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HepatorenalSyndrome:Diagnosis,Management,andNewAdvancesinTherapy
INTRODUCTION
Patientswithadvancedcirrhosisarepredisposedtoseveraldiseasecomplications,includingascites,encephalopathy,varicealhemorrhage,infection,andhepatorenal
disorders.Hepatorenaldisordersisarelativelynewumbrelladescriptorthatcoverstheentirespectrumofpossiblekidneydysfunctiondisordersinpatientswith
concomitantcirrhosis,includinghepatorenalsyndrome(HRS).13HRSisafrequentoccurrenceinpatientswithadvancedcirrhosis,with18%ofpatientsdeveloping
HRSwithin1yearandupto40%developingHRSby5years.4Ifnottreated,patientswithHRSTypeIsurviveonlyamedianof2weeksand95%ofpatientsdiewithin
thefirst30daysafteronset.Themediansurvivaltimeis4to6monthsinpatientswithTypeIIHRS.5
Theassessmentandtreatmentofhepatorenalsyndromeisdauntingbecauseofthedifficultiesinprovidingadefinitivediagnosisandthepooroverallresponserateto
currentlyavailabletherapies.ThisreviewwillhighlightthecurrentstatusoftheassessmentandtreatmentofHRSanddiscusstheroleofthepharmacistinthecareof
thischallengingdiseasestate.

ETIOLOGY,RISK,ANDDIAGNOSTICCRITERIA
HRSisafunctionalrenalfailureoccurringinpatientswithadvancedcirrhosis.ThemajordifferenceinHRSfromothertypesofacutekidneyinjury(AKI)inpatientswith
hepaticdiseaseistheabsenceofparenchymalkidneydisease.PortalhypertensionistheinitiatingfactorforHRSbecauseitcausesthereleaseofvasoactive
mediatorsincludingnitricoxide,carbonmonoxide,cysteinylleukotrienes,thromboxaneA2,endothelin1,andothers.Thisresultsinthedevelopmentofsplanchnic
vasodilation,reducingeffectivearterialbloodvolumeandmeanarterialpressure.Reducedbloodandoxygendeliverytothekidneyactivatescompensatory
mechanisms,includingthesympatheticnervoussystem,thereninangiotensinaldosteronesystem(RAAS),andthereleaseofargininevasopressin.Thiscausesa
shiftintherenalautoregulationcurve,makingrenalperfusionmuchmoresensitivetochangesinmeanarterialpressure.Reducedcardiacoutputastheresultofthe
developmentofcirrhoticcardiomyopathypreventstheheartfromcompensatingforthereducedvascularresistanceandcaninitiatethedevelopmentofHRSinsome
patients.6
Figure1:PathogenesisofCirculatoryAbnormalitiesandRenalFailureinCirrhosis6

(clickontheimageforalargerview)
Incompensatedcirrhosis,increasesincardiacoutputandplasmavolumecanrestoreeffectivearterialbloodvolume.In
decompensatedcirrhosis,theactivationofvasoconstrictorsystemstomaintaineffectivearterialbloodvolumeleadsto
ascitesformationandeventuallytorenalfailure.Reprintedwithpermission6

Allpatientshospitalizedwithacutedecompensatedcirrhosisareathighriskfordevelopingrenalfailure.Additionally,patientswithascites,cardiacdysfunction,
hyponatremia,bacterialinfections,gastrointestinalbleeding,orsevererenalsodiumretention(i.e.,fractionalexcretionofsodiumlessthan1%)areatriskfor
developingHRSandshouldhavetheirrenalfunctionmonitoredregularly.Inpatientswithcirrhosisandascites,bacterialinfectionsappeartobethemostimportantrisk
factorforthedevelopmentofHRS.Infectionresultsincirculatorydysfunctionbyelicitinganinflammatoryresponseandareleaseofvasodilatorfactorsinthe
splanchnicvasculature.Asmanyas1outofevery3patientswhodevelopspontaneousbacterialperitonitiswilldevelopHRS,highlightingtheimportanceofalbumin
therapyforreducingtheriskofHRSanddeathinthisspecificpopulation.7OtherHRStriggeringeventsincludehypovolemiaastheresultofexcessdiuresisor
gastrointestinallosses(bleedingordiarrhea),largervolumeshiftsbetweenintravascularandextravascularcompartments,severealcoholichepatitis,anduseof
medicationsthataffectafferentorefferentarterioleconstrictionorvasodilationinthekidney(e.g.,nonsteroidalantiinflammatorydrugs[NSAIDs],angiotensin
convertingenzymeinhibitors[ACEIs],angiotensinIIreceptorblockers[ARBs]).6
ThediagnosisofHRSfrom2007to2015wasmadebyexcludingallotherpossiblecausesofrenalfailureandutilizingrevisedcriteriapublishedbytheInternational
ClubofAscites(ICA)in2007(Table1).8,9Thisdiagnosticcriteriawasmodifiedin2015(Table2)toincorporatethenewerICAmodificationoftheAcuteKidneyInjury
Network(AKIN)criteriaforevaluatingacutekidneyinjuryinpatientswithcirrhosis(Table3).Thekeychangeinthenewdiagnosticcriteriaistheremovaloftheserum
creatinine(SCr)thresholdvalueof1.5mg/dL.Additionally,itwillnowclassifyTypeIHRSbyAKIstageandTypeIIbychronickidneydiseaseparametersratherthan
simplyasTypeIorTypeII.Giventhatthestudiesdiscussedinthisreviewutilizetheearlierdiagnosticcriteria,theresultswillbereportedaccordingtotheHRS
criterialistedinTable1.
Table1:DiagnosticCriteriaforHepatorenalSyndrome(20072015)6,9
DiagnosticCriteriaforHepatorenalSyndrome
Cirrhosiswithascites

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Serumcreatinine(SCr)>1.5mg/dL(>133mol/L)
NoimprovementinSCrlevels(i.e.,decreaseof1.5mg/dL)afteratleast2dayswithdiureticwithdrawal(ifusingdiuretics)andvolume
expansionwith20%to25%albumin.Therecommendeddoseofalbuminis1g/kgofbodyweightperday,uptoamaximumof100g/day
Absenceofshock
Nocurrentorrecenttreatmentwithnephrotoxicmedications
Absenceofparenchymalkidneydiseaseasdefinedbyproteinuria<500mg/day,nomicrohematuria(i.e.,<50redbloodcellsperhighpower
field),andnormalrenalultrasonography)
ClassificationofHepatorenalSyndrome
TypeIdoublinginSCrtoavalue>2.5mg/dLinaperiodoflessthan2weeks
TypeIIstableormoreslowlyprogressiverenaldysfunction(i.e.,SCr>1.5mg/dL)notmeetingthecriteriaforTypeIHRS
AdaptedfromGinesetal6andSolernoetal9

