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87rrhea, or gastrointestinal bleeding. Daily medications includedronolactone, 100 mg, and furosemide, 40 mg. On physicalmination, the patient showed marked jaundice, lethargy, flap-g tremor, large ascites without abdominal tenderness, and pedalma. Blood pressure was 100/60 mm Hg and heart rate was 90ts/min. Laboratory data at admission showed decreased kidneyliver function, with serum creatinine level of 3 mg/dL (265

ol/L; eGFR, 28 mL/min/1.73 m2 [0.47 mL/s/1.73 m2]), serumium level of 127 mEq/L (127 mmol/L), serum bilirubin level of

plasma norepinephrine concentration of 652 pg/mL (3.85 nmol/L;reference range, 200-214 pg/mL [1.18-1.26 nmol/L]), findingsconsistent with reduced effective arterial blood volume. Despiteimprovement of infection with antibiotics, there was a progressivedecrease in kidney function, with serum creatinine level reaching 5mg/dL (442 mol/mL; eGFR, 15 mL/min/1.73 m2 [0.25 mL/s/1.73m2]) at the time of resolution of the infection. Arterial pressure didnot decrease throughout the infection.

A diagnosis was made of type 1 hepatorenal syndrome (HRS)triggered by spontaneous bacterial peritonitis. Treatment withterlipressin (1 mg/4 h IV) and albumin (1 g/kg the first day,followed by 40 g/d) was started. Treatment was not started earlierbecause of the lack of data for the efficacy and safety of terlipressinin patients with type 1 HRS and ongoing infections. The patientwas not treated with renal replacement therapy (RRT) becausethere was no severe volume overload, hyperkalemia, or metabolicacidosis. Administering albumin and terlipressin was associatedwith marked improvement in kidney function, with a decrease inserum creatinine level, increase in arterial pressure (Fig 1), andmarked decreases in plasma renin activity, aldosterone, and norepi-nephrine concentrations (3.8 ng/mL/h, 46 ng/dL [1.28 nmol/L],and 250 pg/mL [1.48 nmol/L], respectively, at the end of treatmentcompared with 11.6 ng/mL/h, 122 ng/dL [3.38 nmol/L], and 652pg/mL [3.85 nmol/L] at baseline), indicating a remarkable improve-

From the Liver Unit, Hospital Clnic and University of Barce-a School of Medicine, Institut dInvestigacions Biomdiquesgust Pi-Sunyer (IDIBAPS), Ciber de Enfermedades Hepticas ygestivas (CIBERHED), Insituto Reina Sofia de Investigacinfrolgica (IRSIN), Barcelona, Catalunya, Spain.Received July 29, 2011. Accepted in revised form December 7,11. Originally published online April 6, 2012.Address correspondence to Pere Gins, MD, PhD, University ofrcelona, Hospital Clinic, Villarroel 170, Barcelona 08036,ain. E-mail: pgines@clinic.ub.es 2012 by the National Kidney Foundation, Inc.0272-6386/$36.00doi:10.1053/j.ajkd.2011.12.032Hepatorenal Syndrome: A SevKidney Failure

Cludia Fagundes, MD, an

Hepatorenal syndrome (HRS) is a unique type ofcharacterized by functional impairment of the kidneys dof preserved tubular function and absence of significaHRS is due to severe vasodilation of the splanchnic ardecrease in effective arterial blood volume and arteriusually a bacterial infection, that disrupts the arterial circ2 forms of HRS: type 1 is characterized by an acute psurvival without treatment, whereas type 2 featurescompared with type 1. A liver transplant is the preferrvasoconstrictors to reverse splanchnic vasodilation, togwith type 1 HRS and improves survival. The drug of creplacement therapy should not be used as first-line theAm J Kidney Dis. 59(6):874-885. 2012 by the Nationa

INDEX WORDS: Cirrhosis; ascites; chronic liver diseas

CASE PRESENTATION

A 45-year-old man with cirrhosis due to hepatitis C virusection was admitted to the liver unit with weakness and increas-jaundice of recent onset. The patient had long-standing cirrho-with previous episodes of ascites and hepatic encephalopathywas listed for liver transplant 3 months before the admission.

was not receiving prophylaxis with quinolones for preventionspontaneous bacterial peritonitis. The most recent laboratoryt results showed serum creatinine level of 1 mg/dL (88 mol/L;responding to estimated glomerular filtration rate [eGFR] of 98/min/1.73 m2 [1.63 mL/s/1.73 m2] using MDRD [Modification

Diet in Renal Disease] Study equation), serum bilirubin level ofmg/dL (82 mol/mL), serum albumin level of 2.8 g/dL (28), and prothrombin time of 42%. There was no evidence of4, but Treatable, Cause ofCirrhosisre Gins, MD, PhD

y failure that occurs in advanced cirrhosis. It isvasoconstriction of the renal arteries in the settingstologic abnormalities. Renal vasoconstriction inassociated with portal hypertension, leading to assure. HRS commonly develops after a trigger,n, but it also may occur spontaneously. There aressive decrease in kidney function and very short

less severe kidney failure and longer survivaleatment for HRS. Pharmacologic treatment withr with albumin, is effective in 40%-50% of patients

is the vasopressin analogue terlipressin. Renal.ney Foundation, Inc.

