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Hepatorenalsyndrome

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Hepatorenalsyndrome
Author
BruceARunyon,MD

SectionEditor
RichardHSterns,MD

DeputyEditor
JohnPForman,MD,MSc

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Mar2015.|Thistopiclastupdated:Mar16,2015.
INTRODUCTIONThehepatorenalsyndromeisoneofmanypotentialcausesofacutekidneyinjuryinpatients
withacuteorchronicliverdisease.Affectedpatientsusuallyhaveportalhypertensionduetocirrhosis,severe
alcoholichepatitis,or(lessoften)metastatictumors,butcanalsohavefulminanthepaticfailurefromanycause[1
3].Thehepatorenalsyndromerepresentstheendstageofasequenceofreductionsinrenalperfusioninducedby
increasinglyseverehepaticinjury.Thehepatorenalsyndromeisadiagnosisofexclusionandisassociatedwitha
poorprognosis.
Thistopicwillreviewthehepatorenalsyndromeindetail.Overviewsofthecomplicationsoffulminanthepaticfailure
andcirrhosisareprovidedelsewhere.(See"Acuteliverfailureinadults:Managementandprognosis"and"Cirrhosis
inadults:Overviewofcomplications,generalmanagement,andprognosis".)
PATHOGENESISArterialvasodilatationinthesplanchniccirculation,whichistriggeredbyportalhypertension,
appearstoplayacentralroleinthehemodynamicchangesandthedeclineinrenalfunctionincirrhosis[13].The
presumedmechanismisincreasedproductionoractivityofvasodilators,mainlyinthesplanchniccirculation,with
nitricoxidethoughttobemostimportant[1,4,5].
Asthehepaticdiseasebecomesmoresevere,thereisaprogressiveriseincardiacoutputandfallinsystemic
vascularresistancethelatterchangeoccursdespitelocalincreasesinrenalandfemoralvascularresistancethat
resultinpartfromhypotensioninducedactivationofthereninangiotensinandsympatheticnervoussystems(figure
1)[13,6].Thus,thereductionintotalvascularresistanceresultsfromdecreasedvascularresistanceinthe
splanchniccirculation[6],perhapsinpartundertheinfluenceofnitricoxidederivedfromtheendothelium.Bacterial
translocationfromtheintestineintothemesentericlymphnodesmayplayanimportantroleinthisprocess[1,7,8].
Areviewofthehemodynamicchangesseenwithprogressivecirrhosiscanbefoundinaseparatetopicreview.(See
"Pathogenesisofascitesinpatientswithcirrhosis".)
Thedeclineinrenalperfusioninthissettingisassociatedwithreductionsinglomerularfiltrationrate(GFR)and
sodiumexcretion(oftentolessthan10meq/dayinadvancedcirrhosis)[9,10]andafallinmeanarterialpressure,
despitetheintenserenalvasoconstriction[10].Theimportanceofsplanchnicvasodilatationinthesechangescan
beindirectlyillustratedbytheresponsetoornipressin,ananalogofantidiuretichormone(argininevasopressin)that
isapreferentialsplanchnicvasoconstrictor[11].
Inpatientswithadvancedcirrhosis,theadministrationofornipressinorothervasopressinanaloguespartially
correctsmanyofthesystemicandrenalhemodynamicabnormalitiesthatarepresent(figure2)theseincludean
elevationinmeanarterialpressure,reductionsinplasmareninactivityandnorepinephrineconcentration,and
increasesinrenalbloodflow,GFR(from18to29mL/min),andurinarysodiumexcretionandvolume.
Inaddition,acutelyloweringrenalsympathetictoneandrenalvascularresistanceintheearlystagesofhepatorenal
syndromebytheintravenousadministrationofthesympatholyticagent,clonidine,canraisetheGFRbyasmuch
as25percent[12].However,thisbenefitdoesnotappeartobesustainedwithchronicoraltherapy,despitea
persistentreductioninsympatheticactivity[13].
Theresponsetocreationofaportasystemicshuntalsosupportstheimportanceofsplanchnichemodynamicsin
thegenesisofthehepatorenalsyndrome.Portasystemicshuntinghasimprovedrenalfunctioninalimitednumber
ofpatientswiththehepatorenalsyndrome[14],butitisinfrequentlyusedastreatmentforthisdisorder[15].One
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report,however,suggestedthatthereductioninintrahepaticpressureinducedbythismodalitymaypreventthe
developmentofthehepatorenalsyndrome.Thisretrospectivestudyevaluated204patientswithvaricealbleeding
whoweretreatedwitheitheraportasystemicshuntorsclerotherapy(orothernonshuntmodalities)[16].
Portasystemicshuntingwasassociatedwithalowerincidenceofascites(15versus73percent)andhepatorenal
syndrome(4versus21percent),ahigherincidenceofencephalopathy,andnodifferenceinoverallpatientsurvival.
EPIDEMIOLOGYPatientswhodevelopthehepatorenalsyndromeusuallyhaveportalhypertensiondueto
cirrhosis,severealcoholichepatitis,or,lessoften,metastatictumors[13].However,patientswithfulminant
hepaticfailurefromanycausemaydevelophepatorenalsyndrome.
Theincidenceofhepatorenalsyndromewasevaluatedinaprospectivestudyof229nonazotemicpatientswith
cirrhosisandascites:thehepatorenalsyndromedevelopedin18and39percentatoneandfiveyears,respectively
[10].Patientswithhyponatremiaandahighplasmareninactivitywereathighestrisk.Thesesignsofneurohumoral
activationpresumablyreflectedamoreseveredeclineineffectiveperfusion[1,6].
Hepatorenalsyndromealsooccursfrequentlyinpatientswithacuteliverdisease.Inastudyofpatientswith
alcoholichepatitis,forexample,hepatorenalsyndromeoccurredin28of101patients[17].
Althoughhepatorenalsyndromecanbeseeninmostformsofseverehepaticdisease,patientswithprimarybiliary
cirrhosisappearrelativelyprotected[18].Sodiumretention,ascitesformation,andthehepatorenalsyndromeall
tendtooccurlessofteninprimarybiliarycirrhosis,possiblydueinparttothenatriureticandrenalvasodilator
actionsofretainedbilesalts.
CLINICALPRESENTATIONThehepatorenalsyndromeischaracterizedbythefollowingfeaturesinapatient
whohasestablishedorclinicallyevidentacuteorchronicliverdisease[13,10,19]:

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

However,notallpatientswithhepatorenalsyndromehaveoliguria(especiallyearlyinitscourse),aprogressiverise
inserumcreatinine,andabenignurinesediment.Urinevolumesmaybehigherthanpreviouslyappreciated.Some
studies,forexample,havefoundthattheurinevolumemayexceed400mLperday,withmarkedlyloweroutput
beingobservedonlywithinafewdaysfromdeath[20,21].Inaddition,theserumcreatininemayincreasebyaslittle
as0.1mg/dL(9micromol/L)perday,withintermittentperiodsofstabilizationorevenslightimprovement.Lastly,
theurinesedimentmayshowavarietyofabnormalities,suchashematuriaduetobladderinstrumentationand
underlyingcoagulopathy,andgranularcastsduetohyperbilirubinemia.
Basedupontherapidityofthedeclineinkidneyfunction,twoformsofhepatorenalsyndromehavebeendescribed
[1,19,22]:
Type1hepatorenalsyndromeType1hepatorenalsyndromeisthemoreserioustypeitisdefinedasat
leastatwofoldincreaseinserumcreatinine(reflectinga50percentreductionincreatinineclearance)toa
levelgreaterthan2.5mg/dL(221micromol/L)duringaperiodoflessthantwoweeks.Atthetimeof
diagnosis,somepatientswithtype1hepatorenalsyndromehaveaurineoutputlessthan400to500mLper
day[19,21].
Type2hepatorenalsyndromeType2hepatorenalsyndromeisdefinedasrenalimpairmentthatisless
severethanthatobservedwithtype1disease.Themajorclinicalfeatureinpatientswithtype2hepatorenal
syndromeisascitesthatisresistanttodiuretics.
PrecipitantsTheonsetofrenalfailureistypicallyinsidiousbutcanbeprecipitatedbyanacuteinsult,suchas
bacterialinfectionorgastrointestinalbleeding[10,19,23].Spontaneousbacterialperitonitis,forexample,cantrigger
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progressivehepatorenalsyndrome,althoughitismorelikelytooccurinpatientswhoalreadyhavesomedegreeof
renalinsufficiency[24,25].(See"Spontaneousbacterialperitonitisinadults:Treatmentandprophylaxis",section
on'Albuminadministrationforpatientswithrenaldysfunction'.)
Whentype1hepatorenalsyndromeresultsfrombacterialinfection,antibiotictherapyalonedoesnotusuallylead
toimprovementinrenalfunction.Inonestudy,forexample,hepatorenalsyndromefailedtoimprovein47of70
patients(67percent)treatedwithantibioticsalone[26].Thus,patientswithtype1hepatorenalsyndrome
precipitatedbyinfectionshouldreceiveothertherapiesdescribedbelow,particularlyifrenalfunctionfailstoimprove
afterseveraldaysofantibiotictherapy.(See'Treatment'below.)
Althoughoverlyrapiddiuresishasoftenbeenmentionedasaprecipitantofhepatorenalsyndrome,perhaps
becausemostpatientsaretakingdiureticswhenthesyndromeisdiagnosed,diureticsdonotcausehepatorenal
syndrome.Diureticscan,however,causeazotemia,particularlyiffluidisremovedtoorapidlyinpatientswithout
peripheraledema.Diureticinducedazotemiaimproveswiththecessationoftherapyandfluidrepletion.In
comparison,thehepatorenalsyndrometypicallyworsensinexorably,evenafterdiureticsarestopped.(See
"Ascitesinadultswithcirrhosis:Initialtherapy",sectionon'Diuretictherapy'.)
ProblemswithestimatingkidneyfunctionPatientswithhepatorenalsyndromemayhaverenaldysfunction
thatissubstantiallymoreseverethanissuggestedbytheserumcreatinine.Bothureaandcreatinineproduction
maybesubstantiallyreducedinthissetting,duetotheliverdiseaseandtodecreasedmusclemassand
decreasedproteinandmeatintake.Theneteffectisthataserumcreatininethatappearstobewithinthenormal
range(eg,1to1.3mg/dL[88.4to115micromol/L])maybeassociatedwithaglomerularfiltrationrate(GFR)that
rangesfromaslowas20to60mL/mintoaclearlynormalvalueabove100mL/min,dependingprimarilyupon
musclemass.(See"Assessmentofkidneyfunction",sectionon'UsingcreatininetoestimateGFR'.)
Thebloodureanitrogen(BUN)isvariableinthesepatients.ForagivenGFR,itmaybelowerorhigherthan
expected.Ifproteinintakeisverylow,reducedureaproductionmayresultinalowBUNandalowBUNto
creatinineratio.Incontrast,ifproteinintakeisadequate,increasedpassivereabsorptionofureaintheproximal
tubule,drivenbyenhancedproximaltubularreabsorptionofsodiumandwater,canresultinahighBUNandahigh
BUNtocreatinineratio.(See"Etiologyanddiagnosisofprerenaldiseaseandacutetubularnecrosisinacute
kidneyinjury(acuterenalfailure)".)
DIAGNOSISHepatorenalsyndromeisdiagnosedbaseduponclinicalcriteria.Thereisnoonespecifictestthat
canestablishthediagnosis.Investigationalurinarybiomarkerssuchasneutrophilgelatinaseassociatedlipocalin
(NGAL)tendtobelowerinprerenalazotemiaandhepatorenalsyndromethaninacutetubularnecrosis(ATN),but
thereisconsiderableoverlapbetweentheseconditions[2729].Inaddition,hepatorenalsyndromeisadiagnosisof
exclusion,meaningthatotherpotentialetiologiesofacuteorsubacutekidneyinjuryinpatientswithliverdisease
shouldbeconsideredunlikelybeforeadiagnosisofhepatorenalsyndromeismade.
Thefollowingdefinitionanddiagnosticcriteriahavebeenproposedforthehepatorenalsyndrome[1,19,22]:
Chronicoracutehepaticdiseasewithadvancedhepaticfailureandportalhypertension.
Aserumcreatinineabove1.5mg/dL(133micromol/L)thatprogressesoverdaystoweeks(ie,acuteor
subacutekidneyinjury).Asnotedabove,theriseinserumcreatininewithreductionsinglomerularfiltration
rate(GFR)maybeminimalduetothemarkedreductionincreatinineproductionamongsuchpatients.(See
'Problemswithestimatingkidneyfunction'above.)
Theabsenceofanyotherapparentcausefortheacutekidneyinjury,includingshock,currentorrecent
treatmentwithnephrotoxicdrugs,andtheabsenceofultrasonographicevidenceofobstructionor
parenchymalrenaldisease.Spontaneousbacterialperitonitisiscomplicatedbyacutekidneyinjurythatmay
bereversiblein30to40percentofpatients.ItcanbeassociatedwithATN,butitisalsoamajorprecipitantof
thehepatorenalsyndrome.Thus,ongoinginfectionwithspontaneousbacterialperitonitisshouldnotexclude
thepossibilityofhepatorenalsyndrome.Thismeansthattherapyforhepatorenalsyndromecancommence
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whilethebacterialinfectionisstillbeingtreated.Inaddition,hepatorenalsyndromecanoccurinpatientswith
preexistingchronickidneydisease[30].Thus,thepresenceofanotherrenaldiagnosis(eg,diabetic
nephropathy)doesnotnecessarilyexcludehepatorenalsyndrome.(See"Spontaneousbacterialperitonitisin
adults:Treatmentandprophylaxis",sectionon'Albuminadministrationforpatientswithrenaldysfunction'.)
Inconjunctionwithexcludingotherapparentcausesofrenaldisease,thefollowingcriteriaalsoapply:
Urineredcellexcretionoflessthan50cellsperhighpowerfield(whennourinarycatheterisinplace)
andproteinexcretionlessthan500mg/day.
Lackofimprovementinrenalfunctionaftervolumeexpansionwithintravenousalbumin(1g/kgofbody
weightperdayupto100g/day)foratleasttwodaysandwithdrawalofdiuretics.
Asnotedabove,patientsdiagnosedwithhepatorenalsyndromeareclassifiedastype1hepatorenalsyndrome
(moresevere)ortype2hepatorenalsyndrome(lesssevere)basedupontherapidityoftheacutekidneyinjuryand
thedegreeofrenalimpairment.Type1hepatorenalsyndromeispresentiftheserumcreatinineincreasesbyat
leasttwofoldtoavaluegreaterthan2.5mg/dL(221micromol/L)duringaperiodoflessthantwoweeks.Less
rapidlyprogressivediseaseisclassifiedastype2.
DIFFERENTIALDIAGNOSISThediagnosisofthehepatorenalsyndromeisoneofexclusion,entertainedonly
afterotherpotentialcausesofacuteorsubacutekidneyinjuryhavebeenruledout[31].Asexamples:
Bothglomerulonephritisandvasculitiscanoccurinpatientswithliverdiseaseandshouldbesuspectedin
patientswithanactiveurinesedimentcontainingredcellsandredcellandothercasts.(See"Clinical
presentationanddiagnosisofIgAnephropathy"and"OverviewofrenaldiseaseassociatedwithhepatitisC
virusinfection"and"RenaldiseaseassociatedwithhepatitisBvirusinfection".)
Obesitywithfattyliverisarelativelycommoncauseofcirrhosis.Manyofthesepatientshavediabetesandcan
developdiabeticnephropathy.(See"Epidemiology,clinicalfeatures,anddiagnosisofnonalcoholicfattyliver
diseaseinadults".)Aprospectivestudyfrom2011thatanalyzed562patientswithcirrhosisandrenalfunction
impairmentatasinglecenterfoundthathepatorenalsyndromewaslesscommonthanprerenalorinfection
associatedkidneyinjury[31].Ofthe463patientsinthisstudyinwhomadiagnosiscouldbemade,thefollowing
