Renal Dysfunction in Cirrhosis: Diagnosis, Treatment, and Prevention

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MedGenMed Gastroenterology

Renal Dysfunction in Cirrhosis: Diagnosis, Treatment, and Prevention

Posted 12/02/2004

Elaine Yeung, MD; Elaine Yong, MD, FRCPC; Florence Wong, MD, FRCPC

Introduction

Renal dysfunction is a common and serious problem in patients with advanced

liver disease. In particular, alterations in renal physiology in acute liver

failure or cirrhosis with ascites can predispose patients to a specific

functional form of renal failure known as hepatorenal syndrome (HRS).[1] The

first detailed description of HRS was made by Hecker and Sherlock[2] in 1956.

These authors reported 9 patients with cirrhosis or acute hepatitis who

developed renal failure without associated proteinuria and with very low urinary

sodium excretion. On autopsy, these kidneys showed normal histology. It was

later shown that kidneys from patients with HRS regain their function when

transplanted into patients without cirrhosis,[3] and that HRS can be reversible

following liver transplantation.[4]

Definition

HRS is defined as the development of renal failure in patients with advanced

liver failure (acute or chronic) in the absence of any identifiable causes of

renal pathology. In 1996, the International Ascites Club published a consensus

paper subdividing HRS into 2 types.[5] Type 1 HRS is characterized by a rapid

decline in renal function, defined as a doubling of serum creatinine to a level

> 2.5 mg/dL or a halving of the creatinine clearance to < 20 mL/min within 2

weeks (Table 1). The clinical presentation is that of acute renal failure. In

type 2 HRS, renal function deteriorates more slowly, with serum creatinine

increasing to > 1.5 mg/dL or a creatinine clearance of < 40 mL/min. The clinical

presentation is that of stable renal failure in a patient with refractory

ascites.

Epidemiology

In a large prospective study of cirrhotic patients with ascites, 18% developed

type 1 HRS at 1 year and 39% at 5 years.[1] The predictive factors for the

development of HRS include a low serum sodium, high plasma rennin, and absence

of hepatomegaly.[1] Until the recent development of effective therapies, the

median survival following the development of type 1 HRS was 1.7 weeks, with only

10% of patients surviving more than 10 weeks.[1] Survival rate in type 2 HRS is

50% at 5 months and 20% at 1 year.[6]

Pathophysiology

Patients with cirrhosis and portal hypertension develop circulatory dysfunction

characterized by disturbances in systemic and renal hemodynamics.[7] It has been

shown that the severity of circulatory dysfunction correlates with the severity

of cirrhosis.[8]

In compensated cirrhosis (ie, cirrhosis without ascites), the systemic

hemodynamics are normal in the upright position, but become hyperdynamic in the

supine position -- that is, cardiac output increases and systemic vascular

resistance decreases.[9] This is thought to be due to volume expansion secondary

to subtle sodium retention in the upright position.[10-12] The renal circulation

is frequently vasodilated with glomerular hyperfiltration.[13]

With disease progression, circulatory dysfunction worsens, manifested as

vasodilatation and relative intravascular underfilling.[14,15] There is

increased activity of the sympathetic nervous and renin-angiotensin

systems[16-18] in order to maintain hemodynamic stability. Peripheral edema and

ascites can occur as a result of worsening sodium retention despite an increase

in natriuretic substances.[19] Despite activation of various vasoconstrictor

systems, renal perfusion and glomerular filtration rate (GFR) in the early

stages of ascites may be normal or only moderately decreased as a result of

increased renal production of prostaglandins.[20,21] Nitric oxide and

prostacyclin have also been shown to counteract vasoconstrictors to maintain

renal perfusion.[22-24] At this stage of disease, hypersecretion of antidiuretic

hormone (ADH) results in decreased free water excretion.[25] Concurrently,

increased prostaglandin E2 synthesis by the collecting tubules antagonizes ADH

and preserves renal excretion of free water.[26] Therefore, hyponatremia is not

common in early ascites.[27]

As systemic vasodilation progresses, the systemic arterial pressure falls. Renal

perfusion also decreases, leading to decreased renal blood flow.[28] The renal

circulation also becomes hypersensitive to the vasoconstrictive effects of

various activated hormonal systems. When the vasoconstrictors overwhelm the

compensatory effects of the various renal vasodilators, renal vasoconstriction

occurs and GFR falls.[29]

HRS occurs in the latest phases of cirrhosis and is considered the extreme

expression of circulatory dysfunction. Renal GFR decreases to < 40 mL/min.

