living donor liver transplantation across the abo blood ... · living donor liver transplantation...

RecipientO A B AB

O

A

B

AB

Living DonorLiving Donor Liver TransplantationLiver TransplantationAcross Across

The ABO Blood Type BarrierThe ABO Blood Type Barrier

Dept. of Transplant Surgery, Kyoto University HospitalDept. of Transplant Surgery, Kyoto University Hospital

HirotoHiroto EgawaEgawa, M.D. , M.D.

Improving Life Through Innovation Toronto 2004

Surgery 1986;100:342-348

ABO

Cadaveric Liver Transplantation

CONTRAINDICATIONor only in an emergent situation

Living Donor Liver Transplantation

Donor selection is highly limited. ￫ When the only available graft is ABO incompatible

Blood Type Incompatible Liver Transplantation

Annual number of LDLT in KyotoAnnual number of LDLT in Kyoto

0

20

40

60

80

100

120

140

1990 1992 1994 1996 1998 2000 2002 2004Oct

incompatible

Identical or compatible

Annual number of LDLT in KyotoAnnual number of LDLT in Kyoto

0

10

20

30

40

50

60

70

80

90

100

1990 1992 1994 1996 1998 2000 2002 2004Oct

Older than 15 yerars old

incompatible

Identical or compatible

Hepatic necrosisHepatic necrosis IntrahepaticIntrahepaticbiliarybiliary compilcationcompilcation

InfectionInfection

Cause of Death in ABOCause of Death in ABO--I Liver TransplantationI Liver Transplantation

humoralhumoral rejectionrejectionover over immunosuppressionimmunosuppression

Day 26Day 18

Onset: 1-3 weeksFever Increase in antibody titers Decrease in platelet countsIncrease in transaminase levels

Hepatic NecrosisABO-related rejection

Rapid development in the whole graftHepatic failure

0

500

1000

1500

2000

2500

3000

0 7 14 21

0

20000

40000

60000

80000

100000

120000

AST

ALT

PLT

antiA IgG 256 8 16 128 512 512 512 256 256 256antiA IgM 64 2 4 128 256 512 512 256 256 128anti B IgG 2048 128 8 128 128 64 64 64 32 16anti B IgM 32 2 4 64 64 32 32 8 4 2

PE

CTeuphoria

intubation

Hepatic Necrosis

days

AB(+)→O(+),PBC

PltASTALT

Intrahepatic Bile Duct Lesion

Clinical onset: 1-3 months after LTx

Sclerosis or mixture of stenosis and dilatation, similar to PSC

Repeated cholangitisleading to graft failure

ABO-related rejection

Clinical picture

LONG TERM FOLLOWLONG TERM FOLLOW--UP OF UP OF ABOABO--INCOMPATIBLE LIVINGINCOMPATIBLE LIVING--DONOR DONOR LIVER TRANSPLANTATION: RELATION LIVER TRANSPLANTATION: RELATION BETWEEN OUTCOME AND AGE OF BETWEEN OUTCOME AND AGE OF RECIPIENTSRECIPIENTS

EgawaEgawa et al. et al. Transplantation Transplantation ２００４；７７：４０３２００４；７７：４０３

•• June 1990 June 1990 -- February 2000February 2000•• 66 patients (13% in 523 patients)66 patients (13% in 523 patients)•• 10 months to 55 years old (median 2 years)10 months to 55 years old (median 2 years)

CasesCases

IncompatibleIncompatible

IdenticalIdentical

compatiblecompatible

ICUICU<1 y.o.<1 y.o.

1~8 y.o.1~8 y.o.

8~16 y.o.8~16 y.o.

16 y.o.~16 y.o.~

Hosp.Hosp.

At Home

At Home

PatientsPatients

１３％１３％

Transplantation Egawa et al

OKT3 (#25 - #56)

splenectomy (#111 -)

AZA (#175-)

weekly pulse (#266 -

cyclophosphamide (#306 - )

Older children

IHBC →

Adult

hepatic necrosis →

Base: tacrolimus & steroid plasma pheresis, blood exchange

StrategyStrategyPatients and

complication


Until 2000

5 10

50

100

0

identical

compatible

incompatible

(%)

years

Compatibility and SurvivalCompatibility and Survival


ABO Compatibility and Age－Survial after LDLT

< 1y.o.

