sindrome hepatorenal.pdf

The Hepatorenal Syndrome

Santiago J. Munoz, MDa,b,*aDivision of Hepatology, Department of Medicine, Albert Einstein Medical Center,

Philadelphia, PA 19141, USAbJefferson Medical College, Philadelphia, PA 19107, USA

Med Clin N Am 92 (2008) 813–837

The onset of renal failure in a patient with cirrhosis or acute liver failure(ALF, also known as ‘‘fulminant liver failure’’) is alarming because it raisesthe possibility of the hepatorenal syndrome (HRS). HRS is a distinct formof renal failure that occurs in the setting of severe liver disease. HRS is themost frequently fatal complication of cirrhosis, because nearly half of pa-tients die within 2 weeks of this diagnosis (Fig. 1) [1]. The annual incidenceof HRS is estimated at 8% to 40% in cirrhosis [2,3]. The Model for EndStage Liver Disease (MELD) score [4–6] in patients with cirrhosis and asci-tes parallels the risk of developing HRS [3,7]. Onset of ascites in patientswith MELD scores of about 10 is associated with an 8% and 11% risk ofHRS at 1 and 5 years, respectively [7]. If the MELD score approaches 18,nearly 40% of patients develop HRS within 1 year [3]. The frequency ofHRS in severe acute alcoholic hepatitis and in fulminant liver failure isabout 30% and 55%, respectively [8,9]. Most episodes of renal failure inpatients with liver disease, however, are not related to HRS. Commonhigh-risk scenarios for HRS include diuretic-resistant tense ascites, severehyponatremia or coagulopathy, and a MELD score greater than 18. Pro-found jaundice is often present, but HRS can develop in patients withminimal hyperbilirubinemia. Periodic surveillance of renal function is help-ful in patients with severe liver disease to detect HRS early and to helpcorrect reversible contributing factors. Once established, HRS respondsrelatively poorly to medical management, although recent advances havebrought hope for an improved prognosis. In this article, the diagnosis,

* P.O. Box 403, Moorestown, NJ 08057.

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doi:10.1016/j.mcna.2008.03.007 medical.theclinics.com

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Fig. 1. Severe impact on survival associated with onset of hepatorenal syndrome. (FromArroyo

V, TerraC,Gines P. Advances in the pathogenesis and treatment of type 1 and type-2 hepatorenal

syndrome. J Hepatol 2007;45:935–46; with permission.)

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pathophysiology, and management of HRS are discussed in detail, with anemphasis on recent diagnostic and therapeutic advances.

Definition

HRS is a distinct form of acute or subacute renal failure characterized bysevere renal vasoconstriction, which develops in decompensated cirrhosis orALF. This definition, developed by expert consensus in 1996, has been re-cently updated to include albumin as a volume expander [10–12].With greaterunderstanding of HRS, the definition should be refined further to includemore specific parameters and improved tests of renal injury [13,14].

Clinical presentation and classification

Patients with liver failure can develop two distinct clinical forms of HRS,designated as type 1 and type 2, based on the time course and precipitating fac-tors. These syndromes reflect renal injury from circulatory disturbancescaused by profound liver failure. Patients with HRS and underlying acute orchronic kidney disease do not fit into this classification, and are denoted astype 3HRS (Box 1). Themajor diagnostic criteria of HRS are shown in Box 2.

Type 1 hepatorenal syndrome

In type 1 HRS the serum creatinine level doubles to greater than 2.5 mg/dL within 2 weeks [10–12]. The key features of type 1 HRS are its rapidprogression and high mortality, with a median survival of only 1 to 2 weeks

Box 1. Classification of the hepatorenal syndrome

Type 1: cirrhosis with rapidly progressive acute renal failurea

Type 2: cirrhosis with subacute renal failurea

Type 3: cirrhosis with types 1 or 2 HRS superimposed on chronickidney disease or acute renal injuryb

Type 4: fulminant liver failure with HRSb

The clinical characteristics, natural history, and laboratory features of types 3and 4 HRS have not been studied.

a As recently redefined by the International Ascites Club [12,95].b Chronic kidney diseases include diabetic nephropathy, chronic

glomerulonephritis, hypertensive nephropathy, and others. Acute renal injuryincludes acute tubular necrosis and other causes.

815THE HEPATORENAL SYNDROME

(see Fig. 1) [7,11]. Common precipitating events in type 1 HRS includebacterial infections, particularly spontaneous bacterial peritonitis; varicealhemorrhage; major surgery; and acute alcoholic hepatitis. Sometimes acutehepatic injury, superimposed on cirrhosis, may lead to liver failure andHRS. The hepatic injury can occur from acute viral hepatitis; drug-inducedliver injury (acetaminophen; idiopathic drug-induced hepatitis); hepatic

Box 2. Major diagnostic criteria for hepatorenal syndromea

1. Chronic or acute liver disease with advanced hepatic failureand portal hypertension

2. Serum creatinine >1.5 mg/dL, reflecting decreased glomerularinfiltration rate

3. Absence of shock, bacterial infection, and current or recenttreatment with nephrotoxic drugs; absence of gastrointestinalor renal fluid losses

4. No sustained improvement in renal function (decrease inserum creatinine to •1.5 mg/dL) after diuretic withdrawal andplasma volume expansion with intravenous albumin (1 g/kgbody weight up to a maximum of 100 g)b

5. Proteinuria < 500 mg/dL and no evidence of parenchymalrenal disease by urinalysis, or of obstructive uropathy byultrasonographyc

a As defined by expert consensus [10–12].b Albumin favored over isotonic saline for plasma volume expansion [12,95].c This criterion does not apply to patients with liver disease who also have

intrinsic renal disease and develop HRS. No studies have been performed tocharacterize HRS in the presence of renal disease.

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ischemia; flare of chronic hepatitis B virus infection caused by an emergentresistant viral strain or withdrawal of antiviral therapy; or superimposedacute delta virus hepatitis. Early identification of a precipitating event isclinically important because it is frequently preventable or treatable withspecific medical therapy.