Marked renal vasoconstriction occurs due to increased levels of intrarenal

vasoconstrictors (renin and angiotensin II).[30] Increasing levels of renal

vasoconstrictors such as adenosine,[31] endothelin, leukotrienes,[32] and

F2-isoprostanes[32] cause mesangial contraction which further reduces GFR.[33]

Another factor that influences renal hemodynamics is sinusoidal portal

hypertension; this is supported by the fact that an acute increase in sinusoidal

pressure leads to reduction of renal plasma flow,[34] and a reduction in

sinusoidal pressure results in improvement of renal hemodynamics and renal

function.[35] Bataller and colleagues[36] proposed that renal hypoperfusion in

cirrhosis could also be related to liver dysfunction. However, the mechanism

whereby liver dysfunction could directly induce a reduction of renal

vasodilators is unclear. It is possible that the liver is involved in the

synthesis or release of renal vasodilators such as nitric oxide.[24]

The extremely low urinary sodium in HRS results from decreased filtered sodium

(decreased GFR) and increased sodium reabsorption in the proximal renal

tubule.[37] This results in a minimal amount of filtered sodium reaching the

loop of Henle and the distal nephron. Decreased delivery of diuretics to renal

tubules hampers the ability of diuretics to promote natriuresis.[37]

Hyponatremia is common[27] and is caused by a further nonosmotically induced

increase in antidiuretic hormone and possibly decreased prostaglandin E2

activity, resulting in a decrease in water excretion.[26]

Precipitating Factors

It is important to be aware of precipitating factors in order to reduce the

incidence of HRS and related mortality. Watt and colleagues[38] found that the

most common predisposing factors for HRS were bacterial infection (48%),

gastrointestinal bleed (33%), and aggressive paracentesis (27%). Drugs were the

precipitating cause in 7% of cases, and surgery the cause in 7%. Miscellaneous

factors accounted for 11% of cases.[38] Twenty-four percent of patients with

type 1 HRS develop renal failure without an obvious precipitating factor.[39]

Spontaneous Bacterial Peritonitis

Renal impairment is a frequent event in cirrhotic patients with spontaneous

bacterial peritonitis (SBP). It occurs more commonly in patients with

preexisting kidney failure, although it can occur in patients with normal renal

function. Renal impairment is the most important predictor of hospital mortality

in cirrhotic patients with SBP.[40] Renal impairment is related to further

deterioration of systemic hemodynamics, possibly brought about by endotoxins and

various cytokines induced in SBP, causing further vasodilatation.[41] The

incidence of renal impairment is most significant among patients with a serum

bilirubin level > 4 mg/dL (68 mcmol/L) and a serum creatinine level > 1 mg/dL

(88 mcmol/L).[42]

Gastrointestinal Bleeding

Acute gastrointestinal bleeding leads to acute blood volume contraction, with

decreased renal perfusion. In one study, HRS developed in 3 of 85 patients with

hepatic cirrhosis hospitalized for upper gastrointestinal bleeding.[43] The

occurrence of renal failure is mainly related to the severity of bleeding and to

the baseline liver function. In another study, the development of renal failure

and hypovolemic shock were independent predictors of in-hospital mortality.

Patients with renal failure had a mortality rate of 55% as compared with only 3%

in patients without renal failure (P < .01).[44]

Aggressive Paracentesis

Aggressive paracentesis in cirrhotic patients with ascites accentuates the

reduction of effective arterial blood volume and further activates

vasoconstrictor systems, leading to further renal vasoconstriction.[45] HRS

occurs in 10% of patients with ascites treated by total paracentesis.[1]

Drugs

Numerous drugs can precipitate HRS. Overzealous use of diuretics can cause renal

failure, although this may be reversible. Patients with ascites and no edema are

able to mobilize more than 1 L/day during rapid diuresis but at the expense of

plasma volume contraction and renal insufficiency. Aminoglycosides are

nephrotoxic in cirrhotic patients, and frequent assessments of beta-2

microglobulin are no guarantee against the development of renal failure.

Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the synthesis of

prostaglandins. Short-term celecoxib administration induces marked decrease in

GFR in cirrhotic patients with ascites.[46] Cirrhotic patients are dependent on

the activated renin-angiotensin system to maintain systemic blood pressure.

Therefore, the use of angiotensin-converting enzyme inhibitors and angiotensin

II antagonists can result in arterial hypotension and prerenal failure in these

patients.[47-49]

Others

Surgery, acute alcoholic hepatitis, and cholestasis can also act as

precipitating factors of HRS. Acute biliary obstruction is associated with the

development of renal impairment and oxidative stress. The F2-isoprostanes,

formed during oxidant injury, are renal vasoconstrictors acting via

thromboxane-like receptors. Antioxidants such as N-acetylcysteine have been

shown to improve renal function.[50,51]

Diagnosis of HRS

The presence of renal dysfunction is often missed in patients with cirrhosis.

Because of a reduction in muscle mass in these patients, serum creatinine may be

within the normal range, even with a very low GFR. The use of blood urea

nitrogen (BUN) concentration as a measure of renal function is even less

reliable, because BUN levels can be affected by the presence of gastrointestinal

bleeding or by the amount of protein in the diet. It has been suggested that

serum creatinine concentrations of 71 mcmol/L, 88 mcmol/L, 160 mcmol/L, 195

mcmol/L, and 354 mcmol/L, would reflect steady-state GFRs of 100 mL/min, 50

mL/min, 25 mL/min, 12 mL/min, and 6 mL/min, respectively.[52] Therefore, a

creatinine level > 88 mcmol/L in a patient with cirrhosis should alert the

clinician to the presence of renal dysfunction.

HRS should only be diagnosed in patients with decreased renal function in the

presence of advanced cirrhosis, chronic liver disease with severe liver failure

and portal hypertension, or acute liver failure. Other forms of organic renal

disease must be ruled out. Some patients with primary liver diseases are at

higher risk for developing certain forms of kidney diseases (Table 2), while

some systemic processes can affect both the liver and the kidney (Table

3).[53-55]

The International Ascites Club requires major criteria to be fulfilled for the

diagnosis of HRS. These criteria include serum creatinine > 1.5 mg/dL (133

mcmol/L) or 24-hour creatinine clearance < 40 mL/min in the absence of diuretic

therapy and excluding other causes of renal failure (Table 1). Despite the

existence of these criteria, arriving at an accurate diagnosis can be

challenging.[38]

Approach to Renal Failure in Cirrhosis

The diagnostic approach to renal failure in a patient with cirrhosis is outlined

in Table 4 and Table 5. Patients with type 2 HRS are at particularly high risk

for type 1. A thorough history and physical exam can detect intravascular volume

depletion and arterial hypotension. A careful assessment of the patient's

history should identify preceding events such as gastrointestinal bleeding,

overdiuresis, or aggressive paracentesis. Sepsis should be suspected in any

cirrhotic patient with renal deterioration, even in the absence of symptoms.

Fever and leukocytosis may not be present. Appropriate cultures should be

obtained, including examination of the ascitic fluid to rule out SBP. Recent

exposure to nephrotoxins such as NSAIDs, aminoglycosides, or radiocontrast dyes

prior to the increase in serum creatinine level should be ruled out. If

proteinuria and/or hematuria are present, additional investigations should be

undertaken to rule out renal parenchymal diseases. Renal biopsy should be

considered if there is a strong suspicion of glomerulonephritis. An abdominal

ultrasound should be performed to determine whether the patient has

postobstructive renal failure.

Differentiating HRS from acute tubular necrosis (ATN) is often difficult.

Distinguishing the 2 entities is important when considering therapy and for

prognostication purposes. Typically, urine sodium is < 10 mmol/L in HRS and > 20

mmol/L in ATN due to impaired reabsorption of sodium from damaged renal tubules,

but this feature is not always reliable. Heme-granular casts may be seen in ATN.

And ATN should be considered when renal failure develops abruptly following

hypovolemia, septic shock, or exposure to nephrotoxins. A recent study suggested

that fractional excretion of urea ([urine urea nitrogen/ blood urea

nitrogen)/(urine creatinine/plasma creatinine)] X 100) < 35% is specific for

prerenal azotemia, and > 50% is specific for ATN.[56] Because this study

included only 7 patients with hepatic failure, its significance in

distinguishing ATN from HRS awaits further investigation.

