what makes a pancreas allograft marginal? peter j friend university of oxford

What makes a pancreas allograft marginal?

Peter J FriendUniversity of Oxford

• Do we need marginal grafts?• What is a marginal graft – conventionally?• What is a marginal graft – evidence-based?• How can we use marginal grafts safely?• The future

Pancreas transplantation in the UK – the current situation

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1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Year

Nu

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Donors

Transplants

Active Transplant list

Pancreas transplantation (UK) 1999 - 2009 Donor BMI criterion introduced August 2008

Year All HB donors

HB donors aged 8-60 % Offered

% Retrieved if offered

% Transplanted if retrieved

Conversion rate*

2009 613 491 88 70 60 37

2008 620 499 88 66 64 37

2007 607 498 85 68 76 44

2006 633 521 64 60 77 30

2005 630 540 53 55 74 21

Pancreas transplantation from DBD – UKAge range 8 to 60 years

* Percent of HB donors aged 8 to 60 resulting in transplant

• Donors aged 8 to 60 years - decreasing

• Expanding age criteria - offers and retrievals have increased

• Transplant conversion rate -declined by 7 percentage points

Year All HB donors

HB donors aged 8-60 BMI ≤ 30 % Offered

% Retrieved if offered

% Transplanted if retrieved

Conversion rate*

2009 613 409 90 72 60 43

2008 620 422 90 69 67 42

2007 607 428 85 71 78 47

2006 633 441 67 63 81 34

2005 630 464 54 58 78 24

Pancreas transplantation from DBD – UKInclude BMI less than 30

* Percent of HB donors aged 8 to 60 with a BMI ≤ 30 resulting in transplant

• Donors within age & BMI criteria - decreasing

• Including age and BMI criteria, conversion rate still below 50%

Donor age group

HB donors aged 8-60 BMI ≤30 % Offered

% Retrieved if offered

% Transplanted if retrieved

Conversion rate*

0 to <8 6 67 75 100 50

8 to <18 22 86 84 81 59

18 to <30 75 91 87 83 65

30 to <40 72 93 75 78 54

40 to <50 107 89 66 63 37

50 to <60 133 89 66 45 26

Over 60 87 28 42 30 3

Pancreas transplantation from DBD (2009)The influence of age

* Percent of HB donors aged 8 to 60 with a BMI ≤ 30 resulting in transplant

• Highest conversion rate - donors aged 18 to < 30 years

• Very low conversion rates - donors aged over 50 years

BMI group HB donors aged 8-60 % Offered

% Retrieved if offered

% Transplanted if retrieved

Conversion rate*

≤20 34 94 84 78 62

21 to ≤23 80 93 74 76 53

24 to ≤26 153 89 73 67 44

27 to ≤30 142 90 68 55 34

Pancreas transplantation from DBD (2009)The influence of BMI

* Percent of HB donors aged 8 to 60 with a BMI ≤ 30 resulting in transplant

• Lower BMI associated with higher conversion rates

What factors make a graft marginal?

Uncontrollable factors:AgeObesityCardiovascular diseaseAlcohol Amylase

Controllable factors:Inotropes(Warm ischaemia)Cold ischaemiaRewarming timeRetrieval technique

‘Standard’ criteria vs. ‘Extended’ criteria

University of Minnesota 1994-2003

• 937 transplants– 327 SPK– 399 PAK– 211 PTA

• 624 functioning (66.5%) - mean follow-up 45 months• 123 (13%) lost due to ‘technical’ complications -

– 52% thrombosis 6.5% leaks– 19% sepsis 2.4% bleeding– 20% pancreatitis

Humar et al Transplantation 2004

Risk factors for technical failure

Recipient BMI >30 2.42Preservation time >24 hr. 1.87Donor death Non-trauma 1.58Drainage Enteric 1.68Donor BMI >30 1.66

Humar et al Transplantation 2004

The extended criteria donor - results

Oxford data

• Single centre retrospective analysis• Extended criteria

• Age less than 12, more than 45 years• Non-heart-beating donors

• All pancreas transplant recipients 2004 – 2009• End points:

– Graft & patient survival– Delayed graft function– Complications (re-admissions, re-operations)

Muthusamy et al

Patients & Methods

• 265 transplants (261 pts)– 155 male, 106 female– 176 SCD, 89 ECD– Enteric-systemic drainage of grafts

• Immunosuppression:– Campath / Tac / MMF (n = 249)– (ATG n=8, Basiliximab n=4) / Tac/MMF/Steroids

(all SCD)

