MAXIMIZING DONOR AVAILIBILITY AND

RECIPIENT OUTCOMES IN PEDIATRIC

LIVER TRANSPLANTATION

Thomas Heffron
Emory University
Childrens’s Hospital of Atlanta
Maximizing donor availibility
CHOA
• ABO incompatible grafts
• Living Donors
• Partial deceased donor grafts
• Large for size grafts with PTFE
• Applications in urgent cases
 Fulminant hepatic failure
 Neonatal hepatitis
Children’s Healthcare of Atlanta-Egleston
and Emory University
120
Liver Transplant Activity
104
100
87
80 72 68 66 70 70
65 59 64
60

40
25 30 26
17 17 19 21 21 19 18
20

0
1997 1999 2001 2003 2005

Children Adults
 Successful ABO Incompatible
Pediatric Liver Transplantation
Utilizing Selective
Plasmapheresis W
TG Heffron, D Welch, T Pillen, G Smallwood, KC Connor, E Martinez,
C Nam, C Fasola, R Romero
Emory University School of Medicine
Children’s Healthcare of Atlanta
Emory University Hospitals
Atlanta, GA
 Background
• It has been reported that ABO incompatible grafts
during liver transplantation results in lower patient
and graft survival with an increased incidence of
vascular and biliary complications and acute cellular
rejection.
Objective
• The aim of this study is to report our
experience of emergent transplantation of 16
pediatric recipients utilizing ABO
incompatible, mismatched grafts while using
selective plasmapheresis.
• Our standard immunosuppression induction
protocol was utilized with daclizumab,
tacrolimus, mycophenolate and prednisone.
Methods
• All pediatric liver transplant recipients
 Patients transplanted between July 1998, and
July 2005 (n =134)
 Induction utilized in all patients
• Plasmapheresis was not used prior to
transplantation for patients receiving ABO
incompatible grafts
• Serial isohemagglutinins drawn
Immunosuppression
• Daclizumab dosed once @ 1mg/kg
 Given within 24 hours post-transplant
• Mycophenolate 30 mg/kg/day
• Tacrolimus withheld for 7 days post-op
• 20 mg/kg methylprednisolone IV intra operatively
 Tapered over the next 6 days to 0.3 mg/kg/day
• 10 mg/kg methylprednisolone IV day # 5
Hemolysis Treatment
• With evidence of hemolysis by increased ABO
antibody titers on serial isohemagglutinins assay
 Additional intravenous methylprednisolone
(10-20 mg/kg per dose) was administered
• Hemolysis was suggested by increased indirect
bilirubin, hematuria, or increased haptoglobin.
• If the titers did not respond to
methylprednisolone, we instituted
plasmapheresis.
Data Collection
• Demographics • Hepatic artery
• ABO for both donor complications
and recipient
• Date of transplantation
• UNOS listing criteria
and scoring • Rate of plasmapheresis
• Rejection rates and • Steroid dosing
time to rejection
• Both graft and patient
• Disease state survival
Statistics
• Chi-Square for all nominal data

 Fisher’s Exact Test where appropriate

• Student’s unpaired t-Test (2-tailed)

 Continuous data between two groups

• Survival determined by Kaplan-Meier with

significance determined by the log rank method

• Significance was considered p < 0.05

 Diagnosis Leading to Transplant
• Acute fulminant hepatic failure (n=5)
• Post necrotic cirrhosis (n=3)
• Biliary Atresia with acute decompensation (n=3)
• Alagille’s syndrome (n=1)
• Re-transplantation due to primary non-function (n=4)
with initial diagnosis of cryptogenic cirrhosis
(n=1),hemangioendothelioma (n=1), and biliary atresia
(n=2)
Patient Demographics
ABO ABO
p
Incompatible Compatible
No. Grafts 16 122 NS
Mean Age
6.9 (± 6.9) 6.7 ( ± 6.3) NS
(yrs)
Female 8 (50%) 70 (55.1 %) NS
Caucasian 7 66
African-Am 8 46
NS
Asian 1 5
Hispanic 0 10
 Blood Group Pairings
• Blood type B donors
 Blood type B donors to type A liver recipient (B to A, n = 4)