It is interesting to note that in a recent multicenter retrospective study

involving 355 patients with cirrhosis and acute renal failure, 58% had prerenal

failure, with one third of patients fulfilling the definition of type 1 HRS.[57]

Acute tubular necrosis was present in 41.7%. Only 1 patient had obstructive or

postrenal failure. There were no cases of glomerulonephritis. However,

preliminary reports from an ongoing prospective study of renal failure in

patients with cirrhosis revealed a frequency of 32% infection-induced renal

failure, 24% parenchymal renal disease, 22% prerenal failure, 11% ATN, 8% HRS,

and 3% nephrotoxic renal failure.[52]

Management of HRS -- Prevention

The most important aspect in management of HRS is to prevent its occurrence. The

latter is achieved by avoidance, prophylaxis, early recognition, and treatment

or removal of precipitating factors.

Prophylaxis Against Bacterial Infections

Prophylaxis with antibiotics is recommended in patients presenting with

gastrointestinal bleeding or those with a history of SBP. Patients with severe

cirrhosis who are admitted for gastrointestinal bleeding have a higher risk of

developing bacterial infection during their hospitalization;[58] the incidence

of bacterial infection is 6.7% to 20%.[59-65] Also, proven bacterial infection

or antibiotic use are independent prognostic factors for failure to control

bleeding.[66] Short-term antibiotic prophylaxis increases the survival rate at

19 days in cirrhotic patients with gastrointestinal bleeding.[64] The overall

probability of SBP recurrence in cirrhotic patients after 1 episode at 1 year of

follow-up is 68%.[67] Among cirrhotic patients admitted with SBP, renal

impairment occurs in 33%, mainly in those with kidney failure before infection,

and is the most important predictor of mortality in hospital.[40] After 1

episode of SBP, patients with cirrhosis should receive antibiotic prophylaxis.

Volume Expansion

The use of albumin to prevent the development of HRS is still controversial.

Plasma volume expansion with intravenous albumin has been shown in 1 study to

reduce the incidence of renal impairment in cirrhotic patients admitted with

SBP. It also reduces in-hospital and 3-month mortality.[42] However, the same

study has been criticized in that the patients who did not receive albumin did

not receive any other fluid support. Therefore, it is not clear at present

whether fluid support with crystalloids or other colloids would have produced

the same results. Intravenous albumin infusion has also been shown to prevent

activation of endogenous vasoactive systems in cirrhotic patients with ascites

who are treated with repeated large-volume paracentesis.[68] Because

postparacentesis circulatory dysfunction is not always spontaneously reversible,

it then follows that albumin should be able to prevent the development of HRS

after large-volume paracentesis. Albumin seems to be the best plasma expander to

prevent this complication.[69] However, those patients who receive albumin for

their large-volume paracentesis did not demonstrate any survival benefits.

Judicious Use of Diuretics

Diuretic-induced renal impairment occurs in 20% of patients with ascites. The

latter occurs when the rate of diuresis exceeds the rate of ascites

reabsorption, resulting in intravascular volume depletion. The renal failure is

nearly always reversible with cessation of the diuretics. Patients with ascites

and no edema are able to mobilize > 1 L/day during rapid diuresis, but at the

expense of plasma volume contraction and renal insufficiency. Patients with

peripheral edema appear to be protected from these effects because of the

preferential mobilization of edema, and they may safely undergo diuresis at a

rapid rate (> 2 kg/day) until edema disappears.[70]

Avoidance of Nephrotoxic Agents

Patients with cirrhosis and ascites are predisposed to ATN with use of

aminoglycosides; therefore, these agents should be avoided.[71] NSAIDs should

also be avoided because renal failure occurs in 33% of this population compared

with in 3% to 5% of the general population. NSAIDs inhibit formation of

intrarenal prostaglandins, causing a decline in renal function and sodium

excretion. Short-term celecoxib administration also induces a marked decrease in

GFR in patients with cirrhosis and ascites.[46] Angiotensin-converting enzyme

inhibitors and angiotensin receptor antagonists result in arterial hypotension

and cause prerenal failure in cirrhotic patients.[47-49]

