Horizon Scanning on organ perfusion

Kidneys

David Talbot

• Maastricht II and Maastricht III

• Cold machine perfusion its future

• Non used kidneys

Summary of NHBD Kidney Programme 1998- 13th November 2006

NHBD

105 Donors ( 210 kidneys)

138 Renal Transplants

72 Non used Kidneys

II III IV

100 96 14

43 77 14

57 15 0

NHBD

Dual donors

Recipients of dual kidneys

13 4 0

13 4 0

Primary WIT ( minutes) 22.2 + 1.0

Secondary WIT (minutes) 37.7 + 1.0

CIT (minutes) 1486 + 34.8

Survival rates (%) First Year Third Year

KIDNEY

PATIENT

88.4

91.4

84.7 88.7

Transplant Rate ----- Cat II – 45.1% Cat III – 82.1% Cat IV -100% Overall Transplants of NHBD = 62.8%

Maastricht II/III distribution in Newcastle

DCD DONORS

0

5

10

15

20

25

30

35

2003 2004 2005 2006 2007 2008 2009

CAT 2

CAT 3

TOTAL

Active MII programmes

• France• Netherlands• Spain: 2 centres

0 (control) 30 60 90

0.0

0.5

1.0

1.5

2.0a

b

c

d

a-b p=NSa-c p=0.0001c-d p=0.0002

Ischaemic Duration (minutes)

PF

Im

l/m

in/1

00g

/mm

Hg

All centres that utilise uncontrolled DCD use cold machine perfusion as a ‘viability’ test. Poor flow indicates non use.

St Petersburg did use cold machine perfusion for this but now uses in situ normothermia

French DCD programme

• Change in legislation 2007 allowing cannulation after pronouncement of death without consent

• MIII not being allowed• Commenced multiple sites cold perfusion• One Paris site with an ECMO programme for

cardiac arrest continued with a normothermic approach.

• Successful liver transplants from this source also- 11 (3 centres)

• Data from Benoit Barrou

French experience abbreviated from Benoit Barrou

• 670 potential donors• 321 donors realised• 390 kidneys transplanted• 245 kidneys not used• Commenced 2007 virtually all cold perfusion• 2012 only 20% cold perfusion the rest warm• 43 transplants 2007 81 in 2012, improvement

mainly due to more donors rather than warm perfusion

• Best graft outcome seen in 2009 when <10% warm perfusion

Summary from France

• 48% conversion rate from potential MII donors• 61% of these kidneys utilised (29% of total)• Steady increase in proportion of donors

managed by normothermia• Best outcome of grafts in 2007-9 when <8%

normothermia• Utilisation rate hasn’t changed enormously for

kidneys with addition of normothermia (11 Livers so far from 3 units, 2 PNF)

Cold machine perfusion for MIII DCD

Cyril Moers, Jacqueline M Smits, Mark-Hugo J Maathuis, Jurgen Treckmann, et al. The New England Journal of Medicine. Boston: Jan 1, 2009. Vol. 360, Iss. 1; pg. 7

Improved DGF with machine perfusion

Improved graft outcome

DCD and DBD pairs

Perfusate different for static storage

Cold Machine Perfusion Versus Static Cold Storage of Kidneys Donated After Cardiac Death: A UK Multicenter Randomized Controlled Trial. Watson CJ et al. [Am J Transplant] 2010 Sep; Vol. 10 (9), pp. 1991-9.

DCD paired kidneys

Solutions matched

Duration of machine perfusion sometimes short

No difference in outcome

Son of PPART

• Close to 100 kidneys recruited

• Machine perfused from donor hospital

• Therefore close to first analysis

• But intention to treat doesn’t necessarily indicate machine perfused

Long term outcome of Newcastle data (MIII) according to perfusion characteristics at 3 hours

Age and perfusion flow index of MIII kidneys- Newcastle data

Peak flow/100ga

HTD Control0

20

40

60

80

ml/

min

/100g

Peak PFIb

HTD Control0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

ml/

min

/100g

/mm

Hg

Resistancec

HTD Control0.0

0.1

0.2

0.3

0.4

0.5

mm

Hg

/ml/

min

Peak GST/100gd

HTD Control0

20

40

60

80

100

120

140

160

180

200

220U

/100g

Donor hypertension and machine perfusion characteristics

• Hypertensive donors and elderly donors have a higher resistance to flow of cold perfusate through the kidney- (expanded criteria)

• Therefore quality of perfusion if perfused statically is likely to be poorer for expanded criteria donors than standard

• Cold machine perfusion improves the quality of perfusion over static for expanded criteria donors

Postulation:

Machine perfusion attenuates the impact of DGF on GS

Moers C et al. N Eng J Med 2012;366:770–1.