• Blood type A donors

 Blood type A donors to type B liver recipient (A to B, n = 2)
 Blood type A donors to type O liver recipient (A to O, n = 7)

• Blood type AB to A liver recipient (AB to A, n =3)

 Hemolysis Not Requiring Plasmapheresis

• Patient #6 (4.3yrs/23kg, AFHF)

 Received steroid boluses for increased ABO antibody
titers of 1: 512 on (POD 14 -16)
 Increased total bilirubin from 2.4 mg/dl to 6.8 mg/dl
 Patient responded well to IV steroids and did not
require plasmapheresis
Patient Requiring Plasmapheresis
• Patient #3 (13yrs/55kg, primary non-function)
 had anti-B titers of 1:32 or less at baseline and increased
to 1:1024 with hemolysis
 Increase in serum total bilirubin to 8.4 mg/dl from
3.7mg/dl and hematuria on POD #6 with unresponsive
steroid therapy

• Plasmapheresis was instituted for 10 days, 80% total blood

replacement for three days and 150% replacement for 7
days

• Had two biopsy proven episodes of acute cellular rejections

at 95 and 169 days post transplant
ABO Incompatible Liver Allograft
Transplantation
Acute Cellular Rejections
ABO ABO Compatible p
Incompatible
Total patients 16 122
Rejection Episodes 8 121 NS

Mean Time to 1st 144 (± 96) 307 (± 325) <0.001

Rejection (days)
Patient with rejections
6 47 0.04

Mean follow-up 925 ( ± 537) 1185 ( ± 733) NS

Patient Outcomes
ABO ABO
p
Incompatible Compatible
No. Grafts 16 122 NS
HAT 0 7 NS
Biliary comp 2 13 NS
%1yr pat
100 93
survival
%1yr graft
92.3 83.4
survival NS
Mean f/u+/-
925+/-537 1185+/-733
SD days
Actuarial Patient Survival
100%

80%

60%
Survival

40%
ABO Incompatible (n=13)
20% ABO Compatible (n=105)
p = NS

0%
0 1 3 6 12 24 36 48 60

Months
Conclusions
• ABO mismatched grafts may be used without an
increase in patient/graft mortality or rejections
when an enhanced immunosuppressive protocol
of daclizumab/ tacrolimus/ mycophenolate/
prednisone is used.
• Plasmapheresis may be reserved for times of
increased anti-ABO titers with clinical hemolysis
to achieve graft and patient salvage
IS THERE STILL A NEED
FOR LIVING DONOR
PEDIATRIC LIVER
TRANSPLANTATION?
STILL A NEED FOR
LIVING DONOR PLT?
• The development of transplantation from partial
liver grafts has overcome the shortage of full sized
grafts from pediatric donors
• These techniques have been reported to decrease
the waiting list mortality for pediatric patients
• However,waiting list mortality rates for pediatric
patients less than five years of age still remains
several times higher than the adult waiting list
mortality rates
 Stand up
for Reduced Size Liver Transplantation
Hannover 1983
First Living Liver Donation,
November 1989
Georgia's First Living Related Liver Transplant
(March, 1997)

Seven Years Later

Living Liver Transplant Donors
N=108 # Alive=108 %Alive=100
Complications # Episodes % Episodes
Reoperations 3 2.8
Wound Infection 1 0.9
Paresthesia 1 0.9
Mallory Weiss 1 0.9
Bile Leak 2 1.8

