Triumphs & Tribulations:Triumphs & Tribulations:The first 50 The first 50 paediatricpaediatric liver transplants in liver transplants in

New ZealandNew Zealand

Helen M EvansHelen M Evans

PaediatricPaediatric GastroenterologyGastroenterology

Starship HospitalStarship Hospital

Triumphs & TribulationsTriumphs & Tribulations

BackgroundBackground

ResultsResults

Triumphs Triumphs –– things wethings we’’ve done wellve done well

Tribulations Tribulations –– problems weproblems we’’ve facedve faced

Future challengesFuture challenges

AcknowledgementsAcknowledgements

Liver transplantation (LT) in childrenLiver transplantation (LT) in children

Children have very good outcomes following LTChildren have very good outcomes following LT

Most childhood liver diseases are nonMost childhood liver diseases are non--recurrentrecurrent

–– LT potentially curativeLT potentially curative

Established programmes publish 5 yr survival Established programmes publish 5 yr survival

rates > 85%rates > 85%

Innovations breeding successInnovations breeding success

ImmunosuppressionImmunosuppression

–– Cyclosporin & tacrolimusCyclosporin & tacrolimus

–– MycophenolateMycophenolate mofetilmofetil, sirolimus, induction antibodies, sirolimus, induction antibodies

Preservation solutionsPreservation solutions

AntimicrobialsAntimicrobials

Ability to reduce liver in size for use in childrenAbility to reduce liver in size for use in children

–– Surgical reductionSurgical reduction

–– Splitting the liver for use in 2 recipientsSplitting the liver for use in 2 recipients

–– Live donationLive donation

In the good old daysIn the good old days

Liver transplantation in QueenslandLiver transplantation in Queensland

19901990--2002: New Zealand children were 2002: New Zealand children were

referred to Brisbane for LTreferred to Brisbane for LT

Average stay in Australia = 6 months (range Average stay in Australia = 6 months (range

3 3 –– 17 months)17 months)

5 yr graft survival = 64%5 yr graft survival = 64%

5 yr patient survival = 73%5 yr patient survival = 73%

Liver transplantation in AucklandLiver transplantation in Auckland

Adult LT Adult LT programmeprogramme began in 1998began in 1998

Contract awarded in 2001 for 6Contract awarded in 2001 for 6--7 7 paediatricpaediatric cases cases

per yearper year

11stst paediatric transplant in Feb 2002paediatric transplant in Feb 2002

5050thth paediatric transplant in Oct 2009paediatric transplant in Oct 2009

Liver transplantation in AucklandLiver transplantation in Auckland

Patient demographicsPatient demographics

22 Male; 28 Female22 Male; 28 Female

Median age 26 monthsMedian age 26 months

–– Range 4 months Range 4 months –– 16 years16 years

Median weight 12.5 kg Median weight 12.5 kg

–– Range 5.8 Range 5.8 –– 75 kg75 kg

Combined liver & kidney transplant in 2Combined liver & kidney transplant in 2

Indications for liver transplantationIndications for liver transplantation

Metabolic = Wilson (1), Maple syrup urine (1), Oxalosis (1), Protein C deficiency (1)

Biliary atresia58%

Indications for liver transplantationIndications for liver transplantation

BA commonest diagnosis BA commonest diagnosis –– 29/46 primary transplants + 2/4 re29/46 primary transplants + 2/4 re--transplantstransplants

–– 62% of total transplants62% of total transplants

–– 13/14 Maori patients13/14 Maori patients

–– 2 children presented too late for Kasai2 children presented too late for Kasai

ReRe--transplants of 4 children transplanted transplants of 4 children transplanted in Australiain Australia–– 2 chronic rejection2 chronic rejection

–– 1 acute graft failure1 acute graft failure

–– 1 recurrent cirrhosis1 recurrent cirrhosis

Ethnicity of LT recipientsEthnicity of LT recipients

Origin of recipients within NZOrigin of recipients within NZ

** Central Auckland (3); Counties Manukau (13); Waitemata (5)

LT for children commonly uses segments IILT for children commonly uses segments II--III of III of

the adult donor liver the adult donor liver

Segments VSegments V--VIII can then be used for an adultVIII can then be used for an adult

Reduced size liver transplantationReduced size liver transplantation

Type of liver transplantType of liver transplant

32 deceased donors:32 deceased donors:

–– 11 reduced size grafts11 reduced size grafts

–– 11 split grafts11 split grafts

–– 10 whole grafts10 whole grafts

19 live donors:19 live donors:

–– 7 Fathers7 Fathers

–– 4 Mothers4 Mothers

–– 3 Family friends3 Family friends

–– 3 Aunts/Uncles3 Aunts/Uncles

–– 2 Grandparents2 Grandparents

–– 2 live donors used for 2 live donors used for

acute liver failureacute liver failure

–– 1 live liver/kidney donor1 live liver/kidney donor

For 50 patients (51 transplants):

TriumphsTriumphsExcellent graft & patient survivalExcellent graft & patient survival

Shorter length of stayShorter length of stay

Responsive to change & evolving problemsResponsive to change & evolving problems–– EBV surveillanceEBV surveillance

–– Hepatitis B immune status monitoringHepatitis B immune status monitoring

–– Protocol biopsy surveillanceProtocol biopsy surveillance

–– Renal function monitoringRenal function monitoring

–– Establishment for live donor programmeEstablishment for live donor programme

–– Live immunisations following LTLive immunisations following LT

–– De novoDe novo food allergiesfood allergies

Multidisciplinary team with motivated nursesMultidisciplinary team with motivated nurses

Collaboration with shared care centresCollaboration with shared care centres

Graft & patient survivalGraft & patient survival

Compares favourably with overseas Compares favourably with overseas

benchmarksbenchmarks–– ANZLTR 2005ANZLTR 2005--2008: 1 yr patient survival 95%; 5 yr 93%2008: 1 yr patient survival 95%; 5 yr 93%

Overall survival = 96% patient; 94% graftOverall survival = 96% patient; 94% graft

–– 1 patient re1 patient re--transplanted for nontransplanted for non--function day 2function day 2

–– 2 patients died2 patients died

1 yr survival (n=43) = 98% patient; 95% graft1 yr survival (n=43) = 98% patient; 95% graft

5 yr survival (n=16) = 94% patient; 88% graft5 yr survival (n=16) = 94% patient; 88% graft

Psychosocial outcomesPsychosocial outcomes

Good psychosocial outcomesGood psychosocial outcomes

–– Difficult to measureDifficult to measure

All school age children at schoolAll school age children at school

Some mild concentration problemsSome mild concentration problems

Some nonSome non--adherence in adolescentsadherence in adolescents

Live donor outcome excellentLive donor outcome excellent

How long did the patients stay?How long did the patients stay?Median time in PICU = 2 days (range 1 Median time in PICU = 2 days (range 1 –– 8)8)

Median time in Starship = 19 days (range 6 Median time in Starship = 19 days (range 6 –– 109)109)

Median time in Ronald McDonald House = 18 weeks (9 Median time in Ronald McDonald House = 18 weeks (9 –– 34)34)

Median time in Australia 1990Median time in Australia 1990--2002 = 24 weeks 2002 = 24 weeks

EpsteinEpstein--Barr virus (EBV)Barr virus (EBV)

Bad news:Bad news:

Difficult virus to treatDifficult virus to treat

No vaccineNo vaccine

Can lead to PTLDCan lead to PTLD

Good news:Good news:

Good monitoring testsGood monitoring tests

Usually responds to Usually responds to

reducing immune reducing immune

suppressionsuppression

�In most cases there is EBV mismatch between donor and

recipient

Post transplant Post transplant

lymphoprofilerativelymphoprofilerative diseasediseaseUnrestricted EBV replication can lead to Unrestricted EBV replication can lead to

lymphoproliferationlymphoproliferation & malignancy& malignancy

Occurs in up to 5 Occurs in up to 5 –– 10% of LT recipients10% of LT recipients

Initial treatment is reduction of Initial treatment is reduction of

immunosuppressionimmunosuppression

Can also use antiCan also use anti--CD20 antibodies CD20 antibodies

((RituximabRituximab) or chemotherapy) or chemotherapy

Post transplant Post transplant

lymphoprofilerativelymphoprofilerative diseasediseaseMonthly EBV load monitoring for 1Monthly EBV load monitoring for 1stst yearyear

1 biopsy1 biopsy--proven proven BurkittsBurkitts lymphoma (patient lymphoma (patient

died)died)

1 likely PTLD of lung (responded to 1 likely PTLD of lung (responded to

RituximabRituximab) )

Several children have stable high loadsSeveral children have stable high loads–– Largely managed by keeping IS as low as possibleLargely managed by keeping IS as low as possible

5 children have received 5 children have received RituximabRituximab

Hepatitis B infectionHepatitis B infection

2 donors had past hepatitis B infection2 donors had past hepatitis B infection

Recipients felt to be immuneRecipients felt to be immune

Loss of protective antibody in bothLoss of protective antibody in both–– One spontaneousOne spontaneous