frequencieswerenoted:
Kidneyinjuryassociatedwithinfection(suchassepsisorspontaneousbacterialperitonitis)46percent
Prerenalacutekidneyinjury32percent
Hepatorenalsyndrome13percent
Parenchymalrenaldisease(suchasglomerulonephritis)9percent
Thefrequencyofacutetubularnecrosis(ATN)inthisstudywasnotdefined,althougholdercaseseriesreportthat
10to20percentofpatientswithacutekidneyinjuryinthesettingofcirrhosishaveATN[31].ItispossiblethatATN
islesscommonnow,duetoavoidanceofnephrotoxinssuchasnonsteroidalantiinflammatorydrugsand
aminoglycosidesinthesepatients.Inaddition,someexpertsbelievethatsomepatientswithongoinginfection
(principallyspontaneousbacterialperitonitisintheabsenceofsepticshock)canhavehepatorenalsyndromesince
asubstantialproportionofsuchpatients(18percentinonereport)havepersistentorprogressivekidneyinjury
despitesuccessfulantibiotictherapyforperitonitis[22].Thus,asmentionedabove,thepresenceofspontaneous
bacterialperitonitisshouldnotexcludethediagnosisofhepatorenalsyndrome.
Kidneybiopsyisnotcommonlyperformedinpatientswithcirrhosisandacutekidneyinjury,particularlywhenthere
isminimalhematuriaandproteinuria.Asanexample,inaseriesof65patientswithcirrhosisandrenaldisease
whounderwenttransjugularkidneybiopsy,only18patientshadnoproteinuriaandnohematuria[32].Ofthese18
patients,glomerularlesionswereidentifiedin10(suchasIgAnephropathy,membranoproliferative
glomerulonephritis,ordiabeticnephropathy),andATNwasidentifiedin7.Transjugularkidneybiopsy,performedby
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aninterventionalradiologist,canbeconsiderediftheresultmayhaveanimpactontreatmentandifsuchtreatment
couldoutweighthepotentialharmsassociatedwiththeinterventionalprocedure.Althoughthereisacommon
misconceptionthatthekidneysarehistologicallynormal,arelativelyspecificbutsubtleandreversiblerenallesion
hasbeendescribedglomerulartubularreflux[33].
Distinguishingthehepatorenalsyndromefromtheseotherdisordersisclinicallyimportantbecauseofthemarked
differenceinprognosis.ATNandmostcausesofprerenaldiseasearegenerallyreversible.Incontrast,the
prognosisispoorinthehepatorenalsyndrome(especiallytype1),withmostpatientsdyingwithinweeksofthe
onsetofrenalinjuryunlesslivertransplantationisperformedoreffectivetreatmentisgiven[10,34].
AcutetubularnecrosisPatientswithcirrhosismaydevelopATNafteracourseofaminoglycosidetherapy,the
administrationofaradiocontrastagent,oranepisodeofsepsisorbleedingwithadecreaseinbloodpressure[1].
ThepresenceofATNisusuallysuspectedfromthehistoryandfromtheoftenrapidriseintheserumcreatinine,
whichcontraststotheusuallygradualriseinhepatorenalsyndrome.Anunresolvedissueiswhethertheprolonged
renalischemiainthehepatorenalsyndromecan,insomecases,leadtoATN[1,19].
SomeofthetraditionallaboratorymethodsusedtodistinguishprerenaldiseasefromATNmaynotbehelpfulin
patientswithhepaticdisease.Asanexample,ATNisusuallyassociatedwithafractionalexcretionofsodium
above2percentandgranularandepithelialcellcastsintheurinesediment.Calculatorsareavailabletocompute
thefractionalexcretionofsodium:(calculator1)and(calculator2).
However,thefractionalexcretionofsodiummayremainbelow1percentinpatientswithcirrhosiswhodevelopATN
duetothepersistentrenalischemiainducedbythehepaticdisease[35].Theurinalysisalsomaybemisleading.
Granularandepithelialcellcastsmaybeseenwithmarkedhyperbilirubinemiaaloneandarethereforenot
diagnosticofATNhowthisoccursisnotunderstood.(See"Etiologyanddiagnosisofprerenaldiseaseandacute
tubularnecrosisinacutekidneyinjury(acuterenalfailure)"and"Fractionalexcretionofsodium,urea,andother
moleculesinacutekidneyinjury(acuterenalfailure)".)
PrerenaldiseaseThehepatorenalsyndromehasbeendifficulttodistinguishfromprerenalazotemia.Prerenal
diseaseinpatientswithcirrhosiscanbeinducedbygastrointestinalfluidlosses,bleeding,ortherapywithadiuretic
oranonsteroidalantiinflammatorydrug(sincerenalvasodilatorprostaglandinsinpartmaintainrenalperfusionin
thissetting)[1,36].(See"NSAIDs:Acutekidneyinjury(acuterenalfailure)".)
Thus,thediagnosisofthehepatorenalsyndromerequiresthattherebenoimprovementinrenalfunctionfollowing
discontinuationofpotentialnephrotoxinsandatrialoffluidrepletion.Inaddition,emergingkidneybiomarkersmay
provehelpfulindistinguishingprerenaldisease,hepatorenalsyndrome,andATNinpatientswithcirrhosis[27].
TREATMENT
ApproachtotherapyTheidealtherapyforhepatorenalsyndromeisimprovementofliverfunctionfromrecovery
ofalcoholichepatitis,treatmentofdecompensatedhepatitisBwitheffectiveantiviraltherapy,recoveryfromacute
hepaticfailure,orlivertransplantation[37,38].Theabilityofliverfunctiontoimprovewithabstinencefromalcohol
andeffectiveantiviraltherapyofhepatitisBisremarkable.(See'Improvinghepaticfunction'below.)
However,whenimprovementofliverfunctionisnotpossibleintheshortterm,werecommendthatmedicaltherapy
beinstitutedinanattempttoreversetheacutekidneyinjuryassociatedwithhepatorenalsyndrome.Our
suggestionsregardingthechoiceofmedicaltherapydependuponseveralfactors,including:whetherthepatientis
admittedtotheintensivecareunittheavailabilityofcertaindrugs,forwhichthereisnationalandregional
variabilityandwhetherthepatientisacandidateforlivertransplantation:
Inpatientswithhepatorenalsyndromewhoareadmittedtotheintensivecareunit,wesuggestinitial
treatmentwithnorepinephrineincombinationwithalbumin.Norepinephrineisgivenintravenouslyasa
continuousinfusion(0.5to3mg/hr)withthegoalofraisingthemeanarterialpressureby10mmHg,and
albuminisgivenforatleasttwodaysasanintravenousbolus(1g/kgperday[100gmaximum]).Intravenous
vasopressinmayalsobeeffective,startingat0.01units/minandtitratingupwardasneededtoraisethemean
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arterialpressureasnotedbelow.(See'Norepinephrineforpatientsintheintensivecareunit'below.)
Inpatientswithhepatorenalsyndromewhoarenotadmittedtotheintensivecareunit,oursuggestions
dependupontheavailabilityofcertaindrugs:
Whereterlipressintherapyisavailable,wesuggestinitialtreatmentwithterlipressinincombinationwith
albumin.Terlipressinisgivenasanintravenousbolus(1to2mgeveryfourtosixhours),andalbuminis
givenfortwodaysasanintravenousbolus(1g/kgperday[100gmaximum]),followedby25to50
gramsperdayuntilterlipressintherapyisdiscontinued.(See'Terlipressinplusalbuminwhereavailable'
below.)
Whereterlipressintherapyisnotavailable(principallytheUnitedStates),wesuggestinitialtreatment
withacombinationofmidodrine,octreotide,andalbumin.Midodrineisgivenorally(startingat7.5mg
andincreasingthedoseateighthourintervalsuptoamaximumof15mgbymouththreetimesdaily),
octreotideiseithergivenasacontinuousintravenousinfusion(50mcg/hr)orsubcutaneously(100to200
mcgthreetimesdaily),andalbuminisgivenfortwodaysasanintravenousbolus(1g/kgperday[100g
maximum]),followedby25to50gramsperdayuntilmidodrineandoctreotidetherapyisdiscontinued.
(See'Midodrine,octreotide,andalbuminwhereterlipressinisnotavailable'below.)
Inhighlyselectedpatientswhofailtorespondtomedicaltherapywiththeaboveregimensandwhoare
consideredwellenoughtoundergotheprocedure,transjugularintrahepaticportosystemicshunt(TIPS)is
sometimessuccessful.However,thisprocedureisassociatedwithnumerouscomplicationsand,becauseof
theneedforintravenouscontrast,itmaycauseacutekidneyinjury.Forthisreason,someexpertsprefer
dialysisasafirstoption(continuousrenalreplacementtherapy)inmostcases,particularlyforpatientswhose
serumcreatinineremainsabove1.5mg/dLdespitemedicaltherapy.(See'Transjugularintrahepatic
portosystemicshunt'below.)
Inpatientswhofailtorespondtotheabovetherapies,developseverelyimpairedrenalfunction,andeitherare
candidatesforlivertransplantationorhaveareversibleformofliverinjuryandareexpectedtosurvive,we
recommenddialysisasabridgetolivertransplantationorliverrecovery.(See'Dialysis'below.)
ThegoalofmedicaltherapyorTIPSinpatientswithhepatorenalsyndromeisreversaloftheacutekidneyinjury.In
addition,whenpatientsaretreatedwithnorepinephrine,terlipressin,ormidodrineplusoctreotide,animmediate