1< <8y.o.

8< <16y.o.16y.o.<

1 2 3 4 5 6 7 8 9 10

100

50

0

%

year

Identical & Compatible Incompatible ~2000

< 1y.o.

8< <16y.o.

1 2 3 4 5 6 7 8 9 10

50

0

1< <8y.o.16y.o.<

100

%


Age and complications

Age Patients group

Necrosis IHBC Normal Other Total

death

<1 y.o. 0 0 15 6 21

1 y.o.< <8 y.o. 0 8 11 6 25

8 y.o.<<16 y.o. 3 2 5 1 11

16y.o. < 2 2 1 4 9

Total 5 12 32 17 66

p<0.01: chi-square testTwo patients surviving shorter than 1 week were not included in this analysis.


Change of antibody titer Change of antibody titer

BeforeLTX

LTx Peak Long termFollow-up

Antibody titer

Plasma-pheresis


3 – 7 days after transplantation

Uneventful course

Humoral rejection

or

Correlation between pre &post LTx -IgM,IgG peaks

Pre-LTx IgM peak

Pre-LTx IgG peak Post-LTx IgG peak

Post-LTx IgM peak

significant

significantns

ns

0

1000

2000

3000

4000

5000

�16

�8 to <16

�1 to <8

<1

preoperativepeak at LTx postoperative

peaklast

follow-up

IgM

tite

r (tim

es)


Post-operative change of IgM titerin recipient age groups

＞

＞

＞

0

1000

2000

3000

4000

5000

�16

�8 to <16

�1 to <8

<1

preoperativepeak at LTx postoperative

peaklast

follow-up

IgG

tite

r (tim

es)


Post-operative change of IgG titerin recipient age groups

＞

＞

＞

0

1000

2000

3000

4000

5000

other death

uneventful

IHBC

hepatic necrosis

<1 �1 to <8 �8 to <16 �16

preo

pera

tive

peak

tite

r of I

gM (t

imes

)

age groupTransplantation Egawa et al

Preoperative peak IgM titer and postoperative coursein recipient age groups

＞＞＞

0

1000

2000

3000

4000

5000

other death

uneventful

IHBC

hepatic necrosis

<1 �1 to <8 �8 to <16 �16

preo

pera

tive

peak

tite

r of I

gG (t

imes

)

age group Transplantation Egawa et al

Preoperative peak IgG titer and postoperative coursein recipient age groups

＞＞＞

0

1000

2000

3000

4000

5000

other death

uneventful

IHBC

hepatic necrosis

<1 �1 to <8 �8 to <16 �16

post

oper

ativ

e pe

ak ti

ter o

f IgM

(tim

es) 5642±5372

～～～～～～


Postoperative peak IgM titer and postoperative coursein recipient age groups

＞＞＞

0

1000

2000

3000

4000

5000

other death

uneventful

IHBC

hepatic necrosis

<1 �1 to <8 �8 to <16 �16

post

oper

ativ

e pe

ak ti

ter o

f IgG

(tim

es)


Postoperative peak IgG titer and postoperative coursein recipient age groups

＞＞＞

Pathology of ABO-related rejection

Natural antibody against donor blood-type

Binding to the antigen on graft endothelium

Complement activationVasospasms Platelet aggregation

Crisis in total graft circulation

Hepatic Necrosis

Local DIC

Disturbance of microcirculation of terminal arteries for biliary tree

Biliary Lesion

severe mild - moderate

Increase of antibody titers

Decrease of platelet

firstweek

ILIL--66

TNFTNF--αα

ILIL--11ββ

EndotheliumEndothelium

PlateletPlateletThrombus

complimentKupfferKupffer cell cell

B cell

Vascular smooth muscle cell Vascular smooth muscle cell

adhesion molecule

Plasma cell

PeriportalPeriportal Edema and Necrosis (PEN)Edema and Necrosis (PEN)