mg/dL (308 mmol/L), serum albumin level of 2.7 g/dL (27 g/L),prothrombin time of 45%. Urinalysis showed no signs of

ection or intrinsic acute or chronic kidney diseases, with proteinretion of 100 mg per gram of creatinine, sodium excretion of 5q/L (5 mmol/L), urine osmolality of 450 mOsm/Kg, andence of red blood cells or casts. Blood and urine culture resultsre negative. Paracentesis was diagnostic of spontaneous bacte-l peritonitis, with 1,500 leukocytes/L (90% polymorphonu-ar cells) and yielded a culture positive for Escherichia coli.retics were withheld and intravenous (IV) ceftriaxone (2 g

lowed by 1 g/24 h) therapy was started. Albumin was given at ae of 1.5 g/kg the first day and 1 g/kg at day 3 of treatment.od tests taken 48 hours after diuretics were withheld showedsma renin activity of 11.6 ng/mL/h (reference range, 1-1.2mL/h), plasma aldosterone concentration of 122 ng/dL (3.38Am J Kidney Dis. 2012;59(6):874-885

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Hepatorenal Syndroment in circulatory function. HRS did not recur after withdrawal oflipressin therapy, and at the time of liver transplant, his serumatinine level was 1.2 mg/dL (107 mol/L; eGFR, 79 mL/min/3 m2 [1.32 mL/s/1.73 m2]). Evolution after transplant wasemarkable.his case emphasizes the importance of infections, particularlyntaneous bacterial peritonitis, as triggering factors of HRS andusefulness of pharmacologic therapy with terlipressin and

umin in the management of this condition.

INTRODUCTION

Investigations performed in the late 1950s to early70s provided conclusive evidence indicating thatS is a unique form of kidney failure that occurs in

tients with cirrhosis and is due to marked vasocon-iction of the renal circulation.1-3 Since then, it hascome evident that the kidney failure of HRS is ofculatory origin. An extremely dilated splanchnicerial bed triggers a marked disturbance in thestemic circulation, ultimately leading to kidneylure due to vasoconstriction of the kidney arteries.though once considered an irreversible and untreat-le condition (except for liver transplant), studiesrformed within the past decade have shown thatS may be reversible with pharmacologic treat-nt. This review provides an overview of the patho-

nesis, clinical findings, differential diagnosis, andnagement of HRS, with particular emphasis onarmacologic treatment.

DEFINITION AND INCIDENCE

The current definition of HRS proposed by theternational Ascites Club states that HRS is a poten-lly reversible syndrome that occurs in patients withrhosis, ascites and liver failure that is characterized

Figure 1. Serum creatinine concentration and mean arteimpaired kidney function, marked alterations in at

J Kidney Dis. 2012;59(6):874-885rdiovascular function, and over-activity of the sym-thetic nervous system and renin-angiotensin sys-

. Severe renal vasoconstriction leads to a decreaseGFR. HRS may appear spontaneously or can fol-

a precipitating event. This definition was firstoposed in 1999 and subsequently modified in07.4,5 In the former definition, the existence of angoing bacterial infection precluded the diagnosis ofS, whereas in the most recent definition, HRS maydiagnosed in the presence of an infection, except ifre is septic shock.5The definition of acute kidney injury (AKI) pro-sed by the Acute Kidney Injury Network (AKIN)r kidney failure developing in the general popula-n of hospitalized patients has been suggested too apply to kidney failure that occurs in patientsth cirrhosis.6,7 However, this classification has noten validated in patients with cirrhosis. Therefore, items reasonable to keep the term HRS for the uniquerm of kidney failure of functional origin, witheserved tubular function, that occurs in cirrhosisd wait until prospective studies evaluating the use-lness of the AKI definition in cirrhosis are reported.the future, the use of kidney biomarkers theoreti-

lly may help differentiate HRS from AKI. In thisard, 2 recent studies suggest that urine neutrophil

latinase-associated lipocalin (NGAL) levels coulduseful in the differential diagnosis between HRS

d AKI in cirrhosis.8,9There are very few studies of the incidence of HRS.der studies indicated that the incidence of HRS in aneral population of patients with cirrhosis and as-es was high, 40% after 5 years of follow-up.10cent data indicate a much lower incidence of 11%

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Fagundes and Ginstients experiencing an initial episode of ascites; theseividuals have less advanced disease, which may beociated with a lower incidence of HRS relative to theder population of patients with ascites.