In type 2 HRS, the serum creatinine increases slowly and gradually dur-ing several weeks or months with a reciprocal gradual reduction in glomer-ular infiltration rate (GFR). This generally occurs without a precipitatingfactor. The median survival of type 2 HRS is about 6 months, significantlylonger than for type 1 [15]. Nonetheless, type 2 HRS still has an extremelypoor prognosis. Unless liver transplantation is performed, or a dramaticresponse to therapy of the underlying liver disease occurs (such as HBV-related cirrhosis responding to antiviral therapy), many patients with type2 HRS eventually progress to type 1 HRS because of a precipitating factor.

The clinician should distinguish between type 1 and type 2 HRS. Theformer is associated with a rapidly fatal prognosis. Type 1 HRS must beurgently managed, with elimination of precipitating factors and evaluationfor liver transplantation. In contrast, type 2 HRS permits less franticevaluation and therapy [15]. Both types are part of a spectrum of renal dys-function in the setting of severe liver disease. Patients may progress fromtype 2 to type 1 HRS without an obvious precipitating factor other thanworsening liver failure. The mechanisms of this progression are unknown.

Type 3 hepatorenal syndrome: coexistent kidney diseaseand hepatorenal syndrome

Patients with advanced liver disease frequently have coexistent intrinsicrenal dysfunction. A recent study found that 85% of end-stage cirrhoticshad intrinsic renal disease on renal biopsy [16,17]. Patients with pre-existingrenal disease do not meet the traditional diagnostic criteria for HRS [10–12].They have not been included in therapeutic clinical trials. Because they canalso develop HRS from circulatory derangements found in liver failure,patients with pre-existing kidney disease and HRS are best categorized sep-arately (see Box 1). A cirrhotic patient with long-standing diabetic nephrop-athy, obstructive renal disease, or chronic glomerulonephritis can developHRS from a precipitating event or worsening liver failure. Similarly, a pa-tient may develop HRS simultaneous with acute tubular necrosis (ATN) be-cause of the same precipitating factor, such as severe variceal hemorrhage.Given the absence of diagnostic markers for HRS, the evaluation of a cir-rhotic patient with multiple causes of renal failure is complex. It is unclearwhether a chronically reduced baseline GFR, from chronic intrinsic renaldisease, predisposes cirrhotic patients to develop HRS. Patients presentingwith multiple causes for renal failure should be carefully evaluated by


a hepatologist and a nephrologist. In selected cases renal histology may benecessary for the diagnosis and for selection of patients for liver transplantalone versus combined liver-kidney transplant (see later).

Type 4 hepatorenal syndrome: acute liver failure

More than half of patients with ALF develop HRS, although the fre-quency varies depending on the ALF etiology [8,9]. HRS complicatingALF is superimposed on the already poor prognosis of ALF, especiallywhen acetaminophen-related. Nonetheless, both organ failures can bereversed by urgent liver transplantation. The pathophysiology of HRS inALF is believed to be similar to that postulated for HRS occurring in cirrho-sis. This contention remains speculative because of a lack of pathophysiologicstudies. The clinical course, prognosis, and complications are very differentfor patients with cirrhosis than for patients with ALF. The mechanism ofHRS may differ in the setting of ALF versus the setting of cirrhosis.

Diagnosis

A rising serum creatinine in a patient with cirrhosis or ALF is sufficientcause to investigate for possible HRS. In patients with advanced cirrhosis,the normal serum creatinine level is typically 0.6 to 0.8 mg/dL because ofmuscle wasting, and a serum creatinine above 1.4 mg/dL reflects a substan-tially decreased GFR [10–12]. Five major criteria must all be present for thediagnosis of HRS [11,12,18]. Minor additional criteria are supportive butnot essential for the diagnosis (Box 3). Because of the lack of diagnosticmarkers or tests, HRS is diagnosed by the clinical method outlined inBox 2. Despite these straightforward diagnostic criteria, recent studiesfound that HRS was misdiagnosed in 60% to 70% of cases at a tertiarycare center [19,20]. Misdiagnosed patients had intrinsic renal disease, activesepsis, drug-induced renal disease, and ATN. Greater adherence to theconsensus guidelines for the diagnosis of HRS is necessary.

First, other causes of renal failure must be investigated in cirrhotics.Relatively common other causes include volume depletion; obstructive

Box 3. Minor diagnostic criteria for hepatorenal syndromea

Urine volume < 500 mL/24 hUrine sodium <10 mEq/LUrine osmolality greater than plasma osmolalityUrine red blood cells < 50 per high power fieldSerum sodium <130 mEq/L

The minor criteria are supportive but not required for the diagnosis.a Defined by expert consensus [10–12].

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uropathy; shock; drug-induced renal failure; and intrinsic renal disease (eg,hepatitis C–related chronic glomerulonephritis, diabetic nephropathy). It iscritical to ensure an adequate intravascular volume by discontinuing di-uretics and expanding the plasma volume. A significant improvement in re-nal function (serum creatinine) after these maneuvers is inconsistent withHRS. Plasma volume expansion was previously accomplished by intrave-nous administration of 1.5 L of normal saline [10], but sodium chloridecan readily escape from the intravascular compartment, particularly in pa-tients with severe hypoalbuminemia (!2–2.5 g/dL), and minimally expandsthe intravascular volume. Intravenous albumin (1 g/kg body weight up to100 g) is now used (with packed erythrocytes if concomitant severe anemiais present) because of greater efficacy in volume expansion and in achievinga sustained reduction in serum creatinine [11]. In one study, 55% of patientswith HRS who failed a trial of volume expansion with isotonic saline hadreversal of HRS following albumin administration alone [21]. Patientswho respond to volume expansion with albumin do not have HRS, but renalfailure from hypovolemia. If renal failure persists after vigorous volume re-placement with colloids, HRS is likely. A history of recent shock or admin-istration of nephrotoxic agents, imaging evidence of urinary obstruction orscarred kidneys, and a urinary sediment consistent with glomerular diseasesuggest etiologies other than HRS. If intrinsic renal disease is identified, thedilemma consists of determining whether the kidney disease is the sole causeof the renal failure, or whether HRS is a contributing factor (type 3 HRS).

