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
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UK
Aus
tralia
New
Zea
land
Gre
ece
Do
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rs p
er
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op
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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………………