Single Surgeon Experience 12/09/2002

Living Donor Reoperations

• 1992, #46
 Small Bowel Obstruction POD#8
• 1994, #66
 Gastric Outlet Obstruction due to adhesions
POD#7
• 1998, #97
 Exploratory laparotomy for abdominal pain
POD#388
 Most common
complications in the first
living donor series in
recipients were hepatic
artery thrombosis and
biliary
Primary Liver Disease Whole Grafts Partial P Value
(n=80) Grafts (n=70)
Biliary Atresia 27 33 0.133
Primary Sclerosing 2 1 0.636
Cholangitis
Cirrhosis 26 6 <0.001
Autoimmune 18 2
Cryptogenic 6 2
Other 2 2
Metabolic Diseases 6 12 0.132
Malignancy 0 1 0.952
Neonatal Hepatitis 1 1 0.952
Fulminant Liver Failure 10 7 0.823
Other 8 9 0.769
 Variables Whole Grafts Partial Grafts (n=70) P Value
(Mean +/- (n=80)
Standard
Deviation)
Gender 32 male, 48 female 33 male, 37 female 0.474
Age (years) 9.46 +/- 6.92 3.08 +/- 3.46 <0.001
Weight 34.6 +/- 26.0 15.2 +/- 17.6 (Median 10.0) <0.001
(kilograms)
Hepatic Artery 0 4 (2.7%) 0.045
Thrombosis
Pre-Transplant 12.4 +/- 9.6 HAT 5.5 +/- 9.8 (Median=0.7) 0.165
Serum Total Non HAT 13.0 +/- 10.5 0.904
Bilirubin (mg/dl)
Length of 22.7 +/- 21.7 34.9 +/- 35.9 Days 0.290
Hospitalization
After Transplant
(Days)
Conclusion:
• Use of heparin, low molecular weight dextran, warfarin or
other factors was not necessary to avoid HAT.
• Age, weight and use of partial or living left lateral segment
liver graft may increase the risk of HAT after liver
transplant.
• Timely and accurate use of the Doppler ultra sound is
crucial to detect HAT.
• Utilizing the above precepts in 150 procedures provided less
than one percent (0.67%) graft loss secondary to HAT.
• Graft and patient salvage is possible with expedient
detection and surgical treatment.
Results (Children’s Healthcare of
Atlanta)
• Outcomes of biliary complications
• Re-operation for biliary complications was necessary in
only 2 out of 89 transplants (~ 2%)
• Majority of biliary complications were treated by
interventional radiology
 80% (8/10) stented

• No grafts were lost to biliary complications

IS THERE STILL A NEED FOR LD
IN PLT?
• OF COURSE THERE IS!!
• But when and for which patient subset?
• In which culture/country?
• Is living donor a real advantage to the recipient?
• What is the real risk to the donor?
IS THERE STILL A NEED FOR LD
IN PLT?
• COUNTRY/CULTURE
• DECEASED DONOR AVAILIBILITY
 STILL A NEED FOR LD
PLT (USA)
• Which type of liver graft DDS or LD provides the
best patient and graft survival?
• LD
 Children can be transplanted at optimal time
They do not have to compete in a system which
priortizes the sickest patients first
Live donor morbidity and mortality risk-best avoided
if no reicipient advantage
 Influence of Graft Type on
Outcomes After Pediatric Liver
Transplantation