PATHOPHYSIOLOGY

The characterization of HRS as being a functionalfect has been established by the absence of signifi-nt morphologic abnormalities in the kidney histol-y,12 normalization of or improvement in kidneynction after liver transplant,13,14 and reversibility of

syndrome by pharmacologic treatment with vaso-nstrictors and albumin.15 A substantial amount ofidence indicates that the main cause of decreasedney function leading to HRS in cirrhosis is impair-nt in circulatory function.16-22 The defect in sys-ic arterial circulation involves reduced systemic

scular resistance caused by primary arterial vasodi-ion of the splanchnic circulation, which in turn isused by portal hypertension.4,16,17,23 The vasodila-n of the splanchnic arterial circulation likely is ault of greater production and activity of vasodila-s, in particular, nitric oxide, endogenous cannabi-ids, and carbon monoxide.4,17,23-25 Experimentald clinical studies of patients with cirrhosis suggestt bacterial translocation from the intestinal lumenmesenteric lymph nodes may be an important factorcirculatory dysfunction in advanced cirrhosis.26,27cterial translocation elicits an inflammatory re-onse, with proinflammatory cytokines produced ineater amounts in the splanchnic area, leading tosodilatation of the splanchnic arterial vessels.28,29cterial translocations key role in circulatory dys-

nction is substantiated by the observation that admin-ering the antibiotic norfloxacin, which selectivelycontaminates the intestinal tract, improves circula-y function and reduces the likelihood of the devel-ment of HRS.30-32The pathophysiology of HRS is summarized in FigIn early stages of cirrhosis, when patients generallyperience no symptoms, the increased resistance tood flow within the liver is moderate and therefore

rtal hypertension is also moderate. Mechanismsding to portal hypertension involve a passive in-ase in intrahepatic resistance due to fibrosis, dys-

nction of liver endothelial cells, and increased por-blood flow due to vasodilation of splanchnic arteriesviewed in33). In this context, there is a smallcrease in systemic vascular resistance as a result oflanchnic arterial vasodilation. The effect of thecrease in systemic resistance in arterial pressure islanced by increased cardiac output, so that arterialessure and effective arterial blood volume are main-ned at normal levels (Fig 1).16,17 In advanced

ges of cirrhosis, the vasodilation of the splanchnic HR

6eries increases due to progressive bacterial translo-tion and enhanced synthesis of vasodilator factors.oangiogenesis in mesenteric arteries and impairedponse to vasoconstrictors also contribute to theuced vascular resistance in the splanchnic circula-n.33 The progressive decrease in arterial resistancethe splanchnic circulation is associated with an

relenting reduction in total systemic vascular resis-ce. This occurs primarily because the splanchnicculation is a major part of the systemic arterialculation, yet other mechanisms, such as the releasevasodilator factors from the splanchnic to the

stemic circulation, also may contribute (reviewed4). In advanced stages, systemic vascular resistanceso greatly reduced that additional increases in

rdiac output cannot make up for it. As a result, thereunderfilling of the arterial circulation due to theparity between intravascular blood volume and the

eatly enlarged intravascular arterial circulation, andition known as effective arterial hypovole-a.16,17,21,35,36 Moreover, evidence indicates thatre is a decrease in cardiac output, probably relatedthe so-called cirrhotic cardiomyopathy, that also

ntributes to arterial underfilling.18,19,37,38 Althoughative adrenal insufficiency has been reported inrhosis, to date, no evidence has been presented toggest that it may contribute to circulatory dysfunc-n in HRS.39 In the scenario of extreme underfillingthe arterial circulation, the body seeks to maintainerial pressure by activating the vasoconstrictor sys-s, including the sympathetic nervous system, renin-

giotensin system, and, in late stages, nonosmoticpersecretion of arginine vasopressin.17 Althoughse systems assist in preserving effective arterialod volume and arterial pressure, they stronglyuence kidney function, particularly retention of

dium and solute-free water. As a consequence,cites and edema develop, as well as hypervolemicponatremia. If the vasoconstriction systems aretivated to a high degree, renal vasoconstrictioncurs, which leads to greatly decreased glomerulartration and the development of HRS4,15-17 (Fig 2).Vasoactive mediators, which act on intrarenal circu-ion, also may contribute to HRS. Increased synthe-of a number of vasoactive factors in the intrarenal

culation, such as thromboxane A2, cysteinyl leuko-enes, F2-isoprostanes, and endothelin 1, has beenscribed, yet their contributions to the pathogenesisHRS are still undefined.16 It is unlikely that endo-lin 1 has a role because treatment with the endothe-antagonist tezosentan does not lead to improve-nt in kidney function in patients with type 2 HRS.40ntrary to classic belief, vascular beds other thanse in renal circulation also are vasoconstricted in

S; for example, in the extremities and cerebral

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Hepatorenal Syndromeculation.41,42 In HRS, cardiopulmonary pressuresain within normal limits and there is no evidence

circulatory overload despite the intense sodium andid retention.18,20,43,44 The likely explanation fors behavior is that the fluid retained within theneys exists from the intravascular compartment,

rticularly in the splanchnic venous circulation, thusrming ascites because of the high hydrostatic pres-re and increased filtration coefficient in the splanch-

capillaries.45 In addition, fluid exits from thepillaries of the legs to form edema.