–– One following One following RituximabRituximab for high EBV loadsfor high EBV loads

Both developed hepatitis BBoth developed hepatitis B–– More difficult to manage in immunosuppressedMore difficult to manage in immunosuppressed

–– Often leads to recurrent cirrhosisOften leads to recurrent cirrhosis

Hepatitis B monitoringHepatitis B monitoring

Recognition of loss of immune status by 1 Recognition of loss of immune status by 1

year post LTyear post LT–– Not previously reportedNot previously reported

–– Almost universalAlmost universal

More rigorous attention to preMore rigorous attention to pre--transplant transplant

immunisationimmunisation

Regular monitoring of antibodiesRegular monitoring of antibodies

ReRe--immunisation if antibody lostimmunisation if antibody lost

Evans et al. IPTA meeting 2009

Protocol biopsy monitoringProtocol biopsy monitoring

Growing recognition of chronic hepatitis on Growing recognition of chronic hepatitis on

biopsy despite normal liver functionbiopsy despite normal liver function

May be immune phenomenonMay be immune phenomenon

Post LT biopsy at 1, 5, 10 yearsPost LT biopsy at 1, 5, 10 years

Biopsy at 1 yr prior to steroid withdrawalBiopsy at 1 yr prior to steroid withdrawal

Evans. Hepatology 2006; Ekong. Liver Transpl 2009; Scheenstra. Liver Transpl 2009

Renal dysfunction following LTRenal dysfunction following LT

Renal dysfunction common following LTRenal dysfunction common following LT–– Nephrotoxic drugs Nephrotoxic drugs espesp tacrolimustacrolimus

–– MultiMulti--system diseasesystem disease

–– HepatorenalHepatorenal syndromesyndrome

Initially may be reversibleInitially may be reversible

Can respond to immunosuppression Can respond to immunosuppression

adjustmentadjustment

Renal function monitoringRenal function monitoring

Established links with renal teamEstablished links with renal team

PrePre--transplant assessment introducedtransplant assessment introduced–– Awareness that function is not normal prior to LTAwareness that function is not normal prior to LT

Regular Cystatin C measurementsRegular Cystatin C measurements–– NonNon--invasive marker of renal functioninvasive marker of renal function

–– Can use to calculate GFRCan use to calculate GFR

Low threshold for biopsyLow threshold for biopsy

Treatment of hypertensionTreatment of hypertension

Early IS adjustment if neededEarly IS adjustment if neededKara et al. IPTA meeting 2009

Deceased donor numbers are Deceased donor numbers are

decreasingdecreasingShortage of donors continues to be a big Shortage of donors continues to be a big

challenge in New Zealandchallenge in New Zealand

Organ donor rates in different countries

05

10152025303540

Spa

inUSA

Ireland

Aus

tria

Italy

Finland

Franc

e

Norw

ay

Polan

d

Neth

erla

nds

UK

Aus

tralia

New

Zea

land

Gre

ece

Do

no

rs p

er

mil

lio

n p

op

ula

tio

n

Type of LT according to yearType of LT according to year

McCall et al. NZMJ 2009

0

1

2

3

4

5

6

7

8

9

10

2002 2003 2004 2005 2006 2007 2008 2009

Total

Deceased donor

Live donor

Live immunisations following LTLive immunisations following LT

Accelerated immunisations for children with Accelerated immunisations for children with chronic liver diseasechronic liver disease

–– Includes hepatitis A & varicella vaccineIncludes hepatitis A & varicella vaccine

Often children transplanted before vaccines Often children transplanted before vaccines completecomplete

Exposure to measles & VZV a problem laterExposure to measles & VZV a problem later

Increasing international experience of live Increasing international experience of live vaccines following LTvaccines following LT

Some VZV vaccines given with successSome VZV vaccines given with success

MMR immunisation following LTMMR immunisation following LT

Measles outbreak in Auckland 2009Measles outbreak in Auckland 2009

All LT patients tested for measles immunityAll LT patients tested for measles immunity

Those immunised preThose immunised pre--LT mainly still LT mainly still immuneimmune

NonNon--immune patients offered MMR if:immune patients offered MMR if:

–– Tacrolimus monotherapyTacrolimus monotherapy

–– Stable liver functionStable liver function

Some acceptedSome accepted

–– Good response to single doseGood response to single dose

–– No clinical measlesNo clinical measles

De novoDe novo food allergiesfood allergies

Increasing awareness internationallyIncreasing awareness internationally

New food allergies after transplantNew food allergies after transplant

Mechanism not understoodMechanism not understood

Several children with new allergies notedSeveral children with new allergies noted