Haga et alLiver Transplantation 2004;6:16-27

periportal edema and necrosis (PEN)periportal edema and necrosis (PEN)

thrombus in the arteriolethrombus in the arteriole

PEN with cellular rejectionPEN with cellular rejection

lymphocyticlymphocytic infiltration, periportal hemorrhageinfiltration, periportal hemorrhage

centrilobular endothelialitis, without necrosiscentrilobular endothelialitis, without necrosis

C4d – IgG/IgM in a hepatic necrosis case

TacticsTactics

Decrease antibody titer

Decrease antigen-antibody-compliment

reaction

Decrease endothelium injury

Decrease thrombus

Improve microcirculation

Portal Infusion TherapyKeio Protocol

Two successful cases with intraportalinfusion therapy for ABO incompatible liver transplantation PGE1, Steroids, and Gabexate Mesilate

Transplantation, June 27, 2002. Vol.73, No.12

門脈チューブ門脈チューブ

..

Portal Infusion Catheter

Portal Infusion Protocol

Pre Plasma Exchange (anti A IgM、 anti B IgM < 8)Ope. LTx & SplenectomyPost Portal Infusion

Methylprednisolone 125mg/day, ～1w50mg/day, ～2w

Prostaglandine E1 0.01γ, ～3wGabexate Mesilate 1000mg/day, ～3w

General ImmunosuppressionCyclophosphamide 2mg/kg/day, ～2w(iv), ～4w(oral)TacrolimusMethylprednisolone

ABO Incompatible LDLT


Case Original Disease BloodType Outcome Follow-up Hepatic Biliary InfectionDonor Recipient Necrosis Lesion

610 HCV,LC A O alive 897days (-) (-) CMV639 HBV,LC,HCC B A alive 813 (-) (-) CMV98 BA,ReLTx A O alive 794 (-) (-) Abscess, CMV 651 AIH A O dead (37) (-) (-) Pneumonia,CMV666 PSC A O alive 729 (-) (-) CMV675 HCV,LC,HCC A O alive 701 (-) (-) Sepsis676 HCV,LC B O alive 699 (-) (+) Sepsis,CMV691 HBV,LC,HCC AB B dead (38) (-) (-) Sepsis,CMV693 HCV,LC A O alive 640 (-) (-) CMV698 BA B O dead (89) (+)HAT (-) Sepsis,CMV707 PBC AB O dead (18) (+) severe (-)703 ReLTx A O dead (13) (-) (-) Sepsis,CMV733 PBC B O dead (208) (-) (+) Sepsis,CMV741 BA B O alive 479 (+) mild (-) CMV779 BA A O alive 352 (-) (-)239 ReLTx AB A alive 342 (-) (-) CMV848 HCV,LC,HCC B O alive 80 (-) (-) CMV

Portal Infusion ProtocolKyoto experience:17 patients > 14 y.o.

Patient Survival of adult ABO-I LDLT

Actuarial Patient Survival Rate

days0

.2

.4

.6

.8

1

0 100 200 300 400 500 600 700 800

PV infusion

No infusion

Prostaglandin E1

VasodilatationInhibition of platelet aggregationInhibition of proinflammatory cytokine production

Prostaglandin E1 reduces myocardial reperfusion injury by inhibiting proinflammatory cytokines production during cardiac surgery.Kawamura T, et al. Crit Care Med. 2000 Jul;28(7):2201-8. The modulatory effects of prostaglandin-E on cytokine production by human peripheral blood mononuclear cells are independent of the prostaglandin subtype.Dooper MM, et al. Immunology. 2002 Sep;107(1):152-9.

AngiogenesisClinical and experimental evidence of prostaglandin E1-induced angiogenesis in the myocardium of patients with ischemic heart disease.Mehrabi MR,et al. Cardiovasc Res 2002 Nov;56(2):214-24

Immune modulationA new view of prostaglandin E regulation of the immune response.Phipps RP, et al. Immunol Today 1991 Oct;12(10):349-52Effects of prostaglandin E1 on the production of IgM and IgG class anti-dsDNA antibodies in NZB/W F1 mice.Yoshikawa T, et al. J Rheumatol. 1993 Oct;20(10):1701-6.

