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Hepatorenalsyndrome
Author
BruceARunyon,MD

SectionEditor
RichardHSterns,MD

DeputyEditor
JohnPForman,MD,MSc

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Apr2016.|Thistopiclastupdated:Aug18,2015.
INTRODUCTIONThehepatorenalsyndromeisoneofmanypotentialcausesofacutekidneyinjuryin
patientswithacuteorchronicliverdisease.Affectedpatientsusuallyhaveportalhypertensionduetocirrhosis,
severealcoholichepatitis,or(lessoften)metastatictumors,butcanalsohavefulminanthepaticfailurefrom
anycause[13].Thehepatorenalsyndromerepresentstheendstageofasequenceofreductionsinrenal
perfusioninducedbyincreasinglyseverehepaticinjury.Thehepatorenalsyndromeisadiagnosisofexclusion
andisassociatedwithapoorprognosis.
Thistopicwillreviewthehepatorenalsyndromeindetail.Overviewsofthecomplicationsoffulminanthepatic
failureandcirrhosisareprovidedelsewhere.(See"Acuteliverfailureinadults:Managementandprognosis"
and"Cirrhosisinadults:Overviewofcomplications,generalmanagement,andprognosis".)
PATHOGENESISArterialvasodilatationinthesplanchniccirculation,whichistriggeredbyportal
hypertension,appearstoplayacentralroleinthehemodynamicchangesandthedeclineinrenalfunctionin
cirrhosis[13].Thepresumedmechanismisincreasedproductionoractivityofvasodilators,mainlyinthe
splanchniccirculation,withnitricoxidethoughttobemostimportant[1,4,5].
Asthehepaticdiseasebecomesmoresevere,thereisaprogressiveriseincardiacoutputandfallinsystemic
vascularresistancethelatterchangeoccursdespitelocalincreasesinrenalandfemoralvascularresistance
thatresultinpartfromhypotensioninducedactivationofthereninangiotensinandsympatheticnervous
systems(figure1)[13,6].Thus,thereductionintotalvascularresistanceresultsfromdecreasedvascular
resistanceinthesplanchniccirculation[6],perhapsinpartundertheinfluenceofnitricoxidederivedfromthe
endothelium.Bacterialtranslocationfromtheintestineintothemesentericlymphnodesmayplayanimportant
roleinthisprocess[1,7,8].Areviewofthehemodynamicchangesseenwithprogressivecirrhosiscanbe
foundinaseparatetopicreview.(See"Pathogenesisofascitesinpatientswithcirrhosis".)
Thedeclineinrenalperfusioninthissettingisassociatedwithreductionsinglomerularfiltrationrate(GFR)and
sodiumexcretion(oftentolessthan10meq/dayinadvancedcirrhosis)[9,10]andafallinmeanarterial
pressure,despitetheintenserenalvasoconstriction[10].Theimportanceofsplanchnicvasodilatationinthese
changescanbeindirectlyillustratedbytheresponsetoornipressin,ananalogofantidiuretichormone(arginine
vasopressin)thatisapreferentialsplanchnicvasoconstrictor[11].
Inpatientswithadvancedcirrhosis,theadministrationofornipressinorothervasopressinanalogspartially
correctsmanyofthesystemicandrenalhemodynamicabnormalitiesthatarepresent(figure2)theseinclude
anelevationinmeanarterialpressure,reductionsinplasmareninactivityandnorepinephrineconcentration,
andincreasesinrenalbloodflow,GFR(from18to29mL/min),andurinarysodiumexcretionandvolume.
Inaddition,acutelyloweringrenalsympathetictoneandrenalvascularresistanceintheearlystagesof
hepatorenalsyndromebytheintravenousadministrationofthesympatholyticagent,clonidine,canraisethe
GFRbyasmuchas25percent[12].However,thisbenefitdoesnotappeartobesustainedwithchronicoral
therapy,despiteapersistentreductioninsympatheticactivity[13].
Theresponsetocreationofaportasystemicshuntalsosupportstheimportanceofsplanchnichemodynamics
inthegenesisofthehepatorenalsyndrome.Portasystemicshuntinghasimprovedrenalfunctioninalimited
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numberofpatientswiththehepatorenalsyndrome[14],butitisinfrequentlyusedastreatmentforthisdisorder
[15].Onereport,however,suggestedthatthereductioninintrahepaticpressureinducedbythismodalitymay
preventthedevelopmentofthehepatorenalsyndrome.Thisretrospectivestudyevaluated204patientswith
varicealbleedingwhoweretreatedwitheitheraportasystemicshuntorsclerotherapy(orothernonshunt
modalities)[16].Portasystemicshuntingwasassociatedwithalowerincidenceofascites(15versus73
percent)andhepatorenalsyndrome(4versus21percent),ahigherincidenceofencephalopathy,andno
differenceinoverallpatientsurvival.
EPIDEMIOLOGYPatientswhodevelopthehepatorenalsyndromeusuallyhaveportalhypertensiondueto
cirrhosis,severealcoholichepatitis,or,lessoften,metastatictumors[13].However,patientswithfulminant
hepaticfailurefromanycausemaydevelophepatorenalsyndrome.
Theincidenceofhepatorenalsyndromewasevaluatedinaprospectivestudyof229nonazotemicpatientswith
cirrhosisandascites:thehepatorenalsyndromedevelopedin18and39percentatoneandfiveyears,
respectively[10].Patientswithhyponatremiaandahighplasmareninactivitywereathighestrisk.These
signsofneurohumoralactivationpresumablyreflectedamoreseveredeclineineffectiveperfusion[1,6].
Hepatorenalsyndromealsooccursfrequentlyinpatientswithacuteliverdisease.Inastudyofpatientswith
alcoholichepatitis,forexample,hepatorenalsyndromeoccurredin28of101patients[17].
Althoughhepatorenalsyndromecanbeseeninmostformsofseverehepaticdisease,patientswithprimary
biliarycholangitisappearrelativelyprotected[18].Sodiumretention,ascitesformation,andthehepatorenal
syndromealltendtooccurlessofteninprimarybiliarycholangitis,possiblydueinparttothenatriureticand
renalvasodilatoractionsofretainedbilesalts.
CLINICALPRESENTATIONThehepatorenalsyndromeischaracterizedbythefollowingfeaturesina
patientwhohasestablishedorclinicallyevidentacuteorchronicliverdisease[13,10,19]:

Aprogressiveriseinserumcreatinine
Anoftennormalurinesediment
Noorminimalproteinuria(lessthan500mgperday)
Averylowrateofsodiumexcretion(ie,urinesodiumconcentrationlessthan10meq/L)
Oliguria

However,notallpatientswithhepatorenalsyndromehaveoliguria(especiallyearlyinitscourse),aprogressive
riseinserumcreatinine,andabenignurinesediment.Urinevolumesmaybehigherthanpreviously
appreciated.Somestudies,forexample,havefoundthattheurinevolumemayexceed400mLperday,with
markedlyloweroutputbeingobservedonlywithinafewdaysfromdeath[20,21].Inaddition,theserum
creatininemayincreasebyaslittleas0.1mg/dL(9micromol/L)perday,withintermittentperiodsof
stabilizationorevenslightimprovement.Lastly,theurinesedimentmayshowavarietyofabnormalities,such
ashematuriaduetobladderinstrumentationandunderlyingcoagulopathy,andgranularcastsdueto
hyperbilirubinemia.
Basedupontherapidityofthedeclineinkidneyfunction,twoformsofhepatorenalsyndromehavebeen
described[1,19,22]:
Type1hepatorenalsyndromeType1hepatorenalsyndromeisthemoreserioustypeitisdefinedas
atleastatwofoldincreaseinserumcreatinine(reflectinga50percentreductionincreatinineclearance)to
alevelgreaterthan2.5mg/dL(221micromol/L)duringaperiodoflessthantwoweeks.Atthetimeof
diagnosis,somepatientswithtype1hepatorenalsyndromehaveaurineoutputlessthan400to500mL
perday[19,21].
