needed to confirm these results and assess

the place of the Prometheus system in HRS.

3. Single pass albumin dialysis (SPAD). The newly

developed SPAD system dialyzes blood/plasma

against a 4.4% solution of albumin, which is disposed

of after a single pass. A standard renal replacement

therapy machine is used without any additional

perfusion pump system, making the equipment

required simpler. In vitro studies suggest that its

detoxifying capacity is similar to, or even greater than

that of MARS, especially with regard to bilirubin and

ammonia clearance. In vivo, however, the only

clinical use reported has been in a case of fluminant

Wilson’s disease, where it was found to efficiently

clear bilirubin and copper, both protein-bound, from

the plasma. Further experience is required before

considering it for routine clinical use

20

.

LIVER TRANSPLANTATION

The functional nature of HRS was first proposed by

Koppel, et al, in 1969 who noted reversal of renal

dysfunction following transplantation of cadaveric

kidneys from patients with HRS into patients with a

normal liver

13

. This reversal was later confirmed by

Iwatsuki, et al in 1973 who demonstrated recovery from

HRS after OLT

14

. There is now ample literature

documenting recovery of HRS following OLT

15

. Liver

only transplantation rather than CKLT should, therefore,

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Hepatorenal Syndrome: Clinical Considerations

433

be the initial option considered in patients with ESLD

and associated HRS. Liver transplantation is the best

treatment for suitable candidates with HRS, as it offers

a cure to both the diseased liver and the circulatory and

renal dysfunction. Unfortunately, transplantation for

type 1 HRS is limited by the fact that the window

available for LT, when the patient is in good condition

for the surgery, is very narrow due to short survival for

untreated HRS and long waiting times for a suitable

donor organ in most centers, so that there is significant

waiting list mortality or worsening necessitating

removal from the transplant list. The key to successful

LT for HRS type 1 is prolonging survival while

improving renal function, thus improving the outcome

of LT. Patients with HRS 1 treated with vasopressin

analogues and albumin before transplantation have a

good outcome similar to that of non-HRS patients. The

3-year probability for survival after LT for patients with

HRS treated with terlipressin and albumin was excellent

(100%) and slightly better than that of cirrhotic patients

without HRS (83%) in this study

16

.

Prevention

HRS can be prevented in two clinical settings. First,

in patients with SBP the administration of albumin

(1.5 g/kg at diagnosis of infection and 1 g/kg 48 hours

later) prevents the circulatory dysfunction and

subsequent development of HRS

17

. The rationale for

albumin administration is to prevent arterial under-

filling and subsequent activation of vasoconstrictor

systems during the infection. The dose of albumin was

arbitrarily chosen and it is not known whether smaller

doses or other plasma expanders will confer similar

benefit in preventing renal failure in the setting of SBP.

The incidence of HRS in patients with SBP receiving

albumin together with antibiotic therapy is 10%,

compared with an incidence of 33% in patients not

receiving albumin

17

. Second, in patients with acute

alcoholic hepatitis the administration of pentoxifylline,

an inhibitor of tumor necrosis factor, (400 mg tid orally

for 28 days) reduces the incidence of HRS and mortality

(8% and 24%, respectively) with respect to a control

group (35% and 46%, respectively)

17

. Further studies

confirming these results are lacking. However, the use

of albumin infusions in patients with SBP has many

benefits and is supported by other studies confirming

better control of infection and ascites apart from

prevention of HRS. Though popular, the use of

pentoxifylline does not enjoy similar support from

published studies and its use should be evaluated further

before its general use can be recommended.

In conclusion, HRS type 1 remains one of the most

serious complications of advanced liver failure and

carries a high mortality. It is often the knockout blow

for a patient with very poor liver function, reeling from

other complications of ESLD such as variceal bleeding

and severe infections. It is common in patients with

acute-on-chronic liver failure (ACLF) that develops

when a severe hepatitic insult, commony due to severe

acute viral or alcoholic hepatitis, is superimposed on a

cirrhotic liver. Recent advances in the medical

management of this condition, particularly the use of

vasoconstrictors with plasma volume expansion, have

improved the gloomy outlook associated with this

complication. In selected patients with HRS 1, where

the prospects for liver transplantation are bright, careful

management of HRS with optimization of the patient’s

condition followed by successful liver transplantation

can cure this dreaded complication. Judicious use of

therapies such as TIPS or some form of albumin dialysis

allows the clinician to buy time while optimizing the

patient and bridging him to successful liver trans-

plantation. Even in patients who are not transplant

candidates, aggressive management of HRS may reverse

the acute destabilization that has triggered HRS 1,

allowing for recovery from HRS, particularly when there

are reversible precipitating events such as bleeding, SBP,

other serious infections and potentially reversible

illnesses such as ALF and ACLF. Current reports

suggest that recurrence of HRS after successful therapy

is rare. More work and further studies are required to

adequately explore the best ways of applying currently

available therapeutic modalities and to develop better

ways to deal with this dreaded complication.

Fig. 3: Rationale of modern therapy in HRS

---

434

Medicine Update

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