2003 Kyoto University Hospital 2003 Kyoto University Hospital

ILIL--66

TNFTNF--αα

ILIL--11ββ

FOYFOY

EndotheliumEndothelium

PGE1PGE1

Protect endothelium

Inhibition of cytokines

Inhibition of aggregation

Vasodilatation

angiogenesis

PlateletPlateletThrombus

compliment

Inhibition Action

KupfferKupffer cell cell

Vascular smooth muscle cell Vascular smooth muscle cell

adhesion molecule

B cell

steroid

9POD EncephalopathygradeII

antiA IgG 512IgM 512

anti B IgG 64IgM 32

antiA IgG 256antiA IgM 64anti B IgG 2048anti B IgM 32

preope.

Hepatic necrosis under PV infusionCase 707 AB (+) to O(+), PBC

ABO-related rejection

Hepatic necrosis(explant)

Intra-hepatic Biliary Complication(explant)

Inflammationof hepatic artery

Intimal hypertrophyof hepatic artery

Vasculopathy

Liver necrosis

Bile duct injury

Significance of HA circulation Significance of HA circulation in ABOin ABO--I related complicationI related complication

SclerosingSclerosing hepatic arteryhepatic arteryafter ABOafter ABO--I liver I liver transplantaiontransplantaion

For ABO Incompatible LDLT

Hepatic arterial infusion therapy is more directly effective in preventing the arteriole injury by ABO incompatibility!

Portal infusion therapy is not enough for controlling ABO-related rejection.

Severe attack of hepatic necrosis in one case despite the use ofportal infusion therapy

Hepatic Arterial Infusion Protocol

PV + HA Infusion Protocol

Pre Plasma Exchange (anti A IgM、 anti B IgM < 8)Ope. LTx & SplenectomyPost Portal Infusion

Methylprednisolone 125mg/day, ～1w50mg/day, ～2w

Prostaglandine E1 0.01γ, ～3wGabexate Mesilate 1000mg/day, ～3w

General ImmunosuppressionCyclophosphamide 2mg/kg/day, ～2w(iv), ～4w(oral)TacrolimusMethylprednisolone


2003 Kyoto University Hospital 2003 Kyoto University Hospital

Kyoto protocol

Hepatic artery infusion

肝内胆管病変血液型不適合肝移植特有の合併症：

RHA

LHA

PHA

Placement of Hepatic Artery Catheter

GRAFT

HAcatheter

（B)

（C)

（Ａ)

（D)

Placement of Hepatic Artery Catheter


Case OriginalDisease BloodType Outcome Follow-up Hepatic Biliary InfectionDonor Recipient Necrosis Lesion

728 HCV,LC,HCC A O dead （44）days (+)moderate (-) Sepsis,CMV731 HCV,LC A O alive 519 (-) (-) CMV738 BA,HCV,HCC A B alive 500 (-) (-)797 HCV,LC,HCC A O alive 281 (-) (-)134 ReLTx AB A alive 272 (+) mild (-) CMV799 PBC AB B alive 269 (-) (-) CMV817 PBC B O alive 199 (+) HAT (-) Sepsis,CMV820 PBC A O alive 185 (+) mild (-) CMV836 HCC,LC,HCV A O alive 122 (-) (-) CMV

PV+HA Infusion Protocol

PGE1,steroids(Hepatic artery infusion), Gabexate Mesilate (Portal infusion)#728,731,738,797,134,799,817

PGE1,steroids (Hepatic artery infusion), No portal infusion#820,836:

9 patients

No biliary lesion !

0

.2

.4

.6

.8

1

0 100 200 300 400 500 600 700 800

Patient Survival of adult ABO-I LDLTActuarial Patient Survival Rate

days

PV+HA Infusion

Portal Infusion

Before Portal Infusion


High incidence of CMV infection14/17 82.4% portal infusion7/9 77.8% hepatic artery infusion

General immunosuppression should be weakened? Tailored for the risk?