goaloftherapyistoraisethemeanarterialpressurebyapproximately10to15mmHg.Inasystematicreviewof
501patientswithhepatorenalsyndromefrom21studies,themagnitudeoftheincreaseinmeanarterialpressure
inducedbythesevasoconstrictorswassignificantlyassociatedwiththemagnitudeofthedecreaseinserum
creatinine[39].Asanexample,a9mmHgincreaseinmeanarterialpressurepredicteda1mg/dL(88.4
micromol/L)decreaseinserumcreatinine.Theauthorsalsopredictedthatanincreaseinmeanarterialpressureof
9to13mmHgwouldbenecessarytoachieveresolutioninmostpatientswithtype1hepatorenalsyndrome.
Inpatientstreatedwithnorepinephrine,terlipressin,oroctreotide,weusuallytreatforatotaloftwoweeks.
However,weandothersoccasionallytreatforlongerdurations(uptoonemonthormore)ifthereissomebutnot
completeimprovementinrenalfunctionaftertwoweeksoftherapy.Inpatientswhorespondtotherapy,we
occasionallytreatindefinitelywithmidodrinetomaintainahighermeanarterialpressure(oruntilliver
transplantationorresolutionofliverinjury).Manypatientswhorecoverfromtype1hepatorenalsyndromecontinue
tohaverefractoryascites,andmidodrinemaybeeffectiveinsuchpatients[40].Incontrast,ifapatienthasno
improvementinrenalfunctionaftertwoweeks,therapywiththesedrugscanbeconsideredfutile.
Thefollowingsectionswillreviewthedifferenttherapiesthathavebeenevaluatedinthetreatmentofhepatorenal
syndrome.Issuesrelatedtothetreatmentofascitesinpatientswithcirrhosis(eg,fluidandsodiumintake,diuretic
therapy)arediscussedseparately.(See"Ascitesinadultswithcirrhosis:Initialtherapy"and"Ascitesinadultswith
cirrhosis:Diureticresistantascites"and'Precipitants'above.)
ImprovinghepaticfunctionThebesthopeforreversaloftherenalfailureisanimprovementinhepaticfunction
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duetopartialresolutionoftheprimarydiseaseortosuccessfullivertransplantation[4144].Improvementinthe
underlyingliverdiseaseismostimpressiveinpatientswithalcoholicliverdisease(particularlyseverealcoholic
hepatitis)withabstinenceorwithdecompensatedcirrhosisduetohepatitisBvirusinfectiontreatedwithantiviral
therapy[45,46].
Resolutionoftype1hepatorenalsyndromewasexaminedin62patientsundergoinglivertransplantation(meanpre
transplantserumcreatinine,3.4mg/dL[300micromol/L])atasinglecenterovera10yearperiod[44].Ofthese,
resolutionofhepatorenalsyndrome(definedasaserumcreatinine<1.5mg/dL[133micromol/L]andnodialysis
requirement)occurredin47patients(76percent).Theremainingpatientseitherdiedorrequiredlongtermdialysis.
Themeandurationofdialysispriortolivertransplantationwastheonlysignificantpredictorofresolution(10days
amongthosewhoresolvedversus25daysamongthosewhodidnot).
NorepinephrineforpatientsintheintensivecareunitAlthoughnotusuallyavailableonthegeneralmedical
ward,norepinephrinecanbeadministeredintheintensivecareunitandhasbeenusedsuccessfullyinpatientswith
hepatorenalsyndrome[47].Vasopressin,alsoavailableintheintensivecareunit,maybeeffectiveinpatientswith
hepatorenalsyndrome[48].
Ametaanalysisoffouropenlabeltrialsincluding154patientswithtype1hepatorenalsyndrome(rangeinmean
serumcreatinine,2.1to3.2mg/dL[186to283micromol/L])comparedtherapywithterlipressinplusalbuminversus
norepinephrineplusalbumin[49].Thefollowingresultswereobtained,neitherofwhichwerestatisticallysignificant:
Resolutionofhepatorenalsyndrome(definedasafallintheserumcreatininetobelow1.5mg/dL[133
micromol/L])occurredin59percentofpatientsreceivingterlipressinand58percentofpatientsreceiving
norepinephrine.
The30daysurvivalratewas50percentwithterlipressinand47percentwithnorepinephrine.
Althoughtheefficacyofterlipressinandnorepinephrineappearedsimilar,adverseevents(mostlyabdominalpain,
chestpain,orarrhythmia)weresignificantlymorecommonwithterlipressin(28versus8percent).Inaddition,the
costofterlipressintherapyismorethanthreetimesthecostofnorepinephrinetherapy[50].
Thus,wesuggestnorepinephrineratherthanterlipressinorothertherapiesfortreatmentofhepatorenalsyndromein
patientswhoareadmittedtotheintensivecareunit.
PatientsnotintheintensivecareunitOptimalmedicaltherapyforpatientswithhepatorenalsyndromewho
arenotadmittedtotheintensivecareunitvariesaccordingtowhetherterlipressinisavailable.
TerlipressinplusalbuminwhereavailableVasopressinanditsanalogs(ornipressinandterlipressin)
shouldtheoreticallyreducesplanchnicvasodilation.Asanexample,whenornipressinwasadministeredin
combinationwitheitherinfusionofalbuminoraperitoneovenousshunt(toexpandtheeffectivearterialbloodvolume
andreducethereleaseofvasoconstrictorssuchasangiotensinIIandnorepinephrine),therewasanincreasein
glomerularfiltrationrate(GFR)(figure2)[11,51,52].However,thisregimenmayalsoinducesignificantrenal
ischemia[51].
Anothervasopressinanalog,terlipressin,hasalsobeenexaminedasatreatmentforhepatorenalsyndromein
severalrandomizedtrials[5358].A2012Cochranemetaanalysissynthesizedtheresultsfromthesetrials[59]of
thesixtrialsincluded,threecomparedterlipressinplusalbuminwithalbuminalone,onecomparedterlipressin
alonewithalbuminalone,andtwocomparedterlipressinalonewitheitherplaceboornotherapy.Onlyoneofthe
trialswasdoubleblindthedoseanddurationofterlipressintherapyvariedacrossstudies.Thefollowingfindings
werereported:
Terlipressintherapysignificantlyreducedmortalitycomparedwithalbuminaloneornotherapy(54versus73
percent).
Inaddition,terlipressintherapysignificantlyincreasedtheproportionofpatientswhoachievedreversalof
hepatorenalsyndrome(54versus11percent).Reversalofhepatorenalsyndromewasvariablydefined,butin
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mosttrialsmeantachievingaserumcreatininelessthan1.5mg/dL(133micromol/L).
Althoughterlipressindidnotsignificantlyincreasetheriskofgastrointestinalsideeffectsorinfection,itdid
increasetherateofcardiovascularadverseevents(11versus0percent).
Thesedatasuggestthatterlipressintherapymayimproverenalfunctionandreducemortality.Thus,forpatients
withhepatorenalsyndromewhoarenotadmittedtotheintensivecareunit,wesuggestcombinationtherapywith
terlipressinplusalbuminratherthanothertherapies.However,terlipressinisnotavailableintheUnitedStates.
Whenterlipressinisnotavailable,combinationtherapywithmidodrine,octreotide,andalbuminisusedforpatients
notintheintensivecareunit.(See'Midodrine,octreotide,andalbuminwhereterlipressinisnotavailable'below.)
Midodrine,octreotide,andalbuminwhereterlipressinisnotavailableTherapywithmidodrine(a
selectivealpha1adrenergicagonist),octreotide(asomatostatinanalog),andalbuminmaybehighlyeffectiveand
safeinpatientswithhepatorenalsyndrome.Midodrineisasystemicvasoconstrictor,andoctreotideisaninhibitor
ofendogenousvasodilatorrelease(whichproducessplanchnicvasoconstriction)combinedtherapytheoretically
improvesrenalandsystemichemodynamics[60].
Inanonrandomizedstudyof13consecutivepatientswithtype1hepatorenalsyndrome,thefirsteightweretreated
withintravenousdopamine(2to4mcg/kgpermin)andthelastfivepatientsweretreatedwithoralmidodrine(7.5to
12.5mgthreetimesdaily)plusoctreotide(100to200mcgsubcutaneouslythreetimesdaily)[61].Bothgroups
alsoreceivedintravenousalbumindailyduringtreatment.Thegoaloftherapywastoraisethemeanarterial
pressureby15mmHg.Thefollowingresultswerereported:
Amongthefivepatientswhoreceivedmidodrineandoctreotide,meanarterialpressure,renalplasmaflow,
GFR,andurinevolumeallincreased.Amongthosewhoreceiveddopamine,therewasnochangeinthese
parameters.
Threeofthefivepatientstreatedwithmidodrineandoctreotidesurvivedtohospitaldischarge.Ofthese,one
successfullyunderwentlivertransplantation,anotherwasaliveat472days,andthethirdultimatelydiedafter
discontinuingtherapy.Amongthetwowhowerenotdischarged,onediscontinuedtherapyaftertwomonths
andwassuccessfullytransplanted,whiletheotherdiedat29daysofpneumoniadespitetotalrecoveryof
renalfunction.Minimalsideeffects,includingtingling,goosebumps,anddiarrhea,wereobserved.Incontrast,
sevenoftheeightpatientswhoreceiveddopaminediedduringthefirsttwelvedays.Onepatientrecovered
renalfunctionandsurvivedtobetransplanted.