Management of HRS -- Treatment

Initial Management

Initial management of these patients requires exclusion of reversible or

treatable conditions. Patients should be supported until liver recovery or

transplantation. A diligent search should be made for precipitating factors

(infection, gastrointestinal bleeding) and treated accordingly. Likewise,

nephrotoxic drugs should be removed. Patients should be initially challenged

with fluid to assess response and to treat subclinical hypovolemia. Cirrhotic

patients with an acute gastrointestinal bleed and poor liver function and/or

decreased renal function should be managed in intensive care units to protect

effective circulating blood volume and renal perfusion.[72] In patients with

cirrhosis and SBP, treatment with intravenous albumin in addition to an

antibiotic has been shown in one study to reduce the incidence of renal

impairment and death compared with treatment with an antibiotic alone.[42]

Pharmacologic Therapy

The aim of pharmacologic therapy is to increase renal blood flow. This can be

accomplished either by improving the renal perfusion pressure or by inducing

renal vasodilatation. Splanchnic vasoconstriction redistributes some of the

intravascular volume to the systemic circulation and improves circulatory

function and effective arterial volume, thereby improving renal perfusion and

GFR. Such agents can be used as a bridge to liver recovery or liver

transplantation.

Dopamine. This agent has renal vasodilator effects when given in subpressor

doses, but no studies have shown convincing benefit. and colleagues[73]

showed that urine flow rate and GFR did not consistently improve with 12- to

24-hour intravenous infusions. Moreover, in cirrhotic patients without HRS,

dopamine has been shown to decrease arterial pressure and accentuate portal

hypertension.[74]

Noradrenaline. In a study by Duvoux and colleagues,[75] noradrenaline with

albumin and furosemide were used in the management of patients with type 1 HRS.

Reversal of HRS was seen in 10 of 12 patients after a median of 7 days. There

were also associated increases in mean arterial pressure and reductions in

active renin and aldosterone. A similar earlier study did not find noradrenaline

to be effective for type 1 HRS.[76] Therefore, the use of noradrenaline in

patients with HRS awaits further confirmatory investigations.

Midodrine and octreotide. Midodrine is an oral alpha-adrenergic agent and a

sympathomimetic drug. Octreotide is a long-acting analogue of somatostatin.

Combined long-term administration of oral midodrine and subcutaneous octreotide,

in addition to albumin infusion, led to improvement in renal function compared

with nonpressor doses of dopamine after 20 days of treatment.[77] This is

accompanied by a significant reduction in plasma renin activity, plasma

vasopressin, and plasma glucagon levels. No side effects occurred.[77] The

latter has recently been confirmed in another study using oral midodrine and

intravenous octreotide, together with intravenous albumin.[78] Fifty percent of

patients survived for more than 6 months, with or without liver transplantation.

Octreotide alone has been shown to be ineffective for treatment of HRS.[79] The

use of this therapeutic combination is common in countries where terlipressin is

not available, and evidence is accumulating that this may offer an alternative

to terlipressin (see below).

Misoprostol. The role of this synthetic analogue of prostaglandin E1 and renal

vasodilator was examined by Fevery and colleagues[80] in 4 patients with HRS who

were also treated with albumin infusions. All responded with diuresis, a fall in

creatinine level, and normalization of hyponatremia. However, it is not clear

whether the improvement in renal function was due to the misoprostol or the

albumin infusion. Gines and colleagues[81] found in their group of 16 patients

that neither oral misoprostol nor infusion of prostaglandin E2 led to

improvement in renal function.

Ornipressin. This vasopressin analogue is a nonselective agonist of the V1

vasopressin receptors; it preferentially causes vasoconstriction of the

splanchnic vasculature, thus increasing systemic pressure and renal perfusion

pressure. There has been evidence of benefit to renal function shown with the

use of ornipressin.[82,83] However, Salo and colleagues[84] showed that despite

an increase in arterial pressure and suppression of plasma renin activity during

ornipressin and ornipressin plus dopamine administration, there was no

significant improvement in renal function. Another series showed improvement in

urine volume, creatinine clearance, urinary sodium excretion, and serum

creatinine with ornipressin in 4 of 7 patients with type 1 HRS who had failed a

previous course of albumin plus dopamine therapy.[85] Guevara and colleagues[86]

found that prolonged use of ornipressin plus albumin for 15 days of therapy

normalized serum creatinine, was associated with a marked increase in renal

plasma flow and GFR, and suppressed vasoconstrictor system activity -- but with

an increased risk of ischemic complications. Because of the side-effect profile,

the use of ornipressin for HRS is rather limited.