Infections (particularly spontaneous bacterial peritonitis, but also sepsis,cellulitis, urinary tract infection, or pneumonia) can cause transient renaldysfunction in cirrhotics that typically resolves with control of the infection.Infections can, however, precipitate type 1 HRS (see later). This scenario issuspected when the renal failure persists or worsens despite resolution of theinfection. Nonoliguric HRS (urine volumes O500 mL per 24 hours) andHRS with urinary sodium excretion greater than 10 mEq/L can occasionallyoccur [22–24].

Pathophysiology


A series of clinical and experimental studies during the last two decadeshas considerably increased the understanding of the pathophysiology ofHRS (Figs. 2, 3) [11,25–27]. Hepatic fibrosis, architectural distortion, andinflammation from hepatic injury result in portal hypertension that is gener-ally progressive. Both chronic liver disease and ALF can cause portal hyper-tension. Portal hypertension leads to arterial vasodilatation and pooling ofblood in the splanchnic bed, with a decrease in systemic vascular resistance.In response, a systemic hyperdynamic circulatory state develops. Eventually,activation of the renin-angiotensin-aldosterone system and the sympathetic

Progression of liver failureand portal hypertension

Increase in arterialvasodilation

Decrease incardiac output

Centralhypovolemia

Impaired cardiacchronotropic function

Reduction in effectivearterial blood volume

severe extrememoderate

Sodiumretention

Water retentionHyponatremia

Hepatorenalsyndrome

Fig. 2. Pathophysiology of the hepatorenal syndrome. (From Arroyo V, Terra C, Gines P. New

treatments of hepatorenal syndrome. Semin Liver Dis 2006;26:254–64; with permission.)


nervous system and stimulation of antidiuretic hormone release becomenecessary to maintain arterial blood pressure. As the liver disease worsens(ie, from chronic active hepatitis C virus infection), these circulatory changesgradually increase until systemic hemodynamic stability depends on vaso-constriction of the extrasplanchnic vascular beds (renal, hepatic, brain,muscle, skin, adrenal glands, and possibly other regional vascular territo-ries). In very advanced liver disease, prolonged high-level activation of therenin-angiotensin-aldosterone system, sympathetic nervous system, andantidiuretic hormone leads to intense, sustained renal vasoconstriction, re-sulting in decreased renal perfusion, decreased GFR, rising serum creatininelevels, and ultimately to HRS (see Fig. 2). Intrarenal imbalance of vasoac-tive mediators, such as prostaglandins, kallicreine, adenosine, leukotrienes,F2-isoprostanes, and endothelin, may play an important role in this severeand sustained renal vasoconstriction [28–31].

Cardiac and adrenal dysfunction may contribute to the circulatory dis-turbances in type 1 HRS (Fig. 3) [11,32]. Unlike compensated cirrhoticswithout renal failure, the cardiac output is normal or even subnormal inpatients with HRS [26,27]. Similarly, tachycardia is less prominent withHRS. Despite intense sympathetic nervous system activation, inotropicand chronotropic cardiac functions are depressed in HRS. A decreasedcardiac preload and a cirrhotic cardiomyopathy may cause the decreasedcardiac performance in patients with HRS. Additional studies are neededto ascertain the reason for this impaired cardiac function.

In a recent report, 80% of patients with HRS precipitated by sepsis hadadrenal dysfunction [33]. Replacement therapy with hydrocortisone in

Spontaneous bacterial peritonitisor other precipitating event

Increase in arterial vasodilationDecrease in cardiac output

Adrenaldysfunction

Regional arterialvasoconstriction

A-II, NE, ADH

resistance toportal venous flow

Aggravation ofportal hypertension

Kidneys

Brain

Liver

HRS

Encephalopathy

Liver failure

Fig. 3. Pathophysiology of the hepatorenal syndrome and multiorgan failure in advanced

cirrhosis. (From Arroyo V, Terra C, Gines P. New treatments of hepatorenal syndrome. Semin

Liver Dis 2006;26:254–64; with permission.)

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cirrhotics with sepsis and adrenal insufficiency improved systemic hemody-namics and in-hospital survival [34]. The arterial response to endogenousvasoconstrictors depends on adequate levels of adrenal corticosteroidhormones. Adrenal dysfunction may be important in the hemodynamicmechanism of type 1 HRS related to sepsis.

The precipitating event for type 1 HRS is believed rapidly to worsen thehemodynamic disturbances that led to acute renal failure. The magnitudeand pace of circulatory derangement induced by this precipitating eventmay exceed a threshold beyond which the hepatic, brain, and adrenal vascu-lar beds join with the renal vasculature in vasoconstriction, which results inmultiorgan failure (see Fig. 3) [11]. Conceptual differences between HRStypes 1 and 2 have clinical implications for the prevention of HRS andthe management of precipitating events.


The hemodynamic and humoral abnormalities described previously fortype 1 HRS also operate in type 2 HRS, but are present to a lesser extent.Type 2 HRS is related to gradually deteriorating liver function that resultsin circulatory dysfunction. In contrast to type 1 HRS, precipitating factorsare generally not present in type 2HRS.Many patients with type 2HRS even-tually progress to type 1HRS, however, often because of a precipitating event.

A better understanding of circulatory abnormalities associated with HRShas led to a combination of therapeutic interventions to correct these abnor-malities (ie, the decreased intravascular effective arterial volume, the renalvasoconstriction, and the peripheral arterial vasodilatation).