Type2hepatorenalsyndromeType2hepatorenalsyndromeisdefinedasrenalimpairmentthatis
lessseverethanthatobservedwithtype1disease.Themajorclinicalfeatureinpatientswithtype2
hepatorenalsyndromeisascitesthatisresistanttodiuretics.
PrecipitantsTheonsetofrenalfailureistypicallyinsidiousbutcanbeprecipitatedbyanacuteinsult,such
asbacterialinfectionorgastrointestinalbleeding[10,19,23].Spontaneousbacterialperitonitis,forexample,can
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triggerprogressivehepatorenalsyndrome,althoughitismorelikelytooccurinpatientswhoalreadyhavesome
degreeofrenalinsufficiency[24,25].(See"Spontaneousbacterialperitonitisinadults:Treatmentand
prophylaxis",sectionon'Albuminadministrationforpatientswithrenaldysfunction'.)
Whentype1hepatorenalsyndromeresultsfrombacterialinfection,antibiotictherapyalonedoesnotusually
leadtoimprovementinrenalfunction.Inonestudy,forexample,hepatorenalsyndromefailedtoimprovein47
of70patients(67percent)treatedwithantibioticsalone[26].Thus,patientswithtype1hepatorenalsyndrome
precipitatedbyinfectionshouldreceiveothertherapiesdescribedbelow,particularlyifrenalfunctionfailsto
improveafterseveraldaysofantibiotictherapy.(See'Treatment'below.)
Althoughoverlyrapiddiuresishasoftenbeenmentionedasaprecipitantofhepatorenalsyndrome,perhaps
becausemostpatientsaretakingdiureticswhenthesyndromeisdiagnosed,diureticsdonotcause
hepatorenalsyndrome.Diureticscan,however,causeazotemia,particularlyiffluidisremovedtoorapidlyin
patientswithoutperipheraledema.Diureticinducedazotemiaimproveswiththecessationoftherapyandfluid
repletion.Incomparison,thehepatorenalsyndrometypicallyworsensinexorably,evenafterdiureticsare
stopped.(See"Ascitesinadultswithcirrhosis:Initialtherapy",sectionon'Diuretictherapy'.)
ProblemswithestimatingkidneyfunctionPatientswithhepatorenalsyndromemayhaverenal
dysfunctionthatissubstantiallymoreseverethanissuggestedbytheserumcreatinine.Bothureaand
creatinineproductionmaybesubstantiallyreducedinthissetting,duetotheliverdiseaseandtodecreased
musclemassanddecreasedproteinandmeatintake.Theneteffectisthataserumcreatininethatappearsto
bewithinthenormalrange(eg,1to1.3mg/dL[88.4to115micromol/L])maybeassociatedwithaglomerular
filtrationrate(GFR)thatrangesfromaslowas20to60mL/mintoaclearlynormalvalueabove100mL/min,
dependingprimarilyuponmusclemass.(See"Assessmentofkidneyfunction",sectionon'Usingcreatinineto
estimateGFR'.)
Thebloodureanitrogen(BUN)isvariableinthesepatients.ForagivenGFR,itmaybelowerorhigherthan
expected.Ifproteinintakeisverylow,reducedureaproductionmayresultinalowBUNandalowBUNto
creatinineratio.Incontrast,ifproteinintakeisadequate,increasedpassivereabsorptionofureaintheproximal
tubule,drivenbyenhancedproximaltubularreabsorptionofsodiumandwater,canresultinahighBUNanda
highBUNtocreatinineratio.(See"Etiologyanddiagnosisofprerenaldiseaseandacutetubularnecrosisin
acutekidneyinjury(acuterenalfailure)".)
DIAGNOSISHepatorenalsyndromeisdiagnosedbaseduponclinicalcriteria.Thereisnoonespecifictest
thatcanestablishthediagnosis.Investigationalurinarybiomarkerssuchasneutrophilgelatinaseassociated
lipocalin(NGAL)tendtobelowerinprerenalazotemiaandhepatorenalsyndromethaninacutetubularnecrosis
(ATN),butthereisconsiderableoverlapbetweentheseconditions[2729].Inaddition,hepatorenalsyndromeis
adiagnosisofexclusion,meaningthatotherpotentialetiologiesofacuteorsubacutekidneyinjuryinpatients
withliverdiseaseshouldbeconsideredunlikelybeforeadiagnosisofhepatorenalsyndromeismade.
Thefollowingdefinitionanddiagnosticcriteriahavebeenproposedforthehepatorenalsyndrome[1,19,22,30]:
Chronicoracutehepaticdiseasewithadvancedhepaticfailureandportalhypertension.
Acutekidneyinjury,definedasanincreaseinserumcreatinineof0.3mg/dL(26.5micromol/L)ormore
within48hours,oranincreasefrombaselineof50percentormorewithinsevendays[30]thisdefinition
ofacutekidneyinjuryisconsistentwithKDIGOcriteria(see"Definitionofacutekidneyinjury(acuterenal
failure)").However,somecliniciansmayprefertousetheolderdefinitionofacuteorsubacutekidney
injury,specificallyariseinserumcreatininetoabove1.5mg/dL(133micromol/L)thathasprogressed
overdaystoweeks.Asnotedabove,theriseinserumcreatininewithreductionsinglomerularfiltration
rate(GFR)maybeminimalduetothemarkedreductionincreatinineproductionamongsuchpatients.
(See'Problemswithestimatingkidneyfunction'above.)
Theabsenceofanyotherapparentcausefortheacutekidneyinjury,includingshock,currentorrecent
treatmentwithnephrotoxicdrugs,andtheabsenceofultrasonographicevidenceofobstructionor
parenchymalrenaldisease.Spontaneousbacterialperitonitisiscomplicatedbyacutekidneyinjurythat
maybereversiblein30to40percentofpatients.ItcanbeassociatedwithATN,butitisalsoamajor
precipitantofthehepatorenalsyndrome.Thus,ongoinginfectionwithspontaneousbacterialperitonitis
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shouldnotexcludethepossibilityofhepatorenalsyndrome.Thismeansthattherapyforhepatorenal
syndromecancommencewhilethebacterialinfectionisstillbeingtreated.Inaddition,hepatorenal
syndromecanoccurinpatientswithpreexistingchronickidneydisease[31].Thus,thepresenceof
anotherrenaldiagnosis(eg,diabeticnephropathy)doesnotnecessarilyexcludehepatorenalsyndrome.
(See"Spontaneousbacterialperitonitisinadults:Treatmentandprophylaxis",sectionon'Albumin
administrationforpatientswithrenaldysfunction'.)
Inconjunctionwithexcludingotherapparentcausesofrenaldisease,thefollowingcriteriaalsoapply:
Urineredcellexcretionoflessthan50cellsperhighpowerfield(whennourinarycatheterisin
place)andproteinexcretionlessthan500mg/day.
Lackofimprovementinrenalfunctionaftervolumeexpansionwithintravenousalbumin(1g/kgof
bodyweightperdayupto100g/day)foratleasttwodaysandwithdrawalofdiuretics.
Asnotedabove,patientsdiagnosedwithhepatorenalsyndromeareclassifiedastype1hepatorenalsyndrome
(moresevere)ortype2hepatorenalsyndrome(lesssevere)basedupontherapidityoftheacutekidneyinjury
andthedegreeofrenalimpairment.Type1hepatorenalsyndromeispresentiftheserumcreatinineincreases
byatleasttwofoldtoavaluegreaterthan2.5mg/dL(221micromol/L)duringaperiodoflessthantwoweeks.
Lessrapidlyprogressivediseaseisclassifiedastype2.
DIFFERENTIALDIAGNOSISThediagnosisofthehepatorenalsyndromeisoneofexclusion,entertained
onlyafterotherpotentialcausesofacuteorsubacutekidneyinjuryhavebeenruledout[32].Asexamples:
Bothglomerulonephritisandvasculitiscanoccurinpatientswithliverdiseaseandshouldbesuspectedin
patientswithanactiveurinesedimentcontainingredcellsandredcellandothercasts.(See"Clinical
presentationanddiagnosisofIgAnephropathy"and"Overviewofrenaldiseaseassociatedwithhepatitis
Cvirusinfection"and"RenaldiseaseassociatedwithhepatitisBvirusinfection".)
