massimo malago 1

Klinik für Allgemein- und Transplantationschirurgie

Universitätsklinikum Essen

Marginal Donors in Liver Transplantation

Massimo Malagò

Klinik für Allgemein- und Transplantationschirurgie, Universitätsklinikum Essen

EUROPEAN LIVER TRANSPLANT REGISTRY23 Countries - 131 active Institutions

68,776 Transplantations – 61,718 Patients05/1968 - 12/2005

1902

3349440

548

599

11823

10683

10845

254

404

8160

11

1564

442

868

11478277

12421

1605

1098

440

16

ELTR12/2005


LTX and Waiting list Germany

Quelle: ET, DSO

590 586 595699 762 722 757 780 757 756

855

0

200

400

600

800

1,000

1,200

1,400

1,600

1,800

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003

Neuanmeldungen LTX


Organspende in Deutschland


Organ shortageMaximal organ use

MarginalMarginal SPLIT SPLIT Living donorLiving donordonorsdonors

DominoDomino

Essen: mortality on the list 24,2% in 2004Essen: mortality on the list 24,2% in 2004

NHBDNHBD


LIVER TRANSPLANTATIONmarginal grafts

Good graft Good patientGood graft Good patient

Marginal graftMarginal graft High risk patient High risk patient

Is it justified to use marginal grafts ?Is it justified to use marginal grafts ?

Discretional graft allocation: history of transplantation!!Discretional graft allocation: history of transplantation!!


Inreasing Age of Deceased Donors Germany -

!


Graft Survival according to Donor Age in Europe

01/1988 - 12/2005

ELTR12/2005

75

6864

5753

48

41

57

53

72

61

41

32

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10

<55 years : 4606155-65 years : 7607>=65 years : 4763

(%)

Yrs

Total Log Rank test p = 0.0001


Graft Survival according to Donor Agein Elective Liver Transplantation

01/1988 - 12/2005

5660

6771

79

49

42

5966

42

75

55

64

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10

<55 years : 37467

55-65 years : 6405

? 65 years : 4223

(%)

Yrs



Graft Survival according to Donor Agein Urgent Liver Transplantation

01/1988 - 12/2005

5451

47 44

60

37

57

42

4750

34

50

40

33

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10

<55 years : 7799

55-65 years : 1108

?65 years : 493

(%)

Yrs



The use of marginal donor liversIschemia /Reperfusion - Na+

Busuttil & Tanaka Liver Transplantation 2003 9:7, 651-53Busuttil & Tanaka Liver Transplantation 2003 9:7, 651-53


The use of marginal donor liversHepatosteatosis

Differenciate not only micro-macrosteatosisbut particularly Steatohepatis (NASH - NAFL)


Graft Survival according to the Type of Graft 01/1988 - 12/2005

6762

52

6771

79

65

5456

6359

51

556063

65

76

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10

Grafts : 56703

Living donor : 1920

Reduced liver : 2077

Split liver : 3061

Domino : 428

(%)

Yrs

Total Log rank test = 0.0001


Graft Survival according to the Type of Graft in Elective Liver Transplantation

01/1988 - 12/2005

7078

56

79

7168 66

606264

67

5360

667568

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10

Cadaveric Full size : 46675Living donor : 1764Reduced liver : 1278Split liver : 2396Domino : 405

(%)

Yrs


p Log rank :Cadaveric full size vs Living donor : 0.01Cadaveric full size vs Reduced liver : 0.0001 (Wilcoxon test)Cadaveric full size vs Split liver : NSLiving donor vs Reduced liver : 0.0001Living donor vs Split liver : 0.001Reduced liver vs Split liver : NS


Graft Survival according to the Type of Graft in Urgent Liver Transplantation

01/1988 - 12/2005

59

5350

4643

59616764

3941

4345

404243

50

39

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10

Cadaveric Full size : 9068

Living donor : 134

Reduced liver : 779

Split liver : 641

(%)

Yrs


p Log rank :Cadaveric full size vs Living donor : NSCadaveric full size vs Reduced liver : 0.001Cadaveric full size vs Split liver : 0.0001Living donor vs Reduced liver : 0.01Living donor vs Split liver : 0.001Reduced liver vs Split liver : NS


Liver Transplant Graft Survival 2000 - 2003

U.S.

