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Am J Transplant. 2019;00:1–11. amjtransplant.com  | 1© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons

Received:2February2019  |  Revised:18March2019  |  Accepted:28March2019DOI: 10.1111/ajt.15392

M E E T I N G R E P O R T

Frailty in liver transplantation: An expert opinion statement from the American Society of Transplantation Liver and Intestinal Community of Practice

Jennifer C. Lai1 | Christopher J. Sonnenday2 | Elliot B. Tapper3 | Andres Duarte‐Rojo4 | Michael A. Dunn5 | William Bernal6 | Elizabeth J. Carey7 | Srinivasan Dasarathy8 | Binita M. Kamath9 | Matthew R. Kappus10 | Aldo J. Montano‐Loza11 | Shunji Nagai12  | Puneeta Tandon13

1Division of Gastroenterology and Hepatology, University of California‐San Francisco, San Francisco, California2SectionofTransplantation,UniversityofMichigan,AnnArbor,Michigan3DivisionofGastroenterology,UniversityofMichigan,AnnArbor,Michigan4DivisionofGastroenterology&Hepatology,UniversityofArkansasforMedicalSciences,LittleRock,Arkansas5CenterforLiverDiseases,ThomasE.StarzlTransplantationInstitute,andPittsburghLiverResearchCenter,UniversityofPittsburgh,Pittsburgh,Pennsylvania6InstituteofLiverStudies,KingsCollegeHospital,London,UK7DivisionofGastroenterologyandHepatology,MayoClinic,Scottsdale,Arizona8DivisionofGastroenterologyandHepatology,ClevelandClinic,Cleveland,Ohio9Division of Gastroenterology, Hepatology, and Nutrition, University of Toronto, Toronto, Canada10DivisionofGastroenterology,DukeUniversitySchoolofMedicine,Durham,NorthCarolina11DivisionofGastroenterology&LiverUnit,UniversityofAlberta,Edmonton,Alberta,Canada12DivisionofTransplantSurgery,HenryFordHospital,Detroit,Michigan13CirrhosisCareClinic,DivisionofGastroenterology,UniversityofAlberta,Edmonton,Alberta,Canada

Abbreviation:ADLs,activitiesofdailyliving.

CorrespondenceJenniferC.LaiEmail:Jennifer.lai@ucsf.edu

Funding informationMikatiFoundationGrant;NationalInstituteofGeneralMedicalSciences,Grant/AwardNumber:R01GM119174;NationalInstitute of Diabetes and Digestive and KidneyDiseases,Grant/AwardNumber:R01DK113196andU01DK061732;OfficeofAIDSResearch,Grant/AwardNumber:R21AR071046;NationalInstituteonAging,Grant/AwardNumber:K23AG048337andR01AG059183;NationalInstituteonAlcoholAbuseandAlcoholism,Grant/AwardNumber:P50AA024333andU01AA0026976

Frailty has emerged as a powerful predictor of outcomes in patientswith cirrho‐sis and has inevitablymade itsway into decisionmakingwithin liver transplanta‐tion.Inanefforttoharmonizeintegrationoftheconceptoffrailtyamongtransplantcenters,theASTandASTSsupportedtheeffortsofourworkinggrouptodevelopthisstatementfromexpertsinthefield.Frailtyisamultidimensionalconstructthatrepresentstheend‐manifestationofderangementsofmultiplephysiologicsystemsleadingtodecreasedphysiologicreserveandincreasedvulnerabilitytohealthstress‐ors.Inhepatology/livertransplantation,investigationoffrailtyhaslargelyfocusedonphysicalfrailty,whichsubsumestheconceptsoffunctionalperformance,functionalcapacity,anddisability.Therewasconsensus thatevery liver transplantcandidateshouldbeassessedatbaselineand longitudinallyusingastandardized frailty tool,whichshouldguidetheintensityandtypeofnutritionalandphysicaltherapyinindi‐viduallivertransplantcandidates.Theworkinggroupagreedthatfrailtyshouldnotbeusedasthesolecriterionfordelistingapatientforlivertransplantation,butrather

2  |     LAI et AL.

1  | INTRODUC TION

Frailtyhasemergedasafundamentalforceshapingthefieldoflivertransplantation.Liverdiseaseseverityattransplantationisworsen‐ing,theproportionofolderadults(≥65years)awaitingtransplanta‐tion is rising,andtheprevalenceofobesity‐related liverdisease israpidlyescalating—allofwhicharecontributingtoacohortoflivertransplant patients who are sicker, more medically complex, andincreasingly being described as “frail.” Clinicians caring for thesepatientshavelongintuitedtheimportanceoffrailtyonhealthout‐comes before and after liver transplantation, even removing patients fromthewaitlistforbeing“toofrailfortransplant.”Yetdespitethefactthattheconceptoffrailtyhasinevitablymadeitswayintotrans‐plantdecision‐making,itsintegrationintoclinicaltransplantpracticethus far has been haphazard, hindered by a lack of consensus onits definition, tools for assessment, and implications for transplant decision‐making.1

To overcome these barriers, the American Society ofTransplantationsupportedtheeffortsofourworkinggroupofex‐pertsinthefieldtodevelopthisstatementonfrailtyinlivertrans‐plantation.Ourspecificgoalswereto:(a)definefrailty,(b)appraisetoolsforfrailtymeasurement,and(c)developanalgorithmforprac‐tical incorporation of frailty into clinical practice.While much ofthisdocumentappliestopatientswithcirrhosis,regardlessoftheirtransplanteligibility, thisstatementwasprimarily intendedfor thetransplantsetting;wehavehighlightedspecificareas inwhichourrecommendationsmaydifferwhetherornotthepatientislistedforliver transplantation.