100

90

80

70

60

50

40

30

20

10

0

Gra

ft s

urv

ival

(%

)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Months since transplantation

15%

MP no DGF (94%)

MP + DGF (77%)

CS + DGF (62%)

CS no DGF (92%)

The Machine Preservation Trial

100

90

80

70

60

50

40

30

20

10

0

Gra

ft s

urv

ival

(%

)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Months since transplantation

Overall graft survival in ECD kidneys at 3 years

MP (86%)

CS (76%)

HR for graft failure 0.38, p=0.01

Moers C et al. N Engl J Med 2012;366:770–1.

The Machine Preservation Trial

As a consequence Machine perfusion in Europe in 2012

DCD SCD ECD

BeNeLux 79 0 9

France 90 0 276

Germany 0 0 30

Italy 0 0 112

Poland 0 136 112

Scandinavia 0 0 138

Spain 40 0 123

Data from Organ Recovery

France, Spain and Eire recommend machine perfusing of all ECD kidneys.

Future for cold machine perfusion?

• MII all kidneys should be machine perfused• MIII SCD with rapid demise and prompt

cannulation probably no difference between machine or static

• DBD/DCD ECD all should have machine perfusion

• MIII SCD protracted demise, difficult cannulation, blue kidneys should be handled as ECD ie machine perfusion

Kidneys that no one wants

1st April 2012 - 31st March 2013: Kidneys

DBD Organs offered for donation: 1403

Organs not retrieved : 112

Organs retrieved but not transplanted: 95 (donor unsuitable 36, organ unsuitable, clinical 20, poor function 2, other 37)

DCD Organs offered for donation: 1012

Organs not retrieved: 38

Organs retrieved but not transplanted: 177 (donor unsuitable medical 63, donor age 1, organ unsuitable- clinical 56, poor function 4, other 53)

= individual transplant centre

National rate (52%)

99.8% CL

99.8% CL95% CL

95% CL

Centre variation in organ acceptance

DBD kidney offer decline rate

2011 data

Proposal:

• Kidneys from donors with previously normal function- (can be currently abnormal)

• Declined for transplant

• Accepted for testing by may be 3 or 4 national units

Testing the declined kidney:

Biopsy for Rumuzzi score

Kidney arrives

Kidney prepared and placed on cold machine perfusion

NHS BT runs a ‘veteran’ matching run for suitable recipients

Poor score- discard

Good scoreGood flows Poor flows-

discard

2 hours warm perfusion to ‘re-charge’or O2 persufflation or O2 into machine perfusion

Recipient identified, nephrologist contacted

AcceptDecline

Returned to cold machine perfusion for transfer to recipient centre

Transplant

Summary- 1

• MII donor programmes difficult due to declining sudden death of young people

• Expanding MII programmes would have to accept older donors

• Normothermia has some potential here as allows more time and possibly kinder to kidneys from older donors but expensive and return for funding has to be considered- legislation change for England

• Cold machine perfusion mandatory for all kidneys from MII

Summary- 2

• Cold machine perfusion is almost certainly better than static storage for expanded criteria donors whether DBD or DCD

• Kidneys from standard criteria MIII DCD’s are likely to have similar outcome whether or not MPS is used

• If the primary warm ischaemic time is protracted for standard criteria MIII (blue kidneys) MPS is likely to be superior

Summary- 3

• 207 kidneys from DBD and 215 kidneys from DCD were not used in 2012/13 in the UK

• This potentially could be addressed by a restricted number of test stations offering biopsy/ cold flow characteristics/ some sort of re- animation which could be cold as well as warm with kidneys offered to ‘veterans’