Obesitywithfattyliverisarelativelycommoncauseofcirrhosis.Manyofthesepatientshavediabetesand
candevelopdiabeticnephropathy.(See"Epidemiology,clinicalfeatures,anddiagnosisofnonalcoholicfatty
liverdiseaseinadults".)Aprospectivestudyfrom2011thatanalyzed562patientswithcirrhosisandrenal
functionimpairmentatasinglecenterfoundthathepatorenalsyndromewaslesscommonthanprerenalor
infectionassociatedkidneyinjury[32].Ofthe463patientsinthisstudyinwhomadiagnosiscouldbemade,
thefollowingfrequencieswerenoted:
Kidneyinjuryassociatedwithinfection(suchassepsisorspontaneousbacterialperitonitis)46percent
Prerenalacutekidneyinjury32percent
Hepatorenalsyndrome13percent
Parenchymalrenaldisease(suchasglomerulonephritis)9percent
Thefrequencyofacutetubularnecrosis(ATN)inthisstudywasnotdefined,althougholdercaseseriesreport
that10to20percentofpatientswithacutekidneyinjuryinthesettingofcirrhosishaveATN[32].Itispossible
thatATNislesscommonnow,duetoavoidanceofnephrotoxinssuchasnonsteroidalantiinflammatorydrugs
andaminoglycosidesinthesepatients.Inaddition,someexpertsbelievethatsomepatientswithongoing
infection(principallyspontaneousbacterialperitonitisintheabsenceofsepticshock)canhavehepatorenal
syndromesinceasubstantialproportionofsuchpatients(18percentinonereport)havepersistentor
progressivekidneyinjurydespitesuccessfulantibiotictherapyforperitonitis[22].Thus,asmentionedabove,
thepresenceofspontaneousbacterialperitonitisshouldnotexcludethediagnosisofhepatorenalsyndrome.
Kidneybiopsyisnotcommonlyperformedinpatientswithcirrhosisandacutekidneyinjury,particularlywhen
thereisminimalhematuriaandproteinuria.Asanexample,inaseriesof65patientswithcirrhosisandrenal
diseasewhounderwenttransjugularkidneybiopsy,only18patientshadnoproteinuriaandnohematuria[33].
Ofthese18patients,glomerularlesionswereidentifiedin10(suchasIgAnephropathy,membranoproliferative
glomerulonephritis,ordiabeticnephropathy),andATNwasidentifiedin7.Transjugularkidneybiopsy,
performedbyaninterventionalradiologist,canbeconsiderediftheresultmayhaveanimpactontreatmentand
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ifsuchtreatmentcouldoutweighthepotentialharmsassociatedwiththeinterventionalprocedure.Although
thereisacommonmisconceptionthatthekidneysarehistologicallynormal,arelativelyspecificbutsubtleand
reversiblerenallesionhasbeendescribedglomerulartubularreflux[34].
Distinguishingthehepatorenalsyndromefromtheseotherdisordersisclinicallyimportantbecauseofthe
markeddifferenceinprognosis.ATNandmostcausesofprerenaldiseasearegenerallyreversible.Incontrast,
theprognosisispoorinthehepatorenalsyndrome(especiallytype1),withmostpatientsdyingwithinweeksof
theonsetofrenalinjuryunlesslivertransplantationisperformedoreffectivetreatmentisgiven[10,35].
AcutetubularnecrosisPatientswithcirrhosismaydevelopATNafteracourseofaminoglycosidetherapy,
theadministrationofaradiocontrastagent,oranepisodeofsepsisorbleedingwithadecreaseinblood
pressure[1].ThepresenceofATNisusuallysuspectedfromthehistoryandfromtheoftenrapidriseinthe
serumcreatinine,whichcontraststotheusuallygradualriseinhepatorenalsyndrome.Anunresolvedissueis
whethertheprolongedrenalischemiainthehepatorenalsyndromecan,insomecases,leadtoATN[1,19].
SomeofthetraditionallaboratorymethodsusedtodistinguishprerenaldiseasefromATNmaynotbehelpfulin
patientswithhepaticdisease.Asanexample,ATNisusuallyassociatedwithafractionalexcretionofsodium
above2percentandgranularandepithelialcellcastsintheurinesediment.Calculatorsareavailableto
computethefractionalexcretionofsodium:(calculator1)and(calculator2).
However,thefractionalexcretionofsodiummayremainbelow1percentinpatientswithcirrhosiswhodevelop
ATNduetothepersistentrenalischemiainducedbythehepaticdisease[36].Theurinalysisalsomaybe
misleading.Granularandepithelialcellcastsmaybeseenwithmarkedhyperbilirubinemiaaloneandare
thereforenotdiagnosticofATNhowthisoccursisnotunderstood.(See"Etiologyanddiagnosisofprerenal
diseaseandacutetubularnecrosisinacutekidneyinjury(acuterenalfailure)"and"Fractionalexcretionof
sodium,urea,andothermoleculesinacutekidneyinjury(acuterenalfailure)".)
PrerenaldiseaseThehepatorenalsyndromehasbeendifficulttodistinguishfromprerenalazotemia.
Prerenaldiseaseinpatientswithcirrhosiscanbeinducedbygastrointestinalfluidlosses,bleeding,ortherapy
withadiureticoranonsteroidalantiinflammatorydrug(sincerenalvasodilatorprostaglandinsinpartmaintain
renalperfusioninthissetting)[1,37].(See"NSAIDs:Acutekidneyinjury(acuterenalfailure)".)
Thus,thediagnosisofthehepatorenalsyndromerequiresthattherebenoimprovementinrenalfunction
followingdiscontinuationofpotentialnephrotoxinsandatrialoffluidrepletion.Inaddition,emergingkidney
biomarkersmayprovehelpfulindistinguishingprerenaldisease,hepatorenalsyndrome,andATNinpatients
withcirrhosis[27].
TREATMENT
ApproachtotherapyTheidealtherapyforhepatorenalsyndromeisimprovementofliverfunctionfrom
recoveryofalcoholichepatitis,treatmentofdecompensatedhepatitisBwitheffectiveantiviraltherapy,
recoveryfromacutehepaticfailure,orlivertransplantation[38,39].Theabilityofliverfunctiontoimprovewith
abstinencefromalcoholandeffectiveantiviraltherapyofhepatitisBisremarkable.(See'Improvinghepatic
function'below.)
However,whenimprovementofliverfunctionisnotpossibleintheshortterm,werecommendthatmedical
therapybeinstitutedinanattempttoreversetheacutekidneyinjuryassociatedwithhepatorenalsyndrome.
Oursuggestionsregardingthechoiceofmedicaltherapydependuponseveralfactors,including:whetherthe
patientisadmittedtotheintensivecareunittheavailabilityofcertaindrugs,forwhichthereisnationaland
regionalvariabilityandwhetherthepatientisacandidateforlivertransplantation:
Inpatientswithhepatorenalsyndromewhoarecriticallyill,wesuggestinitialtreatmentwith
norepinephrineincombinationwithalbumin.Norepinephrineisgivenintravenouslyasacontinuous
infusion(0.5to3mg/hr)withthegoalofraisingthemeanarterialpressureby10mmHg,andalbuminis
givenforatleasttwodaysasanintravenousbolus(1g/kgperday[100gmaximum]).Intravenous
vasopressinmayalsobeeffective,startingat0.01units/minandtitratingupwardasneededtoraisethe
meanarterialpressureasnotedbelow.(See'Norepinephrineforpatientsintheintensivecareunit'below.)
