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The Future of Living Donor Liver The Future of Living Donor Liver

Transplantation:Transplantation:Technological and Ethical Foundations for Technological and Ethical Foundations for

The Way Forward in AThe Way Forward in A--ALDLTALDLT

Charles M. Miller, MDCharles M. Miller, MD

Professor of SurgeryProfessor of Surgery

Director of Liver TransplantationDirector of Liver Transplantation

Cleveland ClinicCleveland Clinic

75 98 88133

76

15380

230

95

302

84

423

99

698

122

810

130

880

107

916

133

1202

215

1430

0

200

400

600

800

1000

1200

1400

1600

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Deceased Donor Living Donor

LIVER TRANSPLANTATIONLIVER TRANSPLANTATION IN ASIAIN ASIANumber of OperationsNumber of Operations

* Excluding data from mainland China

Total LDLT = 7573

Lo CM, ILTS Milan 2006

90% of transplants were from living donors

4093

60

4334

54

4461

62

4599

85

4844

92

4947

251

4996

385

5108

505

5298

355

5672

321

5846

323

6444

323

0

1000

2000

3000

4000

5000

6000

7000

1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005

Deceased Donor Living Donor

www.optn.org 2006

LIVER TRANSPLANTATION IN USLIVER TRANSPLANTATION IN USNumber of OperationsNumber of Operations

5% of transplants were from living donors

LDLT: Advantages and LDLT: Advantages and

DisadvantagesDisadvantages

AdvantagesAdvantages

�� Assures a healthy organ Assures a healthy organ with minimal with minimal preservation damagepreservation damage

�� Independence from long Independence from long cadavericcadaveric waiting listwaiting list

�� Optimizes the timing of Optimizes the timing of transplantationtransplantation

�� Helps alleviate the Helps alleviate the severe shortage of severe shortage of cadavericcadaveric livers and livers and death on the waiting listdeath on the waiting list

DisadvantagesDisadvantages

�� Finite risk of donor Finite risk of donor

morbidity and mortalitymorbidity and mortality

�� Both operation are Both operation are

technically complex technically complex

�� The program is The program is

extremely laborextremely labor--

intensiveintensive

�� ReputationalReputational riskrisk

Fundamental Dichotomy:Fundamental Dichotomy:

““PrimunPrimun Non Non NocereNocere”” and LDLTand LDLT

�� Donor safety must have primacy at all Donor safety must have primacy at all

timestimes

However,However,

�� The safest thing for a potential donor is not The safest thing for a potential donor is not

to donate ( The null position)to donate ( The null position)

�� How do we move forward from the null How do we move forward from the null

position?position?

The Way ForwardThe Way Forward

�� Maximize donor safetyMaximize donor safety

�� Refine and expand candidate selectionRefine and expand candidate selection

�� MELDMELD

�� Special ConsiderationsSpecial Considerations

�� Review new physiologic understandings Review new physiologic understandings

and applied technological innovationsand applied technological innovations

�� Assure Assure Our Way ForwardOur Way Forward is ethically is ethically

soundsound

Living Liver Donors Living Liver Donors

Morbidity and MortalityMorbidity and Mortality

• Mortality

• Death

• Vegetative State

• Remnant loss

• Morbidity

• Surgical Complications

• Quality of life

• Psycho-social and financial hardship

Graft OptionsGraft Options

A) Left lateral section (S2 and 3)A) Left lateral section (S2 and 3)

B) B) Left lobe (S2, 3 and 4) Left lobe (S2, 3 and 4)

With/without MHV With/without MHV

With/without caudate With/without caudate

C) C) Right lobe (S5, 6, 7 and 8)Right lobe (S5, 6, 7 and 8)

With/without MHVWith/without MHV

D) Right posterior (S6 and 7)D) Right posterior (S6 and 7)

7

3

2

4

56

8

MHV

A

B

C

D

Living Liver DonorsLiving Liver Donors




• Mortality

• Death


• Remnant loss

• Morbidity


• Quality of life


Donor DeathsDonor DeathsVancouver Forum: Transplantation 2006Vancouver Forum: Transplantation 2006