Immunology input in all casesImmunology input in all cases

Multidisciplinary teamworkMultidisciplinary teamwork

Contributions from allied health Contributions from allied health professionals can not be underestimatedprofessionals can not be underestimated

–– DietitiansDietitians ensure adequate nutrition preensure adequate nutrition pre--LTLT

–– PharmacistPharmacist ensures medication compatibility & educates ensures medication compatibility & educates families prefamilies pre--dischargedischarge

–– Social workerSocial worker used frequentlyused frequently

–– Ward staffWard staff & educator receptive to innovation& educator receptive to innovation

–– Charge nurseCharge nurse studied family stressors for Masters thesisstudied family stressors for Masters thesis

–– Specialist nursesSpecialist nurses support families pre & post LT and support families pre & post LT and have ensured consistent longhave ensured consistent long--term followterm follow--upup

Malnutrition in chronic liver diseaseMalnutrition in chronic liver disease

Patient with BA and his twin (same birth weight) – prior to

enteral feeding

Malnutrition in chronic liver diseaseMalnutrition in chronic liver disease

Patient with BA and his twin (same birth weight) – after

3/12 enteral feeding

Patient support & educationPatient support & education

Liver transplant manualLiver transplant manual

Support via Kids FoundationSupport via Kids Foundation

Focus on adolescent healthFocus on adolescent health

CollaborationCollaboration

Guidelines for shared care establishedGuidelines for shared care established

Outreach clinics:Outreach clinics:–– Christchurch/South IslandChristchurch/South Island

–– Hawkes BayHawkes Bay

–– WellingtonWellington

–– PalmerstonPalmerston NorthNorth

–– WhangareiWhangarei

CollaborationCollaborationRegular liaison with South Island Regular liaison with South Island gastroenterologist (Andrew Day)gastroenterologist (Andrew Day)

Joint liver & renal paediatric transplant meetings Joint liver & renal paediatric transplant meetings since 2007since 2007

Study days for shared care paediatriciansStudy days for shared care paediatricians

Auckland Transplant meetingsAuckland Transplant meetings

Paediatric Society Paediatric Society –– Gastroenterology SIGGastroenterology SIG

Data contributed to ANZLTRData contributed to ANZLTR

PLANZ meetings with Australian teamsPLANZ meetings with Australian teams

TSANZ & IPTA representationTSANZ & IPTA representation

TribulationsTribulations

Long wait times and low deceased donor Long wait times and low deceased donor ratesrates

Wait list mortalityWait list mortality

Technical complicationsTechnical complications–– Especially biliary complicationsEspecially biliary complications

Patients becoming more complexPatients becoming more complex

Small numbers mean inability to partake in Small numbers mean inability to partake in much researchmuch research

Wait timesWait times

All:All:

–– Median 99 days (range 0 Median 99 days (range 0 –– 702 days)702 days)

Live donors:Live donors:

–– Median 96 days (range 6 Median 96 days (range 6 –– 313 days)313 days)

Deceased donors:Deceased donors:

–– Median 110 days (range 0 Median 110 days (range 0 –– 702 days)702 days)

Wait timesWait times

All:All:

–– Median 99 days (range 0 Median 99 days (range 0 –– 702 days)702 days)

Blood group A (n = 26)Blood group A (n = 26)

–– Median 89 days (range 8 Median 89 days (range 8 –– 599 days)599 days)

Blood group O (n = 21) Blood group O (n = 21)

–– Median 136 days (range 0 Median 136 days (range 0 –– 702 day)702 day)

Waiting list deathsWaiting list deaths

8/63 (13%) of children died on the waiting 8/63 (13%) of children died on the waiting

list for LTlist for LT–– Sudden death at home in sick neonateSudden death at home in sick neonate 11

–– Variceal bleedingVariceal bleeding 22

–– Other bleedingOther bleeding 11

–– Acute liver failureAcute liver failure 22

–– HepatopulmonaryHepatopulmonary syndromesyndrome 11

–– RSV infectionRSV infection 11

Those who died did not wait longer nor Those who died did not wait longer nor

have higher PELD scorehave higher PELD scoreWilde et al. NZMJ 2007

Strategies to shorten wait timeStrategies to shorten wait time

Live donationLive donation–– Need to make families aware of option without Need to make families aware of option without

coercioncoercion

Donation after cardiac deathDonation after cardiac death

ABO incompatible transplantationABO incompatible transplantation–– Done with some success in JapanDone with some success in Japan