Inpatientswithhepatorenalsyndromewhoarenotcriticallyill,oursuggestionsdependuponthe
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availabilityofcertaindrugs:
Whereterlipressintherapyisavailable,wesuggestinitialtreatmentwithterlipressinincombination
withalbumin.Terlipressinisgivenasanintravenousbolus(1to2mgeveryfourtosixhours),and
albuminisgivenfortwodaysasanintravenousbolus(1g/kgperday[100gmaximum]),followed
by25to50gramsperdayuntilterlipressintherapyisdiscontinued.(See'Terlipressinplusalbumin
whereavailable'below.)
Whereterlipressintherapyisnotavailable(principallytheUnitedStates),wesuggestinitial
treatmentwithacombinationofmidodrine,octreotide,andalbumin.Midodrineisgivenorally
(startingat7.5mgandincreasingthedoseateighthourintervalsuptoamaximumof15mgby
mouththreetimesdaily),octreotideiseithergivenasacontinuousintravenousinfusion(50mcg/hr)
orsubcutaneously(100to200mcgthreetimesdaily),andalbuminisgivenfortwodaysasan
intravenousbolus(1g/kgperday[100gmaximum]),followedby25to50gramsperdayuntil
midodrineandoctreotidetherapyisdiscontinued.(See'Midodrine,octreotide,andalbuminwhere
terlipressinisnotavailable'below.)
Inhighlyselectedpatientswhofailtorespondtomedicaltherapywiththeaboveregimensandwho
areconsideredwellenoughtoundergotheprocedure,transjugularintrahepaticportosystemicshunt
(TIPS)issometimessuccessful.However,thisprocedureisassociatedwithnumerouscomplications
and,becauseoftheneedforintravenouscontrast,itmaycauseacutekidneyinjury.Forthisreason,
someexpertspreferdialysisasafirstoption(continuousrenalreplacementtherapy)inmostcases,
particularlyforpatientswhoseserumcreatinineremainsabove1.5mg/dLdespitemedicaltherapy.(See
'Transjugularintrahepaticportosystemicshunt'below.)
Inpatientswhofailtorespondtotheabovetherapies,developseverelyimpairedrenalfunction,andeither
arecandidatesforlivertransplantationorhaveareversibleformofliverinjuryandareexpectedto
survive,werecommenddialysisasabridgetolivertransplantationorliverrecovery.(See'Dialysis'
below.)
ThegoalofmedicaltherapyorTIPSinpatientswithhepatorenalsyndromeisreversaloftheacutekidney
injury.Inaddition,whenpatientsaretreatedwithnorepinephrine,terlipressin,ormidodrineplusoctreotide,an
immediategoaloftherapyistoraisethemeanarterialpressurebyapproximately10to15mmHg.Ina
systematicreviewof501patientswithhepatorenalsyndromefrom21studies,themagnitudeoftheincreasein
meanarterialpressureinducedbythesevasoconstrictorswassignificantlyassociatedwiththemagnitudeof
thedecreaseinserumcreatinine[40].Asanexample,a9mmHgincreaseinmeanarterialpressurepredicted
a1mg/dL(88.4micromol/L)decreaseinserumcreatinine.Theauthorsalsopredictedthatanincreaseinmean
arterialpressureof9to13mmHgwouldbenecessarytoachieveresolutioninmostpatientswithtype1
hepatorenalsyndrome.
Inpatientstreatedwithnorepinephrine,terlipressin,oroctreotide,weusuallytreatforatotaloftwoweeks.
However,weandothersoccasionallytreatforlongerdurations(uptoonemonthormore)ifthereissomebut
notcompleteimprovementinrenalfunctionaftertwoweeksoftherapy.Inpatientswhorespondtotherapy,we
occasionallytreatindefinitelywithmidodrinetomaintainahighermeanarterialpressure(oruntilliver
transplantationorresolutionofliverinjury).Manypatientswhorecoverfromtype1hepatorenalsyndrome
continuetohaverefractoryascites,andmidodrinemaybeeffectiveinsuchpatients[41].Incontrast,ifa
patienthasnoimprovementinrenalfunctionaftertwoweeks,therapywiththesedrugscanbeconsidered
futile.
Thefollowingsectionswillreviewthedifferenttherapiesthathavebeenevaluatedinthetreatmentof
hepatorenalsyndrome.Issuesrelatedtothetreatmentofascitesinpatientswithcirrhosis(eg,fluidandsodium
intake,diuretictherapy)arediscussedseparately.(See"Ascitesinadultswithcirrhosis:Initialtherapy"and
"Ascitesinadultswithcirrhosis:Diureticresistantascites"and'Precipitants'above.)
ImprovinghepaticfunctionThebesthopeforreversaloftherenalfailureisanimprovementinhepatic
functionduetopartialresolutionoftheprimarydiseaseortosuccessfullivertransplantation[4245].
Improvementintheunderlyingliverdiseaseismostimpressiveinpatientswithalcoholicliverdisease
(particularlyseverealcoholichepatitis)withabstinenceorwithdecompensatedcirrhosisduetohepatitisB
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virusinfectiontreatedwithantiviraltherapy[46,47].
Resolutionoftype1hepatorenalsyndromewasexaminedin62patientsundergoinglivertransplantation(mean
pretransplantserumcreatinine,3.4mg/dL[300micromol/L])atasinglecenterovera10yearperiod[45].Of
these,resolutionofhepatorenalsyndrome(definedasaserumcreatinine<1.5mg/dL[133micromol/L]andno
dialysisrequirement)occurredin47patients(76percent).Theremainingpatientseitherdiedorrequiredlong
termdialysis.Themeandurationofdialysispriortolivertransplantationwastheonlysignificantpredictorof
resolution(10daysamongthosewhoresolvedversus25daysamongthosewhodidnot).
NorepinephrineforpatientsintheintensivecareunitAlthoughnotusuallyavailableonthegeneral
medicalward,norepinephrinecanbeadministeredintheintensivecareunitandhasbeenusedsuccessfullyin
patientswithhepatorenalsyndrome[48].Vasopressin,alsoavailableintheintensivecareunit,maybe
effectiveinpatientswithhepatorenalsyndrome[49].
Ametaanalysisoffouropenlabeltrialsincluding154patientswithtype1hepatorenalsyndrome(rangein
meanserumcreatinine,2.1to3.2mg/dL[186to283micromol/L])comparedtherapywithterlipressinplus
albuminversusnorepinephrineplusalbumin[50].Thefollowingresultswereobtained,neitherofwhichwere
statisticallysignificant:
Resolutionofhepatorenalsyndrome(definedasafallintheserumcreatininetobelow1.5mg/dL[133
micromol/L])occurredin59percentofpatientsreceivingterlipressinand58percentofpatientsreceiving
norepinephrine.
The30daysurvivalratewas50percentwithterlipressinand47percentwithnorepinephrine.
Althoughtheefficacyofterlipressinandnorepinephrineappearedsimilar,adverseevents(mostlyabdominal
pain,chestpain,orarrhythmia)weresignificantlymorecommonwithterlipressin(28versus8percent).In
addition,thecostofterlipressintherapyismorethanthreetimesthecostofnorepinephrinetherapy[51].
Thus,wesuggestnorepinephrineratherthanterlipressinorothertherapiesfortreatmentofhepatorenal
syndromeinpatientswhoareadmittedtotheintensivecareunit.
PatientsnotintheintensivecareunitOptimalmedicaltherapyforpatientswithhepatorenalsyndrome
whoarenotadmittedtotheintensivecareunitvariesaccordingtowhetherterlipressinisavailable.
TerlipressinplusalbuminwhereavailableVasopressinanditsanalogs(ornipressinandterlipressin)
shouldtheoreticallyreducesplanchnicvasodilation.Asanexample,whenornipressinwasadministeredin
combinationwitheitherinfusionofalbuminoraperitoneovenousshunt(toexpandtheeffectivearterialblood
volumeandreducethereleaseofvasoconstrictorssuchasangiotensinIIandnorepinephrine),therewasan
increaseinglomerularfiltrationrate(GFR)(figure2)[11,52,53].