Problems to be solvedOver-immunosuppression

Hepatic arterial& portal catheter infusion therapy:1/9 (11.1%)

portal infusion therapy : 1/17identical/compatible transplantation : 4/350using right lobe

Hepatic Arterial Thrombosis

Catheter-related ? : materialstrong anticoagurant treatmentsposition of the catheter tip

Endothelial injury associated with ABO incompatibility ?

Catheter related complication


9 patients developed portal thrombosisin 26 patients with portal infusion．

Portal infusion therapy： 4/17Hepatic arterial& portal infusion therapy:5/9

Total:35%

Portal thrombosisCatheter related complication


portal catheter

Portal thrombosis

splenectomy

thrombocytosis

lack of splenic venous return

Hepatic arterial infusion therapywithout portal catheter without splenectomy

Next strategy

Patient Survival of adult ABO-I LDLT

100

50

0 1 2 3 4 5 6

(%)

(year)

before infusion era

PV infusion

PV+HA infusion

HA infusion without splenectomy

PVT decrease from 35% to 8%

(HCC rec)

Effect on splenectomy on Post-transplant peak titer

0

500

1000

1500

2000

2500

3000

3500

4000

4500

5000

infusion- PV infusion PV+HA infusion HA infusion

Anti-A or B IgM

P=0.036

0

500

1000

1500

2000

2500

infusion- PV infusion PV+HA infusion HA infusion

Anti-A or B IgG

P=0.037

With splenectomy Without splenectomy

Antibody titer increased !

n=13n=10 n=17 n=9

Tactics: decrease Tactics: decrease AbAb titertiter• Splenectomy

– Possible permanent immuno-defficiecy– Cause of portal thrombus

B cell deletion by Rituximab instead splenectomy

B cell Plasma cell

Correlation between Correlation between PrePre--LTx IgG peak & PostLTx IgG peak & Post--LTx IgG peakLTx IgG peak

Incompatible related complicationIncompatible related complication

2048

512

8

32

128

Pre-LTx peak

8 204832 128 512 8192

8192

Post-LTx peak

Hepatic necrosis

IHBC

Uneventful

Adult cases

0

25

50

75

100

% o

f CD

3, B

-cel

l, an

d N

K-c

ell

0 5 10 15 20Time after graft reperfusion

CD3

B-cell

NK -cell

Tac.

pre 12h 12d5d 19d36h

Change of lymphocyte populationChange of lymphocyte population

Adults (n=15)

(CD20)

IgGIgG peak & CD20 peak peak & CD20 peak after ABOafter ABO--I I LTxLTx with HA infusionwith HA infusion

２０４８

３２

５１２

８

１２８

IgG titer

20 30 40 50

CD20 (%)

Hepatic necrosis

IgMIgM peak & CD20 peakpeak & CD20 peakafter ABOafter ABO--I I LTxLTx with HA infusionwith HA infusion

２０４８

３２

５１２

８

１２８

IgMtiter

20 30 40 50CD20 (%)

Hepatic necrosis

Change of CD20 and antibody titerChange of CD20 and antibody titer

２０４８

３２

５１２

８

１２８

Antibody titer

-1mo LTx 1mo 2mo 3mo

10

20

30

40

50

CD20(%)

IgG

IgM

12yo F re-Tx for CRHA infusion without splenectomy

Day 26 (2004.1.23) Cholangitis-like ductular reaction with cholestasis and centrilobular necrosis (late phase of humoral rejection)

H&E C4d

IgM C3c

１．Rescue therapy for elevated antibody after LTx (n=4)

２．Prophylaxis before LTx (n=6)

Application of Rituximab

IgG

IgＧ(術後peak)

0

200

400

600

800

1000

1200

1400

1600

1800

HA infusion Rituximab rescue Rituximab

抗体

価

IgM(術後peak)

0

200

400

600

800

1000

1200

1400

1600

1800

2000

HA infusion Rituximab rescue Rituximab

抗体

価rescue prophylaxis

rescue prophylaxis

Ritx (-)

Ritx (-)