Table2:RevisedDiagnosticCriteriaforHepatorenalSyndrome(2015)10
DiagnosticCriteriaforHepatorenalSyndrome
Diagnosisofascites
DiagnosisofAKIaccordingtoICAAKIcriteria
Noresponseafter2consecutivedaysofdiureticwithdrawalandplasmavolumeexpansionwithalbumin(1g/kg/day)
Absenceofshock
Norecentorcurrentuseofnephrotoxicdrugs(i.e.,NSAIDs,aminoglycosides,iodinatedcontrastmedia,etc)
Nomacroscopicsignsofstructuralkidneyinjury,whichisdefinedasfollows:
Absenceofproteinuria(>500mg/d)
Absenceofmacrohematuria(>50RBCs/highpowerfield)
Normalfindingsonrenalultrasonography
AdaptedfromAngelietal10
AKI=acutekidneyinjuryICAAKIN=InternationalClubofAscitesAcuteKidneyInjuryNetworkSCr=serumcreatinine
RBC=redbloodcells

Table3:InternationalClubofAscites(ICA)CriteriaforAKIinPatientsWithCirrhosis 10
AKIDefinition
IncreaseinSCrby0.3mg/dLwithin48hours
Or
IncreaseinSCrby50%frombaselinethatisknownorpresumedtohaveoccurredwithintheprior7days
AKIStagesbySCrCriteria
Stage1SCrincreaseby0.3mg/dLwithin48hoursorto1.52timesbaseline
Stage2SCrincreaseto23timesbaseline
Stage3SCrincreaseto3timesbaselineorto>4mg/dLwithanacuteincrease>0.5mg/dLoronrenalreplacementtherapy
AdaptedfromAngelietal10
AKI=acutekidneyinjurySCr=serumcreatinine

TheICAdiagnosticcriteriahavebeenwidelyacceptedhowever,theymaybedifficulttoapplyintheacutecaresettingbecauseofseveralfactors.First,isthe
difficultyinrulingoutrenalfailurecausedbyotherfactors,becausemanypatientswithHRSphysiologymaybereceivingmedicationsdetrimentaltorenalbloodflowor
function(e.g.,NSAIDs,diuretics,radiocontrastagents,orothernephrotoxicmedications),havebacterialinfectionswithorwithoutshock,andarereceivingdiuretic
therapypriortotheirAKI.Inpatientswithcirrhosis,theSCrisfrequentlyinaccuratefordiagnosingrenaldysfunctionandoverestimatesrenalfunctionasaresultof
decreasedhepaticcreatineproduction,musclewasting,andhyperbilirubinemiainthesepatients.11Thenew2015criteriastilldependontheSCrvaluetoestablishthe
diagnosis,althoughitismuchimprovedbyavoidingadependenceonanabsoluteSCrmeasurementgreaterthan1.5mg/dL.Nevertheless,SCrremainsthemost
practicalandwidelyacceptedmethodforestimatingrenalfunctionandisincorporatedintothediagnosticcriteriaforHRS.Considerationofthepatientsestimated
glomerularfiltrationrate(eGFR)andchangeinSCrvalue,asperthenewICAAKIcriteria,isneededwhendeterminingwhetherapatienthasahepatorenal
disorder.12,13ConsiderationofallestimatesofrenalfunctionisadvantageouswhendeterminingwhethertoinitiatetherapyforHRS,becausepatientswithcirrhosisand
AKIcausedbyHRSphysiologymaybenefitfromearliertreatment.Similarly,thediagnosticcriteriarequireswaitingatleast2daystodetermineifalbuminvolume
expansionhasanypositiveeffectandmaydelayinitiationofotherappropriateHRSmanagement.Asaresultoftheselimitations,severalrenalbiomarkers(e.g.,
neutrophilgelatinaseassociatedlipocalin[NGAL])arebeingstudiedtohelpdecipherHRSfromothercausesofAKIinpatientswithcirrhosisbut,furtherstudiesare
requiredbeforetheycanbeappliedinclinicalpractice.12,1416
Afterestablishingthediagnosis,HRShastraditionallybeencategorizedintothefollowing2distincttypes:TypeIandTypeII.TypeIHRSismorerapidlyprogressive
andusuallydevelopsasaresultofatriggeringfactorthatcausesacutedeteriorationofhepaticfunctiontogetherwithotherorgandysfunctions.Themostcommon
triggersforTypeIHRSarebacterialinfectionsandseverealcoholichepatitis.TypeIHRSwashistoricallydiagnosedwhenthereisadoublinginSCrtoavaluegreater
than2.5mg/dLinaperiodoflessthan2weeks.MovingforwardwiththeimplementationofthenewICAAKIcriteria,TypeIHRSwillbediagnosedandlabeledasHRS
AKIandpatientswillbefurtherplacedintostages1,2,or3accordingtotheirSCrchangefrombaseline(Table3).17TypeIIHRSoccursinpatientswithrefractory
ascitesandinvolvesrenaldysfunction(i.e.,SCrlevelgreaterthan1.5mg/dL)thatismoreslowlyprogressiveanddoesnotmeetthecriteriaforTypeIHRS.Patients
withTypeIIHRSwithaneGFRlessthan60mL/min/1.73m2formorethan3monthsareconsideredtohavechronickidneydisease(CKD).Underthenewdiagnostic
criteria,thesepatientswithTypeIIHRSwillbelabeledaccordingtoCKDstages.17Similartopatientswhodonothavecirrhosis,AKIcanoccurontopofCKD.Itis
commonforpatientswithTypeIIHRStoeventuallydevelopTypeIHRSastheresultofaprecipitatingevent.2,8,14