Onewordofcautionwhenimplementingourrecommendations:wedonotsupporttheuseofaone‐timeassessmentoffrailtyasthesole criterion for declining a patient for liver transplantation. Our goalwiththisdocumentistofacilitatethesystematicincorporationofastandardizedfrailtyassessmentforevery patient at evaluation andlongitudinallywhileawaitinglivertransplantationinordertoac‐curatelycaptureprogressionoffrailtyonthewaitlistaswellasserveasthefoundationforfrailtyintervention.

1.1 | Defining “frailty” in the setting of liver transplantation

Theconceptoffrailty ismostcommonlydefinedasadistinctbio‐logicsyndromeofdecreasedphysiologicreserveandincreasedvul‐nerabilitytohealthstressorsthatpredisposesonetoadversehealth

outcomes.2 Frailty is a multidimensional construct, and represents theend‐manifestationofderangementsofmultiplephysiologicsys‐temsincludingallindividualsolidorgansystems(eg,theliver,kidney,heart),inflammatory,endocrine,cognitive,andmusculoskeletalsys‐tems,aswellaspsychosocialfactors.

While frailty has generally been conceptualized in the geriatricsarenaasdistinctfromfunctionalstatus,inthefieldsofhepatology/livertransplantation,theterm“frailty”haslargelyfocusedonphysical frailty (theaspectoffrailtyrelatedtofunctionalimpairment)duetoconsider‐ationsofmeasurementinthehepatologyandtransplantsettings.Tobeclear, functional status refers to one's ability to perform daily activities, fulfill social roles, andmaintain health/well‐being3and subsumes theconcepts of functional performance, functional capacity, and disability. Inthecontextoflivertransplantation,thefocusonthephysicalfunc‐tionalaspectsoffrailtyhastheadvantageoverabroaderconceptual‐izationoffrailty(thatincludescognitive,social,andemotionalaspects)given the need for objectivity of measurement. Although cognitivefrailtyispredictiveofoutcomeincirrhosis,4,5thelackofstandardizedtoolsfortheassessmentofcognitivedysfunctionincirrhosisandtheoverlapwithhepaticencephalopathymakes itdifficult toobjectivelyevaluate this more encompassing definition of frailty at this time.Importantly,“physicalfrailty,”asinvestigatedinpatientswithcirrhosis,isacriticaldeterminantofadversehealthoutcomesinthispopulation,includingwaitlistmortality,6‐11mortalityafterhospitalizationandafterliver transplantation,12‐15needforhospitalization,lengthofstay,14,16‐18 anddischargelocation(ie,rehabilitationfacility)13,14(Table1).

Major components of frailty in all patients include skeletalmuscle mass depletion (sarcopenia), progressive immobility, de‐creased energy expenditure, andmalnutrition.2 In patientswithcirrhosis, there aremultiple liver‐specific factors that exacerbateandacceleratethiscycleoffrailty(Figure1).Chronicinflammationfromtheunderlyingliverdiseaseisoftentheinitialinsult.Hepaticsyntheticdysfunctionresultsintheimpairmentofmuscleproteinsynthetic response that can rapidly lead to progressive musclebreakdown. Anorexia associated with malaise (from chronic in‐flammation)andearlysatiety(fromascites)leadstomalnutrition,furtheracceleratingmusclewasting.Hepaticencephalopathyandcognitivedeclinemagnifytheexpressionoffrailtythroughmulti‐ple pathways, including altered taste perception, fatigue, immo‐bility,anddecreasedenergyexpenditure.Theobligatoryshiftofammoniafromlivertomuscleforexportasglutamine—divertingglutamateneededformuscleproteinsynthesis—isalsorecognizedtobeapivotaldriverofmusclewasting.Ammoniaitselfpromotes

shouldbeconsideredoneofmanycriteriawhenevaluatingtransplantcandidacyandsuitability.Aroadmaptoadvancefrailtyintheclinicalandresearchsettingsoflivertransplantationispresentedhere.

K E Y W O R D S

clinicalresearch/practice,guidelines,livertransplantation/hepatology,nutrition,recipientselection

     |  3LAI et AL.

TAB

LE 1

 Metricsofphysicalfrailty,fitness,ordisabilitystudiedinpatientswithcirrhosis(wherethestudyincludedanadjustmentforliverdiseaseseverity)

Tool

Stud

yD

etai

lsN

Scor

eA

ssoc

iatio

n w

ith o

utco

mes

(ove

rall

mor

talit

y

unle

ss o

ther

wis

e sp

ecifi

ed)

ADL

Lai20146

Out

patie

nt29

4≥1disability(24%)

HR:1.2395%CI(0.91‐1.66)

Sam

oylo

va 2

01728

Out

patie

nt458

≥1disability(49%)

sHR:1.895%CI(1.4‐2.4)

Tapp

er 2

01514

Inpa

tient

73

4ADL<12:9.2%withoutHEand24%

withHE**

ADL<12:HR1.895%CI(1.1‐3.2)

CFS

Ran

ge 1

‐9Ta

ndon

201

616O

utpa

tient

300

CFS>4:18%

CFS>3:51%

OR(per1unit):1.9(1.4‐2.6)

Ney20184

Out

patie

nt35

5MoCA‐CFSscore(cognitive+physical

frailty)

ORofanHE‐relatedhospitalization:

01

13.3(1.5‐7.7)

25.7(1.9‐17.3)

KarnofskyPerformanceScale

(rangeA‐Cor0‐100)

Malinis201429

Tran

spla

nt re

gist

ry

35686

KPS(BorC):63.4%

5‐yrmortality:sHR1.30(1.23‐1.37)

Orm

an 2

01611

Tran

spla

nt re

gist

ry70

092

KPS(BorC):56%

1‐yearmortalitybyKPS:A(11.4%),B(15.5%),C

(27.4%)KPSB:HR1.0895%CI(1.04‐1.111)KPS

C:HR1.2695%CI(1.20‐1.33)