0

20

40

60

80

100

0 1 2 3Years Post Transplant

Sur

viva

l Rat

e (%

)

SCD DCD ECD

2005 UNOS


Marginal liver graft

Donor factorsDonor factors

Graft factorsGraft factors

Associated diseasesAssociated diseases

The use of marginal donor livers



CriteriaCriteria softsoft hardhard

AgeAge > 55 (60)> 55 (60) > 70 (80)> 70 (80)

Hemodynamic stabiltyHemodynamic stabilty cardiac arrest - y/ncardiac arrest - y/n

hypotension hypotension BP Syst < 60 for > 1hBP Syst < 60 for > 1h

anyany Cathecol. > 1Cathecol. > 1/kg/min/kg/min

ICU StayICU Stay > 4 days> 4 days > 10 days> 10 days

Na+Na+ > 155> 155 160 (165)160 (165)

any any max.max.

Amylase, lipaseAmylase, lipase abnormalabnormal x 3x 3

Donor factorsDonor factors




AST, ALTAST, ALT abnormal abnormal x 3 (x 5)x 3 (x 5)

BilirubinBilirubin abnormal abnormal x 3x 3

SteatosisSteatosis Micro , Macro, MixedMicro , Macro, Mixed

> 30%> 30% > > 440% (60%)0% (60%)

FibrosisFibrosis y/ny/n grade >3grade >3

CITCIT >10 h >10 h > 14 h> 14 h

TechnicalTechnical Vessel injuries Vessel injuries Parenchymal injuries Parenchymal injuries

Graft factorsGraft factors




MalignanciesMalignancies anyany past historypast history except neurologicexcept neurologic

HBVHBV anyany Anti HBc Ab Anti HBc Ab HBs AgHBs Ag

HCV HCV HCV Ab RNA + HCV Ab RNA +

Other DiseasesOther Diseases .............. RABIES !!RABIES !!

Associated diseasesAssociated diseases


Definition of Extended Criteria Definition of Extended Criteria Donor (ECD*)Donor (ECD*)

• Donor Age > 65 years

• ICU stay > 7 days

• BMI > 30 kg/m²

• Steatosis (biopsy proven) > 40%

• S - Sodium > 165 mmol/L (at time of organ retrieval)

• S - AST > 3 x normal (at time of organ retrieval) or

• S - ALT > 3 x normal (at time of organ retrieval)

• S - Bilirubin > 3 mg/dL

*According to the Bundesärztekammer Germany BÄK 2004


Patient and Graft survival Patient and Graft survival with ECD organswith ECD organs

(190)(152)(85)(20)

Pairwise Comparison ECD 1 ECD 2 ECD 3

Non-ECD 0.064 n.s. 0.000 0.189 n.s.

ECD 1 0.049

GSR defined as Patient or Graft Loss

Becker T., Hanover Pers. Com. Sept. 06



Study on evaluation of the donor / graft

Mirza et al. Lancet 1999 344:1480-83

• 30 “marginal livers” transplanted

• Study “a posteriori”: questionnaire to 80 centers Response 60 / 80

• Graft survival ( 1 mo. - 1 yr) 83% 72 %

• Pt survival 80%

• Acceptance yes 38%

add data 20%

emergency 17%

refuse 23 %

undecided 2 %


accept % refuse %

Abnormal LFT 19 22

Hypotension 17 37

ETOH 22 22

Hidose inotropes 20 24

ICU > 5d 30 35

Age > 55 y. 50 9

Advanced CV disease 60 5


Evaluation of the donor / graft

Mirza et al. Lancet 1999 344:1480-83


Maximal gain for marginal grafts


The use marginal grafts is justifiedThe use marginal grafts is justified

Can the outcome of marginal grafts Can the outcome of marginal grafts be modified??be modified??

Free graft allocation necessary Free graft allocation necessary for the sake of graft and recipent !!for the sake of graft and recipent !!


HOW??HOW??


Material and Methods

• Study period 2003 - 2004

• ET-Allocation

• Rescue allocation-Definition

• Results analysis according to recipient outcome

Alive vs.dead

• Survival curves Kaplan Meier Ttest statistics (JMP Utah)

• Parameters analyzed Na, CIT, GOT peak last got etc

The use of marginal donor livers“Livers that nobody wants” :

The ET Organ Rescue program in Essen


Algorithm for Organ Rescue Offer• The Liver was refused in regular

allocation in more than 3 different centersbecause of poor organ or donor quality

• In case a regular allocation is not possible, donor instability or unfavourable logistical reasons a rescue allocation is necessary to save the organ

• Eurotransplant selects the centers by recipients suitability criteria and by logistical criteria, according with the MUC & waiting time

•The accepting center is not bound to standard recipient

allocation criteria. Any patient listed

can be transplanted!!