THERAPEUTICOPTIONSFORHRS
AvoidingrelativerenalhypoperfusionisthekeymanagementstrategyforpreventingHRSdevelopment.Fluidmanagementisofcriticalimportancehowever,this
requirestheassessmentofeffectiveintravascularvolumeandrenalperfusionpressure.Standardvitalsigns(e.g.,heartrateandmeanarterialpressure),SCr,urine
output,edema,andascitesshouldbeevaluatedinallpatients.Measurementofrightatrialorpulmonaryarterypressuresmayprovideobjectivedata,buthaveapoor
associationwithpatientresponsivenesstovolumechallengesandrequireahigherlevelofinpatientcare.18,19Avoidinghypovolemiabyappropriatelymanaging
outpatientdiuretictherapyandthediscontinuationofdiureticsatthefirstindicationofAKIiscriticallyimportant.Fluidoverloadastheresultofexcessiveintravenous
fluidadministrationshouldalsobeavoidedbecauseitcanbeequallydetrimental,resultinginhyponatremia,increasedascites,andedema.Largevolumeparacenteses
formanagingascitesshouldalwaysbecoupledwiththeintravenousadministrationof20%to25%albumin(atleast6to8gramsperliterofascitesremoved)toavoid

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largervolumeshiftsfromtheintravascularspace.20,21
EarlyidentificationandmanagementofHRSiscriticaltothesuccessofthechosentherapy.TheonlydefinitivetreatmentestablishedforHRSislivertransplantation.
Thegoalofallotherpharmacologicandnonpharmacologictherapiesistoprolongsurvivaltimeenoughtoallowforlivertransplantation.22Severalsmallandmostly
uncontrolledstudieshaveattemptedtoevaluatevariouspharmacologicagentsforthetreatmentofHRSbutonlysplanchnicvasoconstrictingmedicationscombined
withtheadditionofalbumintherapyhaveemergedasapreferredinitialtreatmentoption.Despitethisrecommendation,applicationofthesetherapiesisaclinical
challengebecausenotallrecommendedmedicationsareavailableandtheindividualizationofdosingandmonitoringisnecessary.Currentandpotentialfuture
treatmentoptionsandconsiderationsforsafeandeffectiveutilizationofpotentialtherapiesarediscussedbelow.

LiverorLiverandKidneyTransplantation
LivertransplantationistheoptimalanddefinitivetherapyforpatientswithHRSbecauseitcurestheunderlyingorgandysfunctionresponsibleforthepathophysiologic
pathwaytoHRS.2325LivertransplantationdrasticallyimprovesmortalityforpatientswithHRS,resultingin5yearsurvivalratessimilartopatientswithoutHRSwho
underwentlivertransplantation(67.1%versus70.1%,respectivelythisdifferenceisnotclinicallymeaningful).24Itisnotyetclearwhethertreatmentandreversalof
HRSpriortolivertransplantationconfersanadditionalsurvivalbenefit.22,26
Renaldysfunctioncanoftenbereversibleand,therefore,patientswithHRSarenotfrequentlylistedforcombinedliverkidneytransplants(LKTx)however,LKTxmay
conferimprovedoutcomesforpatientsthatprogresstoendstagerenaldisease(ESRD)andthosewithacuterenalfailurethatproducespermanentkidneydamage,
whichwasdeterminedbyanSCrlevelgreaterthan1.5mg/dLformorethan12weeksortheneedforhemodialysis(HD)foratleast4weeksinretrospective
studies.2,27Morerecently,recommendationshavebeenmadetolimitLKTxtoHRSpatientswhohavereceivedhemodialysis(HD)forlongerthan8weeks,21withsome
groupsadvocatingforarequirementoflongerthan12weeksofHDpriortotransplantationbeforeconsiderationofLKTx.14Theserecommendationsareconsistentwith
currentevidence,whichhasbeenunabletodemonstrateasurvivalbenefit,reducedpostoperativeHDdays,ordecreasedhospitalresourcewhenutilizingLKTx
comparedwithlivertransplantationaloneinHRSpatientswhoreceivedHDforlessthan8weekspriortotransplantation.25

TransjugularIntrahepaticPortosystemicShunt(TIPS)
TIPSprocedurescansignificantlydecreasetheportosystemicpressuregradient.Thisleadstodecreasedplasmareninandsympatheticactivityand,therefore,has
thepotentialtoimproveorreverseHRSphysiology.28Insertionoftheshuntwithin4to6weeksofHRSonsetmayimproverenalfunctionrecoveryandsurvival.29
ImprovementinrenalfunctionafterTIPSmaytakeseveralweeks,sotheuseofothertherapiesfortreatingHRSistypicallyrequireduntiltheeffectofTIPSplacement
isrealized.TIPScanbebeneficialforpatientswithbothTypeIandTypeIIHRShowever,patientswithTypeIHRSfrequentlyhavecontraindicationstothe
procedure.PatientswithlowerbilirubinandthosewithTypeIIHRSaremorelikelytohaveprolongedsurvivalpostTIPS.29
TIPSplacementisnotwithoutadverseriskandcarefulpatientselectionshouldbeutilizedtooptimizesafetyandefficacyforpatientswithHRS.Substantialadverse
effectsrelatedtotheTIPSprocedureareencephalopathy,gastrointestinalhemorrhage,anddeath.28TIPSisnotrecommendedforpatientswithsevereliverdisease
(i.e.,bilirubinlevelsgreaterthan5mg/dL,internationalnormalizedratio(INR)greaterthan2,orChildPughscorehigherthan11),hepaticencephalopathy,orsevere
cardiopulmonarydisease.2