Tand

on 2

01715

Hospitalized

DecompensatedCirrhosis

954

KPS(BorC):68%

3‐monthpostdischargemortality:ByKPS:A(5%),

B(11%),C(23%)KPS(per1‐unit):OR0.9795%CI

(0.96‐0.98)

BradenScaleRange6‐23

Tapp

er 2

01514

Hospitalized

DecompensatedCirrhosis

734

Moderate‐tohigh‐riskBradenScale:

≤18(28.1%HE,13.7%withoutHE)

90‐d

ay m

orta

lity

Score16‐18:2.7195%CI(1.88‐3.90)

Score<16:1.8595%CI(0.83‐4.12)

Sund

aram

201

713O

utpa

tient

Alltransplantlisted

341

Moderate‐tohigh‐riskBradenScale:

16‐18:(17%),≤16(20%)

Posttransplantmortality:insufficientoutcomes

FFPRange0‐5

Lai20146

OutpatientAlltransplantlisted

294

FFP≥3:17%

Perpoint:1.4595%CI(1.04‐2.02)

Tand

on 2

01616

Out

patie

nt

Cirrhosis

300

FFP≥3:35%

OR

4.0

Sinc

lair

201718

Out

patie

nt

Alltransplantlisted

587

FFP≥3:32%

Hospitalizationdaysper12months

IRR:1.295%CI(1.02‐1.44)

Tapper20185

Out

patie

nt

Alltransplantevaluated

685

FFP≥3:41%

Tran

spla

nt‐f

ree

surv

ival

H

R pe

r FFI

poi

nt:

WithoutHE:1.37(1.20‐1.58)

WithHE:1.14(0.98‐1.33)

(Continued)

4  |     LAI et AL.

Tool

Stud

yD

etai

lsN

Scor

eA

ssoc

iatio

n w

ith o

utco

mes

(ove

rall

mor

talit

y

unle

ss o

ther

wis

e sp

ecifi

ed)

6MWDMeterswalked

Car

ey 2

0109

Out

patie

nt

Alltransplantlisted

121

Mean6MWD

6

9 ±

122

mPer100m:0.5895%CI(0.37‐0.93)

Yadav2015

30O

utpa

tient

Alltransplantlisted

213

Mean6MWD

37

1 ±

121

m

12%≤250m

250mcutoff:HR2.195%CI(0.9‐4.7)

FaustiniPereira

2016

12O

utpa

tient

86Mean6MWD

410±27.8m

<410mwalked(unadjusted):RR4.2195%CI

(1.25‐6.41)

Gaitspeed(meters/second)

Dun

n17O

utpa

tient

373

Meangaitspeed

0.95

± 0

.25

m/s

Hos

pita

l bed

‐day

s Per0.1m/s:RR0.85(0.74‐0.98)

SPPBRange0‐12

Lai20146

Out

patie

nt

Alltransplantlisted

294

SPPB<9:31%

Perpoint:1.1995%CI(1.07‐1.32)

Tand

on 2

01616

Out

patie

nt

Cirrhosis

300

SPPB<10:38%

OR

2.5

LiverFrailtyIndexperpoint

Lai20177

Out

patie

nt

Alltransplantlisted

529

MedianLFI:3.8(3.4‐4.3)

Wai

tlist

mor

talit

y Perpoint:HR2.295%CI(1.7‐2.9)

CardiopulmonaryExercise

TestingmL/kg/min

Ney

201

610Systematicreviewof:Outpatient

Alltransplantlisted

1107

Ventilatoryanaerobicthreshold(AT)

Peakexerciseoxygenuptake(peak

VO2)

Posttransplantmortality(meandifferencebe‐

tweensurvivorandnonsurvivors)

AT:2.095%CI(0.42‐3.59)

PeakVO2:0.7795%CI(−1.36‐2.90)

Abbreviations:6MWT,6‐minutewalktest;6MWD,6‐minutewalktestdistance;ADL,ActivitiesofDailyLiving;AT,anaerobicthreshold;CFS,ClinicalFrailtyScale;CPET,cardiopulmonaryexercisetest

‐ing;FFP,FriedFrailtyPhenotype;HE,hepaticencephalopathy;HR,hazardratio;KPS,KarnofskyPerformanceStatus;IADL,InstrumentalActivitiesofDailyLiving;IRR,incidencerateratio;LFI,Liver

FrailtyIndex;MoCA,MontrealCognitiveAssessment;OR,oddsratio;SPPB,ShortPhysicalPerformanceBattery.

TAB

LE 1

 (Continued)

     |  5LAI et AL.

muscleautophagy,directlyimpairscontractility,andtriggerssyn‐thesis and release ofmyotoxins contributing to sarcopenia.19 In additiontotheseliver‐relatedfactors,patientswithcirrhosisalsoexperiencenon–liver‐relatedfactors includingchronologicaging,non‐hepatic comorbidities (eg, coronary artery disease, diabeticperipheralneuropathy),andage‐relatedmusclewasting.Thecon‐tributions of these non–liver‐related factors are particularly im‐portantfortransplantdecision‐making,astheyarenotmodifiableandwillnotimproveaftertransplantation.20

Whilesarcopeniaisacentralanddominantcomponentoffrailtyinpatientswithcirrhosis,theconceptoffrailtyismoremultifacetedthansarcopeniaalone.Theinclusionoffunctionalmeasures(eg,chairstands,gaitspeed)invalidatedfrailtymetricssuggeststhattheinfluenceofsar‐copenia may be modified by factors related to muscle function ratherthanpurelymusclemass.Furthermore,theinfluenceofpatient‐reportedoutcomes (eg,exhaustion,sedentary time) implies thatan individual'sexperienceoftheirfrailtystatemayalsoinfluencehealthoutcomes.Thisconsensusstatementonlyaddressessarcopeniaasitrelatestotheover‐allconstructoffrailty;aseparateworkinggrouphasbeenassembledtomore specifically address sarcopenia as a single entity.