Type 3 hepatorenal syndrome: pre-existing kidney diseaseand hepatorenal syndrome

Cirrhotics often have long-standing intrinsic renal disorders, such as di-abetic nephropathy, chronic glomerulonephritis, and nephrolithiasis[16,17]. Such patients were traditionally excluded from HRS [10–12], andthe presence of the renal vasoconstriction of HRS in the presence of intrinsicrenal disease has not been analyzed. Without these data, specific diagnosticcriteria have not been developed for type 3 HRS. Except for the absence ofpre-existing kidney disease, clinicians use the other diagnostic criteria ofHRS to assess whether patients with underlying renal disease have HRS.This approach, however, has not been validated. Patients with cirrhosisand pre-existing renal disease may be at higher risk to develop HRS. Thepathophysiology is likely more complex than pure forms of HRS. Studiesare needed to address this growing and complex group of patients at riskfor HRS (see Box 1).

Type 4 hepatorenal syndrome: acute liver failure

ALF patients rarely develop refractory ascites or severe portal hyperten-sion, with a hyperdynamic circulatory state. Acute renal failure in ALFmay share certain pathways with HRS of cirrhosis, but little is knownconcerning the events and mechanisms leading to HRS in the setting ofALF.

Therapy

General management

Patients with types 1 and 4 HRS require monitoring in an intensive careunit. Patients with type 2 and 3 HRS may alternate between intensive care,monitored bed, or standard hospital care. Diuretics are discontinued whenHRS is suspected. The status of the intravascular volume is assessed, andthis volume is restored as needed. It may be difficult to assess the intravas-cular volume status in the presence of ascites and edema. Determination ofthe central venous pressure, and a trial of volume expansion with intrave-nous albumin may be helpful. If acidosis, hyperkalemia, uremic symptoms,or volume overload occurs, continuous hemofiltration or hemodialysis maybe helpful. Discontinuation of nephrotoxic agents is essential, includingnonsteroidal anti-inflammatory agents and aminoglycosides. Angiotensin-converting enzyme inhibitors, nitrates, and other vasodilators should bewithheld during HRS. In a prospective study, administration of radiologiccontrast media to cirrhotics did not precipitate renal failure [35].

Type 1 HRS should be diagnosed early, with vigorous treatment ofthe precipitating event, and management of any multiorgan failure.Because septic processes (spontaneous bacterial peritonitis, urosepsis, and

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gastrointestinal or biliary infections) are the most common precipitatingevents, early systemic antibiotic therapy is critical in patients at high riskfor, or with established, HRS [36,37]. In type 1 HRS, adrenal function shouldbe tested with cosyntropin or another synthetic adrenocorticotropic hor-mone. If adrenal insufficiency is detected, administration of stress doses of in-travenous hydrocortisone improves survival [33,34]. Likewise, control ofesophagogastric variceal hemorrhage in a patient with type 1 HRS enhancesthe probability of reversal or bridging to liver transplantation. If a patientwith type 1 HRS has severe or tense ascites, large-volume paracentesis withalbumin replacement is performed as needed. It is unclear how much massiveascites impairs renal vein outflow and hinders recovery from HRS.

Specific therapy for the underlying liver disease is promptly initiated, asappropriate, such as antiviral therapy for HBsAg-positive cirrhosis (at dosesadjusted for renal failure); alcohol abstinence and nutritional support foracute alcoholic hepatitis; and antidotes for toxic causes of ALF.

Patients with type 2 HRS often survive for several months. During thistime patients should receive prophylaxis for spontaneous bacterial peri-tonitis (SBP) and avoid precipitating events that can lead to type 1 HRS,including volume depletion. This is particularly true during large-volumeparacentesis, because patients with type 2 HRS often have recurrent severeascites. Administration of intravenous albumin during large-volume para-centesis (approximately 10 g/L of ascites removed) is important to maintainthe intravascular volume and minimize circulatory disturbances after para-centesis. Primary or secondary prophylaxis of variceal hemorrhage with var-iceal band ligation is important [38]. Many cirrhotics take nonselective betareceptor antagonists as prophylaxis against bleeding from esophagogastricvarices [38]. The effects of adrenergic beta receptor antagonists in HRSare unstudied. Beta receptor antagonism in a patient with HRS may beundesirable because of a decrease in cardiac output, but may be desirablebecause of an antirenin effect of these agents. Duhamel and colleagues[39] suspected that propranolol therapy may have precipitated HRS in3 of 12 analyzed patients. Responders to beta receptor antagonists hada lower risk of developing HRS in one study [40]. In an informal survey,most experts believed that beta receptor antagonists should be discontinuedduring HRS, but all considered that this issue should be investigated(P. Gines, V. Arroyo, F. Wong, F. Salerno, A. Gerbes, personal communi-cations, 2007). Avoidance of hepatotoxic and nephrotoxic therapeuticagents, such as aminoglycoside antibiotics and nonsteroidal anti-inflamma-tory agents, is also essential during the course of type 2 HRS. Vasodilators,such as angiotensin-converting enzyme inhibitors, prazosin, and nitrates,should be discontinued.

No data on the optimal care of patients with type 3 HRS are available.The medical support for patients with type 4 HRS is similar to that forpatients with type 1 HRS, but there are no studies specifically addressingthe treatment of type 4 HRS.


Patients with types 1, 2, or 4 HRS should undergo prompt evaluation forliver transplantation. If a patient is on an active liver transplant waiting list,development of HRS prompts a high priority status. Patients with type 3HRS should be evaluated for combined liver-kidney transplantation (seelater). Specific treatments described next may be additionally consideredin these desperately ill patients, with the understanding that knowledgeabout these therapies and their limitations is incomplete.