Terlipressin. This agent is a synthetic analogue of vasopressin, with intrinsic

vasoconstrictor activity. It is also a nonselective V1 vasopressin agonist, but

with a lower incidence of ischemic complications than vasopressin. This agent

also has the advantage over vasopressin of a longer half-life, allowing

administration as a 4-hourly bolus. Terlipressin is used in Europe for

management of variceal bleeding and is associated with a decrease in portal

pressure.[87] This agent has been shown to improve systemic hemodynamics[88-90]

and to improve renal function[88-91] in patients with type 1 HRS.[57] Ischemia

is less common, with no patients developing signs of ischemia in 1 study[89];

only 2 of 99 patients in another study developed lower limb ischemia.[57] Other

adverse effects were noted in 23 of 99 of these patients. In addition to

improving renal function, the use of terlipressin has also been found to be

associated with improved survival.[57,90] The use of volume support in addition

to terlipressin is debatable, because albumin made no difference in the

outcome,[57] while patients in 2 other studies needed volume support in addition

to terlipressin to improve their renal function.[92,93] One suggested protocol

consists of 0.5 mg every 4 hours with a titration upward by 0.5 mg every 3 days

up to 2 mg every 4 hours.

Endothelin antagonists. Endothelin, a potent endogenous vasoconstrictor, is

increased in patients with HRS.[94] Endothelin a (ETa) is important in the

pathogenesis of renal failure that occurs in the setting of acute liver failure,

as demonstrated in a rat model of acute liver failure.[95] In this model, plasma

endothelin 1 (ET-1) levels were increased and ETa receptors were upregulated.

Despite the latter, renal failure was prevented by an endothelin antagonist,

bosentan.[95] In an assessment of ET-1 levels before and after orthotopic liver

transplantation, reduction of ET-1 levels was seen with improvement of liver

function after liver transplantation. This finding preceded improvement in renal

function, suggesting ET-1 as one of the causative factors in HRS.[96] A pilot

study of an ETa antagonist, BQ123, in 3 cirrhotic patients with HRS showed a

dose-related improvement in GFR.[97]

N-acetylcysteine. The effects of N-acetylcysteine, a drug with antioxidant

properties, were evaluated in a nonrandomized study of 12 patients with HRS.[50]

Nine of 12 patients had alcoholic cirrhosis and/or alcoholic hepatitis.

Treatment was well tolerated and renal function improved. High survival rates of

67% at 1 month and 58% at 3 months were observed.

Pentoxifylline. This inhibitor of tumor necrosis factor improves short-term

survival in patients with severe alcoholic hepatitis.[98] This benefit appears

to be due to a reduction in the risk of developing HRS.

Renal Support

Dialysis. Renal support in the form of dialysis should only be offered in select

cases if there is a real chance of liver transplantation in the short term.

Dialysis in these patients is fraught with difficulties because of coagulopathy

and hemodynamic instability, as well as risk of sepsis. This support is usually

given as continuous hemofiltration because of the labile systemic blood pressure

during dialysis in these patients. The effectiveness of dialysis in the

treatment of HRS has not been proven.

Molecular adsorbent recirculating system. This system is a modified form of

dialysis using albumin-containing dialysate that is recirculated and perfused

online through charcoal and anion exchanger columns. It enables the removal of

water-soluble and albumin-bound substances. Results of one study conducted in

patients with type 1 HRS and bilirubin level >/= 15 mg/dL demonstrated a

decrease in bilirubin and creatinine as well as mortality rate in the

albumin-dialysis treatment group compared with the hemofiltration-alone

group.[99] These results were again seen in another study conducted in 8 type 1

HRS patients treated with the molecular adsorbent recirculating system.[100] It

is believed that this system removes some of the vasoactive substances that

mediate the hemodynamic changes that lead to HRS, thereby improving systemic

hemodynamics and, hence, renal perfusion.

