Gabriel C. Oniscu Consultant Transplant Surgeon Honorary Clinical Senior Lecturer NRS Career Research Fellow Royal Infirmary of Edinburgh

Gabriel Oniscu

Gabriel C. Oniscu Consultant Transplant Surgeon Honorary Clinical Senior Lecturer NRS Career Research Fellow Royal Infirmary of Edinburgh

50% increase Organ donation Organ retrieval Organ preservation Transplant CLOD network No significant changes Cold static storage Immunossupression SNOD network NORS Surgical techniques Surveillance

Number of deceased and living donors in the UK, 1 April 2003-31 March 2013 1200 1000 DBD donors DCD donors Living donors 961 1062 1046 1055 1101 858 800 Number 600 697 664 472 485 637 634 599 702 609 611 624 637 652 436 705 507 400 288 335 373 200 73 87 127 159 200 0 2003-2004 2004-2005 2005-2006 2006-2007 2007-2008 2008-2009 2009-2010 2010-2011 2011-2012 2012-2013 Year Source: Transplant activity in the UK, 2012-2013, NHS Blood and Transplant

100 90 80 70 Donation and transplantation rates of organs from DBD organ donors in the UK, 1 April 2012 31 March 2013 Transplanted: % of all organs 85% 83% % of all organs 100 meeting age criteria 90 1 85% 83% 80 70 Donation and transplantation rates of organs from DCD organ donors in the UK, 1 April 2012 31 March 2013 Transplanted: % of all organs 79% % of all organs meeting age criteria 79% Percentage 60 50 40 Percentage 60 50 40 30 20 28% 22% 20% 37% 30 26% 20 25% 27% 27% 10 0 Kidney Liver Pancreas Heart Lungs Organs from actual DBD donors Donor age criteria met 1 Consent for organ donation Organs offered for donation Organs retrieved for transplant Organs transplanted 10 0 Kidney Liver Pancreas Lungs Organs from actual DCD donors Donor age criteria met Consent for organ donation Organs offered for donation Organs retrieved for transplant Organs transplanted 8% 6% 14% 8% Hearts in addition to age criteria, donors who died due to myocardial infarction are excluded urce: Transplant activity in the UK, 2012-2013, NHS Blood and Transplant Source: Transplant activity in the UK, 2012-2013, NHS Blood and Transplant

Increased utilisation of ECD and DCD Lower organ recovery rate Higher rate of complications Poorer long term organ function Logistic constrains Pressure on transplant units Cost benefit

Benefits? Outcome? Prediction of function? Reconditioning?

Reduced DGF in MP group (21% vs 27%) Shorter period of DGF Lower risk of graft failure Better one year survival

NO survival benefit in DCD (despite a lower DGF)

MP (n=45) CS (n=45) DGF 26 (58%) 25 (56%) egfr (3 months) (ml/min/1.73m 2 ) egfr (12 months) (ml/min/1.73m 2 ) 46 48.9 46.6 46.2 Transplant survival 42 (93.3%) 44 (97.8%) Patient survival 42 (93.3%) 45 (100%) Watson et al, AJT 2010

5 RCT One cohort study One registry study 4 data review Depends on which trial data is used 844 MP (381 in RCT)? Clinical effectiveness Bond et al, Health Technology Assessment 2009; 13:38

SCS is cheaper DGF related dialysis costs: 7,581$ vs 4,390 MP is better in he long run (survival) Groen et al. Am J Transplant 2012;12:1624-1630 USRDS and Medicare MP associated with $2130 lower hospital costs and lower DGF No difference in long term Medicare costs? MP utilisation or population differences Buchanan et al. Am J Transplant 2008;8:2391-401.

MP trial data 111 Older donor kidneys (>55) Lipid peroxidation markers predict DGF Nagelschmidt et al. J Surg Res 2013;180:337-42. MP trial data 306 donor kidneys GST, NAG and H-FABP predict DGF Moers et al. Transplantation 2010;90:966-703.