Specific treatments

Medical therapies that target the circulatory abnormalities of HRS havebeen developed during the last decade [11,12,22,23,41–47]. Although theresults are generally promising, the total number of patients analyzed inprospective trials is small. Furthermore, some studies may have includedpatients without HRS or with potentially reversible renal failure. Becauseof these trial shortcomings, these treatments may have limitations andunappreciated toxicity. Despite these problems, the new therapies seem rea-sonably safe and possibly effective in sometimes reversing HRS [48]. Con-ventional renal replacement therapy (RRT) does not improve theprognosis of HRS, but can help manage specific complications of HRS, in-cluding fluid overload in anuric patients, acidosis, uremic symptoms, or se-vere hyperkalemia. Adjuvant therapy of these complications with RRT isappropriate in liver transplant candidates, or in patients with severe acutealcoholic hepatitis and HRS. RRT is unjustified, however, for HRS with ter-minal liver failure. RRT may be useful in patients with chronic renal diseasewho develop superimposed HRS (see Box 1), but these patients have beeninadequately studied.

Renal vasodilator therapy with low-dose intravenous dopamine infusionor the prostaglandin E1 analogue misoprostol did not prove efficacious andare rarely used for HRS [49,50]. Experimental therapy with N-acetylcysteineseems logical, but has not been evaluated in large studies [51,52]. Adminis-tration of the nonselective endothelin antagonist tezosentan was associatedwith further deterioration of renal function in patients with type 2 HRS [53].As knowledge increases on the mechanisms of renal vasoconstriction, renalvasodilator therapy may be re-evaluated for HRS in the future.

Specific therapies for type 1 hepatorenal syndrome

Vasoconstrictors plus plasma volume expansion
Use of vasoconstrictors in HRS is intended to increase renal perfusion
caused by vasoconstriction of the splanchnic vascular bed. Intravenousalbumin is simultaneously infused to support the effective plasma volume.These simultaneous interventions presumably reduce renal vasoconstrictionand improve renal perfusion (Table 1). Vasoconstrictor therapy for HRS isinappropriate in the setting of terminal liver failure, intractable hepatocellu-lar carcinoma, or when otherwise contraindicated (Box 4).

Table 1

Effect of noradrenaline and albumin versus terlipressin and albumin in hepatorenal syndrome

Noradrenaline and albumin

(N ¼ 10)

Terlipressin and albumin

(N ¼ 12)

Baseline End of therapy Baseline End of therapy

Serum creatinine (mg/dL) 2.3 � 0.2 1.3 � 0.1a 2.5 � 0.3 1.3 � 0.2a

Mean arterial

pressure (mm Hg)

71 � 2 84 � 2a 74 � 3 84 � 3a

Central venous

pressure (mm H2O)

11 � 1 12 � 1 12 � 1 13 � 3

Urine volume (mL/d) 788 � 84 1583 � 243a 698 � 113 1578 � 314a

MELD score 26 � 1 24 � 2 26 � 2 20 � 2a

Plasma renin (ng/mL/h) 15 � 3 9 � 3 21 � 5 7 � 3a

Abbreviation: MELD, Model for End Stage Liver Disease.a P!.05 with respect to baseline.

Data from Alessandria C, Ottobrelli A, Debernardi-Venon W, et al. Noradrenaline vs terli-

pressin in patients with hepatorenal syndrome: a prospective randomized unblinded pilot study.

J Hepatol 2007;47:499–505.

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About 12 pilot studies conducted during the last decade have suggestedthat vasopressor therapy plus intravenous albumin improves the prognosisof HRS. The total number of studied patients is less than 250, however,and the results may be subject to sampling bias because of inconsistent studyinclusion criteria [54,55]. Nevertheless, prudent use of this combined therapyseems justified in type 1 HRS given the consistently reported benefits in thecontext of the otherwise rapidly fatal outcome of type 1 HRS. In some re-ports, responders to vasoconstrictor plus albumin therapy had improvedsurvival, and a significant proportion of patients were successfully bridgedto liver transplantation [56–60]. Patients with type 1 HRS typically have

Box 4. Contraindications to vasoconstrictor therapyin hepatorenal syndrome

Coronary artery diseaseCardiomyopathiesCardiac arrhytmiasCardiac or respiratory failureArterial hypertensionCerebrovascular diseasePeripheral vascular diseaseBronchospasm, asthmaTerminal liver diseaseAdvanced hepatocellular carcinomaAge >70 years


actual or impending multiorgan failure. Use of vasoconstrictors and plasmavolume expansion should be closely monitored, with continuous monitoringof central venous and arterial blood pressures.

The effect of these therapies on the probability of liver transplantation iscontroversial. In countries where organ allocation is determined by theMELD score, such as the United States, the significant improvement inMELD score, induced by vasoconstrictor therapy, can reduce the chancesof receiving a liver transplantation, particularly for type 1 HRS patients.Whether improvement of HRS induced by vasopressor therapy is betterthan liver transplantation is debatable. HRS often recurs after discontinua-tion of vasoconstrictor therapy and then has a high mortality. Thesepatients should be maintained at a high level on the waiting list, despite theirreduced MELD score secondary to vasoconstrictor therapy, by an exceptionrequest to the regional review boards.

Therapies with a vasoconstrictor plus albumin are very promising fortype 1 HRS, an entity with nearly universal mortality without urgent livertransplantation, but the risks of noradrenaline infusions require furtherstudy.

Terlipressin plus albumin
Terlipressin is the most studied vasopressor agent, given its efficacy and
better safety profile [56,58–68]. This synthetic vasopressin derivative is be-lieved to have a much greater effect on vascular receptors (V1) than renalvasopressin receptors (V2) [48]. A recent meta-analysis of 10 clinical trialsof terlipressin reported that this therapy was well tolerated and reversedHRS in 52% of cases [48]. About 29% of treated patients experiencedside effects, including abdominal pain, self-limited cardiac arrythmias, cuta-neous necrosis, finger ischemia, bronchospasm, and diarrhea. Most sideeffects did not mandate treatment discontinuation and responded to lower-ing the dosage [48]. Terlipressin therapy is associated with improved serumcreatinine, urinary output, urinary sodium excretion, and plasma renin andaldosterone levels (see Table 1) [56]. The terlipressin dose schedules used inthe prospective randomized studies are shown in Box 5. A randomized,prospective, placebo-controlled clinical trial completed in the United Statesused terlipressin at doses of 1 mg intravenously every 6 hours until the se-rum creatinine level decreased to less than 1.5 mg/dL on two measurements48 hours apart, or for up to 14 days [60,61]. If after 3 days the serum creat-inine did not decline by at least 30% from baseline, the dose of terlipressinwas increased to 2 mg every 6 hours. In this clinical trial, terlipressin was sig-nificantly more effective than placebo in reversing type 1 HRS with a similarsafety profile [60,61]. A later report from the same group demonstrated thatearlier therapy with terlipressin increases the probability of HRS reversal,whereas patients with a baseline serum creatinine greater than 5.6 mg/dLhad no reversal of HRS in this study [61]. The minimum duration for success-ful therapy is 3 to 5 days [56,61].