CLINICAL TYPES OF HRS

HRS may occur in 2 different clinical patterns,cording to the severity and rate of progression ofney failure4,5,46 (Box 1). The main clinical featurestype 1 HRS are those of acute kidney failure with aid increase in serum creatinine level.4,5 If un-

igure 2. Pathogenesis of circulatory abnormalities in (left) comm Gins & Schrier15 with permission of the Massachusetts Medicated, serum creatinine levels usually increase rap- S

J Kidney Dis. 2012;59(6):874-885y to 5 mg/dL (440 mol/L). In approximatelyo-thirds of cases, there is hypervolemic hyponatre-a on account of disruptions to solute-free watercretion.46 Serum potassium levels usually are around

upper normal limit or slightly higher. Potassium-aring diuretics obviously are absolutely contraindi-ted because they may induce severe hyperkalemia.

ated cirrhosis and (right) hepatorenal syndrome. Reproducedciety.

Box 1. Clinical Types of HRSType 1: Rapidly progressive decrease in kidney function,fined as a 100% increase in serum creatinine to a final value

2.5 mg/dL (221 mol/L) in2 weeks. The clinical presenta-n is usually that of acute kidney failure. Average medianrvival is only 2 weeks if not treated.Type 2: Stable or slowly progressive decrease in kidney

nction that does not meet the criteria of type 1. The clinicalcture is that of ascites refractory to diuretic therapy. Averageedian survival is6 months.

Abbreviation: HRS, hepatorenal syndrome.5idltwmiexthespca

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Fagundes and Ginsven that HRS constitutes functional kidney failure,urine features are similar to those of prerenal

otemia, including low urine sodium and fractionalcretion of sodium and high urine osmolality andine to plasma osmolality ratio.4 Ascites and edema

constantly present. Urine volume usually is nottremely reduced and some patients may have nor-l urine volumes.47 A transition from HRS to acuteular necrosis (ATN) in patients with progressiveney failure not responding to treatment has been

ggested, but no studies have been reported to datealuating this possibility.In addition to severe kidney failure, patients withe 1 HRS have signs of severe circulatory dysfunc-n, evidenced by arterial hypotension (mean arterialessure usually is 70 mm Hg) and very low sys-

ic vascular resistance. This arterial hypotensioncurs despite marked activation of the vasoconstric-systems and severe vasoconstriction in extrarenal

scular beds.4,41,42 In some patients, the differentialgnosis between type 1 HRS and severe sepsis isficult and represents a clinical challenge. As dis-ssed later, all patients with cirrhosis presenting withute kidney failure should be checked for signs ofection. Cardiac output may be low in patients withe 1 HRS, either in absolute values or relative to the

crease in total systemic vascular resistence.18-20,38spite this possible decrease in cardiac output, pa-nts with type 1 HRS do not show signs of circula-y overload.18,44,48Finally, in addition to kidney and circulatory fail-e, the great majority of patients with type 1 HRSve features of advanced liver disease, with jaun-e, coagulopathy, low albumin levels, hepatic en-

phalopathy, poor nutritional status, and large ascitesd edema. A significant proportion of patients withe 1 HRS have acute-on-chronic liver failure.49

In sharp contrast to the progressive kidney failuretype 1 HRS, some patients have moderately severeney failure of functional origin that remains stable

r variable periods. This condition is known as type 2S, and patients usually have serum creatinine lev-of 2.0 mg/dL (176.8 mol/L). Patients withe 2 HRS generally have less severe clinical con-

rns than those with type 1 HRS and their mainnical problem is ascites, which usually is resistantdiuretic therapy because of the combined influenceprofound sodium retention, reduced GFR, andrkedly increased levels of aldosterone and norepi-

phrine.4,5,46 During follow-up, some patients withe 2 HRS develop type 1 HRS,50 which may arise

ontaneously or as a result of some complication,ually a bacterial infection. Patients with type 2 HRSve much longer survival expectancy than their

46unterparts with type 1 HRS (Fig 3). It currently is lar

8known whether type 1 and type 2 HRS represent 2ferent entities or a single entity with the samederlying pathophysiology, but different intensity.