Anothervasopressinanalog,terlipressin,hasalsobeenexaminedasatreatmentforhepatorenalsyndromein
severalrandomizedtrialsand,whenavailable,ispreferredtherapyinpatientswithhepatorenalsyndromewho
cannotreceivenorepinephrine(typicallythosenotinanintensivecaresetting)[5460].Thebestdatacome
fromatrialthatrandomlyassigned49patientstoterlipressin(startingat3mginfusedover24hours,titratedas
neededto12mgover24hours)ormidodrineplusoctreotide(midodrinestartingorallyat7.5mgthricedailyand
octreotideat100mcgsubcutaneouslythricedaily,increasedasneededto12.5mgthricedailyand200mcg
thricedaily,respectively)allpatientsalsoreceivedintravenousalbumin(1g/kgonday1,andthen20to40
g/daythereafter)[54].Terlipressinsignificantlyincreasedtherateofcompleteresponse(adecreaseinserum
creatininetolessthan1.5mg/dL[133micromol/L]at14days)comparedwithmidodrineandoctreotide(56
versus5percent),andthetrialwasterminatedearlybecauseofthisresult.Apartialresponse(a50percentor
greaterimprovementinserumcreatininewithoutfallingbelowthecompleteresponsethreshold)occurredin15
percentofpatientsreceivingterlipressinandin24percentofpatientsreceivingmidodrineandoctreotide.
Survivaldidnotdifferbetweenthegroups,althoughsixpatientswhofailedtorespondwithmidodrineand
octreotideweretreatedwithterlipressinandhadimprovementintheirrenalfunction.Treatmentrelatedadverse
eventsdidnotdifferbetweenthetwotherapies.
Thisstudyhasseverallimitations.Asanexample,bloodpressurewassignificantlyhigherinpatientsreceiving
terlipressinthaninpatientsreceivingmidodrine,andmidodrinedoseswerenotincreasedto15mgthricedaily
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astheyoftenareinclinicalpractice.Thus,thedifferenceinoutcomescouldrepresentadifferenceinthe
degreeofsplanchnicvasoconstrictionandbloodpressureratherthanadifferenceattributabletodrugclass
[61].Also,thestudydidnottreattoatargetincreaseinbloodpressure(see'Approachtotherapy'above).Asa
result,studiesareneededinwhichthemidodrinedoseischosentoattainanincreaseinbloodpressure
comparabletoterlipressin.
Althoughthisheadtoheadtrialwassmallandunblinded,theprevioustrialsofterlipressininpatientswith
hepatorenalsyndromecomparedthedrugwithalbuminalone,placebo,ornotherapy,ratherthananactive
comparator.Inametaanalysisoftheseearliertrials,terlipressintherapysignificantlyreducedmortality
comparedwithalbuminaloneornotherapy(54versus73percent)andincreasedtheproportionofpatientswho
achievedreversalofhepatorenalsyndrome(54versus11percent),butitalsoincreasedtherateof
cardiovascularadverseevents(11versus0percent)[62].
Thesedatasuggestthatterlipressintherapymayimproverenalfunctioncomparedwithothertherapiesand
mayreducemortalitycomparedwithalbuminaloneornotherapy.Thus,forpatientswithhepatorenalsyndrome
whoarenotadmittedtotheintensivecareunit,wesuggestcombinationtherapywithterlipressinplusalbumin
ratherthanothertherapies.However,terlipressinisnotavailableintheUnitedStates.Whenterlipressinisnot
available,combinationtherapywithmidodrine,octreotide,andalbuminisusedforpatientsnotintheintensive
careunit.(See'Midodrine,octreotide,andalbuminwhereterlipressinisnotavailable'below.)
Midodrine,octreotide,andalbuminwhereterlipressinisnotavailableTherapywithmidodrine(a
selectivealpha1adrenergicagonist),octreotide(asomatostatinanalog),andalbuminmaybehighlyeffective
andsafeinpatientswithhepatorenalsyndrome.Midodrineisasystemicvasoconstrictor,andoctreotideisan
inhibitorofendogenousvasodilatorrelease(whichproducessplanchnicvasoconstriction)combinedtherapy
theoreticallyimprovesrenalandsystemichemodynamics[63].
Inanonrandomizedstudyof13consecutivepatientswithtype1hepatorenalsyndrome,thefirsteightwere
treatedwithintravenousdopamine(2to4mcg/kgpermin)andthelastfivepatientsweretreatedwithoral
midodrine(7.5to12.5mgthreetimesdaily)plusoctreotide(100to200mcgsubcutaneouslythreetimesdaily)
[64].Bothgroupsalsoreceivedintravenousalbumindailyduringtreatment.Thegoaloftherapywastoraise
themeanarterialpressureby15mmHg.Thefollowingresultswerereported:
Amongthefivepatientswhoreceivedmidodrineandoctreotide,meanarterialpressure,renalplasma
flow,GFR,andurinevolumeallincreased.Amongthosewhoreceiveddopamine,therewasnochangein
theseparameters.
Threeofthefivepatientstreatedwithmidodrineandoctreotidesurvivedtohospitaldischarge.Ofthese,
onesuccessfullyunderwentlivertransplantation,anotherwasaliveat472days,andthethirdultimately
diedafterdiscontinuingtherapy.Amongthetwowhowerenotdischarged,onediscontinuedtherapyafter
twomonthsandwassuccessfullytransplanted,whiletheotherdiedat29daysofpneumoniadespite
totalrecoveryofrenalfunction.Minimalsideeffects,includingtingling,goosebumps,anddiarrhea,were
observed.Incontrast,sevenoftheeightpatientswhoreceiveddopaminediedduringthefirsttwelve
days.Onepatientrecoveredrenalfunctionandsurvivedtobetransplanted.
Additionaldatasubstantiatethepotentialefficacyandsafetyofoctreotideandmidodrine.Inaretrospective
study,60patientswithhepatorenalsyndromeweretreatedwithmidodrine(upto15mgthreetimesdaily),
octreotide(200mcgsubcutaneouslythreetimesdaily),andalbumin,and21concurrentpatientsonlyreceived
albumin[21].Therapywithmidodrineandoctreotidewasassociatedwithsignificantlylowermortality(43
versus71percent)andasignificantlyhigherproportionofpatientswhohadresolutionofhepatorenalsyndrome
(40versus10percent).
Inourexperience,thespeedwithwhicheffectivetreatmentisachievedappearstobeimportant.Thus,we
prefercontinuousinfusionofoctreotideat50mcg/hrratherthansubcutaneousinjection.Thiscanbedelivered
onageneralmedicalward.Themidodrinedoseshouldbeincreasedwitheachconsecutivedoseinorderto
achieveanincreaseinbloodpressurerapidly.Itisourexperiencethat15mgthreetimesperdaymaybemore
effectivethan12.5mgthreetimesperday.Changingthedoseafter24hoursonthepriordoseraisestheblood
pressuretooslowlyandmayleadtofailureoftherapy.
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Incontrasttocombinationtherapywithmidodrineandoctreotide,octreotidemonotherapydoesnotappeartobe
beneficial.Inarandomizedcrossoverstudy,14patientswithhepatorenalsyndromeweretreatedwithfourdays
ofoctreotideplusalbuminandfourdaysofalbuminaloneinrandomorder[65].Responsetotherapywas
identicalwithbothtreatments.Midodrinealoneorincombinationwithalbumin(butwithoutoctreotide)hasnot
beenevaluatedinpatientswithtype1hepatorenalsyndrome.
Thus,forpatientswithhepatorenalsyndromewhoarenotadmittedtotheintensivecareunitandforwhom
terlipressinisunavailable,wesuggestcombinationtherapywithoctreotide,midodrine,andalbuminratherthan
othertherapies.
PatientswhodonotrespondtoinitialmedicaltherapyTreatmentoptionsforpatientswhodonot
respondtooneofthemedicaltherapieslistedaboveincludeTIPSanddialysis.
TransjugularintrahepaticportosystemicshuntThetransjugularintrahepaticportosystemicshunt
(TIPS)hasbeenusedinthetreatmentofrefractoryascites.(See"Transjugularintrahepaticportosystemic
shunts:Indicationsandcontraindications".)