Box 5. Typical treatment protocol of noradrenalineor terlipressin for hepatorenal syndrome

NoradrenalineInitial dose: 0.1 mg/kg/min intravenous infusionIf no increase in mean arterial pressure by 10 mm Hg:

increase dose by 0.05 mg/kg/min every 4 h up toa maximum dose of 0.7 mg/kg/min

Or

TerlipressinInitial dose: 1 mg intravenous bolus every 4 hAt day 3: if baseline serum creatinine not reduced ‚25%

increase terlipressin dose up to 2 mg every 4 h

AlbuminWith either noradrenaline or terlipressin, administer IV

albumin as needed to maintain central venous pressureof 10–15 cm H2O

Treatment duration: until reversal of HRS or a maximum of 2 weeks.Therapy can be repeated if HRS recurs.Diuretics: not used during vasoconstrictor plus albumin therapy in this

protocol [56], but others use furosemide in combination with albumin to keepcentral venous pressure within desirable range [23].

Data from Alessandria C, Ottobrelli A, Debernardi-Venon W, et al. Noradrenalinevs terlipressin in patients with hepatorenal syndrome: a prospective randomizedunblinded pilot study. J Hepatol 2007;47:499–505.

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For patients whose HRS reversed with terlipressin and albumin, theprognosis after liver transplantation is excellent and similar to that of trans-planted patients without HRS [57]. The rate of postoperative hemodialysis,severe infections, bleeding complications, recurrence of renal failure, andsurvival and the mean hospital length of stay are similar to recipients trans-planted without HRS [57]. Limitations of terlipressin therapy include a fail-ure to reverse HRS in 40% to 45% of patients, high cost, and a high rate ofHRS recurrence after treatment discontinuation. Terlipressin cannot beused in patients with vascular disorders (see Box 4). It is presently unavail-able in the United States. Where available, terlipressin plus albumin therapyseems relatively safe, well tolerated, and able to reverse the renal failure inabout half of treated patients. Additional studies are necessary to optimizethis therapy [54,55].

Noradrenaline plus albumin
Intravenous noradrenaline plus albumin has been evaluated as a therapy
for HRS in countries where terlipressin is unavailable. Alessandria and


colleagues [56] recently reported a prospective randomized comparison ofnoradrenaline versus terlipressin for HRS, according to the protocol out-lined in Box 5. Both study groups received volume expansion with albumin.Therapy with noradrenaline led to a complete response in 75% of type 1HRS patients, similar to the 80% response achieved with terlipressin.Eighty-three percent of the patients responding to noradrenaline were suc-cessfully bridged to liver transplantation, with improved survival (Fig. 4).No significant ischemic complications occurred in either group. HRS re-curred after discontinuation of therapy, however, in 33% to 50% of patients[56]. The costs of terlipressin therapy are about 15-fold greater than thecosts of noradrenaline therapy [56]. This study confirms previous observa-tions and suggests that noradrenaline plus albumin may be a useful alterna-tive to terlipressin. Patients included in this clinical trial, however, had early,moderately severe HRS (mean baseline serum creatinine, 2.4 mg/dL). Halfof the patients had baseline serum creatinine levels less than 2 mg/dL, andsubstantial urinary output (see Table 1). Whether these favorable resultsapply to patients with severe or advanced HRS (creatinine O4 mg/dL, orsevere hepatic decompensation with bilirubin O10 mg/dL, and INR O3)is unknown.

Fig. 4. Response of hepatorenal syndrome to vasoconstrictor plus albumin therapy results in

improved probability of survival. Solid line, responders; broken line, nonresponders. (From

Alessandria C, Ottobrelli A, Debernardi-Venon W, et al. Noradrenaline vs terlipressin in

patients with hepatorenal syndrome: a prospective randomized unblinded pilot study. J Hepatol

2007;47:499–505; with permission.)

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Midodrine and octreotide
An oral a-adrenergic agonist (midodrine) in combination with octreotide
has been shown in three clinical trials, using variable dose regimens, toimprove type 1 HRS with results comparable with those reported forterlipressin [22,50,69,70]. Midodrine is a direct vasoconstrictor, whereasoctreotide inhibits endogenous vasodilators. In two of the studies the intra-vascular volume was supported with albumin [22,50]. In a recent report of81 patients treated with midodrine-octreotide (without concurrent albumin),40% of patients responded with sustained reduction in serum creatinine, andthe 30-day survival was 57%, significantly superior to the 30% survival ofcontrols [69]. The combination of oral midodrine and subcutaneous oct-reotide is appealing because of its suitability for outpatient use. The protocolof midodrine-octreotide in the most recent study is summarized in Box 6[69].