Clinical detailsSCD ECD P value

Creatinine – donor 85 ± 31 85 ± 28 NS

Cause of death: vascular 43% 66% 0.0006

Cause of Death: head injury 30% 16% 0.013

Donor Body Mass Index 24 ± 3 25 ± 9 NS

Recipient age (years) 42±7 46±8 <0.0001

Recipient Body mass index 24±4 26 ± 4 0.03

Recipient ethnicity %Caucasian/Asian/Afro-Caribbean

90/ 7 /3 94 / 6 / 0 NS

HLA (median) 4 4 NS

Cold Ischemia (mins) 692±159 717±177 NS

Hospital stay (days) 19 ±12 20 14 NS

Median F/U (months) 23 16 0.0043

Results - Outcomes

SCD ECD P value

DGF - kidney 11% 19% 0.13

DGF - pancreas 1.7% 6.7% 0.06

PNF - kidney 0 0 NS

PNF - pancreas 0 1.5% NS

Re-operation 25% 25% NS

Re-admission 20% 33% 0.03

Rejection episodes 15% 10% NS

Patient & graft survival: SCD vs ECD

Graft function SCD vs. ECD

Conclusions – the expanded criteria donor pancreas

• Equivalent graft and patient survival

• Equivalent pancreatic & renal graft function at 3 months

• Higher risk of delayed graft function of kidney & pancreas

• Greater morbidity related to pancreatitis

• Feasible source to expand the organ pool

Pre-procurement pancreas suitability score (P-PASS) - Eurotransplant

Vinkers et al 2008

P-PASS predicts organ acceptance, not viability

But – more complications and longer hospital stay

Bochum, Germany

Analysis of 24,703 donors 2000 – 2004 (OPTN)44,529 kidney transplants21,079 liver transplants5521 solid organ pancreas transplants1041 pancreases used for islets

Reasons for non-retrieval of pancreas in 64% multi-organ donors

Poor organ function 33%Donor medical history 12%No recipient 7%Intra-operative evaluation 6%Hepatitis serology 6%Anatomical anomaly 3%Unstable haemodynamics 3%Time constraints 2%Other 28%

Stegall et al 2007

Effect of donor age

Age PAK SPK

Less than 50 79.7 85.6*

More than 50 66.7 75.5

* p=0.05

Stegall et al 2007

1 year graft survival

Effect of donor BMI

BMI PAK SPK

Less than 30 79.6 85.7*

More than 30 78.1 82.7

*p=0.06

1 year graft survival

Stegall et al 2007

Effect of cold ischaemia time

Cold ischaemia (hrs)

PAK SPK

0 – 12 79.7 86.7

12 – 18 79.3 85.2

18 – 24 75.7 85.8

24 + 79.3 76.2

Stegall et al 2007

(UK results show significant effect of cold ischaemia time at 3 months)

The effect of donor age

OPTN data Salvalaggio et al (St Louis) 2007

Increased complications of older donors (+/- 45 years) more than compensated by reduced morbidity whilst waiting longer

Paediatric donors

• University of Wisconsin 1986 – 2001• 680 SPK including 142 paediatric donors

– 47 aged 3 to 12 years– 95 aged 12 – 17 years

• 10 year survival and function better in paediatric donors

• No difference between smaller and larger cohorts

Fernandez et al 2004

(Concerns about islet mass & technical complications)

Pancreas graft survival

Fernandez et al 2004

Kidney graft survival

Fernandez et al 2004

Pancreas transplantation from NHB donors

• Salvalaggio et al 2006• Analysis of UNOS data 1993 to 2003

– 57 NHBD (47 SPK, 10 PA)– 4038 HBD (2431 SPK, 1607 PA)

• Equivalent patient & graft survival rates• Shorter time on waiting list• Longer hospital stay• More pancreas thrombosis (12.8% vs. 6.1%)• More renal DGF (28.2% vs. 7.6%)

Kidney graft survival

Pancreas graft survival

Patient survival

Salvalaggio et al 2006

Higher-risk transplants

Postoperativemortality

Waiting listmortality

Mortality on Tx waiting list

Mortality after pancreas Tx

IPTR, UNOS data Gruessner et al 2004

The future

• Improved method of assessment needed– Objective rather than subjective

• Improved graft protection needed– Prevent ischaemia-reperfusion

• Minimise cold ischaemia• Free radical scavenging; Haemoxygenase-1;

Complement inhibition etc.• Machine perfusion +/- normothermia

Conclusions

• Pancreas donor organs poorly utilised• Marginal donor organs are the reality• Published data are inconsistent• Risk-benefit analysis favours early transplant• Innovative preservation and viability

assessment methods needed