PRECIPITATING FACTORS

HRS develops without a discernable trigger inme patients, whereas in others, it occurs directlyer effective arterial blood volume is decreased byother condition.51-55 Bacterial infections and, inrticular, spontaneous bacterial peritonitis, are lead-

triggers of HRS.4,5,51-54 Approximately one-thirdpatients with spontaneous bacterial peritonitis de-lop HRS at the time of infection or immediatelyreafter, in the absence of septic shock.5,52 Of these

tients, about one-third experience reversal of HRSen the infection is resolved.55-58 However, in theainder, the condition is not reversible and they

velop either stable (type 2) or progressive HRSpe 1).55,56,59 Patients who develop type 1 HRS as ault of spontaneous bacterial peritonitis have a dis-l outcome, with almost 100% hospital mortality ift treated appropriately (discussed later).53-55 Infec-ns other than spontaneous bacterial peritonitis alsoy cause HRS, but its frequency and severity usu-y is lower than that of patients with spontaneouscterial peritonitis.56,57,60Other conditions that may act as precipitating fac-s of HRS are gastrointestinal bleeding and large-lume paracentesis (5 L) in the absence of albuminministration. Even so, the development of kidneylure after gastrointestinal bleeding is not very com-n in patients who have cirrhosis (10%) and it isost fully confined to patients with hypovolemic

ock. In most instances, it is associated with isch-ic hepatitis, which implies that the kidney failurest likely is related to ATN and not HRS.47,61

rge-volume paracentesis without albumin may triggerS in 15% or more of cases.62 This risk is one of thein rationales for administering IV albumin when

63

igure 3. Survival of patients with cirrhosis according to typehepatorenal syndrome (HRS). Reproduced from Alessandriaal46 with permission of John Wiley & Sons.ge-volume paracenteses are performed. Diuretic

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Hepatorenal Syndromeatment also has been suggested as a potential triggerHRS, but there are no clear supportive data for this.Several factors have been suggested to be linked toincreased risk of HRS, including severe sodium

ention, hypervolemic hyponatremia, low mean arte-l blood pressure (80 mm Hg), and low cardiactput. Of note, there is no demonstrated correlationth either the extent of liver failure, gauged byical assessments of liver function (serum bilirubin,umin, and prothrombin time) or Child-Pugh classi-ation.10,18,19,64

DIAGNOSIS

Currently, the diagnosis of HRS rests on severalteria (Box 2).5 The minimum serum creatinineel required to diagnose HRS is 1.5 mg/dL (133ol/L), which corresponds to GFR 30 mL/min/3 m2.65 In patients treated with diuretics, serumatinine should be measured again after the diureticrapy is withdrawn because serum creatinine levely decrease after stopping diuretics.Because no specific laboratory tests exist for diag-sing HRS and kidney failure from other causesrug-induced nephrotoxicity, ATN, prerenal failuree to volume depletion, and glomerulonephritis intients with hepatitis B or C, among others) can arisepatients with advanced cirrhosis, the key step ingnosing HRS is to exclude the possibility of kidneylure secondary to these conditions.4,5,15,66 Gastroin-tinal fluid losses as a result of vomiting or diarrheakidney fluid losses arising from diuresis should beught in all patients with cirrhosis who present withney failure. If the kidney failure is secondary to

lume depletion, kidney function will improveickly after volume repletion (ie, with IV salinelution or albumin) and treatment of the underlyinguse. Shock, either septic or hypovolemic, is anotherndition frequently seen in patients with cirrhosis,

Box 2. Diagnostic Criteria of HRSCirrhosis with ascitesSerum creatinine1.5 mg/dL (133 mol/L)No improvement in serum creatinine level (decrease to1.5mg/dL [133 mol/L]) after at least 2 days with diureticwithdrawal and volume expansion with albumin. The recom-mended dose of albumin is a single infusion of 1 g/kg of bodyweight (maximum, 100 g)Absence of shockNo current or recent treatment with nephrotoxic drugsAbsence of parenchymal kidney disease as indicated byproteinuria 500 mg/d, microhematuria (50 red blood cells/high-power field), and/or abnormal renal ultrasonographyAbbreviation: HRS, hepatorenal syndrome.dapted from Salerno et al5 with permission of the BMJ

blishing Group Ltd.d this may cause kidney failure through ATN. In wh

J Kidney Dis. 2012;59(6):874-885tients with septic shock, HRS sometimes is mistak-ly diagnosed if indicators of infection (such as cellunt in ascitic fluid) are not carefully consideredcause the low arterial pressure of sepsis may errone-sly be attributed to arterial hypotension of HRS.eatment with nonsteroidal anti-inflammatory drugsfortunately is another relatively common reason forute kidney failure in patients with cirrhosis andcites; this condition manifests in a manner clinicallyntical to HRS.47,57,67,68 Before making a diagnosisHRS, it is vital that clinicians always satisfy them-

lves that treatment with nonsteroidal anti-inflamma-y drugs was not a factor. Patients with cirrhosiso have been treated with aminoglycosides also areincreased risk of developing kidney failure.67 Indition, patients with cirrhosis may reach kidneylure because of glomerulonephritis and patientsth cirrhosis arising from nonalcoholic steatohepati-

have a high incidence of chronic kidney dis-se.69-71 In cases of glomerulonephritis, proteinuriad/or hematuria usually are present and help guidegnosis, which in selected instances may be con-

med by kidney biopsy.47,72

MANAGEMENT OF HRS

neralMeasures

The general management of patients with cirrhosisd HRS depends on the severity of kidney failured associated complications. Patients with type 1S who are waiting for a liver transplant are man-