Key points

• Frailty is amultidimensional construct that represents theend‐manifestation of derangements ofmultiple physiologic systemsthatleadstodecreasedphysiologicreserveandincreasedvulner‐abilitytohealthstressors.

• Inhepatology/livertransplantation,theinvestigationoffrailtyhaslargely focused on physicalfrailtywhichsubsumestheconceptsoffunctional performance, functional capacity, and disability.

• Whilesarcopeniaisaprimarydriveroffrailtyinpatientswithcir‐rhosis,frailtyismoremultifacetedthansarcopeniaalone,offeringacomprehensiveassessmentofmusclefunctionandtheindividualpatient'sexperienceoftheirfrailtystatein addition to muscle mass.

1.2 | Measuring frailty in adult liver transplant patients

Table2 liststhetoolstocapturetheconstructoffrailtythathavebeen studied in patients with cirrhosis, including those awaiting

liver transplantation.We,again,emphasize that thestudies in thispatientpopulationhavelargelyfocusedonthephysicalcontributorsto frailty, including functional performance, functional capacity, and disability.

Intheresearcharena,frailtyindicesthatbestcapturethemulti‐dimensionalityoffrailtysuchastheFriedFrailtyPhenotype2ortheFrailty Index (“deficitmodel”21)may be necessary to demonstrateconstructvalidityofnewtoolsinpatientswithcirrhosis.However,these“traditional”modelsoffrailtyhavelimitedapplicabilitytotheclinicalpracticeoflivertransplantationinthattheyarenotcontin‐uously scored, display strong ceiling and/or floor effects, or are too complextouseinabusyclinicalpractice.1

With respect to the application of frailty tools in the clinicalarena,werecommendthateverytransplantcentershouldincorpo‐ratea standardized tool tomeasure frailty in their liver transplantpatientsbothatinitialevaluationandlongitudinallyonthewaitlist.This recommendation was based on evidence that standardizedfrailtymetrics can improve the accuracy of the “eyeball test” andtraditionalliverdiseasemetricstopredictmortalityinpatientswithcirrhosis.5,7‐14,21

Giventhatthereisnosinglefrailtytoolthathasemergedintheliteratureassuitable forevaluationofpatientswithcirrhosis inallclinicalscenarios (outpatientvs. inpatient; transplantvs.nontrans‐plant),werecommendafrailtytool kittoprovidearangeoftoolsthatcanbeuseddependingupontheclinicalsetting,availableresources,andintendedclinicaldecisionsthatwillbemadebasedonthetestresult. Here, we offer several points for each center to considerwhendecidingonwhichstandardized frailty tool(s) to incorporateinto clinical practice:

1. Frailty tools have been best studied in the outpatient setting.Measuressuch as the Fried Frailty Phenotype2 or Liver Frailty Index7 have, to date, only been studied in the outpatient hepatology/liver transplant settings where patients are in their “steadystate.” Hospitalized patients often have transient perturbationsin physical and cognitive function, which limit the ability ofthese performance‐based frailty assessments to represent trueunderlyingphysiologicreserve.However,whileperformance‐based tests may have limited use in the inpatient setting, provider‐and patient‐assessed tools such as the Karnofsky PerformanceStatus (KPS)andActivitiesofDailyLiving (ADL)scalehavebeenevaluated in the inpatient settings and demonstrated to predict

F I G U R E 1  Liver‐relatedandnon–liver‐relatedfactorsthatcontributetothedevelopmentofphysicalfrailtyinpatientswithcirrhosis

6  |     LAI et AL.

TAB

LE 2

 Propertiesofthetoolsevaluating“frailty”thathavebeenevaluatedinpatientswithcirrhosisa

Subj

ectiv

e ←

——

——

——

——

——

——

——

——

——

——

→

O

bjec

tive

CFS

KPS

AD

L/IA

DL

Brad

en s

cale

FFP

SPPB

LFI

Grip

str

engt

hG

ait s

peed

6MW

TCP

ET

Subj

ectiv

ityRe

quire

s cl

inic

ian

judg

men

t✔

✔✗

✔✗

✗✗

✗✗

✗✗

Can

be

bias

ed b

y pa

tient

repo

rtin

g ✔

✔✔

✔✔

✗✗

✗✗

✗✗

Predictivevalidity

For p

retr

ansp

lant

ou

tcom

es✔

✔✔

✔✔

✔✔

✔✔

✔✔

For p

ostt

rans

plan

t ou

tcom

es−

✔−

−−

−−

−−

−✔

Testcharacteristics

Reliability(internal

cons

iste

ncy

and

repeatability)

✔−

−−

−−

−✔

✔−

−

Resp

onsi

vene

ss to

changeovertime

✗✗

✗✗

✗✔

✔✔

✔−

−

Clin

ical

feas

ibili

tyEstimatedtimetaken

(minutes)

<1<1

<2<5

<10

<5<5

<1<2

<10

<60

Needforspecialized

equi

pmen

t✗

✗✗

✗✗

✗✔

✔✗

✗✔✔

Needforhighly

trai

ned

pers

onne

l ✗

✗✗

✗✗

✗✗

✗✗

✗✔✔

Abbreviations:6MWT,6‐minutewalktest;ADL,ActivitiesofDailyLiving;CFS,ClinicalFrailtyScale;CPET,cardiopulmonaryexercisetesting;IADL,InstrumentalActivitiesofDailyLiving;FFP,Fried

FrailtyPhenotype;KPS,KarnofskyPerformanceStatus;LFI,LiverFrailtyIndex;SPPB,ShortPhysicalPerformanceBattery.