Additionaldatasubstantiatethepotentialefficacyandsafetyofoctreotideandmidodrine.Inaretrospectivestudy,
60patientswithhepatorenalsyndromeweretreatedwithmidodrine(upto15mgthreetimesdaily),octreotide(200
mcgsubcutaneouslythreetimesdaily),andalbumin,and21concurrentpatientsonlyreceivedalbumin[21].
Therapywithmidodrineandoctreotidewasassociatedwithsignificantlylowermortality(43versus71percent)and
asignificantlyhigherproportionofpatientswhohadresolutionofhepatorenalsyndrome(40versus10percent).
Inourexperience,thespeedwithwhicheffectivetreatmentisachievedappearstobeimportant.Thus,weprefer
continuousinfusionofoctreotideat50mcg/hrratherthansubcutaneousinjection.Thiscanbedeliveredona
generalmedicalward.Themidodrinedoseshouldbeincreasedwitheachconsecutivedoseinordertoachievean
increaseinbloodpressurerapidly.Itisourexperiencethat15mgthreetimesperdaymaybemoreeffectivethan
12.5mgthreetimesperday.Changingthedoseafter24hoursonthepriordoseraisesthebloodpressuretoo
slowlyandmayleadtofailureoftherapy.
Incontrasttocombinationtherapywithmidodrineandoctreotide,octreotidemonotherapydoesnotappeartobe
beneficial.Inarandomizedcrossoverstudy,14patientswithhepatorenalsyndromeweretreatedwithfourdaysof
octreotideplusalbuminandfourdaysofalbuminaloneinrandomorder[62].Responsetotherapywasidentical
withbothtreatments.Midodrinealoneorincombinationwithalbumin(butwithoutoctreotide)hasnotbeen
evaluatedinpatientswithtype1hepatorenalsyndrome.
Thus,forpatientswithhepatorenalsyndromewhoarenotadmittedtotheintensivecareunitandforwhom
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terlipressinisunavailable,wesuggestcombinationtherapywithoctreotide,midodrine,andalbuminratherthan
othertherapies.
PatientswhodonotrespondtoinitialmedicaltherapyTreatmentoptionsforpatientswhodonotrespond
tooneofthemedicaltherapieslistedaboveincludeTIPSanddialysis.
TransjugularintrahepaticportosystemicshuntThetransjugularintrahepaticportosystemicshunt(TIPS)
hasbeenusedinthetreatmentofrefractoryascites.(See"Transjugularintrahepaticportosystemicshunts:
Indicationsandcontraindications".)
Whenusedinthissetting,theremayalsobeadelayedimprovementinrenalfunction[6367].Inonestudy,for
example,theaverageplasmacreatinineconcentrationwas1.5mg/dL(132micromol/L)atbaseline,wasunchanged
atoneweek,andfellto0.9mg/dL(80micromol/L)bysixmonths[63].Inanotherseries,therewasanonsignificant
trendtowardanincreaseinGFR(65mL/minatbaselineto76mL/minatfourweeks)[65].
ThereismuchlessinformationontheuseofTIPSinpatientswhofulfillcriteriaforthehepatorenalsyndrome[15].
Onereportdescribed16suchpatients,sixofwhomhadseverehepatorenalsyndrome(definedasaserum
creatinineof2.5mg/dL[220micromol/L]orhigher,oracreatinineclearancebelow20mL/min)[66].Withintwo
weeks,therewasanapproximatedoublingofthecreatinineclearancewithaproportionatereductionintheserum
creatinineandanincreaseinurinarysodiumexcretion.Additionalimprovementsinrenalfunctionoccurredoverthe
ensuingsixtoeightweeks.Onlythreepatientsfailedtorespond,allofwhomdiedwithinsixweeksafterTIPS.
Anotherseriesevaluatedsevenpatientswithcirrhosisandhepatorenalsyndrome,definedasadoublingofthe
serumcreatininetomorethan2.5mg/dL(221micromol/L)ora50percentreductionincreatinineclearanceto
below20mL/mininlessthantwoweeks,despitevolumeexpansion[67].InsertionofaTIPSwasassociatedwitha
gradualimprovementinGFR(9to27mL/min),reductionsinthebloodureanitrogen(BUN)andserumcreatinine,
and,inmostpatients,areductionintheactivityofthereninangiotensinandsympatheticnervoussystems
suggestinganimprovementinsystemichemodynamics.TheaveragesurvivalfollowingTIPSplacementwas
approximatelyfivemonths,whichislongerthantheexpectedsurvivalofsuchpatients.
Unfortunately,manypatientswithhepatorenalsyndromearetooilltoundergoTIPS.Inastudythatdeviseda
predictionmodeltodeterminesurvivalfollowingelectiveTIPS,thosepatientswithtype1hepatorenalsyndrome
haveapredicted90daymortalityfollowingTIPSofatleast25percentifcirrhosisisduetoalcoholicorcholestatic
liverdiseaseandatleast80percentifcirrhosisisduetoothercauses[68].Apredictionmodelscoringsystem
baseduponthesurvivalof231patientswhounderwentelectiveTIPSwasdevisedtopredictsurvivalafterthe
procedure.
Inaddition,TIPSisassociatedwithvariouscomplications[15]:
Anincreaseintherateofhepaticencephalopathy
Aworseningofliverfunction(markedbyariseinserumbilirubin)
Ableedingcomplicationduetotheprocedure
Ariskofrenalinjuryassociatedwithintravenouscontrast,whichisoftennecessary,evenifcarbondioxideis
usedasthemaincontrastagent
Overall,theseresultssuggestthat,inselectedpatientswithhepatorenalsyndrome,TIPSmayprovideshortterm
benefit.Giventherisksassociatedwiththisprocedure(particularlythehighincidenceofencephalopathy),itshould
beconsideredonlyasalastresortinselectedpatients.
DialysisPatientswithhepatorenalsyndromewhoprogresstorenalfailurecanbetreatedwithdialysis,which
ismostcommonlydonewhenpatientsareawaitingalivertransplantorwhenthereisthepossibilityofimprovement
inliverfunction.Inaddition,dialysisimprovesthepriorityscoreforthetransplantintheUnitedStates.Inone
retrospective,singlecenterstudy,30percentofpatientswhorequireddialysissurvivedtolivertransplantation[69].
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Survivalondialysisisgenerallylimitedbytheseverityofthehepaticfailure[70],aswellasconcurrentrespiratory
failure[71].Patientswithanacuteandpotentiallyreversiblehepaticinsultmayparticularlybenefitfromdialysis
sincerenalfunctionwillrecoverinparallelwithimprovinghepaticfunction[42].
Hemodialysisisfrequentlydifficulttoperforminpatientswithhepatorenalsyndromesincedecompensatedhepatic
functionisassociatedwithhemodynamicinstability.Somesuccesshasbeenrealizedwithcontinuousrenal
replacementmodalities[72].(See"Continuousrenalreplacementtherapyinacutekidneyinjury(acuterenal
failure)".)
OthertherapiesAnumberofotherdrugshavebeentriedforthetreatmentofhepatorenalsyndrome,suchas
misoprostol,Nacetylcysteine,andangiotensinconvertingenzymeinhibitors.Noneoftheseapproachesare
consistentlyassociatedwithbenefit,andthereforenonearerecommended.Inrarepatients,aperitoneovenous
shuntisused.
PeritoneovenousshuntAperitoneovenousshunt,whichdrainsperitonealfluidfromtheperitoneumintothe
internaljugularvein,reinfusesascitesintothevascularspace.Thismodalityhasbeenusedinpatientswith
refractoryascitesandrenalfailureduetothehepatorenalsyndrome[34,7377].Inthesesettings,theincreasein
fluidreturntothecardiopulmonarycirculationcanleadsequentiallytodecreasedactivityofsodiumretainingand
vasoconstrictivemechanisms(suchasthereninangiotensinaldosteronesystem),amarkedriseinurinarysodium
excretion,andamodestelevationinGFR[34,73,76].
However,itisnowrarelyusedbecauseofanappreciablerateofcomplicationsandthelackofevidencethat
peritoneovenousshuntingprolongspatientsurvival,whichmaybeseveralyearsinpatientswithnormalornear
normalhepaticandrenalfunctiontestsbutlessthansixweeksinpatientswiththehepatorenalsyndrome
[34,74,75,78,79].
Themajorproblemwiththeperitoneovenousshuntistherelativelyhighrateofcomplications,including
disseminatedintravascularcoagulation(duetoentryintothebloodstreamofendotoxinorotherprocoagulant
materialintheasciticfluid),infectionoftheshunt,whichcanleadtobacteremia,varicealbleedingresultingfrom
volumeexpansionandaconcurrentriseinportalvenouspressure,andsmallbowelobstruction[73,80,81].
Theneteffectisthattheperioperativemortalitycanreach25percentinpatientswithadvanceddisease[80,81].In
comparison,peritoneovenousshuntingisrelativelywelltoleratedinpatientswithascitesbutrelativelynormalrenal
function[74,75].Furthermore,theperioperativemorbiditycanbediminishedif,priortoinsertionoftheshunt,there
isintraoperativedrainageoftheascites,whichisthenreplacedby5litersofisotonicsaline[74,81].Thisregimen
canminimizethosecomplicationsrelatedtomassiveascitesinfusion:disseminatedintravascularcoagulationand
increasedportalpressure.
Theonlyremainingindicationsforperitoneovenousshuntare:
Unusualformsofascitessuchaschylousascites.