ArtificialOrganSupport
ArtificialliversupporttherapieshavebeenevaluatedforthetreatmentofHRSincludingmolecularadsorbentrecirculatingsystem(MARS),Prometheus,singlepass
albumindialysis(SPAD),andsinglepassalbuminextendeddialysis(SPAED).3034Theseextracorporealsystemsprovidecombinedhepaticandrenalsupportby
removingwatersolubleandalbuminboundtoxins,resultinginimprovedlaboratoryvalues(e.g.,reducedconjugatedbilirubin,totalbileacids,INR,plasmaammonia,
SCr,andserumurea.)Additionally,newercellbasedsystemsarebeinginvestigatedbecausetheycanprovidetheexcretory,synthetic,andmetabolicfunctionofthe
liverbyusinglivehepaticcells.35
DespitethecommercialavailabilityoftheMARSsystemintheUnitedStatesandEurope,itsobtainabilityandtheclinicalexpertiserequiredtodelivertheartificial
hepaticsupportsystemsareabsentatmanyhealthcarefacilities.Otherchallengestotherapyincludehypotension,bloodlosseachtimethecircuitisreplaced,and
thefrequentneedforanticoagulantadministrationintotheextracorporealcircuittopreventclottingofthecircuit.Continuedadvancesincircuitfunctionality,plasma
separationtechniques,andadsorptioncolumnandfiltercapabilitiesareneededbeforethesesystemscanbeeffectivelyutilizedformanagingpatientswithcirrhosis
andHRS.Untilfunctionalityimprovesandmeaningfulclinicaloutcomes(e.g.,improvedsurvivalandtransplantationrates)canbedemonstrated,useofartificialliver
supporttherapiesshouldbelimitedtoresearchprotocols.2
Fewstudieshaveevaluatedrenalreplacementtherapy(RRT)forthetreatmentofHRS.3638TheuseofRRTcanimproveshorttermsurvivalforpatientswithHRSand
maybehelpfulwithbridgingpatientstotransplantortreatingpatientswhohaveanacutereversiblecauseofhepaticdecompensation.Usebypatientswhoarenot
transplantcandidatesandthosewithoutanacutereversiblecomponentisunlikelytochangeapatientsdiseasecourseandmerelyresultsinresourceoverutilization
andsubstantialcoststothehealthcaresystem.37Therefore,theinitiationofcontinuousorintermittentRRTforpatientswithHRSisgenerallyreserveduntila
significantindicationfordialysisarises(e.g.,severehyperkalemia,metabolicacidosis,orvolumeoverload).Individualpatientselection,accordingtotheseverityof
illness,ChildPughandMELDscores,andthepotentialforlivertransplantationshouldallbeconsideredpriortotheinitiationofRRT.

AdjunctiveAlbumin
AlbuministhepreferredintravascularvolumeexpanderforpatientswithHRS.AfterutilizationofalbumintodeterminethediagnosisofHRS,continuedalbumin
administrationcombinedwiththechosenvasoconstrictormayimproveresponseratescomparedwithvasoconstrictormonotherapy.39Ifalbuminisutilized,the
admixtureshouldprovideahighconcentrationofalbumin(e.g.,20%to25%albumin)andthetypicaldoseis1g/kg(upto100g)onday1or2,then25to50g/dayof
25%albumin(or20to40g/dayof20%albumin)thereafter.2,40Albumintherapyistypicallycontinued,alongwithvasoconstrictortherapy,untilacompleteresponsein
SCrisrealizedoruntilfutilityoftherapyisdetermined.However,doseanddurationofalbumintherapyshouldbedictatedbyvolumestatusalbuminisinitiallyeffective
atimprovingintravascularvolume,butwilleventuallyresultinthirdspacevolumeexpansion.Volumestatusshouldbeassessedbyhemodynamicmonitoring,although
theoptimalmethodforevaluatingvolumestatusiscontroversialandlikelyincludestheinterpretationofseveralpossiblemeasurements,includingheartrate,mean
arterialpressure(MAP),centralvenouspressure,pulsepressurevariation,strokevolumevariation,echocardiography,urineoutput,ascites,andedema.

Terlipressin
TheeffectsofvasopressinandvasopressinanaloguesontheV1receptorarethepredominatemechanismfortreatingtheunderlyingsplanchnicvasodilationpresentin
thosewithHRS.TherearealargenumberofV1receptorsinthesplanchnicvasculature,makingthisareaespeciallysensitivetothevasoconstrictiveeffects.41
VasoconstrictionofthesplanchnicvascularbedsisbelievedtoreverseHRSbyincreasingeffectivearterialbloodvolume,therebysuppressingactivationoftherenin
angiotensinaldosteronesystem(RAAS)andthesympatheticnervoussystem,reversingcompensatoryrenalvasoconstrictionandultimatelyincreasingrenalperfusion.