Note:Doublecheckmarkindicatesthatthesetestsreallyneedspecializedtechniciansandequipmentmoresothantheotherteststhathaveonlyonecheckmark.

a No

data

ava

ilabl

e; ✔

yes

; ✗ n

o.

     |  7LAI et AL.

nontransplant mortality,11,14,15 re‐admissions,14,16 and mortality after liver transplantation.11

2. Subjective tools for “screening” versus more objective frailty as‐sessment. Becauseof thepotential implications of frailty in thedecision to proceed with transplant, there was a consensusthatwaitlisted patients require assessmentwith objective, per‐ formance‐based frailty tools (eg, Liver Frailty Index, 6‐minutewalktest).Provider‐orpatient‐assessedmetricsoffrailty(eg,KPS,ADLs,ClinicalFrailtyScale),whilesimpleandfeasibletoadminister systematically in a busy clinical setting, may be insensitive to sub‐tle,butprognostic,gradientsofthefrailtyspectrum.Thatbeingsaid,inthelargerpopulationofpatientsinthenontransplantset‐ting, a stepwise approachwherepatients are screenedwith an“easy‐to‐perform” test, followedby amore comprehensive testtoeitherconfirmordefinitivelyruleoutfrailtymaybethemostpractical.

3. Measurement of longitudinal changes in frailty is clinically relevant in the transplant setting and requires frailty tools that are sensitive to change.Longitudinalchanges in frailtyarepredictiveofwait‐list mortality above and beyond a single assessment alone.22 MetricssuchasthecompositeLiverFrailtyIndex,whichiscon‐tinuous,lacksafloor/ceilingandhasbeenshowntobereliable/repro ducible,23areparticularlywell‐suitedforlongitudinalmeas‐urement, although additional research is needed to validatethe prognostic value of “Δfrailty” using the Liver Frailty Index.Identificationof frailty tools thataresensitivetochange ispar‐ticularlyrelevantasanendpointforclinicaltrialsaimingtoslowtheprogressionof—orevenreverse—frailty.

Basedonthesethreecriteria,weofferaparsimonioustoolkitcon‐sistingoftheKPSscale,ADL/IADLs,LiverFrailtyIndex,andthe6‐min‐utewalktestfortransplantclinicians (Table3).Whilenosingletool isperfectforeveryclinicalscenario,weselectedthesefourtoolsspecifi‐callytobalancetheneedsforspeed,low‐cost,patient‐centeredness,andobjectivity.

1.3 | Measuring frailty in pediatric liver transplantation

Arecent17‐centerstudydemonstratedthatfrailtyassessmentwiththeFriedFrailtyPhenotype is feasible in school‐agedchildrenwithchronicliverdisease;nearlyhalfofchildrenwithend‐stageliverdis‐ease met criteria for being frail.24 It isnotyetknowntheextent towhich frailty measures impact mortality. Metrics that incorporateperformance‐basedtestshavelimitedapplicationininfantsandtod‐dlerswhomaynotbeabletofullycooperatewithtestinginstructions(eg,gripstrength,chairstands).Frailtyassessment inpediatric livertransplantpatients<5yearsofagewilllikelyrequireacombinationofquantitativemusclemassmeasurement,laboratoryand/oranthropo‐metricnutritionalbiomarkers,andobservedassessmentsofactivity.

Key points

• Everypatientwithcirrhosisawaiting liver transplantation shouldbeassessedatbaselineandlongitudinallyusingastandardizedfrailtytool.

• Frailtymeasurementwithobjectiveperformance‐basedmeasures(eg,LiverFrailty Index) isbest studied in theoutpatient settingwhenpatientsareintheir“steadystate.”However,provider‐andpatient‐assessed instruments (eg, KPS, ADLs) have prognosticvalueamonghospitalizedpatients.

• Todate,theLiverFrailtyIndexhasthebroadestapplicabilityamongallthefrailtyinstrumentsforpracticalfrailtyassessmentinthelivertransplantsettingandhastheadvantagesofbeingobjective,per‐formance‐based, and suitable for longitudinal measurement.

1.4 | Incorporating frailty into clinical decision‐making

Webelieve that a single assessmentof frailty shouldnotbeusedasthesolecriterionforremovingapatientfromthelivertransplant

F I G U R E 2  Aconceptualmodelofsomeofthepatientcomponentsthatcliniciansincorporateintotheirglobalassessment of a patient's transplant candidacyandthetoolsthattheyusetoinformthisholisticassessment.Anobjectivefrailtytoolkitshouldbeusedtoinform clinicians’ assessments of muscle wasting,under‐nutrition,andphysicalinactivity—which,together,formthemajorcomponentsofphysicalfrailty—toimproveobjectivityandaccuracyoftheclinician's global assessment of transplant candidacyforthepurposesoftransplantdecision‐making(adaptedfromLaiJC,AJG2017)8

GlobalAssessment ofTransplantCandidacy

Patient Components

MELDNaChild Pugh Score

Vital signsEchocardiogram

CreatinineUrinalysis

Spirometry,Hemoglobin A1c,

Colonoscopy

Synthetic dysfunctionPortal hypertension

Measurement Tools

Cardiac function

Renal function

Other co-morbidities

Muscle wastingUnder-nutritionPhysical inactivity Objective Frailty Tool Kit

Eyeball test

8  |     LAI et AL.

waitlist, as there are no data to support a single frailty cutoff atwhich a patient should not undergo liver transplantation. Instead,weadvocatethatastandardizedtoolforfrailtybeconsideredasone of manyobjectivecomponentsthatareroutinelyincorporatedintoaclinician'sassessmentofapatient'sglobalhealthstatusthatulti‐matelydetermineshisorhertransplantcandidacy(Figure2).8

Incorporating frailty into transplant decision‐making can offerthe liver transplant communitymore than simply prognostication.Whatmakes frailty suchaunique risk factor forpatientswithcir‐rhosis is that,unlikemore“traditional” transplantriskfactorssuchasage,sex,orModelforEnd‐StageLiverDiseasescore, individualcomponents of frailty (eg, physical function, sarcopenia, andmal‐nutrition) are potentially modifiable with exercise and nutritionalinterventions.25,26