Transjugular intrahepatic portosystemic shunt
Transjugular intrahepatic portosystemic shunt (TIPS) is a theoretically
attractive therapy because it dramatically lowers both the portal pressureand the pooling of blood in the splanchnic vascular bed, key pathogeneticfactors in HRS. The increased venous return produced by TIPS may be in-appropriately handled, however, and even aggravate the cardiac dysfunctionobserved in HRS. Furthermore, patients with HRS often have contraindica-tions for TIPS, such as hepatic encephalopathy, severe jaundice, or veryadvanced liver disease. TIPS in these circumstances may lead to liver failure

Box 6. Typical protocol of midodrine plus octreotide for therapyof type 1 hepatorenal syndrome

OctreotideInitial dose: 100 mg tid subcutaneous

Goal to increase dose up to 200 mg tid

MidodrineInitial doses: 5 mg, 7.5 mg, or 10 mg tid orally

Goal to increase dose up to 12.5 mg or 15 mg tid if necessary

Doses of both agents are increased to induce a 15 mm Hg increase in meanarterial pressure.

During diagnostic phase of HRS: volume expansion with 1.5 L normal salineplus 120 g albumin. Discontinue albumin once HRS is established, and startmidodrine plus octreotide.

Data from Estrailian E, Pantangco ER, Kyulo NL, et al. Octreotide/midodrinetherapy significantly improves renal function and 30-day survival in patientswith type 1 hepatorenal syndrome. Dig Dis Sci 2007;52:742–8.


or intractable hepatic encephalopathy. Three studies have evaluated theefficacy of TIPS in type 1 HRS in a combined total of only 35 patients[22,71,72]. Improved serum creatinine and reversal of HRS was observedin some patients who later became long-term survivors. The hazards and ir-reversible nature of TIPS have prevented broad application of this modalityfor type 1 HRS. Many patients with type 1 HRS do not meet the criteria forTIPS insertion (ie, serum bilirubin !5 mg/dL, INR !2, and Childs-Pughscore !12). Further studies are needed to determine if and when TIPS ishelpful for HRS. TIPS is currently considered an experimental therapyfor HRS, that can be considered in a Childs-Pugh class A or B patient,who meets the criteria for TIPS insertion, and who fails to respond to vaso-constrictor therapy and plasma volume expansion.

Specific therapy for type 2 hepatorenal syndrome

Type 2 HRS is more commonly seen in clinical practice than type 1 HRS.All patients with type 2 HRS should be evaluated for liver transplantation.Transplantation can potentially permanently reverse HRS and other com-plications of chronic liver failure. Severe ascites and hyponatremia are oftenassociated with type 2 HRS. Treatment expectations include HRS reversaland survival improvement, and control of ascites and hyponatremia. Theavailable therapies for type 2 HRS are summarized in Box 7.

Vasoconstrictor therapy in type 2 hepatorenal syndrome
In four small pilot studies of therapy with terlipressin and albumin
[47,63,65] and one prospective controlled trial of therapy with noradrenalineplus albumin [56], the combined reversal rate of type 2 HRS was about 80%.HRS, however, frequently recurred after discontinuation of therapy.Further studies are needed on vasoconstrictor therapy and plasma volumeexpansion for type 2 HRS to determine the optimal vasoconstrictor andthe optimal dosing schedules. Currently, intravenous vasoconstrictor ther-apy can be cautiously considered in selected patients with type 2 HRS. Aliver transplant is substantially more beneficial if HRS is reversed by vaso-constrictor and albumin therapy before transplantation [57]. The effect oforal midodrine plus subcutaneous octreotide in type 2 HRS has not beenstudied. This combination is appealing because a significant proportion oftype 2 HRS patients are ambulatory.

Box 7. Available treatments for type 2 hepatorenal syndrome

Terlipressin plus albuminNoradrenaline plus albuminLiver transplantationTransjugular intrahepatic portosystemic shunt

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Transjugular intrahepatic portosystemic shunt for type 2 hepatorenalsyndrome

Several studies on the use of TIPS in type 2 HRS noted improvement inascites control, serum creatinine level, and GFR, but no firm conclusionscan be made on reversal rate, effect on survival, or bridging to transplanta-tion [47,71,73–75]. Given the potential hazards of TIPS in patients with veryadvanced liver disease, it should be cautiously applied as therapy for type 2HRS. Refractory ascites often precedes development of type 2 HRS. A re-cent meta-analysis concluded that refractory ascites treated with TIPS wasassociated with better survival and less portal hypertensive complications,including HRS, than large-volume paracentesis [76].

Specific therapies for type 3 and type 4 hepatorenal syndrome

No specific therapies have been investigated for these types of HRS be-cause of their exclusion from the traditional HRS classifications and thelow frequency of ALF. Controlled therapeutic trials with vasoconstrictorsand albumin are needed. Terlipressin has been evaluated in patients withALF to treat arterial hypotension, but the effects on HRS were not reported[77,78]. One report found that terlipressin caused a slight increase in intra-cranial pressure in ALF [77], but a more recent study found that terlipressinincreased cerebral perfusion without increasing intracranial pressure [78].Patients with ALF and HRS may require dialysis. Continuous venovenoushemofiltration is preferred over intermittent hemodialysis because ofenhanced hemodynamic and intracranial pressure stability [79].

Artificial liver support

Liver-assist technology may help in HRS by eliminating circulatingmediators of splanchnic vasodilatation and renal vasoconstriction. Severalsystems have been tested in pilot studies of patients with acute or chronic liverfailure, with and without HRS [80–83]. Hemodynamic benefit and improve-ment of hepatic encephalopathy have been observed and lowered serumcreatinine. The latter effect is predictable in systems that include standard di-alysis or continuous venovenous hemofiltration [81,82]. ALF patients treatedwith a porcine hepatocyte-based bioartificial liver developed renal failure athalf the rate of controls [80]. No details were provided, however, regardingthe specific types of renal failure observed in this prospective randomized,controlled study. Recently, selective plasma hemofiltration liver-assist de-vices have been used in HRS with acute-on-chronic end-stage liver disease[83,84]. Currently, liver-assistance therapies cannot be advocated for HRS.