ed appropriately in an intensive care setting. Consid-ng the high mortality rate of type 1 HRS, decisionsout the management of patients who are not candi-tes for transplant or who have important comorbidnditions should be made on an individual basis. Antral venous catheter is important to keep track ofntral venous pressure in patients who will be treatedth vasoconstrictors and albumin.73 Use of a bladdertheter may be associated with urinary tract infectiond is not necessary except when marked oliguria isesent. There should be vigilant monitoring of thessibility of associated complications, in particularcterial infections and gastrointestinal bleeding, andy that arise should be treated as quickly as possible.fluids should be administered carefully because of

vere kidney failure together with sodium and solute-e water retention due to cirrhosis. Excessive admin-ration of fluids may result not only in an increase incites and edema, but also in substantial increases inntral venous pressure and pulmonary edema.Patients with type 2 HRS without associated com-cations are managed as outpatients. Spironolactoned other potassium-sparing diuretics generally should

avoided because of the risk of hyperkalemia,

ereas loop diuretics, such as furosemide, usually

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Fagundes and Ginsk efficacy.63 Thus, treatment of ascites is based oneated large-volume paracentesis and albumin ad-nistration (8 g/1 L of ascites removed).63,74

nagement of Type1HRS

Administration of vasoconstrictor drugs currentlyconsidered the best therapy for managing type 1S.15,63 This approach is intended to cause vasocon-

iction of the greatly dilated splanchnic arterial bed,s improving circulatory function. This in turn alle-tes arterial underfilling, lessens the activation of

endogenous vasoconstrictor systems, and in-ases kidney perfusion and GFR. Treatment with

sodilator drugs is ineffective. Albumin infusionne improves cardiac function, but is not associatedth an improvement in kidney function.73 The avail-le vasoconstrictors are vasopressin analogues, suchterlipressin, which acts on V1 vasopressin recep-s in vascular smooth muscle cells, and -adrener-

agonists, such as noradrenaline or midodrine,ich act on 1-adrenergic receptors in vascularooth muscle cells. In most published reports, vaso-nstrictors (frequently terlipressin) are given with IVumin to further alleviate the arterial underfilling.75-82sults from randomized controlled studies and sys-atic reviews show that treatment with the combina-

n of terlipressin and albumin is associated withersal of HRS in 40%-50% of patients, making this

proach the preferred initial therapy (Box 3).63 Re-onse to treatment with terlipressin and albumin issociated with a progressive decrease in serum creat-ne concentration, increased urine output, and im-

80,81

Box 3. Pharmacologic Treatment of HRS

soconstrictors

Terlipressin: 1 mg/4-6 h intravenously; the dose is increasedup to a maximum of 2 mg/4-6 h after 3 days if there is noresponse to therapy, defined by a decrease in serum creati-nine 25% of pretreatment values. Response to therapy isindicated by a marked decrease in the high serum creatininelevels, at least 1.5 mg/dL (133 mol/L). Treatment isusually given from 5-15 daysMidodrine: 7.5 mg orally 3/d, increased to 12.5 mg 3/d ifneededOctreotide: 100 g subcutaneously 3/d, increased to 200g 3/d if neededNorepinephrine: 0.5-3 mg/h as continuous intravenous infu-sion aimed at increasing mean arterial pressure by 10 mmHg. Treatment is maintained until serum creatinine de-creases1.5 mg/dL (133 mol/L)

lbumin administrationConcomitant administration of albumin together with vaso-nstrictor drugs (1 g/kg body weight at day 1 followed by-40 g/d)Abbreviation: HRS, hepatorenal syndrome.ovement in hyponatremia. Factors that predict a the

0ponse to treatment are an increase in arterial pres-re during treatment and low baseline creatinineel.83-86 -Adrenergic agonists, such as noradrena-e or midodrine, are a reasonable alternative tolipressin due to their low cost and broad availabil-; however, data for their use are limited.48,87-89 Astematic review of randomized controlled studiess shown that vasoconstrictor therapy of HRS im-oves survival.82 Responders to terlipressin and albu-n in terms of improvement in kidney function afterrapy have increased survival compared with nonre-

onders. After withdrawal of therapy, HRS recurs in15% of patients, and in these cases, a second treat-nt with terlipressin usually is effective. The inci-

nce of side effects (usually ischemic) that mandatecontinuation of treatment is12%. Attention shouldpaid to early detection of ischemic side effects.RRT has been used in patients with type 1 HRS,rticularly in candidates for liver transplant.90 Disap-intingly, RRT has not been evaluated side by sideth other forms of therapy in randomized compara-e studies. RRT is not considered the first-line treat-nt for patients with type 1 HRS because it does not

rrect the underlying pathogenesis. Nevertheless,her continuous or intermittent RRT is an option fortients with type 1 HRS for whom vasoconstrictors