Recently, the concept of “prehabilitation” has gained signifi‐cant momentum in transplant and nontransplant surgical fields.27 Prehabilitation refers to multidisciplinary “training” to enhancephysicalstrengthandnutritionalstatus—withthetheoreticalbenefitofimprovingphysiologicreservepriortosurgery.Althoughdataontheimpactofprehabilitationinlivertransplantationarelimitedtoasmallcohortatasinglecenter,27thereisemergingevidenceinstud‐iesofpatientsundergoingmajorabdominalsurgeriesthatprehabil‐itationprogramsimproveoutcomesandreducecosts.Examplesofspecific interventionshaveincludedcomprehensivephysicalactiv‐ity programs, supervised and home‐based exercises, educational/behavioralmodification,and/ornutritioncounseling.

Basedonthesedata,wehavedevelopedasimplealgorithmthatleveragesthepotential“modifiability”offrailtythroughprehabilita‐tion(Figure3).Specifically,thisalgorithmusesastandardizedfrailtymetrictoguiderecommendationsregardingtheintensityofpreha‐bilitation for liver transplant candidates.Whileourworkinggroupagreedthatalllivertransplantcandidatesshouldbeprovidedexer‐ciseandnutritionalrecommendations,inlightoflimitedavailability

ofoutpatientphysicaltherapyanddieticianresources—nottomen‐tionlimitedreimbursement—ouralgorithmallowsforintensificationof resources in those patientswho aremost vulnerable (ie, frail).Thespecificgoalsofthisalgorithmwereto:(a)increasephysiologicreservepretransplantsothatpatientsmaybetterwithstandacutedecompensating events, (b) improve clinical outcomes after livertransplantation, and (c) more efficiently and effectively allocatehealthcareresourcesinlivertransplantation.

Ouralgorithminvolvesthefollowingsteps:

• Step 1: Stratify risk by frailty status. All liver transplant candidatesshould undergo risk stratification using a standardized frailty as‐sessment tool. Our proposed frailty stratification system, based on expertopinion,foraselectnumberoftools,ispresentedinTable4.

• Step 2: Recommend a prehabilitation program based on risk stra‐tum.Theintensityoffrailtyinterventionshouldbetailoredtothedegree of frailty. Patientswith severe frailtymay benefit fromintensiveprehabilitation,withconsiderationofreferraltoan in‐patient rehabilitationcenter.We recommend thatpatientswitha moderate degree of frailty engage in a home‐based exerciseprogramdevelopedbyacertifiedexerciseprofessionalthattar‐getsthepatient'sgreatestfunctional impairment(s) (eg,balance,chairstands)butalsoincorporatesaerobictrainingandsimulatesADLs(toimprovequalityoflife).Patientswithmildornofrailtyshouldfollowrecommendationsdevelopedforthegeneralpop‐ulation(iemoderate‐intensityexercise≥150minutesperweek),withgradualbuildupphysicalenduranceandstrength.Physicalactivitytrackers(eg,accelerometers)maybeconsideredtoassessadherence.

• Step 3: Reassess and re‐stratify. Reversal of frailty among liver transplant candidates is feasible but has not been systemat‐ically studied. Lack of progression, however, is a clinically rele‐vant achievement that should incentivize liver transplantation,

F I G U R E 3  Algorithmtotailorprehabilitationrecommendationsbasedon frailty assessment

     |  9LAI et AL.

particularlyifearlyposttransplantrehabilitationwillbeprovided.Werecommendclosemonitoringofpatientsonthewaitlist,withreassessmentintervalsbasedonthepatient'sseverityoffrailtyatthelastavailableexamination(Figure3).

Key points

• Standardizedassessmentsoffrailtymaybeusedtotailorthein‐tensity and type of nutritional and physical therapy in patientsawaitingandundergoinglivertransplantation.

• Frailtyshouldnotbeusedasthesolecriterionfordelistingapa‐tient for liver transplantation, but rather should be consideredoneofmany criteriawhen evaluating transplant candidacy andsuitability(Figure2).

2  | A ROADMAP TO ADVANCE FR AILT Y IN THE CLINIC AL AND RESE ARCH SET TINGS OF LIVER TR ANSPL ANTATION

Frailtyisnowwell‐recognizedinthescientificliteratureasastrongpredictor of outcomes in patients with cirrhosis, including in theliver transplant setting.While the frailty literature in hepatology/livertransplantationiscurrentlyrichwithhighqualitystudies,manyquestions remain: (a) the impact of frailty onmortality after liver transplantation, (b)the impactof longitudinalchanges infrailtyonoutcomes,and(c)therelationshipbetweenliverdiseaseprogressionandfrailty.Perhaps,themostexcitingtargetforfutureinvestigationisthenotionthatfrailtyisactionable,andthatitscomponentscanbearrestedorevenreversed.Hereweproposeapathforwardtoadvanceourunderstandingof frailty and improve the careof ourpatients:

ToolRationale for inclusion in the frailty tool kit

Estimated time to assess

Populations studied

Karnofskyperfor‐mance status

Intuitive and instant <10s Inpatient and outpatientNo cost

Lowflooreffects

Canbeassessedbythepatientortheprovider

Activitiesofdailyliving/instrumental activities of daily living

No cost 2‐4 min Inpatient and outpatientPatientreported

Well‐accepted patient‐oriented outcome

Liverfrailtyindex Objective, performance‐based 1‐3 min Outpatient

Continuousscalewithoutceilingorfloor effects

Quicklyadministered

Can be repeatedly performed in theoutpatientsetting

6‐minutewalktest Objective, performance‐based 6 min Outpatient

Continuousscalewithoutceilingorfloor effects

Noneedforspecializedequipment

TA B L E 3  Suggestedfrailtytoolkit

Stages of frailty

Severe Moderate Mild/Absent

ADL14,31 Difficultywith≥2ADLs Difficultywith1ADL

No difficulty withADLs

Clinical Frailty Scale16 ≥7 6 1‐5

FriedFrailtyPhenotype6 ≥3 1‐2 0

KarnofskyPerformanceStatus Scale11,15

0‐40 50‐70 ≥80

LiverFrailtyIndex7 ≥4.5 3.2‐4.4 <3.2

6‐minutewalktest9 <250m <350‐250m >350 m

Abbreviation:ADL,activitiesofdailyliving.