3 Left Liver3 Left Liver 11 + 11 + (3)(3) Right LiverRight Liver

US US 11 US US 2 2 Egypt Egypt 1 1

Brazil Brazil 11 BrazilBrazil 2 2 China (HK) China (HK) 1 1

Germany Germany 11 GermanyGermany 2 2 India India 1 1 (1)*(1)*

France France 1 1 (1)(1) S. America S. America 1 1

Japan Japan 11

•• 4 Right lobe Donors4 Right lobe Donors have had remnant loss and liver transplantation have had remnant loss and liver transplantation

•• 1 Right lobe Donor is in a persistent vegetative state 1 Right lobe Donor is in a persistent vegetative state **

Right liver donor:Right liver donor: mortality = 0.5%mortality = 0.5%

Left liver donor:Left liver donor: mortality = 0.1%mortality = 0.1%

Cause of death Number

Sepsis 5

Liver failure 2

Unknown 3

Myocardial infarction 1

Cerebral hemorrhage 1

Pulmonary embolus 1

Peptic ulcer complication 1

Total 14

Trotter et al, Liver Transplantation 2006





• Mortality

• Death


• Remnant loss

• Morbidity


• Quality of life


Donor ComplicationsBy Graft Type

ELTR 6/2003: Adam et al

No major complication

Complications

Biliary leak

Biliary stenosis

Liver insufficiency

PT<30%

[30%-50%]

PT>=50%

PE

Vascular

Infection

GI

General*

Right liver Left liver

385 (79%)

103 (21%)

28 (6%)

11 (2%)

12 (2.4%)

12 (3%)

181 (48%)

188 (49%)

4 (0.8%)

8 (1.6%)

19 (4%)

3 (0.6%)

18 (3.6%)

88 (92%)

8 (8%)

5 (5%)

0 (0%)

1 (0%)

1 (3%)

6 (20%)

23 (77%)

0 (0%)

0 (0%)

2 (2%)

0 (0%)

0 (0%)

Left lobe

357 (89.5%)

42 (10.5%)

6 (1.5%)

0 (0%)

2 (0.5%)

2 (2%)

8 (9%)

79 (88%)

5 (1%)

6 (1.5%)

16 (4%)

3 (1%)

4 (1%)

P

0.0001

0.005

0.004

ns

0.0001

ns

ns

ns

ns

0.03

Overall complication rate = 15%

Umeshita et al, Lancet 2003


Morbidity and MortalityMorbidity and MortalityJapanese Liver Transplantation SocietyJapanese Liver Transplantation Society

LL (n=598) L (n=327) R (n=554)

Bile leakage 33 8 34

Biliary stricture 1 0 6

Hyperbilirubinaemia 2 0 41

PV thrombosis 0 0 3

Small bowel obstruction 5 1 4

Pulmonary embolism 0 1 3

Intraabdominal bleeding 0 0 3

Intraabdominal collection 0 0 20

Pancreatitis 1 0 2

Bleeding duodenal ulcer 1 0 2

Wound infection 9 10 26

Gastric outlet obstruction 4 3 1

Pneumonia 0 1 2

Pleural effusion 0 0 6

Pressure sore 0 0 1

Peroneal nerve palsy 0 0 1

Total 56 (9.4%) 24 (7.3%) 155(28%)

CM Lo et al, Transplantation 2003

Living Liver DonorsLiving Liver DonorsSurgical Complications: Asian Collective Surgical Complications: Asian Collective

Adult Patient / Graft SurvivalAdult Patient / Graft Survival

Left LobeLeft Lobe

0

20

40

60

80

100

3 6 12 18 24 36 48

MonthsMonths

% S

urv

ival

% S

urv

ival

78%

57%

45%

34%

Patient -----

Graft Graft ----------

Adult LD Patient / Graft SurvivalAdult LD Patient / Graft Survival

Right LobeRight Lobe

0

20

40

60

80

100

3 6 12 18 24

MonthsMonths

% S

urv

ival

% S

urv

ival

87%

84%

81%

76%

Patient -----

Graft Graft ----------




�� MELDMELD

�� Special ConsiderationsSpecial Considerations




soundsound

Functional Graft SizeFunctional Graft Size

•• ChildChild’’s classification s classification

(MELD)(MELD)