Paired donor exchangePaired donor exchange

Hepatocyte transplantation for metabolic Hepatocyte transplantation for metabolic diseasedisease

Technical complicationsTechnical complications

Primary nonPrimary non--function function 1 (2%)*1 (2%)*

Bile duct complications Bile duct complications 18 (36%)**18 (36%)**–– ReRe--operations in 9 (18%)operations in 9 (18%)

Vascular complications Vascular complications 11 (22%)*11 (22%)*

Intestinal ischaemia Intestinal ischaemia 1 (2%)*1 (2%)*–– Patient diedPatient died

Allograft ischaemia Allograft ischaemia 3 (6%)*3 (6%)*–– Gram negative sepsis 2Gram negative sepsis 2

–– Hepatic artery dissection 1Hepatic artery dissection 1

*Comparable to or lower than international series

**Higher than international series

Biliary complicationsBiliary complications

Small patientsSmall patients

Reliance on technical variant graftsReliance on technical variant grafts–– Fewer complications in whole liver recipientsFewer complications in whole liver recipients

–– Incidence may be increasing in other centresIncidence may be increasing in other centres

Initial learning curve issueInitial learning curve issue

Aggressive management with biliary Aggressive management with biliary stentingstenting +/+/-- rere--operationoperation

Some later strictures identified recentlySome later strictures identified recently

Gunawansa. In press 2010

Increasingly complex patientsIncreasingly complex patients

Combined liverCombined liver--kidney transplantskidney transplants

–– OxalosisOxalosis

–– Protein C deficiencyProtein C deficiency

High risk High risk hepatoblastomahepatoblastoma patientspatients

PFIC type 2 with malignancyPFIC type 2 with malignancy

Acute liver failure following lymphomaAcute liver failure following lymphoma

Unusual metabolic disordersUnusual metabolic disorders

Sclerosing cholangitis, ulcerative colitis & Sclerosing cholangitis, ulcerative colitis & spherocytosisspherocytosis

Children with significant social problemsChildren with significant social problems

The Balancing Act after transplantThe Balancing Act after transplant

RejectionInfection

PTLD

Poor

growth

Kidney

damage

Graft

loss

Recurrence

Future challengesFuture challenges

Excellent survival means focus of followExcellent survival means focus of follow--up is up is

minimisation of morbidityminimisation of morbidity

–– How can we safely minimise immunosuppression?How can we safely minimise immunosuppression?

–– Will our patients ever come off immunosuppression?Will our patients ever come off immunosuppression?

–– Is 100% survival achievableIs 100% survival achievable

As programme has progressed patients are older & As programme has progressed patients are older &

young persons clinic is requiredyoung persons clinic is required

Good outcomes mean indications for LT are likely Good outcomes mean indications for LT are likely

to become extendedto become extended

–– Eg metabolic diseasesEg metabolic diseases

–– But this needs to be balanced by availability of donor But this needs to be balanced by availability of donor

organsorgans

AcknowledgementsAcknowledgementsAlison WesleyAlison Wesley

AnaesthetistsAnaesthetists

Blood donors & transfusion serviceBlood donors & transfusion service

ChildrenChildren’’s Therapy Servicess Therapy Services

ChildrenChildren’’s Emergency Departments Emergency Department

ChildrenChildren’’s Outs Out--patient Departmentpatient Department

Consult Liaison Consult Liaison

Day Stay UnitDay Stay Unit

DietitiansDietitians

Donor familiesDonor families

Fellows & registrars at StarshipFellows & registrars at Starship

Home Care NursingHome Care Nursing

Kids FoundationKids Foundation

LaboratoriesLaboratories

Live donorsLive donors

NZLTAGNZLTAG

Organ Donation New ZealandOrgan Donation New Zealand

Operating theatresOperating theatres

Paediatric surgeonsPaediatric surgeons

PathologyPathology

PharmacyPharmacy

PICUPICU

Planet Espresso coffeePlanet Espresso coffee

Play therapyPlay therapy

Queensland Liver Transplant Queensland Liver Transplant ServiceService

RadiologyRadiology

Ronald McDonald HouseRonald McDonald House

Shared care paediatriciansShared care paediatricians

Social workersSocial workers

Specialist nursesSpecialist nurses

Staff of NZLTUStaff of NZLTU

Starship colleaguesStarship colleagues

Team support & schedulersTeam support & schedulers

Ward 26BWard 26B

Patients & their familiesPatients & their families

Anyone we have forgottenAnyone we have forgotten………………