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Terlipressin(N3Triglycidyl8LysineVasopressin)isauniquevasopressinanaloguewithpotentialadvantagesthatmakeitthepreferredvasoconstrictorforpatients
withHRS.TerlipressinreducesportalveinpressureandincreasesMAPinpatientswithcirrhosisandsplanchnicvasodilation.Itimprovessplanchnicbloodflowand
downregulatestheexcessivesaltandwaterretentionthatleadstoasciticfluidaccumulation.TerlipressinhasagreatereffectontheV1receptorthanontheV2
receptorithasalongerhalflife,allowingformoreconvenientintermittentintravenousdosing,andalowerincidenceofischemiccomplicationswhencomparedwith
ornipressinandhighdosevasopressin.42Althoughthenumberofprospectivecontrolledtrialsissmall,terlipressinhasbeenoneofthemoststudiedvasopressor
agentsforthetreatmentofHRS(Table4).42FDAapprovalofterlipressinispendingtheirreviewoftheresultsfromthepivotalPhaseIIIMultiCenterRandomized,
PlaceboControlled,DoubleBlindStudytoConfirmtheReversalofHepatorenalSyndromeType1WithLucassin(Terlipressin)(REVERSE)trial.Thisstudycompared
terlipressin6mgIVevery6hoursplusalbuminwithplaceboplusalbuminforupto14days.Thetrialhasbeencompletedandpreliminaryresultsofthestudywere
recentlypresented[ClinicalTrials.govidentifierNCT01143246].43Onehundredandninetysixpatientswereenrolledinthestudy.Theprimaryendpointofthestudywas
confirmedHRSreversal,definedas2SCrvaluesgreaterthanorequalto1.5mg/dLatleast48hoursapart.Despiteasignificantlygreaterdecreaseincreatininelevels
forpatientstreatedwithterlipressinascomparedwiththeplacebogroup,therateofconfirmedresponsesbetweenthe2groupswasnotstatisticallymeaningful(20%in
terlipressinversus13%inplacebo).Whenthedatawerepooledwithapreviousprospectivestudy(totaln=308)asignificantimprovementintherateofconfirmed
HRSreversalwasobserved(24.2%versus12.9%,respectivelyP=0.01).Survivalwassignificantlyhigher(P<0.01)andtheneedforrenalreplacementtherapy
lower(7%versus43%P<0.01)inpatientsachievingreversal.44IftheseadditionaldataprovideenoughevidencetosatisfyFDArequirements,itwillbethefirstagent
intheUnitedStatesapprovedforthetreatmentofTypeIHRS.
Table4:SelectedClinicalStudiesofVasopressinAnaloguesintheTreatmentofHRS42
StudyDesignandCitation No.ofPatients
Therapy
SignificantOutcomes
Prospective,randomized
N=46(35TypeIand11 Terlipressin+albumin
Renalfunctionimprovementmorelikelyinterlipressin+albumin(43.5%
52
MartinLlahi,etal
TypeIIHRS)
versusalbumin
versus8.7%P=0.017)
Prospective,observational
N=21(16TypeIand5
Terlipressin+albumin
Albuminadministrationfoundtopredictrenalfunctionresponse(77%
Ortega,etal39
TypeIIHRS)
versusTerlipressin
respondersversus25%respondersP=0.03)
Prospective,randomized
N=24(TypeIHRS)
Terlipressinversus
TerlipressinsignificantlyimprovedUOP,CrCl,MAP,anddecreasedSCr
SolankiP,etal53
placebo
comparedwithplacebo.Atday15,5of12patientsreceivingterlipressin
survivedcomparedwith0of12patientsreceivingplacebo(P<0.05)
International,multicenter,
N=112(TypeIHRS)
Terlipressinversus
Treatmentsuccess:terlipressin25%versusplacebo12.5%P=0.093.HRS
randomizedSanyalAJ,et
placebo
reversal:terlipressin34%versus13%P=0.008.Relatedadverseeffects:
al48
terlipressin9%versusplacebo2%P=NS
Prospective,randomized
N=52(TypeIHRS)
Terlipressin+albumin
80%completeresponsewithterlipressin+albuminversus19%response
47
Nerietal
versusalbumin
withalbumin(P<0.01).Improvedsurvivalat180dayswithterlipressin+
albumin(P<0.01)
International,multicenter,
N=196(TypeIHRS)
Terlipressin+albumin
ConfirmedHRSreversal:terlipressin20%versusplacebo13%P>0.05.
randomizedBoyer,TDet
versusplacebo+albumin SCr1.5mg/dLin24%terlipressinvs15%placeboP>0.05.SCr
al43
decreasedby1.2mg/dLterlipressinvs0.6mg/dLplaceboP<0.05.No
differenceinsurvival
MetaanalysisPaulo
N=154(95TypeIand
Terlipressinversus
HRSreversalforbothTypeIandII:RR=0.97,95%CI,0.761.23P>
NassarJr.etal54
59TypeIIHRS)
norepinephrine
0.05.Nodifferencein30daymortalityRR=0.89,95%CI,0.691.49P>
0.05.AdverseeffectslesscommonwithnorepinephrineOR=0.36,95%CI,
0.150.83P=0.02
Prospective,randomized
N=48(44TypeIand4
Terlipressin+albumin
Renalfunctionrecoveryin70.4%ofterlipressinversus28.6%of
55
Cavallinetal
TypeIIHRS)
versusOctreotide+
midocrine/octreotideP=0.01.Nodifferencein1or3monthsurvivalrates
Midodrine+Albumin
amonggroups(70%versus59%and67%versus43%,respectivelyP=
NS)
RetrospectiveKiser,THet
N=43(32TypeIand11 Vasopressin+Octreotide Completeresponsehigherinpatientsreceivingvasopressinorvasopressin+
al50
TypeIIHRS)
versusVasopressin
octreotideversusoctreotidemonotherapy(P=0.01)
versusOctreotide
HRS=hepatorenalsyndromeUOP=urineoutputCrCl=creatinineclearanceMAP=meanarterialpressureSCr=serumcreatinine
AdaptedfromKiseretal42

AcomprehensivereviewoftheterlipressinliteratureforHRSpriortoJanuary2012canbefoundintheCochraneDatabase.45Combinedanalysisof6prospective
studiesdemonstratesthatterlipressintreatmentimprovesrenalfunctionandmortalityforpatientswithHRS.HRSreversaloccursin25%to50%ofpatientstreated
withterlipressin(reversalorcompleteresponseisdefinedasadecreaseinSCrtoavaluelessthanorequalto1.5mg/dL).Unfortunately,relapseratesafterstopping
therapycanbehighandretreatmentwithvasoconstrictortherapymaybenecessary.Therearelimiteddataavailableaboutterlipressinuseintheoutpatientsettingfor
managingHRSrelapseswhileawaitinglivertransplantation.46Adverseeffectsrelatedtoterlipressinareobservedinapproximately10%ofpatientsandinclude
tachycardia,arrhythmias,chestpain,diarrhea,abdominalpain,bronchospasm,andperipheralischemia.47Terlipressindosereductionmayberequired,dependingon
theseverityoftheadverseevent.Seriousischemicadverseeventsrequirediscontinuationofterlipressintherapy(e.g.,nonfatalmyocardialinfarction,livedoreticularis,
andcyanosisofthefingers).48
Terlipressindosinghasrangedfrom0.5to2mgintravenouslyevery4to12hours.Continuousinfusionterlipressinhasalsobeenutilized,butitdoesnotappearto
offeranefficacyorsafetyadvantageoverintermittenttherapyandisnotasconvenient.Terlipressinshouldbeinitiatedat0.5mgevery4to6hours.Stepwisetitration
indose(e.g.,0.5mgincrements)shouldbedoneevery1to2daysastoleratediftheurineoutput(UOP)hasnotimprovedandtheSCrhasnotdecreasedfrom
baseline(Table5).2Itmaytake2to3daysforaresponseinSCrtobeobserved,soearlydosingtitrationdecisionsshouldfocusonachievingaMAPincreaseof10
mmHg,UOPimprovement,andavoidanceofischemicadverseeffects.TherapyshouldbediscontinuedifpatientsdemonstratenoresponseinSCrbyday4of
therapy,despiteadequatetitrationandanincreaseinMAP,becausearesponsetotherapyatthispointisunlikely.
Table5:DosageandAdministrationofVasoconstrictorMedicationsforHRS2,16
VasoconstrictorAgents
DosingRecommendations
Terlipressin
0.5to2mgIVq4to6hoursincreasedoseby0.5mgincrementsevery1to2daysifthereisnoimprovementinSCr
aslongasnosideeffectsarepresent.GoalMAPincreaseof10mmHgfrombaseline.Maximumdose=12mg/day.
Vasopressin
0.01to0.8units/mincontinuousIVinfusion.Increasedoseby0.05units/minevery30to60minutestoachievea10
mmHgincreaseinMAPfrombaselineoraMAP>70mmHg
Norepinephrine
0.05to1mcg/kg/min(5to75mcg/min)continuousIVinfusion.Titrateevery30minutestoachievea10mmHg
increaseinMAPfrombaseline
Midodrine+Octreotide
Midodrine5to15mgPOTID.Titratetoachievea10to15mmHgincreaseinMAPfrombaselineOctreotide:100to
200mcgSQ/IVTIDor25to50mcgIVbolus,followedby25to50mcg/hourcontinuousinfusion(notitration)
SCr=serumcreatinineMAP=meanarterialpressureIV=intravenousclearance
1.Adjunctivealbuminadministrationisrecommended:1g/kg(upto100g)onday1or2,then25to50g/dayof25%albumin(or20to40g/dayof20%albumin)thereafter
2.Therapyshouldbediscontinuedafter4daysifnoresponseinSCrisobserved,despiteadequatedosagetitration,becausethelikelihoodofaresponsetotherapyislow