Liver transplantation

Because a failing liver and portal hypertension are the key initial events inthe development of HRS, liver transplantation is the ultimate treatment of


choice for either type of HRS. Indeed, many reports have demonstrated res-olution of HRS and long-term survival following liver transplantation.Patients with HRS undergoing liver transplantation, however, have a slightlyincreased perioperative morbidity and mortality compared with trans-planted patients without HRS [85–88]. Nevertheless, HRS is not a contrain-dication to liver transplantation. Allocation of liver donors is now primarilyguided by the MELD score, an index of disease severity and indicator ofshort-term prognosis [4–6]. Serum creatinine is the highest weighted factorin calculating the MELD score. Patients with HRS, particularly type 1, fre-quently achieve the highest priority for donor organ allocation. Despitetheir generally high priority, patients with HRS often are not transplanted.The precipitating event, such as SBP or sepsis, may prevent transplant sur-gery [36,37]. Additionally, type 1 HRS patients are often extremely ill, withmultiorgan failure, in whom the risks of transplant surgery may be prohib-itive. In regions with a severe shortage of liver donors, the progression oftype 1 HRS within several weeks may provide insufficient time to receivea donor liver. In contrast, liver transplantation may be more practical andsuccessful in type 2 HRS, because of an absence of precipitating events,its longer clinical course, and the relatively less severe renal failure. Patientswith any type of HRS have a very poor short-term prognosis without livertransplantation [15]. They should have the highest priority for liver alloca-tion, even if this requires requesting an exception to upgrade the MELDscore.

With MELD scores governing liver allocation, more patients with simul-taneous liver and renal failure are achieving a high priority for transplanta-tion. An important dilemma is whether to transplant both the liver and thekidney in these extremely ill patients. Some patients have HRS, whereasothers have coexisting intrinsic renal disease (type 3 HRS; see Box 1). Thesemixed clinical syndromes include chronic renal failure plus HRS, and non-HRS acute renal failure (ATN) plus simultaneous HRS. Determining thediagnostic category in a specific patient is complex and requires urgent con-sultation by a team consisting of a hepatologist, nephrologist, and livertransplant surgeon because of the poor short-term prognosis of HRS.This determination should be done as expeditiously and as precisely as pos-sible given the time constraints. Liver transplantation without renal trans-plantation is the best choice for patients with pure forms of HRS, andperhaps in those with HRS and ATN, given the prospects of recoverywith postoperative RRT. Two recent reports found a possible benefit ofcombined liver-kidney transplantation in HRS patients selected on the basisof requirement for RRT for longer than 8 weeks [89,90]. Simultaneous liver-kidney transplantation may be the preferred approach for HRS in a patientwith chronic renal failure or with ATN superimposed on chronic renalfailure. Unfortunately, little data are available on these combined clinicalscenarios. Several large studies have reported the outcomes of patientswith elevated serum creatinine undergoing liver transplantation, but these

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studies did not report the proportion of patients with HRS, chronic renalfailure, ATN, or combinations thereof [91]. Cohorts with elevated serumcreatinine include different types of renal dysfunction [89].

The success of vasoconstrictor therapy for HRS in liver transplant candi-dates is important. Reversal of HRS before liver transplantation lowers thepostoperative risks of severe infections, bleeding complications, need forhemodialysis, and recurrence of renal failure, while improving survivaland shortening postoperative hospital length of stay [57].

After liver transplantation, patients with HRS slowly recover renal func-tion. The persistent postoperative renal impairment frequently requiresdecreasing the dosage of calcineurin inhibitors (cyclosporine A, tacrolimus),or renal-sparing immunosuppressive protocols.

Prevention of hepatorenal syndrome

Sepsis, variceal hemorrhage, shock, severe acute alcoholic hepatitis, oruse of nephrotoxic drugs often precipitate type 1 HRS. The risk of HRSmay be lowered by following standard guidelines to prevent these events,particularly SBP or variceal bleeding [18,38]. Infections other than SBPshould be promptly identified and vigorously treated to minimize the riskof HRS. Debilitated patients with advanced cirrhosis often have chronicleukopenia and may not develop leukocytosis or fever, even with severeinfections. A high index of suspicion is necessary to identify infections earlyin decompensated cirrhotics.

Prevention of type 1 HRS has been demonstrated in three prospectiverandomized clinical trials [3,92,93]. In the most recent trial, administrationof norfloxacin for primary prophylaxis for SBP reduced the 1-year probabil-ity of HRS to 28%, compared with 41% in controls not administered anti-biotic prophylaxis (Fig. 5) [3]. This study strongly suggested that HRS canbe prevented in patients with advanced cirrhosis and ascites with a lowprotein content (!1.5 g/dL). In another study, the administration of albu-min (1 g/kg intravenously) at diagnosis and at day 3 in patients with SBPsignificantly reduced the incidence of type 1 HRS and the 3-month mortality[92]. Administration of pentoxifylline, 400 mg three times a day, to patientswith severe acute alcoholic hepatitis was associated with a marked reductionin HRS incidence and in-hospital mortality [93]. A recent prospective con-trolled trial, however, failed to confirm these benefits [94]. Prevention ofHRS by use of antibiotic prophylaxis for SBP [3], or of albumin for SBP[92], in patients with liver failure or acute alcoholic hepatitis [94] has notyet been confirmed by subsequent large studies. The magnitude of theseeffects in the context of the otherwise poor prognosis of HRS, however,has led to broad acceptance of these prophylactic measures.

Specific preventive measures for type 2 HRS have not been identified. Pa-tients developing this variant of HRS do not usually have precipitatingevents. Because type 2 HRS is often associated with tense refractory ascites

Fig. 5. Primary prophylaxis of hepatorenal syndrome with norfloxacin. (From Fernandez J,

Navasa M, Planas R, et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hep-

atorenal syndrome and improves survival in cirrhosis. Gastroenterology 2007;133:818–24; with

permission.)


or severe hyponatremia, optimal management of refractory ascites or severehyponatremia could reduce the risk of developing type 2 HRS [7,76].Further research is necessary to determine how to prevent type 2 HRS inpatients with advanced cirrhosis.

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