“Livers that nobody wants”: Prerequisites for participating to the

ET Organ Rescue program

Large waiting listConsenting patients“Daring” transplant teamDedicated transplant center


LTX ESSEN April 1998 – October 2006 n = 881

Split (115)

LDLT (185)

Standard-Tx (573)

Reduced Liver (8)


37

467

53

Lebendspende OLTx reduzierte Leber Split

Pediatric n = 143

148

528

1 61

Lebendspende OLTx reduzierte Leber Split

Adults n = 738

LTX ESSEN April 1998 – October 2006 n = 881

140

8

Right Left

ALDLT n =148


1691

39

32

CLTX

reduced size

LDTX

SLTx

LTx n=241LTx n=241

124

45

normal CLTx

LNW

Cadaver LTx n=169Cadaver LTx n=169

„„LNW“ n=45LNW“ n=45

““Liver that nobody wants” (LNW)Liver that nobody wants” (LNW)

Liver Transplantation in Essen 01/03-12/04Liver Transplantation in Essen 01/03-12/04


Main reasons for declining offers by other centersEurotransplant Database - Klinikum Essen 2001-03

Donor Data Overall

n

recipient alive

n

recipient death

n

“Poor organ/donor quality” 7 (21%) 6 1

“Recipient reasons” 3 (9%) 3 -

“Organisational reasons” 5(15%) 5 -

“Combined reasons”(“Poor organ quality”, “Size-match”, „Poor donor quality“, “Recipient reasons”, “Incompatible age” , “Organisational reasons”)

19(55%) 15 4

Total n 34 29 5

Overall 159 refusals for 34 livers (5 refusals/graft in median)


Donor Data overall

n

recipient alive

n

recipient dead

n

Age 41.8 years (1-81) 41.0 years (1-72) 46.3 years (21-81)

Sex 20m/25w 21m/17w 4m/3w

BMI 24.1 (12.3-37.0) 24.0 (12.3-37.0) 25.0(21.9-27.5)

Cause of death

Trauma

ICB

Cerebral Ischemia

Suicide

21

9

13

2

19

8

10

2

2

1

3

-

Cardiac arrest 6/45 6/38 0/7

Vasopressors 27/45 22/38 5/7

Cold ischemic time 528 min (260-900) 513min (260-745) 661 min (388-900)

ICU-stay 5 days (1-15) 5.3 days(1-15) 5.6 days (2-12)

Donor - Graft characteristicsET Organ Rescue - Essen 2003-04 n=45


Organ Data overall

n

recipient alive

n

recipient dead

n

GOT 87 U/l (9-381) 81 U/l (9-301) 130 U/l (25-381)

GOT-max 175 U/l (16-1055) 175 U/l (16-1055) 118 U/l (32-381)

GPT 88 U/l (4-694) 103 U/l (8-694) 74 U/l (11-176)

GPT-max 162 U/l (11-882) 91 U/l (6-694) 107 U/l (11-231)

Na+ 147.7 mmol/l (127-167) 148.1 mmol/l (127-167) 145.9 mmol/l (141-154)

Na+-max 150,2 mmol// (137-169) 150.7 mmol// (137-169) 147.5 mmol/l (141-156)

Na+ >150mmol/l 16/45 14/38 2/7

Cold ischemic time 528 min (260-900) 513min (260-745) 661 min (388-900)

Donor - Graft characteristicsET Organ Rescue - Essen 2003-04 n=45


Recipient demographics ET Organ Rescue - Essen 2003-04 n=45

Recipient Data overall

n

alive

n

dead

n

Age 53.0 years (20-69) 52.8 years (20-69) 54.2 years (28-65)

Sex 30m/15w 24m/14w 6m/1w

MELD-Score 16 15 18

T-Status

HU (1)

T2 (<2A)

T3 (<2B)

T4 (3)

1

8

26

10

0

8

21

9

1

-

5

1

Indication

HBV-cirrhosis

HCV-cirrhosis

Alcoholic-cirrhosis

HCC in cirrhosis

PSC/PBC

SBC

Cryptogenic

Biliary atresia

Acute liver failure

3

14

6

7

4

3

5

2

1

2

11

5

7

4

3

4

2

-

1

3

1

-

-

-

1

-

1


Postoperative liver function

0

200

400

600

800

1000

1200

1400

1. post-LTx

2. post-LTx

3. post-LTx

4. post-LTx

5. post-LTx

GOT (U/l)GPT (U/l)

GOT/GPT>1000U/l in 16 patients (36%)

Standard deviation

GOT

(U/l)

GPT

(U/l)