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3.Allpatientsshouldbemonitoredforsignsofischemia(i.e.,visualevaluationofdigits,distalpulses,abdominalpain,serumlactate,and/ortroponin)atleastevery12hoursandafteranydosing
titration.Useofvasoconstrictorsinpatientswithactiveischemiccardiovasculardiseasesshouldbedonewithextremecautionandisgenerallyconsideredcontraindicated
4.Inpatientsthatdemonstrateacompleteresponsetotherapy,dosagereductionorvasoconstrictordiscontinuationshouldbeattemptedbyday14oftherapytodeterminethesustainabilityofthe
response.Restartingtherapymaybenecessaryifarelapseoccurs
AdaptedfromNadimetal2Durandetal16

Contraindicationstoterlipressintherapyincludeischemiccardiovasculardiseases.Similartoothervasopressoragents,patientsshouldbecarefullymonitoredfor
cardiacarrhythmias,signsofsplanchnicordigitalischemia,andfluidoverload.Skinnecrosisisararedosedependentsideeffectofterlipressinandnecessitatesdrug
discontinuationifobserved.49Incountrieswhereterlipressinisnotcommerciallyavailable,othervasoconstrictortreatmentoptions(e.g.,vasopressinornorepinephrine)
muststillbeconsidered.

VASOPRESSIN
Vasopressin(8argininevasopressinor[AVP])isanendogenoushumanhormonethataffectsthefollowing3vasopressinreceptors:V1,V2,andV3.Itisless
selectivethanterlipressinandmustbeadministeredbyacontinuousinfusionbecauseofitsshorterhalflife.Thereisapaucityofdataevaluatingvasopressinforthe
treatmentofHRShowever,thewideavailabilityofvasopressinhasledtoitsuseincountrieswhereterlipressinisunavailable.Thebasisofvasopressinuseforthe
treatmentofHRScomesfromaretrospectivestudythatevaluated43patientswhohadreceivedvasopressinand/oroctreotideforthetreatmentofHRS.Responsein
SCr(SCrlevellessthan1.5mg/dL)wasobservedin41%ofthepatientsthatreceivedvasopressintherapy.Therapywithvasopressin,eitheraloneorincombination
withoctreotide,wasanindependentpredictorofrenalfunctionrecovery(oddsratio[OR]6.495%confidenceinterval[CI],1.331.8).PatientswithanincreaseinMAP
greaterthanorequalto10mmHgfrombaselinehadanincreasedresponsetotherapy(OR3.895%CI,0.9515.5).Themeanvasopressindoseinpatientsthat
respondedtotherapywas0.230.19units/minandissubstantiallyhigherthantypicallyutilizedinshocksyndromes.50Similartoterlipressin,adverseeffectsrelated
tovasopressinareischemicinnatureanddosedependent.Ischemicskinlesions,ischemicdigitsandextremities,myocardialinfarction,cardiacarrhythmias,and
cardiacarresthaveallbeenobservedwiththeuseofvasopressindosesgreaterthan0.04units/mininthetreatmentofvasodilatoryshock.51Althoughpatientswith
cirrhosisandHRSappeartobemoretoleranttohigherdosesofvasopressin,cautionandcarefulmonitoringofserumlactatelevelsandthemonitoringofextremities
forischemiashouldbemaintainedforpatientsreceivingvasopressindosesgreaterthan0.1units/min.Contraindicationstovasopressinaresimilartothoseof
terlipressintherapyandprimarilyincludeischemiccardiovasculardiseases.
TheoptimalvasopressindosingstrategyforthetreatmentofHRSisnotknown.However,itisrecommendedthatvasopressinbeinitiatedat0.04units/mincontinuous
intravenousinfusionandtitratedinincrementsofapproximately0.05unit/minevery30to60minutestoachieveanincreaseinMAPofatleast10mmHgfrom
baselineoraMAPgreaterthan70mmHg(Table5).SomeresponseinUOPandSCrshouldbeobservedby2to4dayswith,completeSCrresponseoccurringa
medianof7daysafterstartingtherapy.2

Norepinephrine
Norepinephrineisafrequentlyutilizedvasoconstrictorforvasodilatoryshock.Itsalphaadrenergicagonistactivitymakesitapotentvasoconstrictorofboththevenous
andarterialvasculature.Similartoterlipressin,inpatientswithHRS,norepinephrineeffectivelyimprovesUOP,sodiumexcretion,serumsodiumconcentration,
creatinineclearance(CrCl),MAP,plasmareninactivity,andaldosteroneactivity.Insmallcomparativestudies,norepinephrinehasdemonstratedasimilarrateofHRS
reversalandpatientsurvivalwhencomparedwithterlipressin.54,5658Adverseeffectsbetweennorepinephrineandterlipressinaresimilar,withreversiblecardiacand
digitalischemiabeingthemostcommonadverseevents.57Thecostofnorepinephrinetherapyisalsosignificantlylowerthanterlipressin(10731versus153640
EurosP<0.0001),makingitanattractivealternativetherapy.56
ForthetreatmentofHRS,norepinephrineshouldbeinitiatedat0.05units/kg/min(approximately5mcg/min)andtitratedevery30minutestoachieveaMAPincrease
ofatleast10mmHgfrombaseline(Table5).Similartovasopressin,someresponseinUOPandSCrshouldbeobservedby2to4days,withacompleteSCr
responseoccurringamedianof7daysafterinitiatingtherapy.2