Transjugular Intrahepatic Portosystemic Shunt

In the early 1990s, the transjugular intrahepatic portosystemic shunt (TIPS) was

developed for the treatment of bleeding varices. In this procedure, a

self-expandable metal stent is inserted between the hepatic vein and the

intrahepatic portion of the portal vein using a transjugular approach, with a

resulting decrease in portal pressure. In certain cases, ascites disappeared

after TIPS insertion.[101] Urinary sodium excretion increased 1-2 weeks after

TIPS,[102-104] with an associated decrease in plasma renin activity and serum

aldosterone levels[105,106] and an improvement in renal function.[102,103]

Initial reports have suggested that TIPS may improve renal function in

HRS[107-109] and may reduce the risk of progression from type 2 to type 1

HRS.[35,110-114]

In a study by Guevara and colleagues,[106] GFR and renal blood flow improved

significantly 30 days after TIPS insertion in patients with type 1 HRS. These

beneficial effects on renal function were associated with a reduction in plasma

renin activity, aldosterone, and norepinephrine levels. Mean survival was 4.7 ±

2 months (range, 0.3-17 months). In a larger study evaluating TIPS in patients

with type 1 and type 2 HRS not eligible for liver transplantation, renal

function initially deteriorated but improved within 2 weeks.[35] There was

marked suppression of plasma renin activity, vasopressin level, and

catecholamines. Survival at 3, 6, and 12 months was 48%, 38%, and 16%,

respectively. One-year survival was 20%. Subgroup analysis suggested better

survival for those patients with better baseline liver function and those with

HRS type 2. One-year survival of type 2 HRS patients was 70%.

The survival benefits of TIPS vs repeated paracentesis plus intravenous albumin

in patients with refractory ascites, a population at high risk for type 1 HRS,

is controversial.[110,113,114-116] It has also been argued that the predicted

survival without TIPS was no different from observed survival with

TIPS.[117,118] The majority of patients in these studies had alcoholic

cirrhosis. The main limitation to using TIPS in HRS includes worsening

encephalopathy and liver failure from reduced liver venous perfusion, thereby

causing relative liver ischemia.[119] However, in those patients whose main

problem is one of hemodynamic instability and renal failure rather than severe

liver dysfunction, TIPS may be a viable option, at least as a bridge to liver

transplantation.

Liver Transplantation

The only effective and permanent treatment for end-stage cirrhosis and HRS is

liver transplantation. Patients with severe impairment in renal or circulatory

function, such as in refractory ascites and spontaneous bacterial peritonitis,

should be evaluated and given priority for liver transplantation. GFR improves

in patients with HRS after transplantation.[120] However, patients who are

transplanted with HRS have a lower probability of both graft and patient

survival after liver transplantation compared with patients without HRS.

Additionally, patients with HRS are sicker and require longer stays in intensive

care, longer hospitalization, and more dialysis treatments after liver

transplantation.[78,121]

Summary

Renal failure is a common complication of cirrhosis and is a poor prognostic

indicator. Patients with severe liver dysfunction can develop HRS, characterized

by a marked reduction in renal blood flow and hemodynamic disturbances. HRS is

now subdivided into 2 types. Type 1 HRS carries a worse prognosis than type 2;

these patients also do worse after liver transplantation. Precipitants of HRS

need to be sought out and managed early. It is also important to rule out other

organic causes of renal disease that can occur in these patients. The most

common precipitants are bacterial infection, gastrointestinal bleeding, and

aggressive paracentesis. Antibiotic prophylaxis should be used in patients with

a history of SBP and in those admitted to hospital for gastrointestinal

bleeding. Any nephrotoxic drugs should be removed and volume status of the

patient should be maintained. Albumin infusions may be used in patients admitted

with SBP and those undergoing large-volume paracentesis. Diuretic use in

patients with ascites needs to be monitored, and these agents should be stopped

if renal function worsens.

Many treatment options are now showing promise for patients with HRS. Numerous

studies have shown the benefit of terlipressin in this setting, with fewer side

effects; however, there is also some evidence for the combination of midodrine

and octreotide when terlipressin is not available. Intravenous albumin should be

considered in adjunct. If there is no response to these therapies, TIPS or the

molecular adsorbent recirculating system could be considered. Orthotopic liver

transplantation is the most effective strategy for treatment of HRS.

Unfortunately, some patients with HRS are not candidates for liver

transplantation. For those patients who are to receive liver transplantation,

their chances for survival are improved if their renal function is optimized

before transplantation.

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