Whenusedinthissetting,theremayalsobeadelayedimprovementinrenalfunction[6670].Inonestudy,for
example,theaverageplasmacreatinineconcentrationwas1.5mg/dL(132micromol/L)atbaseline,was
unchangedatoneweek,andfellto0.9mg/dL(80micromol/L)bysixmonths[66].Inanotherseries,therewas
anonsignificanttrendtowardanincreaseinGFR(65mL/minatbaselineto76mL/minatfourweeks)[68].
ThereismuchlessinformationontheuseofTIPSinpatientswhofulfillcriteriaforthehepatorenalsyndrome
[15].Onereportdescribed16suchpatients,sixofwhomhadseverehepatorenalsyndrome(definedasa
serumcreatinineof2.5mg/dL[220micromol/L]orhigher,oracreatinineclearancebelow20mL/min)[69].
Withintwoweeks,therewasanapproximatedoublingofthecreatinineclearancewithaproportionatereduction
intheserumcreatinineandanincreaseinurinarysodiumexcretion.Additionalimprovementsinrenalfunction
occurredovertheensuingsixtoeightweeks.Onlythreepatientsfailedtorespond,allofwhomdiedwithinsix
weeksafterTIPS.
Anotherseriesevaluatedsevenpatientswithcirrhosisandhepatorenalsyndrome,definedasadoublingofthe
serumcreatininetomorethan2.5mg/dL(221micromol/L)ora50percentreductionincreatinineclearanceto
below20mL/mininlessthantwoweeks,despitevolumeexpansion[70].InsertionofaTIPSwasassociated
withagradualimprovementinGFR(9to27mL/min),reductionsinthebloodureanitrogen(BUN)andserum
creatinine,and,inmostpatients,areductionintheactivityofthereninangiotensinandsympatheticnervous
systemssuggestinganimprovementinsystemichemodynamics.TheaveragesurvivalfollowingTIPS
placementwasapproximatelyfivemonths,whichislongerthantheexpectedsurvivalofsuchpatients.
Unfortunately,manypatientswithhepatorenalsyndromearetooilltoundergoTIPS.Inastudythatdeviseda
predictionmodeltodeterminesurvivalfollowingelectiveTIPS,thosepatientswithtype1hepatorenal
syndromehaveapredicted90daymortalityfollowingTIPSofatleast25percentifcirrhosisisduetoalcoholic
orcholestaticliverdiseaseandatleast80percentifcirrhosisisduetoothercauses[71].Apredictionmodel
scoringsystembaseduponthesurvivalof231patientswhounderwentelectiveTIPSwasdevisedtopredict
survivalaftertheprocedure.
Inaddition,TIPSisassociatedwithvariouscomplications[15]:
Anincreaseintherateofhepaticencephalopathy
Aworseningofliverfunction(markedbyariseinserumbilirubin)
Ableedingcomplicationduetotheprocedure
Ariskofrenalinjuryassociatedwithintravenouscontrast,whichisoftennecessary,evenifcarbon
dioxideisusedasthemaincontrastagent
Overall,theseresultssuggestthat,inselectedpatientswithhepatorenalsyndrome,TIPSmayprovideshort
termbenefit.Giventherisksassociatedwiththisprocedure(particularlythehighincidenceofencephalopathy),
itshouldbeconsideredonlyasalastresortinselectedpatients.
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DialysisPatientswithhepatorenalsyndromewhoprogresstorenalfailurecanbetreatedwithdialysis,
whichismostcommonlydonewhenpatientsareawaitingalivertransplantorwhenthereisthepossibilityof
improvementinliverfunction.Inaddition,dialysisimprovesthepriorityscoreforthetransplantintheUnited
States.Inoneretrospective,singlecenterstudy,30percentofpatientswhorequireddialysissurvivedtoliver
transplantation[72].
Survivalondialysisisgenerallylimitedbytheseverityofthehepaticfailure[73],aswellasconcurrent
respiratoryfailure[74].Patientswithanacuteandpotentiallyreversiblehepaticinsultmayparticularlybenefit
fromdialysissincerenalfunctionwillrecoverinparallelwithimprovinghepaticfunction[43].
Hemodialysisisfrequentlydifficulttoperforminpatientswithhepatorenalsyndromesincedecompensated
hepaticfunctionisassociatedwithhemodynamicinstability.Somesuccesshasbeenrealizedwithcontinuous
renalreplacementmodalities[75].(See"Continuousrenalreplacementtherapyinacutekidneyinjury(acute
renalfailure)".)
OthertherapiesAnumberofotherdrugshavebeentriedforthetreatmentofhepatorenalsyndrome,such
asmisoprostol,Nacetylcysteine,andangiotensinconvertingenzymeinhibitors.Noneoftheseapproachesare
consistentlyassociatedwithbenefit,andthereforenonearerecommended.Inrarepatients,aperitoneovenous
shuntisused.
PeritoneovenousshuntAperitoneovenousshunt,whichdrainsperitonealfluidfromtheperitoneuminto
theinternaljugularvein,reinfusesascitesintothevascularspace.Thismodalityhasbeenusedinpatients
withrefractoryascitesandrenalfailureduetothehepatorenalsyndrome[35,7680].Inthesesettings,the
increaseinfluidreturntothecardiopulmonarycirculationcanleadsequentiallytodecreasedactivityofsodium
retainingandvasoconstrictivemechanisms(suchasthereninangiotensinaldosteronesystem),amarkedrise
inurinarysodiumexcretion,andamodestelevationinGFR[35,76,79].
However,itisnowrarelyusedbecauseofanappreciablerateofcomplicationsandthelackofevidencethat
peritoneovenousshuntingprolongspatientsurvival,whichmaybeseveralyearsinpatientswithnormalor
nearnormalhepaticandrenalfunctiontestsbutlessthansixweeksinpatientswiththehepatorenalsyndrome
[35,77,78,81,82].
Themajorproblemwiththeperitoneovenousshuntistherelativelyhighrateofcomplications,including
disseminatedintravascularcoagulation(duetoentryintothebloodstreamofendotoxinorotherprocoagulant
materialintheasciticfluid),infectionoftheshunt,whichcanleadtobacteremia,varicealbleedingresulting
fromvolumeexpansionandaconcurrentriseinportalvenouspressure,andsmallbowelobstruction
[76,83,84].
Theneteffectisthattheperioperativemortalitycanreach25percentinpatientswithadvanceddisease
[83,84].Incomparison,peritoneovenousshuntingisrelativelywelltoleratedinpatientswithascitesbut
relativelynormalrenalfunction[77,78].Furthermore,theperioperativemorbiditycanbediminishedif,priorto
insertionoftheshunt,thereisintraoperativedrainageoftheascites,whichisthenreplacedby5litersof
isotonicsaline[77,84].Thisregimencanminimizethosecomplicationsrelatedtomassiveascitesinfusion:
disseminatedintravascularcoagulationandincreasedportalpressure.
Theonlyremainingindicationsforperitoneovenousshuntare:
Unusualformsofascitessuchaschylousascites.
Postlivertransplantpatientwithrefractoryascites.
PatientswithcirrhosisanddiureticresistantasciteswhoarenotcandidatesfortransplantationorTIPS
andwhoaretooobeseorhavetoomanyabdominalsurgicalscarstopermitsafe,successful
paracentesis.(See"Ascitesinadultswithcirrhosis:Diureticresistantascites".)
PREVENTIONHepatorenalsyndromeregularlydevelopsinpatientswithsystemicbacterialinfection(eg,
spontaneousbacterialperitonitis[SBP])and/orseverealcoholichepatitis.Thefollowingtherapiesmayprevent
thedevelopmentofhepatorenalsyndromeinthesepatients:
IntravenousalbuminInpatientswithSBP,theadministrationofintravenousalbumin(1.5g/kg)atthe
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timeofdiagnosisofinfectionandanotherdoseofalbumin(1g/kg)onday3ofantibiotictreatment
reducestheincidenceofbothrenalimpairmentandmortality.Ametaanalysisoffourcontrolledtrials
(withatotalof288patients)evaluatedtheimpactofalbumininfusion(inadditiontoantibiotics)onrenal
impairmentandmortalityinpatientswithSBP[85].Albumininfusionwasassociatedwithasignificant
decreaseintheincidenceofrenalimpairment(8versus31percent)andasignificantreductioninmortality
(16versus35percent).ThesedatasupporttheuseofalbumininfusioninpatientswithSBP.(See
"Spontaneousbacterialperitonitisinadults:Treatmentandprophylaxis",sectionon'Albumin
administrationforpatientswithrenaldysfunction'.)