Midodrine
Midodrineisanorallyadministeredalphaadrenergicagonistmedicationthatcausesvasoconstrictionofthevascularsmoothmuscle.ItsmechanismfortreatingHRS
is,therefore,similartonorepinephrine.Todate,themajorityofevidenceevaluatestheuseofmidodrinecombinedwithoctreotidetherapy,sotheefficacyofmidodrine
monotherapyisunknown.Whenusedincombinationwithoctreotidealbuminitmayimprovelengthofsurvivalandtransplantationrates,particularlyforpatientswith
TypeIIHRS.59Itsoraladministrationandimprovedtolerability,comparedwithintravenousvasoconstrictors,makesitanintriguingoptionforpatientsthatneedchronic
therapyorthosebeingtreatedoutsideoftheintensivecareunit.
TheusualmidodrinedosagerangeforthetreatmentofHRSis5to15mgorallyTID.Patientsshouldbeinitiatedon5mgorallyTID.IfanincreaseinMAPofatleast
10mmHgisnotobservedwithin24hoursofinitiation,thenthedoseshouldbeincreasedto10mgorallyTID.IfgoalMAPcannotbeachievedandthereisno
responseinUOPorSCr,despitetitrationto15mgorallyTID,considerationofswitchingtoamorepotentintravenousvasoconstrictormaybenecessary.2

Octreotide
Octreotideisalongactingsomatostatinanaloguethatreducesportalhypertensionandsplanchnichyperemia.60Itmayalsocausesplanchnicvasoconstrictionvia
inhibitionofglucagonsynthesisoradirecteffectonvascularsmoothmusclehowever,itspotencyissubstantiallylessthanthatofvasopressinanaloguesand
norepinephrine.61ThissignificantlyreducestheabilityforoctreotidemonotherapytoreverseHRSphysiologyandislikelythereasonitdoesnotappeartobeanymore
effectivethanplacebofortreatingpatientswithHRS.50,62,63
OctreotideiswelltoleratedandmaybebeneficialwhenutilizedasadjunctivetherapyforHRSpatientswithesophagealvaricealhemorrhageorasacombination
therapywithmidodrineorothervasoconstrictors.Whenusedincombinationwithothervasoconstrictors,itcanbeadministeredaseitherasubcutaneousinjectionoran
intravenousinfusion.SubcutaneousinjectionwithmidodrineallowsfornonICUadministrationandmaybeamoresustainableoptionforpatientsawaitingliver
transplantation.Subcutaneousoctreotideistypicallyadministeredat100to200mcgTID.Intravenousoctreotideisstartedwitha25to50mcgintravenousbolus,
followedbyaninfusionof25to50mcg/hour.UnlikeothervasoconstrictorsutilizedforthetreatmentofHRS,octreotidedosingisbaseduponusualinstitutionpractices
andisnottitratedtoagoalMAP.Ratherthantitrationofoctreotide,titrationoftheadjunctivevasoconstrictoragentisrecommended.2,14

Dopamine
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Dopaminehasbeenshowntomarkedlyreducerenalvascularresistanceandincreaserenalbloodflow,soithasbeenhypothesizedthatthiswouldconferbeneficial
efficacyforpatientswithHRS.However,theuseofdopaminemonotherapyoritsadditiontovasoconstrictortherapyhasnotproducedanysubstantialimprovementsin
renalfunction.50,64,65Similartoothertypesofrenalfailure,itappearsthatthetheoreticalbenefitsofdopaminearenotdemonstratedinpatientswithHRS,soitsuse
cannotberecommendedatthistime.

OtherAgents
SeveralothermedicationshavebeenstudiedforthemanagementofHRSwithmixedresults.Themajorityofthesemedicationsaffectrenalsodiumexcretion,urine
flow,and/orafferentandefferentarteriolevasoconstrictionorvasodilation.Althoughinvestigationsarebasedonsoundtheoreticalintentions,noneofthefollowing
medicationscanberecommendedaspartofroutinecareatthistime.
Theophylline,anadenosineantagonist,hasbeenshowntoincreasesodiumexcretionandimproveurineflowinpatientswithcirrhosis.66Thenatriureticpeptides,atrial
natriureticpeptide(ANP),urodilatin,andnesiritide,couldpotentiallyreversetheimpairmentofrenalsodiumbalanceandvolumeregulationseeninpatientswith
cirrhosisandHRS.Despitetheirabilitytoincreaseurinesodiumexcretionandurineflowinpatientswithcirrhosis,theyhavenotdemonstratedtheabilitytoreverse
acuterenalfailure.67,68
ItisknownthatpatientswithHRShaveincreasedlevelsofendothelin1,apotentrenalvasoconstrictor.Therefore,itwasbelievedthatantagonizingendothelin1would
decreaserenalvascularresistanceandimproverenalbloodflow.Apilotstudyoftezosentandemonstratedworseningrenalfunctionwitholiguria,increasedSCr,and
hypotensionaffectingthemajorityofpatients.69Nitricoxidesynthaseinhibitors,suchasNmonomethylLarginineacetate(LNMMA),havealsobeenusedto
counteractportalhypertensionandthehemodynamicconsequencesresultingfromreducedrenalplasmaflow.LNMMAadministrationhasshownimprovementin
hemodynamics,renalbloodflow,andGFRforpatientswithcirrhosis.However,theeffectsdependedontheseverityofcirrhosis,thepresenceofHRS,andthedose
andadministrationtechniqueutilized.70,71WhethernitricoxidesynthaseinhibitionwouldprovideanybenefittopatientswithHRSrequiresfurtherelucidation.

