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 105 Donors ( 210 kidneys) 138 Renal Transplants 72 Non used Kidneys II III IV 100 96 14 43 77 14 57 15 0 Dual donors Recipients of dual kidneys 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

Active MII programmes France Netherlands Spain: 2 centres 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 Improved DGF with machine perfusion Improved graft outcome DCD and DBD pairs Perfusate different for static storage 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

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

Donor hypertension and machine perfusion characteristics

Postulation: 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

Machine perfusion attenuates the impact of DGF on GS The Machine Preservation Trial Machine perfusion attenuates the impact of DGF on GS 100 90 80 70 60 50 40 30 20 10 Graft survival (%) 2 4 6 8 12 14 16 18 22 24 26 28 32 34 36 Months since transplantation MP no DGF (94%) CS no DGF (92%) MP + DGF (77%) 15% CS + DGF (62%) Moers C et al. N Eng J Med 2012;366:770–1.

Overall graft survival in ECD kidneys at 3 years The Machine Preservation Trial Overall graft survival in ECD kidneys at 3 years 100 90 80 70 60 50 40 30 20 10 Graft survival (%) 2 4 6 8 12 14 16 18 22 24 26 28 32 34 36 Months since transplantation HR for graft failure 0.38, p=0.01 MP (86%) CS (76%) Notes Main data set n=188 recipients of ECD only kidneys Machine perfusion vs. cold storage: 86% vs. 76% adjusted hazard ratio for graft failure 0.38 (95% CI 0.18–0.80, p=0.01) Moers C et al. N Engl J Med 2012;366:770–1.

As a consequence Machine perfusion in Europe in 2012 DCD SCD ECD BeNeLux 79 9 France 90 276 Germany 30 Italy 112 Poland 136 Scandinavia 138 Spain 40 123 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)

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: Kidney arrives NHS BT runs a ‘veteran’ matching run for suitable recipients Biopsy for Rumuzzi score Kidney prepared and placed on cold machine perfusion Poor score- discard Good score Good flows Poor flows- discard Recipient identified, nephrologist contacted Accept Decline 2 hours warm perfusion to ‘re-charge’ or O2 persufflation or O2 into machine perfusion 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’