NorfloxacinArandomizedtrialreportedsignificantbenefitswiththeoraladministrationofnorfloxacinat
400mg/dayto68patientswithcirrhosisandasciticfluidtotalprotein<1.5g/dLwhofulfilledeitherofthe
followingtwocriteria:aChildPughscore>9pointsandserumbilirubin>3mg/dL(51.3micromol/L)ora
serumcreatinine>1.2mg/dL[106micromol/L]orbloodureanitrogen(BUN)>20mg/dLorserumsodium
<130meq/L[86].Norfloxacinwasassociatedwiththefollowingsignificantbenefits:decreasedoneyear
probabilityofSBP(7versus61percent)andhepatorenalsyndrome(28versus41percent),andimproved
survivalatthreemonths(94versus62percent)andoneyear(60percentversus48percent).Basedupon
theseandotherfindings,werecommendtheuseofnorfloxacininselectedpatientswithcirrhosisand
ascitesspecificrecommendationsarediscussedelsewhere.(See"Spontaneousbacterialperitonitisin
adults:Treatmentandprophylaxis",sectionon'Prophylaxis'.)
PentoxifyllineAninitialtrialof61patientswithcirrhosis,ascites,andabaselinecreatinineclearanceof
41to80mL/minper1.73m2showedsignificantbenefitwithpentoxifylline(1200mg/day)forsixmonths
ascomparedwithplacebo[87].However,asubsequentmetaanalysisdemonstratednobenefiton
hepatorenalsyndromeormortality[88].(See"Alcoholichepatitis:Naturalhistoryandmanagement",
sectionon'Pentoxifylline'.)
PROGNOSISOverall,themortalityofpatientswithliverfailureissubstantiallyworseiftheydevelop
hepatorenalsyndrome[89].Withouttherapy,mostpatientsdiewithinweeksoftheonsetoftherenal
impairment.Inturn,theoutcomeofpatientswithhepatorenalsyndrome,aswellasrecoveryofkidneyfunction,
isstronglydependentuponreversalofthehepaticfailure,whetherspontaneous,followingmedicaltherapy,or
followingsuccessfullivertransplantation[90].
Therateofrecoveryofkidneyfunctionfollowingrecoveryofliverfailureisuncertainreportedratesare
affectedbyvaryingpretransplantkidneyfunctionanddifferencesovertimeinindicationsfordialysisandin
eligibilityforlivertransplantation.However,asubstantialproportionofpatientswhohaveprogressedtodialysis
andsurvivetoreceivealivertransplantdorecoverkidneyfunction[91].(See"Renalfunctionandnonrenal
solidorgantransplantation".)
SUMMARYANDRECOMMENDATIONS
Thehepatorenalsyndromeisoneofmanypotentialcausesofacutekidneyinjuryinpatientswithacuteor
chronicliverdisease.Affectedpatientsusuallyhaveportalhypertensionduetocirrhosis,severealcoholic
hepatitis,or(lessoften)metastatictumors,butcanalsohavefulminanthepaticfailurefromanycause.
(See'Introduction'above.)
Arterialvasodilatationinthesplanchniccirculation,whichistriggeredbyportalhypertension,appearsto
playacentralroleinthehemodynamicchangesandthedeclineinrenalfunctioninthehepatorenal
syndrome.Thepresumedmechanismisincreasedproductionoractivityofvasodilators,mainlyinthe
splanchniccirculation,withnitricoxidethoughttobemostimportant.Asthehepaticdiseasebecomes
moresevere,thereisaprogressiveriseincardiacoutputandfallinsystemicvascularresistancethe
latterchangeoccursdespitelocalincreasesinrenalandfemoralvascularresistancethatresultinpart
fromhypotensioninducedactivationofthereninangiotensinandsympatheticnervoussystems(figure1).
(See'Pathogenesis'above.)
Patientswhodevelopthehepatorenalsyndromeusuallyhaveportalhypertensionduetocirrhosis,severe
alcoholichepatitis,and,lessoften,metastatictumors.However,patientswithfulminanthepaticfailure
fromanycausemaydevelophepatorenalsyndrome.Inpatientswithcirrhosisandascites,the
hepatorenalsyndromeoccursinapproximately20and40percentatoneandfiveyears,respectively.In
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patientswithacuteliverdisease,thehepatorenalsyndromeoccursinapproximately25to30percent.
(See'Epidemiology'above.)
Thehepatorenalsyndromeisusuallycharacterizedbythefollowingfeaturesinapatientwhohas
establishedorclinicallyevidentacuteorchronicliverdisease(see'Clinicalpresentation'above):
Aprogressiveriseinserumcreatinine
Abenignurinesediment
Noorminimalproteinuria(lessthan500mgperday)
Averylowrateofsodiumexcretion(ie,urinesodiumconcentrationlessthan10meq/L)
Oliguria
Basedupontherapidityofthedeclineinkidneyfunction,twoformsofhepatorenalsyndromehavebeen
described(see'Clinicalpresentation'above):
Type1hepatorenalsyndromeType1hepatorenalsyndromeisthemoreserioustypeitisdefined
asatleastatwofoldincreaseinserumcreatinine(reflectinga50percentreductionincreatinine
clearance)toalevelgreaterthan2.5mg/dL(221micromol/L)duringaperiodoflessthantwo
weeks.Atthetimeofdiagnosis,somepatientswithtype1hepatorenalsyndromehaveaurine
outputlessthan400to500mLperday.
Type2hepatorenalsyndromeType2hepatorenalsyndromeisdefinedasrenalimpairmentthatis
lessseverethanthatobservedwithtype1disease.Themajorclinicalfeatureinpatientswithtype2
hepatorenalsyndromeisascitesthatisresistanttodiuretics.
Theonsetofrenalfailureistypicallyinsidiousbutcanbeprecipitatedbyanacuteinsult,suchas
bacterialinfection(oftenspontaneousbacterialperitonitis)orgastrointestinalbleeding.Diureticsdonot
causehepatorenalsyndrome.(See'Precipitants'above.)
Patientswithhepatorenalsyndromemayhaverenaldysfunctionthatissubstantiallymoreseverethanis
suggestedbytheserumcreatinine.(See'Problemswithestimatingkidneyfunction'above.)
Hepatorenalsyndromeisdiagnosedbaseduponclinicalcriteria.Thereisnoonespecifictestthatcan
establishthediagnosis.Thefollowingdefinitionanddiagnosticcriteriahavebeenproposedforthe
hepatorenalsyndrome(see'Diagnosis'above):
Chronicoracutehepaticdiseasewithadvancedhepaticfailureandportalhypertension.
Acutekidneyinjury,definedasanincreaseinserumcreatinineof0.3mg/dL(26.5micromol/L)or
morewithin48hours,oranincreasefrombaselineof50percentormorewithinsevendays.
Theabsenceofanyotherapparentcausefortheacutekidneyinjury,includingshock,current,or
recenttreatmentwithnephrotoxicdrugs,andtheabsenceofultrasonographicevidenceof
obstructionorparenchymalrenaldisease.Spontaneousbacterialperitonitisiscomplicatedbyacute
kidneyinjurythatmaybereversiblein30to40percentofpatients.Itcanbeassociatedwithacute
tubularnecrosis(ATN),butitisalsoamajorprecipitantofthehepatorenalsyndrome.Thus,ongoing
infectionwithspontaneousbacterialperitonitisshouldnotexcludethepossibilityofhepatorenal
syndrome.Thismeansthattherapyforhepatorenalsyndromecancommencewhilethebacterial
infectionisstillbeingtreated.Inaddition,hepatorenalsyndromecanoccurinpatientswith
preexistingchronickidneydisease.Thus,thepresenceofanotherrenaldiagnosis(eg,diabetic
nephropathy)doesnotnecessarilyexcludehepatorenalsyndrome.