THEROLEOFTHEPHARMACIST
ThepharmacistisakeymemberofthemultidisciplinarycareteamtreatingpatientswithHRS.Thefirststepforthepharmacistinmanagingpatientswithpotential
HRSistoidentifymedicationsthatcouldbecontributingtoAKI(i.e.ACEIs,ARBs,NSAIDs,diuretics,nephrotoxins[e.g.,aminoglycosides],radiocontrast,etc).
Discontinuationofpotentialnephrotoxinsisnecessaryforallpatientsandlesscommonnephrotoxinsarefrequentlymissedbynonpharmacistpractitioners.Volume
resuscitationwithalbuminisnotoftenutilizedatmostinstitutions,soassistancewithalbumindosing,infusion,andmonitoringparametersisanimportantroleforthe
pharmacistwhenassistingwithdeterminationoftheHRSdiagnosis,aswellas,whendesigningthetreatmentofHRS.
Manyofthemedicationsemployedareexpensive,arealimitedresource,orhavethepotentialtocausesignificantpatientharm.Pharmacistsareinanidealpositionto
discussthepotentialbenefitsandrisksofpotentialtherapeuticoptions,aswellastherealisticexpectationsoftherapy.Thisdiscussionisofparticularimportancefor
patientswhodonothaveareversiblecauseofacutehepaticdecompensationandforthosewhowillneverbetransplantcandidates.Althoughterlipressinisthemost
studiedvasoconstrictorfortreatingHRSandisthepreferredfirstlinetreatmentinclinicalpracticeguidelines,2,10,14itiscurrentlyunavailableinmanycountries,
includingtheUnitedStates.Pharmacistsareresponsibleforprovidinganalternativetreatmentstrategyrecommendation.Commonly,thisisarecommendationtouse
vasopressin,norepinephrine,oracombinationofoctreotideandmidodrine.Assessmentofpotentialcontraindications,includingactiveischemicheartdisease,
peripheralvasculardisease,orcerebrovasculardiseaseisacriticalstepwhenchoosingavasoconstrictor.Additionally,pharmacistswillberesponsiblefordeveloping
policiesandproceduresthatoutlinewhichmedicationsmustbeinitiatedandadministeredinanICUversusageneralmedicinefloor,baseduponmedicationsafety
profilesandtheabilityofstafftoroutinelyassessthesafetyoftherapy.
TheuseofvasoconstrictorsforthetreatmentofHRSisdifferentthanitisforthetreatmentofpatientswithtypicalvasodilatoryshock.Outliningaplanfortitrationof
vasopressiniscriticalbecausemostcliniciansareunfamiliarwithusingthismedicationoutsideofafixeddosingstrategyforthemanagementofsepticshock.
Additionally,thepharmacistshoulddesignamonitoringstrategyforthephysicianandnursingstafftoquicklyidentifyadversedrugevents,includingcardiac
arrhythmiasandsignsofsplanchnicordigitalischemia.Responsetotherapyisusuallymuchslower,sothetitrationofmedicationsisalsomoremethodical.Education
forthephysicianandnursingstaffisnecessarytoensurethegoalsoftherapyareachievedinasafemanner.Pharmacistscanoutlinerealisticexpectationsfor
vasoconstrictortherapy.Itshouldbediscussedthatresponsetovasoconstrictortherapyisonly25%to50%andcanbevariablebetweenpatients,dependingontheir
underlyingreasonforhepaticdecompensation.Itmaytake2to3daysforUOPtoimproveandSCrtostabilizeandstarttodecreaseafterstartingtherapy.
Additionally,ifnoresponseinUOPorSCrhasoccurredafter4daysofappropriatevasoconstrictortherapy,initiatingthediscussionaboutthefutilityofcontinued
therapyisneeded.

CONCLUSIONS
HRSisthemostsignificantdiseasewithinthespectrumofhepatorenaldisordersandcariesasubstantialmortalityrate.HRSphysiologyischaracterizedbythe
following4mainfeatures:splanchnicarterialvasodilationcausingreducedeffectivearterialvolume,renalvasoconstrictionasaresultofactivationofthesympathetic
nervoussystemandtheRAAS,reducedcardiacoutputastheresultofcirrhoticcardiomyopathy,andreleaseofvasoactivemediatorsthataffectrenalbloodflowand
glomerularmicrocirculatoryhemodynamics.PatientswithType1HRS(HRSAKI)haveamorerapidriseintheirSCrvaluesandshortersurvivaltimeswhencompared
withpatientswithTypeIIHRS.
TheabsenceofparenchymalkidneydamageinpatientswithHRSmakeslivertransplantationthedefinitivetreatmentoptionandresultsinasustainedreversalofrenal
failure.HRSpatientswhoundergolivertransplantationhavesimilarmortalitytopatientswithoutHRS.Othertherapeuticoptionscanbeusedasabridgeto
transplantationhowever,mostevidenceisderivedfromsmall,uncontrolledstudies.Artificialhepaticsupportdevicesandrenalreplacementtherapyareeffectivefor
correctingabnormallaboratoryvalues,butthedecisiontodeliverthesetherapiesshouldbelimitedtopatientswhohaveanindicationfordialysisandarehighonthe
livertransplantlist.DuetocontraindicationsinmanypatientswithTypeIHRS,TIPSiscommonlyreservedforpatientswithTypeIIHRSwithrefractoryascites.
Thebestpharmacologictherapiesarethosethatreverseportalhypertension,splanchnicvasodilation,and/orrenalvasoconstriction.Thevasopressinanalogue,
terlipressin,incombinationwithalbuminvolumeexpansion,isthepreferredpharmacologictherapyforthemanagementofpatientswithHRS2,10,16norepinephrineand
vasopressinarealternativesifterlipressinisunavailable.TitratingvasoconstrictorstoincreaseMAPbygreaterthan10mmHgfrombaselineistheinitialstepbecause
aresponseinUOPandSCrmaytakeafewdays.SomeSCrresponse(e.g.,agreaterthan25%decreaseinSCr)totherapyshouldbeobservedwithinthefirst4days
oftreatment,withcompleteresponseoccurringamedianof7daysaftertherapyinitiationformostpatients.72AfteracompleteresponseinSCrisobtained,titrationoff
ofvasoconstrictortherapyshouldbeattemptedtoevaluatethesustainabilityofresponse.ReinitiationoftherapyshouldbeconsideredifanHRSrelapseoccurs.
Octreotideandmidodrineappeartobeaneffectivepharmacologicregimen,particularlyforpatientswithTypeIIHRS.Additionally,itmayprovideaconvenient
alternativetointravenoustherapy.Regardlessofchosenvasoconstrictortherapy,carefulmonitoringisneededtoensuretissueischemiaandsevereadverseeffects
donotoccur.
SubstantialprogressinunderstandingthepathophysiologyandmanagementofHRShasbeenmadeoverthelastdecade.Nevertheless,currentpharmacologic

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treatmentoptionsareonlyusefultoimproveshorttermsurvivalandthenecessarybridgetolivertransplantation.Giventhesignificantgapsinknowledgeregardingthe
treatmentofHRSandthemorbidity,mortality,andcostassociated,moreevidenceisurgentlyneededtohelpimprovepatientoutcomesinthisdifficultpopulation.

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