ineffective and who present signs of uremia,lume overload, severe metabolic acidosis, or hyper-lemia. The best modality of RRT is still an unre-lved issue. In recent years, alternative methods tonventional RRT have been evaluated in type 1S. These include molecular readsorbent recirculat-systems (an alternative to dialysis that clears

umin-bound substances, including vasodilators) andctionated plasma separation and adsorption (theometheus system), but more evidence is needed ifse procedures are to be accepted as having therapeu-value for HRS.91-93 A recent small study evaluat-a molecular readsorbent recirculating system as

cue therapy in patients with type 1 HRS not re-onding to treatment with vasoconstrictors showedimprovement in GFR and renal blood flow.94An implantable stent inserted through a transjugu-approach that reduces portal pressure by establish-communication between the portal vein and a

patic vein (known as TIPS [transjugular intrahe-tic portosystemic shunt]) has been proposed as anernative treatment for type 1 HRS, but informationvery limited.95,96 As a result, the current role of thisvice in the management of this condition is un-own. A recent study including a very small numberpatients showed that vasoconstrictor therapy fol-ed by stent placement was effective in patients

th type 1 HRS.87 This approach using a sequential

rapy merits evaluation in larger studies.

Am J Kidney Dis. 2012;59(6):874-885

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Hepatorenal SyndromeLiver transplant is the first choice of treatment fortients with cirrhosis and type 1 HRS. Becauseney failure is reversible after liver transplant, pa-

nts should not be treated with combined liver-ney transplant. Combined liver-kidney transplantappropriate only for patients who have been onT for more than 6-8 weeks who have a lowelihood of recovery of kidney function.97,98 Abstantial problem in liver transplant for patientsth type 1 HRS is the high mortality rate fortients on the waiting list owing to the short lifepectancy and long waiting times at many trans-ant centers. This may be dealt with by assigningese patients a high priority for transplant. Theestion arises as whether to treat patients withpe 1 HRS with vasoconstrictors before transplantth the aim of performing transplant on patientsth normal or near-normal kidney function. Excel-t survival has been reported with the 2 ap-

oaches, transplant-without treating HRS oreat HRS before transplant.99-101 However, infor-tion is scarce and studies either did not assess compli-

tions after transplant or included a small number oftients. Therefore, use of pharmacologic treatment ofe 1 HRS before transplant remains an open question,

hough transplant of patients without kidney failureoretically seems better than transplant of patients with

ute severe kidney failure.102 A proposed algorithm ofnagement of type 1 HRS based on the current knowl-

ge is shown in Fig 4.

nagement of Type2HRS

There are very few data regarding the use of vaso-nstrictors in combination with albumin for patientso have type 2 HRS. Uncontrolled trials support the

igure 4. Proposed treatment algo-m for patients with type 1 hepatorenaldrome (HRS). Abbreviation: MELD,del for End-Stage Liver Disease.

otentially reversible chronic liver dis-ses (alcoholic hepatitis, acute-on-onic liver failure, etc) with no impor-

t associated comorbid conditions.

J Kidney Dis. 2012;59(6):874-885cacy of vasoconstrictors in improving kidney func-n, but recurrence after treatment withdrawal is veryquent (P. Gins, unpublished observations). Moredies are required to more fully understand the rolet vasoconstrictors plus albumin may have in treat-type 2 HRS.48,81 TIPS may improve kidney func-

n and reduce the risk of progression to type 1S,103 but randomized studies are lacking. RRT is

t indicated in the management of patients with typeHRS because of the lack of a severe decrease inney function. A proposed algorithm of manage-nt of type 2 HRS based on current knowledge is

own in Fig 5.

PREVENTION OF HRS

As discussed, the chance of HRS is considerable intients with cirrhosis and spontaneous bacterial peri-itis, and a study published in 1999 showed that IV

ministration of albumin (1.5 g/kg body weight atgnosis and 1 g/kg 48 hours later) can greatlyuce this risk.55 In that study, it was observed that

tients with normal serum creatinine levels and nor-l or slightly increased serum bilirubin levels at thee of diagnosis of spontaneous bacterial peritonitis

d very low risk of developing HRS even if albumins not given. This has led to the suggestion thattients of this type should not be given albuminatment. Nevertheless, because this was not a pre-fined subanalysis of the study, it seems reasonablesuggest that albumin should be administered to alltients with spontaneous bacterial peritonitis untils observation is confirmed in further prospectivedies, as proposed in the guidelines of the Europeansociation for the Study of the Liver (EASL).63ng-term oral administration of norfloxacin (400effitiofrestuthaingtioHRno2kidmesh

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Fagundes and Gins/d) in patients with ascitic fluid protein 15 g/Ld associated decreased liver and/or kidney functionilirubin 3 mg/dL [51.3 mol/L], Child-Pughore10, serum sodium130 mEq/L [130 mmol/, and/or serum creatinine 1.2 mg/dL [106.1

ol/L]) reduces the risk of HRS and improvesrvival.32 These effects probably are related to pre-ntion of bacterial translocation, suppression of pro-ammatory cytokines, and improvement in circula-y function.26,27,30,31 In patients with acute alcoholicpatitis, pentoxifylline was shown to decrease theidence of HRS in one study104; however, theseults were not confirmed in a study recently pub-hed in abstract form.105 Although hyponatremia intients with ascites is a risk factor for HRS,10 there

no studies assessing whether vaptans, drugs thatprove serum sodium levels by antagonizing selec-ely the V2 receptors in the kidney,106 may helpevent HRS.