Inconjunctionwithexcludingotherapparentcausesofrenaldisease,thefollowingcriteriaalso
apply:
Urineredcellexcretionoflessthan50cellsperhighpowerfield(whennourinarycatheterisin
place)andproteinexcretionlessthan500mg/day.
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Lackofimprovementinrenalfunctionaftervolumeexpansionwithintravenousalbumin(1g/kgof
bodyweightperdayupto100g/day)foratleasttwodaysandwithdrawalofdiuretics.
Asnotedabove,patientsdiagnosedwithhepatorenalsyndromeareclassifiedastype1hepatorenal
syndrome(moresevere)ortype2hepatorenalsyndrome(lesssevere)basedupontherapidityofthe
acutekidneyinjuryandthedegreeofrenalimpairment.Type1hepatorenalsyndromeispresentifthe
serumcreatinineincreasesbyatleasttwofoldtoavaluegreaterthan2.5mg/dL(221micromol/L)duringa
periodoflessthantwoweeks.Lessrapidlyprogressivediseaseisclassifiedastype2.(See'Diagnosis'
above.)
Thediagnosisofthehepatorenalsyndromeisoneofexclusion,entertainedonlyafterotherpotential
causesofacuteorsubacutekidneyinjuryhavebeenruledout.Alternateetiologiesinclude,butarenot
limitedto,glomerulonephritis,prerenaldisease,andATN.(See'Differentialdiagnosis'above.)
Theidealtherapyforhepatorenalsyndromeisimprovementofliverfunctionfromeitherrecoveryof
alcoholichepatitis,treatmentofdecompensatedhepatitisBwitheffectiveantiviraltherapy,recoveryfrom
acutehepaticfailure,orlivertransplantation.(See'Approachtotherapy'aboveand'Improvinghepatic
function'above.)
However,whenimprovementofliverfunctionisnotpossibleintheshortterm,medicaltherapyshouldbe
institutedinanattempttoreversetheacutekidneyinjuryassociatedwithhepatorenalsyndrome.Our
suggestionsregardingthechoiceofmedicaltherapydependuponseveralfactors,including:whetherthe
patientisadmittedtotheintensivecareunittheavailabilityofcertaindrugs,forwhichthereisnational
andregionalvariabilityandwhetherthepatientisacandidateforlivertransplantation.(See'Approachto
therapy'above.)
Inpatientswithhepatorenalsyndromewhoareadmittedtotheintensivecareunit,wesuggestinitial
treatmentwithnorepinephrineincombinationwithalbuminratherthanothermedicaltherapies(Grade
2B).Norepinephrineisgivenintravenouslyasacontinuousinfusion(0.5to3mg/hr)withthegoalof
raisingthemeanarterialpressureby10mmHg,andalbuminisgivenforatleasttwodaysasan
intravenousbolus(1g/kgperday[100gmaximum]).Intravenousvasopressinmayalsobeeffective,
startingat0.01units/min.(See'Norepinephrineforpatientsintheintensivecareunit'above.)
Inpatientswithhepatorenalsyndromewhoarenotadmittedtotheintensivecareunit,oursuggestions
dependupontheavailabilityofcertaindrugs:
Whereterlipressintherapyisavailable,wesuggestinitialtreatmentwithterlipressinincombination
withalbuminratherthanmidodrine,octreotide,andalbumin(Grade2C).Terlipressinisgivenasan
intravenousbolus(1to2mgeveryfourtosixhours),andalbuminisgivenfortwodaysasan
intravenousbolus(1g/kgperday[100gmaximum]),followedby25to50gramsperdayuntil
terlipressintherapyisdiscontinued.(See'Terlipressinplusalbuminwhereavailable'above.)
Whereterlipressintherapyisnotavailable(principallytheUnitedStates),wesuggestinitial
treatmentwithacombinationofmidodrine,octreotide,andalbumin(Grade2C).Midodrineisgiven
orally(7.5to15mgbymouththreetimesdaily),octreotideiseithergivenasacontinuous
intravenousinfusion(50mcg/hr)orsubcutaneously(100to200mcgthreetimesdaily),andalbumin
isgivenfortwodaysasanintravenousbolus(1g/kgperday[100gmaximum]),followedby25to
50gramsperdayuntilmidodrineandoctreotidetherapyisdiscontinued.(See'Midodrine,octreotide,
andalbuminwhereterlipressinisnotavailable'above.)
Inhighlyselectedpatientswhofailtorespondtomedicaltherapywiththeaboveregimens,whoare
awaitinglivertransplantation,andwhoareconsideredwellenoughtoundergotheprocedure,transjugular
intrahepaticportosystemicshunt(TIPS)issometimessuccessfulhowevertheprocedureisassociated
withnumerouscomplications.(See'Transjugularintrahepaticportosystemicshunt'above.)
Inpatientswhofailtorespondtotheabovetherapies,developseverelyimpairedrenalfunction,arenot
consideredcandidatesforTIPS,andeitherarecandidatesforlivertransplantationorhaveareversible
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formofliverinjuryandareexpectedtosurvive,werecommenddialysisasabridgetolivertransplantation
orliverrecovery(Grade1B).Hemodialysisisfrequentlydifficulttoperforminpatientswithhepatorenal
syndrome,andsurvivalisgenerallylimitedbytheseverityofthehepaticfailure,aswellasconcurrent
respiratoryfailure.(See'Dialysis'above.)
ThegoalofmedicaltherapyorTIPSinpatientswithhepatorenalsyndromeisreversaloftheacutekidney
injury.Inaddition,whenpatientsaretreatedwithnorepinephrine,terlipressin,ormidodrineplusoctreotide,
animmediategoaloftherapyistoraisethemeanarterialpressurebyapproximately10to15mmHg.
(See'Approachtotherapy'above.)
Inpatientstreatedwithnorepinephrine,terlipressin,oroctreotide,weusuallytreatforatotaloftwo
weeks.However,weandothersoccasionallytreatforlongerdurations(uptoonemonthormore)ifthere
issomebutnotcompleteimprovementinrenalfunctionaftertwoweeksoftherapy.Inpatientswho
respondtotherapy,weoccasionallytreatindefinitelywithmidodrinetomaintainahighermeanarterial
pressure(oruntillivertransplantationorresolutionofliverinjury).Incontrast,ifapatienthasno
improvementinrenalfunctionaftertwoweeks,therapywiththesedrugscanbeconsideredfutile.(See
'Approachtotherapy'above.)
Thefollowingtherapiesmaypreventthedevelopmentofhepatorenalsyndromeinthesepatients(see
'Prevention'above):
Inpatientswithspontaneousbacterialperitonitis,werecommendtheadministrationofintravenous
albumin(1.5g/kg)atthetimeofdiagnosisofinfectionandanotherdoseofalbumin(1g/kg)onday3
ofantibiotictreatment(Grade1B).(See"Spontaneousbacterialperitonitisinadults:Treatmentand
prophylaxis".)
Inselectedpatientswithcirrhosisandascites,werecommendchronicnorfloxacintherapy(400
mg/day)(Grade1B).Adiscussionofwhichpatientsshouldreceivechronicnorfloxacintherapy,as
wellastheevidenceforthisgradedrecommendation,arepresentedelsewhere.(See"Spontaneous
bacterialperitonitisinadults:Treatmentandprophylaxis".)
Withouttherapy,mostpatientswithhepatorenalsyndromediewithinweeksoftheonsetoftherenal
impairment.Theoutcomeofpatientswithhepatorenalsyndrome,aswellasrecoveryofkidneyfunction,
isstronglydependentuponreversalofthehepaticfailure,whetherspontaneous,followingmedical
therapy,orfollowingsuccessfullivertransplantation.(See'Prognosis'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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