1. post-LTx 1556 834

2. post-LTx 1557 933

3. post-LTx 749 758

4. post-LTx 571 658

5. post-LTx 607 708



0

500

1000

1500

2000

2500

3000

1. post-LTx

2. post-LTx

3. post-LTx

4. post-LTx

5. post-LTx

GOT (U/l)GPT (U/l)

0

500

1000

1500

2000

2500

3000

1. post-LTx

2. post-LTx

3. post-LTx

4. post-LTx

5. post-LTx

GOT (U/l)GPT (U/l)

Patients expired Patients survived



0,00

1,00

2,00

3,00

4,00

5,00

6,00

1. post-LTx

2 .post-LTx

3. post-LTx

4. post-LTx

5 .post-LTx

Bilirubin (mg/dl)Standard deviation

Bilirubin

(mg/dl)

1. post-LTx 3.91

2. post-LTx 2.37

3. post-LTx 2.67

4. post-LTx 2.63

5. post-LTx 2.81



0,00

1,00

2,00

3,00

4,00

5,00

6,00

7,00

8,00

1. post-LTx

2 .post-LTx

3. post-LTx

4. post-LTx

5 .post-LTx

Bilirubin (mg/dl)

0,00

1,00

2,00

3,00

4,00

5,00

6,00

7,00

8,00

1. post-LTx

2 .post-LTx

3. post-LTx

4. post-LTx

5 .post-LTx

Bilirubin (mg/dl)

Patients expired Patients survived


Morbidity and mortalityMorbidity Patients

n

Re-LTx

n

Primary dysfunction/non-function 8 3

Myocardial ischemia 1 -

Arterial thrombosis 4 1

Re-operations 7 -

Acute cellular rejection 2 -

4/45 (9%)

Mortality

7/45 (16%)

Patients

n

MOF in PNF 2

MOF in IPF 1

Pulmonary embolism 1

ICB 1

Heart failure 2

Graft survival: 9/45 (80%)Patient survival: 7/45 (84%)


Donor Data overall

n

recipient alive

n

recipient dead

n

Pearson

test

Age > 70 3/45 2/38 1/7 0.379

BMI > 30 1/45 1/38 0/7 0.664

GOT > 200 4/45 3/38 1/7 0.585

GOTmax > 200 7/45 5/38 2/7 0.334

GPT > 200 5/45 5/38 0/7 0.315

GPTmax > 200 7/45 6/38 1/7 0.912

Amylase > 95 9/45 6/38 3/7 0.099

Liver acceptable 12/45 9/38 3/7 0.117

Steatosis >30 % 5/45 5/38 2/7 0.109

CIT > 600 min 9/45 7/38 2/7 0.537

Na+ > 160 4/45 4/38 0/7 0.368

Na+Max > 160 4/45 4/38 0/7 0.368

Cardiac arrest 6/45 6/38 0/7 0.258

Vasopressors 27/45 22/38 5/7 0.502

Cold ischemic time

528 min (260-900) 513min (260-745) 661 min (388-900)

Marginal donors / organs - Risk analysis Organ Rescue - Essen 2003-04 n=45


Recipient Data overall

n

alive

n

dead

n

pearson

Age >60 14/45 11/38 3/7 0.465

MELD >20 10/45 7/38 3/7 0.212

T2 4/45 4/38 0/7 0.339

Critical recipients - Risk analysis Organ Rescue - Essen 2003-04 n=45


Survival

• 1-year-survival: 84%• 2-years-survival: 84%• Median follow-up: 12.4 months

(range 0-31 months)

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

Sur

viva

l rat

e

0 6 12 18 24

survival [months]

“Livers that nobody wants”: The ET Organ Rescue program in Essen


Definition of Extended Criteria Definition of Extended Criteria Donor (ECD*)Donor (ECD*)

• Donor Age > 65 years

• ICU stay > 7 days

• BMI > 30 kg/m²

• Steatosis (biopsy proven) > 40%

• S - Sodium > 165 mmol/L (at time of organ retrieval)

• S - AST > 3 x normal (at time of organ retrieval) or

• S - ALT > 3 x normal (at time of organ retrieval)

• S - Bilirubin > 3 mg/dL

*According to the Bundesärztekammer Germany BÄK 2004


Recipient Demographics - “LNW”Recipient Demographics - “LNW”

LNW/non ECD n=19

ECD n=26

p-value

Age (years) 47 ± 19 47 ± 18 n.s.Sex (m / f) 9/10 21/5 n.s.Urgency (Status 1 excluded)

T2 (Eurotransplant)

T3/4 (Eurotransplant)

MELD >25

MELD 19-24

MELD 11-18

MELD < 10

4 (21%)

14 (74%)

1 (5%)

5 (26%)

7 (14%)

3 (16%)

4 (16%)

22 (84%)

2 (7%)

3 (11%)

12 (46%)

7 (27%)

n.s.