•• Actual graft sizeActual graft size

•• RecipientRecipient’’s portal flow s portal flow

dynamics & HABRdynamics & HABR

•• Restricted venous outflow Restricted venous outflow

(global or segmental)(global or segmental)

Adult to Adult LDLT: US ExperienceAdult to Adult LDLT: US ExperienceRecipient CharacteristicsRecipient Characteristics

MELD Status at TransplantMELD Status at Transplant

(%) (%) Meld 6Meld 6--1010 Meld 11Meld 11--2020 Meld 21Meld 21--3030 Meld 31 Meld 31

++

live live

donorsdonors19.8 %19.8 % 49.2 %49.2 % 6.6 %6.6 % 1.0 %1.0 %

cad cad

donorsdonors13.4 %13.4 % 39.9 %39.9 % 19.9 %19.9 % 11.7 %11.7 %

2003 UNOS / 2003 UNOS / UStransplant.orgUStransplant.org / SRTR/ SRTR

Improvement in Survival Associated With Adult-to-Adult Living Donor Liver TransplantationCARL L. BERG,* and the A2ALL Study Group

GASTROENTEROLOGY 2007;133:1806–1813

Conclusions:

Adult LDLT was associated with lower mortality than the alternative of waiting for DDLT. This reduction in mortality wasmagnified as centers gained experience with LDLT.

Results:

Overall (n = 807) a LDLT (n= 389) Non-LDLT (n = 418)

MELD 15.6 +/-6.8 14.8+/- 6.4 16.4+/- 7.2 ( p=.002)

Berg for the A2ALLBerg for the A2ALL

�� ““Thus, in plainer language, once centers in Thus, in plainer language, once centers in A2ALL had done 20 A2ALL had done 20 LDLTsLDLTs, there was marked , there was marked survival benefit (reduction in mortality hazard survival benefit (reduction in mortality hazard ratio) to proceeding to LDLT even if the ratio) to proceeding to LDLT even if the candidate's MELD was under 15 at time of their candidate's MELD was under 15 at time of their donor's evaluation.donor's evaluation.””

Special ConsiderationsSpecial Considerations

�� Blood Type O or BBlood Type O or B

�� Large shunts with severe encephalopathyLarge shunts with severe encephalopathy

�� Tumors outside Milan criteria (UnTumors outside Milan criteria (Un--MELDableMELDable))

�� Severe itching in PBCSevere itching in PBC

�� Multiple episodes of Multiple episodes of cholangitischolangitis in PSCin PSC

�� NeuroendocrineNeuroendocrine tumorstumors

�� All small childrenAll small children




�� MELDMELD

�� Special Special ConsidertionsConsidertions




soundsound

Functional Graft SizeFunctional Graft Size

•• ChildChild’’s classifications classification

•• Actual graft sizeActual graft size

•• RecipientRecipient’’s portal flow s portal flow

dynamics & HABRdynamics & HABR

•• Restricted venous outflow Restricted venous outflow

(global or segmental)(global or segmental)

GRBWR

outflow capacity portal hypertension

(+)

(-) (+)(+) (-)

(-)

Balance of Critical Factors for Success in LDLT

1)The larger the size of the triangle, the greater the functional graft size

Adopted from A. Marcos

GRBWR

outflow capacity portal hypertension

(+)

(-) (+)(+) (-)(-)

Balance of Critical Factors for Success in LDLT

This is the balance that is necessary for success when using left lobes

Yamada, T et al, American

Journal of Transplantation 2008;

8: 847–853

This is the Fuel Injector

What about What about ““Fuel Additives?Fuel Additives?””

�� Pharmacologic manipulationsPharmacologic manipulations

�� OctreotideOctreotide

�� AdenosineAdenosine

�� ProstaglandinsProstaglandins

�� Can these help tip the balance from Can these help tip the balance from

cholestatic hypertrophy to normal cholestatic hypertrophy to normal

regeneration?regeneration?

Recent Strategy in 3 Transplant CentersRecent Strategy in 3 Transplant Centers

UCSFUCSF

Since inception,15 left lobe LDLTs out of 117. However, 10 of Since inception,15 left lobe LDLTs out of 117. However, 10 of

the 20 LDLTs in the past 2 years were left lobes. the 20 LDLTs in the past 2 years were left lobes.