Postlivertransplantpatientwithrefractoryascites.
PatientswithcirrhosisanddiureticresistantasciteswhoarenotcandidatesfortransplantationorTIPSand
whoaretooobeseorhavetoomanyabdominalsurgicalscarstopermitsafe,successfulparacentesis.(See
"Ascitesinadultswithcirrhosis:Diureticresistantascites".)
PREVENTIONHepatorenalsyndromeregularlydevelopsinpatientswithsystemicbacterialinfection(eg,
spontaneousbacterialperitonitis[SBP])and/orseverealcoholichepatitis.Thefollowingtherapiesmaypreventthe
developmentofhepatorenalsyndromeinthesepatients:
IntravenousalbuminInpatientswithSBP,theadministrationofintravenousalbumin(1.5g/kg)atthetimeof
diagnosisofinfectionandanotherdoseofalbumin(1g/kg)onday3ofantibiotictreatmentreducesthe
incidenceofbothrenalimpairmentandmortality.Ametaanalysisoffourcontrolledtrials(withatotalof288
patients)evaluatedtheimpactofalbumininfusion(inadditiontoantibiotics)onrenalimpairmentandmortality
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inpatientswithSBP[82].Albumininfusionwasassociatedwithasignificantdecreaseintheincidenceof
renalimpairment(8versus31percent)andasignificantreductioninmortality(16versus35percent).These
datasupporttheuseofalbumininfusioninpatientswithSBP.(See"Spontaneousbacterialperitonitisin
adults:Treatmentandprophylaxis",sectionon'Albuminadministrationforpatientswithrenaldysfunction'.)
NorfloxacinArandomizedtrialreportedsignificantbenefitswiththeoraladministrationofnorfloxacinat400
mg/dayto68patientswithcirrhosisandasciticfluidtotalprotein<1.5g/dLwhofulfilledeitherofthefollowing
twocriteria:aChildPughscore>9pointsandserumbilirubin>3mg/dL(51.3micromol/L)oraserum
creatinine>1.2mg/dL[106micromol/L]orbloodureanitrogen(BUN)>20mg/dLorserumsodium<130
meq/L[83].Norfloxacinwasassociatedwiththefollowingsignificantbenefits:decreasedoneyearprobability
ofSBP(7versus61percent)andhepatorenalsyndrome(28versus41percent),andimprovedsurvivalatthree
months(94versus62percent)andoneyear(60percentversus48percent).Basedupontheseandother
findings,werecommendtheuseofnorfloxacininselectedpatientswithcirrhosisandascitesspecific
recommendationsarediscussedelsewhere.(See"Spontaneousbacterialperitonitisinadults:Treatmentand
prophylaxis",sectionon'Prophylaxis'.)
PentoxifyllineAninitialtrialof61patientswithcirrhosis,ascites,andabaselinecreatinineclearanceof41
to80mL/minper1.73m2showedsignificantbenefitwithpentoxifylline(1200mg/day)forsixmonthsas
comparedwithplacebo[84].However,asubsequentmetaanalysisdemonstratednobenefitonhepatorenal
syndromeormortality[85].(See"Alcoholichepatitis:Naturalhistoryandmanagement",sectionon
'Pentoxifylline'.)
PROGNOSISOverall,themortalityofpatientswithliverfailureissubstantiallyworseiftheydevelophepatorenal
syndrome[86].Withouttherapy,mostpatientsdiewithinweeksoftheonsetoftherenalimpairment.Inturn,the
outcomeofpatientswithhepatorenalsyndrome,aswellasrecoveryofkidneyfunction,isstronglydependentupon
reversalofthehepaticfailure,whetherspontaneous,followingmedicaltherapy,orfollowingsuccessfulliver
transplantation[87].
Therateofrecoveryofkidneyfunctionfollowingrecoveryofliverfailureisuncertainreportedratesareaffectedby
varyingpretransplantkidneyfunctionanddifferencesovertimeinindicationsfordialysisandineligibilityforliver
transplantation.However,asubstantialproportionofpatientswhohaveprogressedtodialysisandsurvivetoreceive
alivertransplantdorecoverkidneyfunction[88].(See"Renalfunctionandnonrenalsolidorgantransplantation".)
SUMMARYANDRECOMMENDATIONS
Thehepatorenalsyndromeisoneofmanypotentialcausesofacutekidneyinjuryinpatientswithacuteor
chronicliverdisease.Affectedpatientsusuallyhaveportalhypertensionduetocirrhosis,severealcoholic
hepatitis,or(lessoften)metastatictumors,butcanalsohavefulminanthepaticfailurefromanycause.(See
'Introduction'above.)
Arterialvasodilatationinthesplanchniccirculation,whichistriggeredbyportalhypertension,appearstoplay
acentralroleinthehemodynamicchangesandthedeclineinrenalfunctioninthehepatorenalsyndrome.The
presumedmechanismisincreasedproductionoractivityofvasodilators,mainlyinthesplanchniccirculation,
withnitricoxidethoughttobemostimportant.Asthehepaticdiseasebecomesmoresevere,thereisa
progressiveriseincardiacoutputandfallinsystemicvascularresistancethelatterchangeoccursdespite
localincreasesinrenalandfemoralvascularresistancethatresultinpartfromhypotensioninducedactivation
ofthereninangiotensinandsympatheticnervoussystems(figure1).(See'Pathogenesis'above.)
Patientswhodevelopthehepatorenalsyndromeusuallyhaveportalhypertensionduetocirrhosis,severe
alcoholichepatitis,and,lessoften,metastatictumors.However,patientswithfulminanthepaticfailurefrom
anycausemaydevelophepatorenalsyndrome.Inpatientswithcirrhosisandascites,thehepatorenal
syndromeoccursinapproximately20and40percentatoneandfiveyears,respectively.Inpatientswith
acuteliverdisease,thehepatorenalsyndromeoccursinapproximately25to30percent.(See'Epidemiology'
above.)
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Thehepatorenalsyndromeisusuallycharacterizedbythefollowingfeaturesinapatientwhohasestablished
orclinicallyevidentacuteorchronicliverdisease(see'Clinicalpresentation'above):
Aprogressiveriseinserumcreatinine
Abenignurinesediment
Noorminimalproteinuria(lessthan500mgperday)
Averylowrateofsodiumexcretion(ie,urinesodiumconcentrationlessthan10meq/L)
Oliguria
Basedupontherapidityofthedeclineinkidneyfunction,twoformsofhepatorenalsyndromehavebeen
described(see'Clinicalpresentation'above):
Type1hepatorenalsyndromeType1hepatorenalsyndromeisthemoreserioustypeitisdefinedas
atleastatwofoldincreaseinserumcreatinine(reflectinga50percentreductionincreatinineclearance)
toalevelgreaterthan2.5mg/dL(221micromol/L)duringaperiodoflessthantwoweeks.Atthetimeof
diagnosis,somepatientswithtype1hepatorenalsyndromehaveaurineoutputlessthan400to500mL
perday.
Type2hepatorenalsyndromeType2hepatorenalsyndromeisdefinedasrenalimpairmentthatisless
severethanthatobservedwithtype1disease.Themajorclinicalfeatureinpatientswithtype2
hepatorenalsyndromeisascitesthatisresistanttodiuretics.
Theonsetofrenalfailureistypicallyinsidiousbutcanbeprecipitatedbyanacuteinsult,suchasbacterial
infection(oftenspontaneousbacterialperitonitis)orgastrointestinalbleeding.Diureticsdonotcause
hepatorenalsyndrome.(See'Precipitants'above.)
Patientswithhepatorenalsyndromemayhaverenaldysfunctionthatissubstantiallymoreseverethanis
suggestedbytheserumcreatinine.(See'Problemswithestimatingkidneyfunction'above.)
Hepatorenalsyndromeisdiagnosedbaseduponclinicalcriteria.Thereisnoonespecifictestthatcan
establishthediagnosis.Thefollowingdefinitionanddiagnosticcriteriahavebeenproposedforthehepatorenal
syndrome(see'Diagnosis'above):
Chronicoracutehepaticdiseasewithadvancedhepaticfailureandportalhypertension.
Aserumcreatinineabove1.5mg/dL(133micromol/L)thatprogressesoverdaystoweeks(ie,acuteor
subacutekidneyinjury).Asnotedabove,theriseinserumcreatininewithreductionsinglomerular
filtrationrate(GFR)maybeminimalduetothemarkedreductionincreatinineproductionamongsuch
patients.
Theabsenceofanyotherapparentcausefortheacutekidneyinjury,includingshock,current,orrecent
treatmentwithnephrotoxicdrugs,andtheabsenceofultrasonographicevidenceofobstructionor
parenchymalrenaldisease.Spontaneousbacterialperitonitisiscomplicatedbyacutekidneyinjurythat
maybereversiblein30to40percentofpatients.Itcanbeassociatedwithacutetubularnecrosis(ATN),
butitisalsoamajorprecipitantofthehepatorenalsyndrome.Thus,ongoinginfectionwithspontaneous
bacterialperitonitisshouldnotexcludethepossibilityofhepatorenalsyndrome.Thismeansthattherapy
forhepatorenalsyndromecancommencewhilethebacterialinfectionisstillbeingtreated.Inaddition,
hepatorenalsyndromecanoccurinpatientswithpreexistingchronickidneydisease.Thus,the
presenceofanotherrenaldiagnosis(eg,diabeticnephropathy)doesnotnecessarilyexclude
hepatorenalsyndrome.
Inconjunctionwithexcludingotherapparentcausesofrenaldisease,thefollowingcriteriaalsoapply:

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Urineredcellexcretionoflessthan50cellsperhighpowerfield(whennourinarycatheterisinplace)
andproteinexcretionlessthan500mg/day.
Lackofimprovementinrenalfunctionaftervolumeexpansionwithintravenousalbumin(1g/kgofbody
weightperdayupto100g/day)foratleasttwodaysandwithdrawalofdiuretics.
Asnotedabove,patientsdiagnosedwithhepatorenalsyndromeareclassifiedastype1hepatorenal
syndrome(moresevere)ortype2hepatorenalsyndrome(lesssevere)basedupontherapidityoftheacute
kidneyinjuryandthedegreeofrenalimpairment.Type1hepatorenalsyndromeispresentiftheserum
creatinineincreasesbyatleasttwofoldtoavaluegreaterthan2.5mg/dL(221micromol/L)duringaperiodof
lessthantwoweeks.Lessrapidlyprogressivediseaseisclassifiedastype2.(See'Diagnosis'above.)
Thediagnosisofthehepatorenalsyndromeisoneofexclusion,entertainedonlyafterotherpotentialcauses
ofacuteorsubacutekidneyinjuryhavebeenruledout.Alternateetiologiesinclude,butarenotlimitedto,
glomerulonephritis,prerenaldisease,andATN.(See'Differentialdiagnosis'above.)
Theidealtherapyforhepatorenalsyndromeisimprovementofliverfunctionfromeitherrecoveryofalcoholic
hepatitis,treatmentofdecompensatedhepatitisBwitheffectiveantiviraltherapy,recoveryfromacutehepatic
failure,orlivertransplantation.(See'Approachtotherapy'aboveand'Improvinghepaticfunction'above.)
However,whenimprovementofliverfunctionisnotpossibleintheshortterm,medicaltherapyshouldbe
institutedinanattempttoreversetheacutekidneyinjuryassociatedwithhepatorenalsyndrome.Our
suggestionsregardingthechoiceofmedicaltherapydependuponseveralfactors,including:whetherthe
patientisadmittedtotheintensivecareunittheavailabilityofcertaindrugs,forwhichthereisnationaland
regionalvariabilityandwhetherthepatientisacandidateforlivertransplantation.(See'Approachtotherapy'
above.)
Inpatientswithhepatorenalsyndromewhoareadmittedtotheintensivecareunit,wesuggestinitial
treatmentwithnorepinephrineincombinationwithalbuminratherthanothermedicaltherapies(Grade2B).
Norepinephrineisgivenintravenouslyasacontinuousinfusion(0.5to3mg/hr)withthegoalofraisingthe
meanarterialpressureby10mmHg,andalbuminisgivenforatleasttwodaysasanintravenousbolus(1
g/kgperday[100gmaximum]).Intravenousvasopressinmayalsobeeffective,startingat0.01units/min.
(See'Norepinephrineforpatientsintheintensivecareunit'above.)
Inpatientswithhepatorenalsyndromewhoarenotadmittedtotheintensivecareunit,oursuggestions
dependupontheavailabilityofcertaindrugs:
Whereterlipressintherapyisavailable,wesuggestinitialtreatmentwithterlipressinincombinationwith
albuminratherthanmidodrine,octreotide,andalbumin(Grade2C).Terlipressinisgivenasan
intravenousbolus(1to2mgeveryfourtosixhours),andalbuminisgivenfortwodaysasanintravenous
bolus(1g/kgperday[100gmaximum]),followedby25to50gramsperdayuntilterlipressintherapyis
discontinued.(See'Terlipressinplusalbuminwhereavailable'above.)
Whereterlipressintherapyisnotavailable(principallytheUnitedStates),wesuggestinitialtreatment
withacombinationofmidodrine,octreotide,andalbumin(Grade2C).Midodrineisgivenorally(7.5to15
mgbymouththreetimesdaily),octreotideiseithergivenasacontinuousintravenousinfusion(50
mcg/hr)orsubcutaneously(100to200mcgthreetimesdaily),andalbuminisgivenfortwodaysasan
intravenousbolus(1g/kgperday[100gmaximum]),followedby25to50gramsperdayuntilmidodrine
andoctreotidetherapyisdiscontinued.(See'Midodrine,octreotide,andalbuminwhereterlipressinisnot
available'above.)
Inhighlyselectedpatientswhofailtorespondtomedicaltherapywiththeaboveregimens,whoareawaiting
livertransplantation,andwhoareconsideredwellenoughtoundergotheprocedure,transjugularintrahepatic
portosystemicshunt(TIPS)issometimessuccessfulhowevertheprocedureisassociatedwithnumerous
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complications.(See'Transjugularintrahepaticportosystemicshunt'above.)
Inpatientswhofailtorespondtotheabovetherapies,developseverelyimpairedrenalfunction,arenot
consideredcandidatesforTIPS,andeitherarecandidatesforlivertransplantationorhaveareversibleformof
liverinjuryandareexpectedtosurvive,werecommenddialysisasabridgetolivertransplantationorliver
recovery(Grade1B).Hemodialysisisfrequentlydifficulttoperforminpatientswithhepatorenalsyndrome,
andsurvivalisgenerallylimitedbytheseverityofthehepaticfailure,aswellasconcurrentrespiratoryfailure.
(See'Dialysis'above.)
ThegoalofmedicaltherapyorTIPSinpatientswithhepatorenalsyndromeisreversaloftheacutekidney
injury.Inaddition,whenpatientsaretreatedwithnorepinephrine,terlipressin,ormidodrineplusoctreotide,an
immediategoaloftherapyistoraisethemeanarterialpressurebyapproximately10to15mmHg.(See
'Approachtotherapy'above.)
Inpatientstreatedwithnorepinephrine,terlipressin,oroctreotide,weusuallytreatforatotaloftwoweeks.
However,weandothersoccasionallytreatforlongerdurations(uptoonemonthormore)ifthereissomebut
notcompleteimprovementinrenalfunctionaftertwoweeksoftherapy.Inpatientswhorespondtotherapy,we
occasionallytreatindefinitelywithmidodrinetomaintainahighermeanarterialpressure(oruntilliver
transplantationorresolutionofliverinjury).Incontrast,ifapatienthasnoimprovementinrenalfunctionafter
twoweeks,therapywiththesedrugscanbeconsideredfutile.(See'Approachtotherapy'above.)
Thefollowingtherapiesmaypreventthedevelopmentofhepatorenalsyndromeinthesepatients(see
'Prevention'above):
Inpatientswithspontaneousbacterialperitonitis,werecommendtheadministrationofintravenous
albumin(1.5g/kg)atthetimeofdiagnosisofinfectionandanotherdoseofalbumin(1g/kg)onday3of
antibiotictreatment(Grade1B).(See"Spontaneousbacterialperitonitisinadults:Treatmentand
prophylaxis".)
Inselectedpatientswithcirrhosisandascites,werecommendchronicnorfloxacintherapy(400mg/day)
(Grade1B).Adiscussionofwhichpatientsshouldreceivechronicnorfloxacintherapy,aswellasthe
evidenceforthisgradedrecommendation,arepresentedelsewhere.(See"Spontaneousbacterial
peritonitisinadults:Treatmentandprophylaxis".)
Withouttherapy,mostpatientswithhepatorenalsyndromediewithinweeksoftheonsetoftherenal
impairment.Theoutcomeofpatientswithhepatorenalsyndrome,aswellasrecoveryofkidneyfunction,is
stronglydependentuponreversalofthehepaticfailure,whetherspontaneous,followingmedicaltherapy,or
followingsuccessfullivertransplantation.(See'Prognosis'above.)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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Topic2308Version15.0