MANAGEMENT OF HRS ACCORDING TOGUIDELINES OF INTERNATIONAL SOCIETIES

The most recent guidelines, published in 2010 byEuropean Association for the Study of the Liver

ASL), recommend terlipressin (1 mg/4-6 h as IVlus) together with albumin as first-line treatment fortients with type 1 HRS.63 The aim of treatment is tocrease serum creatinine levels to1.5 mg/dL (133

ol/L). Modifications of the dose are guided byanges in serum creatinine concentration; if serumatinine level decreases by at least 25% after 3 daystreatment, the dose is maintained, and if not, these is increased to 2 mg/4-6 h. If there is recurrenceany time after treatment discontinuation, patientsould be re-treated with terlipressin and albumin.ternatives to terlipressin are noradrenaline and mido-

Candidate for Tx Not candida

Stable SCr SCr increasing

Evaluat

Evaluate kidney function

Prioritize patients on transplant list;repeated large-volume paracentesis and albumin; norfloxacin, 400 mg/d

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norfloxa

Repeated large-volume paracentesis and albumin

Treat with vasoconstrictorsb

Type 2 HRS

Diureticsaine plus octreotide, both in combination with albu- Ca

2n, yet information about efficacy is very limited.tients treated with vasoconstrictors should be fol-ed up carefully throughout treatment for early

tection of side effects, particularly cardiovascularents and pulmonary edema. Main contraindicationsvasoconstrictor drugs are severe cardiovasculareases. The use of TIPS is not recommended andT should be used only in patients not responding to

soconstrictors who fulfill criteria for kidney sup-rt. As far as patients who are candidates for trans-nt is concerned, EASL guidelines recommend treat-nt of HRS with vasoconstrictors before livernsplant. Moreover, liver transplant alone is appro-iate, with combined liver-kidney transplant re-rved for only patients who have been on RRT forre than 6-8 weeks. Although the guidelines statet vasoconstrictor therapy is effective for the treat-nt of type 2 HRS, no specific recommendation isde to treat these patients due to limited data.The AASLD (American Association for the Studythe Liver) guidelines published in 2009 recom-nd that patients with type 1 HRS be treated withdodrine and octreotide together with albumin.107 Itould be noted that terlipressin is not available in theited States. These guidelines also emphasize that

tients who are candidates for liver transplant shouldreferred immediately to transplant centers becausetheir low survival expectancy.

ACKNOWLEDGEMENTS

Support: Dr Fagundes was recipient of a grant from the Institutoina Sofa de Investigacin Nefrolgica (IRSIN). Some of thedies reported in this review were performed with the support ofnts from the Fondo de Investigacin Sanitaria (FIS PI080126EC/90077) and Ciber de Enfermedades Hepticas y Digestivas

IBEREHD). CIBEREHD is funded by the Instituto de Salud

Tx

liver transplant

e-volume d albumin;00 mg/d Figure 5. Proposed treatment algo-

rithm for patients with type 2 hepatorenalsyndrome (HRS). Abbreviations: SCr, se-rum creatinine; Tx, transplant. aOnly inpatients without adverse reactions to di-uretics and with sodium excretion underdiuretic treatment of 30 mEq/d. bEitherterliprerssin if available or norepineph-rine; therapy with a combination of midro-dine and octreotide also could be anoption.ofmemishUnpabeof

Restugraand(Crlos III, Ministerio de Sanidad, Espaa.

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Hepatorenal SyndromeFinancial Disclosure: Dr Gins has been an advisor for Otsukaarmaceuticals, Orphan Therapeutics, Ikaria, and Ferring Int. Drundes declares that she has no relevant financial interests.

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Hepatorenal Syndrome8. Solanki P, Chawla A, Garg R, Gupta R, Jain M, Sarin SK.neficial effects of terlipressin in hepatorenal syndrome: a pro-ctive, randomized placebo-controlled clinical trial. J Gastroen-

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Hepatorenal Syndrome: A Severe, but Treatable, Cause of Kidney Failure in CirrhosisCase presentationIntroductionDefinition and IncidencePathophysiologyClinical Types of HRSPrecipitating FactorsDiagnosisManagement of HRSGeneral MeasuresManagement of Type 1 HRSManagement of Type 2 HRS

Prevention of HRSManagement of HRS According to Guidelines of International SocietiesAcknowledgementsReferences