U of NebraskaU of Nebraska

6 left lobes in the past 2 years. Now with a 6 left lobes in the past 2 years. Now with a ““philosophical philosophical

commitment to move exclusively to the left lobe in all but commitment to move exclusively to the left lobe in all but

exceptional casesexceptional cases””

Cleveland ClinicCleveland Clinic

In 15 adultIn 15 adult--toto--adult LDLTs since 2004, 50% was left lobe LDLT. adult LDLTs since 2004, 50% was left lobe LDLT.

Our philosophy is to prefer left lobes if at all possible.Our philosophy is to prefer left lobes if at all possible.

Nebraska/UCSF Left Lobe LDLT With PCSNebraska/UCSF Left Lobe LDLT With PCS

PCSPCS1.001.00 GoodGood22M22MAHNAHN --2020

PCSPCS0.930.93 Poor, SFSSPoor, SFSS24M24MHCVHCV --2323

PCSPCS0.960.96 GoodGood33M33MPBCPBC --1818

PCSPCS0.640.64 GoodGood37M37MCryptogenicCryptogenic ----

PCSPCS0.510.51 GoodGood26M26MHCVHCV 4254251212

PCSPCS0.620.62 GoodGood42F42FNASH/HCCNASH/HCC ----

PCSPCS0.530.53 GoodGood42M42MHCVHCV --2020

Inflow Inflow

modulationmodulationGBWRGBWR

Graft Graft

functionfunctionDemoDemoDiagnosisDiagnosis PVFPVF

PV pressure PV pressure

gradientgradient

PCSPCS0.370.37 GoodGood25F25FPBCPBC --1717

PCSPCS0.880.88 GoodGood40F40FPBCPBC --1414

PCSPCS0.740.74 GoodGood46F46FPBCPBC 100010001010

LDLT at Cleveland ClinicLDLT at Cleveland Clinic

�� June 2005 June 2005 –– May 2009May 2009

�� 20 LDLTs (5 pediatrics and 15 Adults)20 LDLTs (5 pediatrics and 15 Adults)

�� Graft type Graft type

�� Left lateral segment (n = 5)Left lateral segment (n = 5)

�� Left lobe (n = 8)Left lobe (n = 8)

�� Right lobe (n = 7)Right lobe (n = 7)

CCF Left Lobe LDLTCCF Left Lobe LDLT

PCS, SAL, OctPCS, SAL, Oct

Shunt stentShunt stent21.921.90.590.59

GoodGood51M51MHCVHCV52/M52/M

PCS, SALPCS, SAL22.122.10.460.46PoorPoor

SFSSSFSS55M55MPSCPSC38/M38/M

SALSAL4.74.70.730.73 GoodGood37M37MPSCPSC71/F71/F

NoneNone3.53.50.650.65 GoodGood42F42FNASHNASH62/F62/F

OctOct3.23.20.910.91 GoodGood56M56MPSCPSC60/F60/F

OctOct1.81.81.001.00 GoodGood53F53FNETNET50/F50/F

NoneNone1.11.11.541.54 GoodGood26F26FCaroliCaroli’’s s

diseasedisease10/M10/M

Inflow Inflow

modulationmodulationPostPost--opeope

Peak BiliPeak BiliGBWRGBWR

Graft Graft

functionfunctionDemoDemoDiagnosisDiagnosisAge/SexAge/Sex

SAL, OctSAL, Oct7.17.10.650.65 GoodGood30F30FPSCPSC28/F28/F

14261426

896896

350350

15401540

536536

480480

930930

PVFPVF

833833

2424

2020

1010

1111

1111

22

--

PV pressure PV pressure

gradientgradient

44

Case # 8 Spontaneous Spleno-renal shunt

Pre and IntraPre and Intra--op Hemodynamic Studiesop Hemodynamic Studies

Case #8Case #8

�� PressuresPressures� Free hepatic pressure = 6 mm Hg

� Hepatic wedge pressure = 11 mm Hg

�� Cardiac Output Cardiac Output 7.57 L/min

�� Cardiac IndexCardiac Index 3.88 L/min/m(2)

�� Estimated L lobe graft volume/wt: Estimated L lobe graft volume/wt:

610cc/ 555g 610cc/ 555g

�� GRBWR = 0.84 / 0.76GRBWR = 0.84 / 0.76

Pre and IntraPre and Intra--op Hemodynamic Studiesop Hemodynamic Studies

Case #5Case #5

�� PressuresPressures�� Right atrium Right atrium 12 mmHg12 mmHg

�� Portal vein Portal vein 40 mmHg40 mmHg

�� Cardiac Output Cardiac Output 7.78 L/min7.78 L/min

�� Cardiac IndexCardiac Index 3.5 3.5 L/min/m2L/min/m2

�� Actual graft volume: 620g Actual graft volume: 620g (GRWR 0.57)(GRWR 0.57)

Shunt Flow Shunt Flow --AnhepaticAnhepatic

CO =10 L/min

CI = 4.4 CO/M2

Final Pressures and FlowsFinal Pressures and Flows

Hepatic Artery Augumentation Post Hepatic Artery augumentation

CO = 9.2 L/min

Portal Pressure = 19

0

5

10

15

20

25

5 10 15 20

Bil INR Cr

Post-operative Course

5

4

3

2

1

Bili

INR, Cr

Shuntgram,Ex lapa

Shunt stenting

LRLTDC

MRI

POD

0

5

10

15

20

25

5 10 15 20

Bil INR Cr

Post-operative Course

5

4

3

2

1

BiliINR, Cr

Shuntgram,

Ex lapa

Shunt stenting

LRLTDC

MRI

POD

Ethical PrinciplesEthical Principles

�� Respect for AutonomyRespect for Autonomy

�� Full, voluntary Informed ConsentFull, voluntary Informed Consent

�� BeneficenceBeneficence

�� Psychological or spiritualPsychological or spiritual

�� No physical benefitNo physical benefit

�� NonNon--maleficencemaleficence

�� Justice Justice

Transplantation • Volume 81,

Number 10, May 27, 2006

Vancouver Ethics StatementVancouver Ethics Statement

�� Donor SelectionDonor Selection�� Legal Competency and NonLegal Competency and Non--Traditional SituationsTraditional Situations

�� Informed Consent and AutonomyInformed Consent and Autonomy�� VoluntaryVoluntary

�� Autonomy and consent is necessary but not sufficient Autonomy and consent is necessary but not sufficient (Paternalism vs. autonomy)(Paternalism vs. autonomy)

�� Provide full R/B/A/P information and a comprehensive processProvide full R/B/A/P information and a comprehensive process

�� Responsibility of the Transplant CenterResponsibility of the Transplant Center�� Donor Advocacy Team Donor Advocacy Team

�� Establish Establish medical, psychological and social suitability

�� Provides freedom to withdraw with supportive environmentProvides freedom to withdraw with supportive environment

�� Provide a period of reflectionProvide a period of reflection

�� Assure full retention of informationAssure full retention of information

Who Should Do Living Donor Liver Who Should Do Living Donor Liver TransplantsTransplants??

�� Centers where the need is greatCenters where the need is great�� Significant waiting list and relative donor scarcitySignificant waiting list and relative donor scarcity

�� A well resourced program in a financially secure A well resourced program in a financially secure institutioninstitution

�� Centers with excellent surgical/transplant/ancillary Centers with excellent surgical/transplant/ancillary experience, commitment and planningexperience, commitment and planning

�� An experienced surgeon who really believes in it. An experienced surgeon who really believes in it. �� Living donor surgery should be an academic focus, not a hobby. Living donor surgery should be an academic focus, not a hobby.

�� Participating team members should be committed to the Participating team members should be committed to the growth and development of the field.growth and development of the field.

Fundamental Ethical DimensionsFundamental Ethical Dimensions

�� Need (chance to timely DD?) Need (chance to timely DD?) �� Individual Individual notnot globalglobal

�� Not too much, not too littleNot too much, not too little

�� Donor SafetyDonor Safety

�� MorbidityMorbidity

�� MortalityMortality

�� Probability of a good recipient outcomeProbability of a good recipient outcome�� ShortShort--termterm

�� LongLong--termterm

Ethical Dimensions of Equipoise inLiving Donor Liver Transplantation

The larger the size of triangle, the greater the ethical good.This is the average situation for a right lobe aLDLT

Expected Recipient Outcome

Donor safety Need

Ethical Dimensions of Equipoise inLiving Donor Liver Transplantation

The fundamental tension between autonomy and nonon--

maleficencemaleficence is best equated with the length of the blue line. In

fact, ERO and DS may be the most important two factors

influencing public opinion and in promulgating public policy.