TA B L E 4   Recommended criteria to stage frailty in liver transplant candidates

10  |     LAI et AL.

1. Obtain funding for multicenter consortia for prospective studies on frailty in liver transplantation. Now is an opportune timefor formal financial sponsorship of multicenter consortia toaccelerate progress. Engagement with other teams studyingfrailty in other chronic diseases, geriatrics/gerontology, andother solid organ transplant disciplines may have a highvalue.

2. Implement evidence‐based, objective frailty measurement as part of standard‐of‐care.Givenitsstrongassociationswithhealth‐relatedoutcomes,frailtyshouldbeconsideredavitalsignandmeasuredsystematically and routinely during clinic visits.

3. Develop interventions targeting modifiable aspects of physical frailty through rigorous multicenter randomized clinical trials. Specific modi‐fiable targets include muscle mass, muscle function, activity level, and nutrition. Interventions can focus on a single aspect or offer a more comprehensive approach (eg, prehabilitation program).Randomizationshouldofferclinicalequipoise:becausewebelievethatallpatientswithcirrhosiswouldbenefitfromsomeformofactivity andnutritional counseling, trials should explore varyingintensities(eg,twotimesperweekvs.daily)ortypesofinterven‐tion (eg, home‐ vs. center‐based; telephone calls vs. text mes‐sages)ratherthanrandomizingpatientstoa“nointervention”arm.

4. Investigate nonphysical aspects of frailty.These includecognitive,emotional, social, and environmental aspects that expand theconceptoffrailtybeyondphysicalfrailtyalone.

5. Integrate the concept of frailty into training curricula for hepa‐tology/surgery trainees and into national society guidelines for management of patients with cirrhosis. Educational modulesshould be developed to assess transplant trainees’ ability toobjectively assess, document, and incorporate frailty into clini‐caldecision‐making.Assessmentof frailtyshouldbe formallyincorporated into national guidelines for evaluation of liver transplant candidates.

6. Include objective measurement of frailty into research studies and national registries. Frailty can be treated as a predictor, a con‐founder,orevenanoutcomeinresearchstudies.Inclusionofob‐jectivemeasurementoffrailtyintonationalregistrydatawouldaccelerateresearchinthisfieldandenableadjustmentforfrailtyinanystudyevaluatingpre‐andposttransplantmortality.Basedontheevidencetodateandtheneedforuniformityofobjective frailtymeasurement in this setting,we recommend use of theLiverFrailtyIndexforthispurpose.

ACKNOWLEDG MENTS

This manuscript is a work product of the American Society ofTransplantation's Liver and Intestine Community of Practice andhas been endorsed by the American Society of Transplantationand theAmericanSocietyofTransplantSurgeons.This studywasfundedbyNIHK23AG048337(Lai),NIHR01AG059183(Lai),NIHRO1GM119174 (Dasarathy); P50 AA024333 (Dasarathy); R21AR71046 (Dasarathy); UO1 AA0026976 (Dasarathy); UO1DK061732(Dasarathy); RO1DK113196 (Dasarathy); Mikati Foundation Grant

(Dasarathy).Thesefundingagenciesplayednoroleintheanalysisofthedataorthepreparationofthismanuscript.

DISCLOSURE

Theauthorsof thismanuscripthavenoconflictof interest todis‐closeasdescribedbytheAmerican Journal of Transplantation.

DATA AVAIL ABILIT Y S TATEMENT

Datasharingnotapplicabletothisarticleasnodatasetsweregener‐atedoranalyzedduringthecurrentstudy.

ORCID

Shunji Nagai https://orcid.org/0000‐0003‐2612‐8427

R E FE R E N C E S

1. Lai JC. Advancing adoption of frailty to improve the care of pa‐tientswithcirrhosis:timeforaconsensusonafrailtyindex.Am J Gastroenterol.2016;111(12):1776‐1777.

2. FriedLP,TangenCM,WalstonJ,etal.Frailtyinolderadults:evidenceforaphenotype.J Gerontol A Biol Sci Med Sci.2001;56(3):146‐156.

3. American Thoracic Society: Quality Life Resource. FunctionalStatus. Available at: http://qol.thoracic.org/sections/key‐concepts/functional‐status.html.AccessedFebruary23,2018.

4. NeyM,TangriN,DobbsB,etal.Predictinghepaticencephalopa‐thy‐relatedhospitalizationsusingacompositeassessmentofcog‐nitive impairment and frailty in 355 patientswith cirrhosis.Am J Gastroenterol.2018;113(10):1‐10.

5. Tapper EB, KonermanM,Murphy S, Sonnenday CJ. Hepatic en‐cephalopathy impacts the predictive value of the Fried FrailtyIndex.Am J Transplant.2018;18(10):2566‐2570.

6. Lai JC, Feng S, Terrault NA, Lizaola B, Hayssen H, Covinsky K.Frailtypredictswaitlistmortalityinlivertransplantcandidates.Am J Transplant.2014;14(8):1870‐1879.

7. LaiJC,CovinskyKE,DodgeJL,etal.Developmentofanovelfrailtyindextopredictmortalityinpatientswithend‐stageliverdisease.Hepatology.2017;66(2):564‐574.