PNF: no difference PS/ GS: no difference Lower early dysfunction rates (5% vs 25%) Biliary complications 10% vs 20% Shorter hospital stay Guarrera et al. Am J Transplant 2010

First Results on End-Ischemic Hypothermic Oxygenated Machine Perfusion (HOPE) of Human Liver Grafts Donated after Cardiac Arrest. Philipp Dutkowski, Andrea A. Schlegel, Michelle DeOliveira, Olivier DeRougemont, Fabienne Neff, Pierre-Alain Clavien. Department of Surgery& Transplantation, University Hospital Zurich, Zurich, Switzerland. 5 DCD livers Early function comparable with DBD No biliary complications in the first 6 months

It s About Increasing Organ Quality It s About More Transplants

Bridge between asystole and organ transplantation In the donor Ex situ Rehabilitation at a cellular level (replenish mitochondrial stores of ATP) Dynamic organ assessment

Reference Sanchez-Fructoso, 2006 Madrid, Spain Valero, 2000 Barcelona, Spain Reznik, 2010 St Petersburg, Russia Magliocca, 2005 Michigan, USA Farney, 2008 North Carolina, USA Lee, 2005 Taiwan Potential/ Actual donors n) Transplanted Kidneys (n) Maastricht category NR 320 I (85.3%) II (14.7%) Uncontrolled 17 8 (47%) 16 II Uncontrolled Function comparable with living donors and DBD kidneys Lower rate of DGF Increases organ pool (DCD II) Expansion of acceptance criteria NR 10 20 II Uncontrolled 20 15 (75%) 24 III Controlled NR 25 III Controlled 16 16 (100%) 31 III Controlled Koyama, 2002 Tokyo, Japan 23 23 (100%) 46 IV Controlled

Reference Potential Actual donors IC rates: 5-10% Fondevila, 2007 40 10 (25%) Barcelona, Spain 80% graft survival Maastricht category Jimenez-Galanes, PNF 2009 rates 1/10 and 2/20 40 20 (50%) II Madrid (Octubre), Liver Spainrecovery rate 25-50% (DCD II) II Otero, 2003 Madrid, (San Carlos) Spain Pelletier, 2009 Michigan, USA NR 14 II 19 12 (63%) III

16 DCD donors 47 organs (29 kidneys, 8 livers, 4 pancreata and 3 lung pairs) 37 recipients 24 kidneys 8 livers 2 SPK 3 lung transplants 3 organs/donor Kidney DGF rate 20% Organ recovery rate: kidney (93% vs 82%) liver (50% vs 30%) lungs (18% vs 4%).

Assessment of grafts Biochemistry & Appearance No Possibly Yes

Renal Transplantation After Ex Vivo Normothermic Perfusion: The First Clinical Study S Hosgood, Leicester American Journal of Transplantation 2013; 13:1246-52 ECD kidneys Pre-implantation EVNP DGF 5.6% vs 36.2% No survival difference

10 patients 6.5-16.5 h preservation DBD No biliary complications 1 pt 6 months King s College unpublished data

20 lungs 4 hours on the EVLP Primary graft dysfunction at 72h: 15% vs 30% No difference in mortality bronchial complications duration of ventilation hospital stay

Twelve-hour Reanimation of a Human Heart Following Donation After Circulatory Death. Rosenfeldt F, Ou R, Woodard J, Esmore D, Marasco S.SourceDepartment of Cardiothoracic Surgery, Cardiac Surgical Research Unit, Alfred Hospital and the Department of Surgery, Monash University, Melbourne, Australia. Case report Ex situ, warm perfusion of a DCD heart for 12 hours

Which machine? When? How do we evaluate them? Implementation? Future?

Liver: 3 Kidneys :2 Lung: 2 1-completed 2-recruiting 2-recruiting 1- not recruiting yet

normothermic preservation of the liver ECD donor kidneys with HMP reconditioning after cold storage. Oxygenated vs. non oxygenated machine perfusion in kidney transplantation

NRP vs cold perfusion / HMP in DCD donors Kidney NMP reconditioning In situ vs/ and ex-situ warm perfusion for livers

Implementation of in situ NRP in a UK DCD programme

Technology development

Technology development In the UK, pre-mortem interventions (cannulation, heparin administration) are not permitted. Technology adaptations: Post-mortem heparin Butler shunt / Oniscu shunt Cold perfusion option Venting option

Staff training and competency Regulatory support Self sufficiency Staff training Scottish Government Donation Ethics Committee NHSBT and organ specific advisory boards NHS Lothian operational level SNODs- operational level Local laboratories - operational support Transplant units organ acceptance and utilisation

Model for further developments This was well supported by the community and was feasible within the setting of transplantation. Further clinical developments will be required and should follow a similar pattern for implementation.

Integrated/ fully portable Console H/E Oxygenator Controlled by i-pad.

Machine perfusion is here to stay In situ and ex situ perfusion required Normothermic perfusion is likely to be the future Further technological refinements are needed Graft assessment and modulation Wider applicability

THE REVOLUTION BEGINS THIS YEAR