Donor safety Need

Pediatric LRD as a ModelPediatric LRD as a Model

Why is it less conflictedWhy is it less conflicted??

�� Donor usually a parent with clear cut motivationDonor usually a parent with clear cut motivation

�� Donor morbidity and mortality very lowDonor morbidity and mortality very low

�� Minimal concerns regarding graft size or Minimal concerns regarding graft size or recipient statusrecipient status

�� Major indication is Biliary Atresia; a disease that Major indication is Biliary Atresia; a disease that does not recurdoes not recur

�� Recipient outcomes with LRD are better than DDRecipient outcomes with LRD are better than DD

�� Waiting list now dramatically reducedWaiting list now dramatically reduced

Ethical Dimensions of Equipoise in LDLT

This is the equipoise that exists for pediatric living donor transplantation.


Donor safety Need



Donor safety NeedThis is the equipoise that exists in Asia

where deceased donor options are small


This is the equipoise represents the use of standard right lobe LDLT for “Beyond Milan” HCC’s. The blue line is

shorter and the perceived ethical tension is higher, despite great need.


Donor safety Need



Donor safety NeedThis is the equipoise that would exist where excessive recipient need influenced the decision to use a high risk

donor for high risk recipient: Not a good situation


This is the equipoise that might support the use of low risk left lobes for “ Beyond Milan” HCC’s,


Donor safety Need


This is the equipoise that exists for left Lobe transplantation for patients with MELD 10-15.


Donor safety Need

Summary: TechnologicalSummary: Technological

•• It is not all about size!It is not all about size!

•• PrePre--operative measurements of CI and hepatic operative measurements of CI and hepatic wedge pressure, along with GRWR, should wedge pressure, along with GRWR, should guide the choice of left lobe or right lobe guide the choice of left lobe or right lobe

•• The extent of inflow modification should be The extent of inflow modification should be determined by intradetermined by intra--operative hemodynamic operative hemodynamic measurements (flow and pressure).measurements (flow and pressure).

•• Normalization of hepatic Normalization of hepatic -- portal pressure portal pressure gradient (<10 mmHg) with parenchymal flow gradient (<10 mmHg) with parenchymal flow between 1between 1--2 ml/g/min should be achieved2 ml/g/min should be achieved

Summary: EthicalSummary: Ethical

�� Ethical equipoise in LDLT demands the careful Ethical equipoise in LDLT demands the careful balance of need, donor safety and chance for a balance of need, donor safety and chance for a good outcomegood outcome

�� The proper balance is effected by societal The proper balance is effected by societal beliefs that effect deceased donor organ beliefs that effect deceased donor organ donation and availability, and specific recipient donation and availability, and specific recipient and donor characteristicsand donor characteristics

�� There is continuous tension between personal There is continuous tension between personal autonomy and physician/center/society desire autonomy and physician/center/society desire for nonfor non--maleficencemaleficence

ConclusionsConclusions

�� Use of left lobes improves donor safety, satisfies our Use of left lobes improves donor safety, satisfies our ethical principles and is expanding.ethical principles and is expanding.

�� There is a continuing shortage of livers that can be There is a continuing shortage of livers that can be relieved by expanded utilization of living donorsrelieved by expanded utilization of living donors

�� The clear indications (ex. HCC) that existed prior to The clear indications (ex. HCC) that existed prior to MELD are now more vague and candidate selection is MELD are now more vague and candidate selection is more complexmore complex

�� Carefully selected patients with even with MELDCarefully selected patients with even with MELD’’s < 15 s < 15 show survival benefit with Ashow survival benefit with A--toto--A LDLTA LDLT

�� Left lobe grafts should be used preferentially if graft size Left lobe grafts should be used preferentially if graft size and recipient parameters are favorableand recipient parameters are favorable

�� ““Primum Non NocerePrimum Non Nocere”” is The Way Forward is The Way Forward

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