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GRAPHICS
Hormonalresponsetocirrhosis

Cirrhosisofinc reasingseveritynoasc ites,asc ites,andasc itesplus


renalfailure(RF)duetohepatorenalsyndromeisassoc iatedwitha
progressiveinc reaseinplasmareninac tivity(ng/mLperhour)andin
theplasmalevelsofnorepinephrine(pg/mL),andantidiuretic hormone
(pg/mL).Thisprogressiveriseinthesec retionofhypovolemic
hormonesisassoc iatedwithavasodilatationinduc edfallinmean
arterialpressure(from89to75mmHg)andareduc tionintheplasma
sodiumc onc entration(from138to128mEq/L).
Datafrom:AsbertM,GinesA,GinesP,etal.Gastroenterology1993
104:1485.
Graphic74244Version2.0

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Ornipressinimprovesrenalfunctioninadvanced
hepaticcirrhosis

Effec tofinfusionofornipressin,ananalogofantidiuretic hormone


thatc ausespreferentialsplanc hnic vasoc onstric tion,inpatientswith
advanc edhepatic c irrhosisandfunc tionalrenalfailure(the
hepatorenalsyndrome).Ornipressinraisedtheglomerularfiltrationrate
(GFR)from18to29mL/min,loweredtheplasmareninac tivityfrom28
to14(normalequalslessthan3ng/mLperhouronaregularsalt
intake),andraisedthefrac tionofthec ardiac outputdeliveredtothe
kidneysfrom2to5perc ent(normalequals20perc ent).Eac hofthese
abnormalitieswasonlypartiallyc orrec ted,althoughitisnotknownif
agreaterresponsewouldbeseenwithlessseverediseaseorwitha
higherdose.
DatafromLenz,K,Hortnagl,H,Druml,W,etal,Gastroenterology1991
101:1060.
Graphic68506Version1.0

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Disclosures

Disclosures:BruceARunyon,MDNothingtodisclose.RichardHSterns,MDNothingtodisclose.JohnPForm an,MD,MScNothing
todisclose.
Contributordisclosuresarereview edforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthroughamultileve
contentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
Conflictofinterestpolicy

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