8. LaiJC,CovinskyKE,McCullochCE,FengS.Theliverfrailtyindeximproves mortality prediction of the subjective clinician assess‐mentinpatientswithcirrhosis.Am J Gastroenterol.2017;10:1‐8.

9. Carey EJ, Steidley DE, Aqel BA, et al. Six‐minute walk distancepredicts mortality in liver transplant candidates. Liver Transpl. 2010;16(12):1373‐1378.

10. NeyM,HaykowskyMJ,VandermeerB,ShahA,OwM,TandonP.Systematic review: pre‐ and post‐operative prognostic value ofcardiopulmonary exercise testing in liver transplant candidates.Aliment Pharmacol Ther.2016;44(8):796‐806.

11. Orman ES, Ghabril M, Chalasani N. Poor performance status isassociatedwithincreasedmortalityinpatientswithcirrhosis.Clin Gastroenterol Hepatol.2016;14(8):1189‐1195.e1.

12. Faustini Pereira JXL,Galant LH,RossiD, et al. Functional capac‐ity, respiratorymusclestrength,andoxygenconsumptionpredictmortality in patients with cirrhosis. Can J Gastroenterol Hepatol. 2016;2016(1):1‐6.

13. SundaramV,LimJ,TholeyDM,etal.TheBradenScale,astandardtoolforassessingpressureulcerrisk,predictsearlyoutcomesafterliver transplantation. Liver Transpl.2017;23(9):1153‐1160.

     |  11LAI et AL.

14. Tapper EB, Finkelstein D, Mittleman MA, Piatkowski G, LaiM. Standard assessments of frailty are validated predictors ofmortality in hospitalized patients with cirrhosis. Hepatology. 2015;62(2):584‐590.

15. TandonP,ReddyKR,O'LearyJG,etal.AKarnofskyperformancestatus‐based score predicts death after hospital discharge in pa‐tientswithcirrhosis.Hepatology.2017;65(1):217‐224.

16. TandonP,TangriN,ThomasL,etal.Arapidbedsidescreentopre‐dict unplanned hospitalization and death in outpatientswith cir‐rhosis: a prospective evaluation of the clinical frailty scale.Am J Gastroenterol.2016;111(12):1759‐1767.

17. DunnMA,JosbenoDA,TevarAD,etal.Frailtyastestedbygaitspeedisanindependentriskfactorforcirrhosiscomplicationsthatrequirehospitalization.Am J Gastroenterol.2016;111(12):1768‐1775.

18. SinclairM,PoltavskiyE,DodgeJL,LaiJC.Frailtyisindependentlyassociatedwith increased hospitalisation days in patients on thelivertransplantwaitlist.World J Gastroenterol.2017;23(5):899.

19. DasarathyS,MerliM.Sarcopeniafrommechanismtodiagnosisandtreatment in liver disease. J Hepatol.2016;65(6):1232‐1244.

20. LaiJC.Aframeworktodeterminewhenlivertransplantationisfu‐tile. Clin Liver Dis.2016;8(6):137‐139.

21. RockwoodK,MitnitskiA.Frailtyinrelationtotheaccumulationofdeficits. J Gerontol A Biol Sci Med Sci.2007;62(7):722‐727.

22. LaiJC,DodgeJL,SenS,CovinskyK,FengS.Functionaldeclineinpatientswithcirrhosisawaiting liver transplantation: results fromtheFunctionalAssessmentinLiverTransplantation(FrAILT)study.Hepatology.2016;63:574‐580.

23. WangCW,LebsackA,ChauS,LaiJC.Therangeandreproducibilityof the Liver Frailty Index (publishedonline aheadof printMarch2019).Liver Transpl.https://doi.org/10.1002/lt.25449..

24. LurzE,QuammieC,EnglesbeM,etal.Frailtyinchildrenwithliverdis‐ease: a prospective multicenter study. J Pediatr.2018;194:109‐115.

25. Duarte‐Rojo A, Ruiz‐Margáin A, Montano‐Loza AJ, Macías‐RodríguezRU,FerrandoA,KimWR.Exerciseandphysicalactivityforpatientswithend‐stageliverdisease:improvingfunctionalsta‐tusandsarcopeniawhileonthetransplantwaitinglist.Liver Transpl. 2017;24(1):122‐139.

26. TandonP,IsmondKP,RiessK,etal.Exerciseincirrhosis:translatingevidenceandexperiencetopractice.J Hepatol.2018;69:1164‐1177.

27. VolkML,SonnendayC.Patient‐centeredlivertransplantation.Clin Liver Dis.2016;8(1):24‐27.

28. SamoylovaML,CovinskyKE,HaftekM,KuoS,RobertsJP,LaiJC.Disabilityinpatientswithend‐stageliverdisease:resultsfromthefunctional assessment in liver transplantation study. Liver Transpl. 2017;23(3):292‐298.

29. MalinisMF,ChenS,AlloreHG,QuagliarelloVJ.Outcomesamongolderadultlivertransplantationrecipientsinthemodelofendstageliverdisease(MELD)era.Ann Transplant.2014;19:478‐487.

30. YadavA,ChangY‐H,CarpenterS,etal.Relationshipbetweensar‐copenia,six‐minutewalkdistanceandhealth‐relatedqualityoflifein liver transplant candidates. Clin Transpl.2015;29(2):134‐141.

31. RakoskiMO,McCammonRJ,Piette JD,etal.BurdenofcirrhosisonolderAmericans and their families: analysis of thehealth andretirement study. Hepatology.2012;55(1):184‐191.

How to cite this article:LaiJC,SonnendayCJ,TapperEB,etal.Frailtyinlivertransplantation:AnexpertopinionstatementfromtheAmericanSocietyofTransplantationLiverandIntestinalCommunityofPractice.Am J Transplant. 2019;00:1‐11. https://doi.org/10.1111/ajt.15392