Mean MELD 16.4 ± 6.8 15.0 ± 5.4 n.s.Diagnosis Groups

Cholestatic

Cirrhotic

HCC

Metabolic and others

2 (11%)

15 (78%)

2 (11%)

0 (0%)

4 (15%)

15 (58%)

6 (23%)

1 (4%)

n.s.

Cold Ischemia Time (min) 595.4 ± 166 497.1 ± 133 n.s.


Frequency of ECDFrequency of ECDin „Livers that Nobody Wants“in „Livers that Nobody Wants“

56%56%-87%-87%

15.38%

46.15%

3.85%

53.85%

7.69%

15.38%

0% 10% 20% 30% 40% 50% 60%

Donor Age >65 yrs

ICU > 7 d

BMI > 30

Steatosis >40%

Sodium >165

LFTs >3x

17

7

2

0

2

4

6

8

10

12

14

16

18

20

1 2 3


The use of marginal donor liversObjective evaluation: scoring systems


Scoring Criterium: 1- 3 vs > 4 risk factorsScoring Criterium: 1- 3 vs > 4 risk factors

The use of marginal donor liversCumulative risk factors

Essen 2003 -2004 n=45

Risk factorsRisk factors N=N= GraftGraft PatientPatient

1-31-3 2828 76 %76 % 82 %82 %

> 4> 4 1717 60 %60 % 76 %76 %


0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

Sur

vivi

ng

0 10 20 30 40 50

Follow-up (months)

0123

Log-Rank

Wilcoxon

Test

24,4945

23,8246

ChiSquare

3

3

DF

<.0001

<.0001

Prob>ChiSq

The use of marginal donor liversCumulative risk factors Essen 2003 -2004 n=45

ECD liver to “sick recipient” (Age> 60 MELD > 20)

Klinik für Allgemein- und Transplantationschirurgie, Universitätsklinikum EssenJ Belghiti ILTS ‘03


Graft Survival according to the number of the Liver Transplantation in Urgent Cases

01/1988 - 12/2005

4750

545763

3235

404349

2931

33

3134

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10

1st liver transplantations : 2nd liver transplantations : 3151

3rd liver transplantations : 342 4th liver transplantations : 39

(%)

Yrs

1st LT vs 2nd LT : 0.0001 2nd LT vs 3rd LT : 0.0001

1st LT vs 3rd LT : 0.0001 2nd LT vs 4th LT : NS

1st LT vs4th LT : 0.04 3rd LT vs 4th LT : NS

p Log Rank :

Klinik für Allgemein- und Transplantationschirurgie, Universitätsklinikum EssenJ Belghiti ILTS ‘03


Donor / Recipient Analysis Donor / Recipient Analysis - - “LNW”“LNW”

Cox Regression, Backward Stepwise (Likelihood Ratio)

Donor Age n.s.

ICU Stay n.s.

BMI n.s.

Sodium n.s.

LFTs n.s.

Recipient Age n.s.

Diagnosis Group n.s.

MELD Score 0.0253

CIT n.s.

DonorsDonors RecipientRecipient


Donor Criteria Analysis Donor Criteria Analysis - “LNW”- “LNW”Appropriate “allocation buffer”Appropriate “allocation buffer”

0.0009ICU Stay

n.s.ALAT

0.005ASAT

n.s.Sodium

n.s.BMI

n.s.Donor Age

Log-Rank (Mantel-Cox)

Cox Regression, Backward Stepwise (Likelihood Ratio)


Summary

• The use of marginal livers has entered the clinical practice

• “Critcal” liver grafts evaluated differently by experienced, high volume

centers - Key for success is the free allocation of graft-recipient

• The use of true marginal livers can be dangerous

• Appropriate recipient, center, surgeon selection is imperative

• Objective criteria to define the true marginal organs are needed

• A multifactorial score system seems a promising approach

different strategies needed

Marginale Spenderlebern


Summary

• Match ECD livers to patients not too sick !!!• Reduce cold ischemia time• Retransplant early in PPF/PNF

• Accept ECD livers with judgment• Allow «rescue allocation» of ECD livers: flexible allocation rules• Time for a match program for ECDs to appropriate risk recipients


massimo malago 1

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