• Roberts JP et al:American Journal of

Transplantation 2004;4:373-377
• Looked at 6467 United States liver transplant
recipients of first OLTX <30yrsFrom 1989-2000
STILL A NEED FOR
LIVING DONOR PLT?
• RECIPIENTS 0-2 YEARS OF AGE
• For patients 0-2 years of age,LD had a 51% lower
relative risk(RR) of graft failure than DDS and a
30% less risk of graft failure than DDF
• Differences in mortality risks for patients less than
2 years of age favored LD recipients were over
DDS recipients(RR=.71,p=.08) but not over DDF
Living Donor Versus Deceased Split and Full
Size Grafts
STILL A NEED FOR
LIVING DONOR PLT?
• FOR RECIPIENTS 2-10 YEARS
• The relative risks of mortality and graft loss were
higher after LD than after DDF for both mortality
• (RR=1.78,p=.02) and graft loss(RR=1.53,p=.02)
• But no significant difference between LD and DDS
• In graft loss or mortality.
STILL A NEED FOR
LIVING DONOR PLT?
• For older children LD does not seem to offer any
benefit
• It is accompanied by a higher risk of graft loss and
• A trend toward higher mortality
• It may represent the use of LLS grafts in larger
children which may be a small for size graft
STILL A NEED FOR
LIVING DONOR PLT?
• In patients aged 17-29 years, the relative risk of
graft failure was significantly higher for DDS than
for DDF(RR=2.55.p=.02) while mortality risks
were also higher but did not reach significance
• (RR=2.31,p=.10)
Influence of Graft Type on
Outcomes after PLT
• LD grafts in the 0-2 age group appear to offer the
lowest risk of post transplant graft failure and
mortality.
• Living donor is the preferred donor source in the
most common pediatric age group(< 2 years)
undergoing liver transplantation.
Influence of Graft Type on
Outcomes after PLT
• Combined with the expected advantages associated
with earlier transplantation in children and the
risk of death associated with waiting for
transplantation
• Living donor as an option should be explored with
the families of transplant candidates who are
younger than 2 years
Ethical Issues in Split vs Whole
liver transplant
• Vulchev,Roberts and Stock
• American Journal of Transplantation 2004;4:1737-
40
• While splitting a liver maximizes the number of
patients receiving an organ transplant
• It may increase the morbidity and mortality for
the individual patient receiving the split liver
LIVER TRANSPLANTATION
• Pediatric patients listed at programs with
expertise in living donor and partial deceased
donor transplantation will be at less risk of
wait-related death

• In the past eight years, no child listed for

transplant at Children’s Healthcare of Atlanta
with chronic end stage liver disease has died
waiting for liver transplantation
 Pediatric Actuarial Survival
Since Daclizumab Induction (01/01/99 to 06/07/04)
99 98 94 94 93
.7 .7 91
100 .3 .6 89 89
93

80
91
.1
.3
87

86
.6

.6

82

77

77

77
% Survival

.1

.1

.1
60

40

20
Patient (n=102) Graft (n=118)
0
0 6 12 18 24 30 36 42 48 54 60
Months
 Actuarial Patient Survival by Type of Liver
Transplant (02/17/97 to 06/07/04)
100 100%
88.9%
83%
80
% Survival

60
(R) Lobe, (L) Lobe, & Living Donors

40 Deceased donor LLS

Partial deceased donor grafts (n=62)
20
Cadaveric Whole Liver (n=80)

0
0 6 12 18 24 30 36 42 48 54 60
Months
Laparoscopic living donor
hepatectomy for PLT
• Daniel Cherqui and Olivier Soubrane
• 20 donor and recipients
• Without hand assist
• Pfannenstiel incision for removal
 Acute Hepatic Failure in
Pediatric Liver Transplantation
TG Heffron, T Pillen, D Welch, G Smallwood, C Fasola, R Romero
Emory University School of Medicine
Children’s Healthcare of Atlanta
Emory University Hospitals
Atlanta, GA
Christine and Dante – Fulminant
Failure, ABO Incompatible Living
Donor Liver Transplant Donor and
Recipient
Results FHF
ABO ABO
p
Incompatible Compatible
No. Grafts 6 15 NS
Patient
Survival 100% 94.1% NS
(1& 3 yr)
1 yr Graft
100% 86.1% p=0.1773
Survival
3 yr Graft
100% 66.4% NS
Survival
Rejections 1/5 (20%) 12/15 (84.6%) p=0.058
A miracle for Easter
Joel Hewins was fussy. His nap pattern
changed. He said his tummy hurt. At age 3,
Joel was the youngest of four children. Mom
Angie checked him out: no diarrhea, no
vomiting, no fever, no visible signs of illness.
She was alert but not concerned, until she
noticed that his urine was unusually dark.
Maybe she and her husband, Gary, ought to
take him to the pediatrician. As the family's
mint green Chevy van pulled out of their
Cumming driveway on Feb. 21, nobody had
any idea how many lives were about to
change. This is a story of sacrifice and new
beginnings, of a flock of the faithful gathering
around a little lamb in their midst. It is an
Easter story.
 Summary:
2. Overall patient and graft survival was better than
expected in the FHF patients.
3. ABO mismatched grafts, partial deceased donor
grafts, living donors and large for size grafts with
the temporary use of gortex mesh for abdominal
closure can be aggressively utilized.
4. Reduced wait-times with expected or increased
patient/graft survival may be acheived in a patient
group which is at risk of poor outcomes.
Neonatal Hemochromatosis
Emory University/CHOA Experience
• 6 patients from 2-99 to 10-01
• 2 survivors with antioxidant therapy
• 3 transplanted (2.8 kg, 1.9 kg, 2.3 kg) -2 alive
• These represent the 3 smallest liver transplant recipients in the world
(Clinical Transplants 2000)
• 1 death from MOSF prior to transplant (1.6 kg)
• All survivors referred before 2 weeks of age, nonsurvivor
referred at 2 months of age
NH survival : 4/6 patients (66%)
Brother and Sister
transplanted for
neonatal
hemachromatosis
29 days old at
Liver
Transplant
2.3 kg
 Large-For-Size
Temporary involution of the graft
 PEDIATRIC LIVER
TRANSPLANTATION
• Living donation in children has been required
three times in the last three years for indication of
fulminant hepatic failure
 Pediatric patients listed at programs with
expertise in Living Donor/Split Liver
transplantation will be at less risk of wait-
related death