Post-LTx peak IgG

Post-LTx peak IgM

All cases： HA infusion without splenectomy

6 cases with Rituximab Prophymaxis

Case name sex age day of Rituxpre-ope

IgMpre-ope

IgGpost-ope

IgMpost-ope

IgGPEN result

1 S.M f 29 ー２ 128 256 512 256 y D(peritonitis)2 I.Y. f 65 ー６ 64 1 4 1 n alive3 M.Y. f 58 ー１５ 128 2048 64 128 n alive4 N.T. f 38 ー３ 512 1024 32 128 y D(pneumonia)5 H.K. m 57 ー２ 1024 64 128 32 n alive6 S.H. f 61 ー４ 64 256 1 2 n alive

ResultsHA infusion HA infusion HA infusionRituximab (-) Rituximab Rituximab

rescue prophylaxis

Pathological 3 / 13 2 / 4 2 / 6humoral rejection

Total necrosis 0 / 13 2 / 4 0 / 6(1:without Bx)

Intrahepatic 0 / 13 0 / 4 0 / 6biliary complication

death 2 / 13 2 / 4 2 / 6peritonitis hepatic necrosis peritonitisHA aneurysm hepatic necrosis pneumonia

OKT3 (1991)splenectomy (1994)

AZA (1995)weekly pulse (1997)cyclophosphamide (1997)

IHBC →hepatic necrosis

→

Older children

Adults

Base: tacrolimus & steroid plasma pheresis, blood exchange

Strategy for the Blood Type Barrier in KyotoStrategy for the Blood Type Barrier in Kyoto

Portal infusion (2000)

HA+PV infusion(2001)

Rituximab(2004)

HA infusion(2003)

Infants

Keep spleen(2004)

Japanense Registry of

ABO incompatible Liver Transplantation 2004

••194 patients in 31 centers194 patients in 31 centers

••All living donor liver transplantationAll living donor liver transplantation

ABOABO--I LDLT in JapanI LDLT in Japan

0

5

10

15

20

25

30

'91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03 '04

16<

8< <16

1< <8

<1yo

( until March/31)

Japanense Registry 2004

malefemale

Gender Preoperative status

At home

hospitalized

ICU

unknown

RecipientJapanense Registry 2004

parentchild

sibling

spouse

Ground father Brother in law

Donor


IndicationsIndications• Biliary atresia 85• HCC 16• LC due to viral hepatitis 10• FHF 14• Re-Tx 14• PBC 11• PSC 4• Metabolic 11• AIH 3• others 11• unknown 4


Infusion therapyInfusion therapy

CatheterCatheter patient #patient # Spleen keptSpleen kept

PVPV 2929 11PV+HAPV+HA 1515 44HAHA 2424 1818

Age of children with a HA catheter0,5,8,10,10,14,14,14 y.o.


HA Catheter related ComplicationsHA Catheter related Complications

BleedingHATDislocationBile anastomosis injury by pulling HA catheter


HumoralHumoral rejectionsrejections• Intrahepatic biliary complication 17

death 7infection 5esophageal varices 1pulmonary hypertension 1

• Hepatic necrosis ２３death 17

graft failure 16infection 1

Patients began to survive necrosis in “infusion era”.


100

50

05 10

1才未満

1〜8才16才以上

8〜16才

（％）

（年）

Survival of ABO-I LTx Patients

< 1 y.o.

8-16 y.o.

1–8 y.o.16 y.o.<

Year


Blood Type Combination and Mortality

O

AB

A B

3 (100%)19(42%)

22(30%)

26(8%)26(27%)

38(32%)61(21%)

All age


Blood Type Combination and Mortality

O

AB

A B

3 (100%)

10(50%)

36(42%)

12(33%)

10(40%)

12(42%)

15(33%)

Age >8 y.o.


Causes of DeathCauses of Death• Infection 23• Hepatic necrosis 16• Graft failure 4• Vascular Complication 3• Gastric ulcer 1• Esophageal varices 1• Chronic rejection 1• Pulmonary hypertension 1• Recurrence of native disease 1• others 7


What is next?What is next?

Introducing accommodationby

Inactivating blood type antigensby

Modulating glycosyltransferase

living donor liver transplantation across the abo blood ... · living donor liver transplantation...

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