In the past eight years, no child listed for transplant

at Children’s Healthcare of Atlanta with chronic
end stage liver disease has died waiting for liver
transplantation
Children’s Healthcare of Atlanta –
Egleston Liver Transplant Survivals
CHOA
Patient Survival Rate Since Transplant
Pittsburgh
105.0%
Jackson Memorial,
100.0% 100.0% Florida
UCLA
95.0% 93.6%
91.7% Nebraska Medical
90.0% Center
Children's Hospital
85.0%
Medical Center, OH
80.0% Children's Memorial
Hospital, IL
75.0% Texas Children's
Hospital
70.0% National Average
65.0%
1 month (7/1/01-12/31/03) 1 year (7/1/01-12/31/03) 3 years (1/1/99-6/30/01)

Graft Survival Rate Since Transplant CHOA

Pittsburgh
110.0%
Jackson Memorial, Florida
100.0%
UCLA
93.6%
90.0% Nebraska Medical Center
83.0% 80.4%
80.0% Children's Hospital Medical
Center, OH
Children's Memorial Hospital,
70.0%
IL
Texas Children's Hospital
60.0%
National Average
50.0%
1 month (7/1/01-12/31/03) 1 year (7/1/01-12/31/03) 3 years (1/1/99-6/30/01)
 Percent of Liver Waitlist
Transplanted by Center
Percent Transplanted for w aitlist patients 7/1/98 - 6/30/01

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

75%
28%

71%

75%
CHOA

47%
14%

35%

44%
Pittsburgh

58%
16%

53%

57%
Jackson Mem orial, Florida

69%
21%

67%

69%
UCLA

25%

67%

69%
69%
Nebraska Medical Center
31%

68%

73%
73%
Children's Hospital Medical Center, OH
17%

38%

44%
44%
Children's Mem orial Hospital, IL
29%

51%

56%
56%
Texas Children's Hospital

30 day 1 year 2 years 3 years

United States SRTR

CHILDRENS HOSPITAL OF
ATLANTA
• SRTR DATA JANUARY 2006
• Transplant rate per year on wait list=1.46
• National average=.59 p=.01
Mom, Jackie, Dad and
Some of the liver transplant team
Left lobe living donor
(small for size)
Recipient
Daughter 68kg
Donor father 83kg
Left lobe CAT scan volume 680 ccs
Actual weight 403 grams
.59% predicted
LIVER TRANSPLANTATION 2005
LIVER TRANSPLANTATION 2005
Maximizing donor availibility
CHOA
• ABO incompatible grafts
• Living Donors
• Partial deceased donor grafts
• Large for size grafts with PTFE