Disclosure Statement 3/9/2018. James V. Guarrrera, MD, FACS. Novel Strategies to Expand the Availability and Function of Donor Livers

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1 Novel Strategies to Expand the Availability and Function of Donor Livers Professor and Division Chief Liver Transplant and Hepatobiliary Surgery Department of Surgery Rutgers New Jersey Medical School Disclosure Statement Portions of this work was supported by a United States Health Resource and Service Administration grants R38OT01301 (completed) and R38OT10588 (completed) The opinions and statements within are those of the author and do not represent the opinions of HRSA or the U.S. government I have a research and consulting collaboration with Organ Recovery Systems 2002 Liver Perfusion at New York Presbyterian Hospital: Bench to Bedside Circa Medtronic PBS Centrifugal Pump 1

2 Liver Machine Perfusion in Context: Cold Storage/ Ice: The Gold Standard Static Cold Storage Simple cheap Portable Its so easy that A monkey can do it Reliable Cold ischemic injuries limit ability to use some marginal organs, (moderate steatosis, DCD etc) Ex Vivo Perfusion Not so Simple More expensive Not as easy to transport Hey, Who are you calling a monkey! Risk of device failure HMP ameliorates Cold ischemic injury and lengthen possible CIT NMP may essentially eliminate concern of Cold ischemia injuries, and time limitations y/o donor liver 2

3 Temperature probe AJT 2012 IVC CHA PV Cannulae Surgery 2011 Reduction of early pro-inflammatory injury cytokines HMP down-regulates adhesion mediators Relative expression HMP SCS TNF-α Relative expression HMP SCS IL Relative expression HMP SCS ICAM-1 p= Relative expression HMP SCS P-Selectin p= p= D S R 0 D S R 0 D S R 0 D S R NS p= NS p= NS p= p= p= p= p= TNF-ɑ, tumour necrosis factor ɑ; HMP, hypothermic machine perfusion; SCS, static cold storage; NS: not significant; D, donor visualization; S, post-storage; R, recipient; IL-8, interleukin factor-8; HMP, hypothermic machine perfusion; SCS, static cold storage; ICAM-1, intercellular adhesion molecule-1; D, donor visualization; S, post-storage; R, recipient; NS: not significant Henry SD et al. Am J Transpl 2012;12: Henry SD et al. Am J Transpl 2012;12: Immunofluorescence: Anti-CD68-activated Kupfer cells Ultra structural comparison: Transmission electron microscopy HMP vs. CS post reperfusion CS 1 01 C N Lip Lip Damaged mitochondria (arrowhead) Disrupted cell membrane (arrows) * Disrupted nuclear membrane (N) MP207 C CS203 C Lipofuscin (*) granules were prominent Large electron dense granules lipid droplets (Lip) * Lip CS, cold storage; HMP, hypothermic machine perfusion Henry SD et al. Am J Transpl 2012;12: Henry SD et al. Am J Transpl 2012;12:

4 Ultra structural comparison: Transmission electron microscopy HMP vs. CS post reperfusion HMP 1 05 C Intact Nuclear Membrane (N) Intact cell membrane and endothelial cells (arrows) Intact ER (arrowhead) Lipofuscin granules (*) N Li Hypothermic Machine Perfusion: Columbia University Data Summary We have reported characteristics of HMP preserved livers compared to CS controls Improved early clinical allograft function Fewer biliary complications Less renal dysfunction post transplant Shorter length of hospital stay Diminished preservation injury based on robust molecular and ultra structural evidence Lower costs at our center based on hospital charge data CS, cold storage; HMP, hypothermic machine perfusion Henry SD et al. Am J Transpl 2012;12: LifePort Liver Transporter From Bench to Reproducible Device A Long Journey Circa

5 Perfusion Based Liver Preservation Rapid growth in research and technology and clinical trial development University Medical Center, Groningen, Netherlands DHOPE in DCD Liver Transplantation First in Man Study Aim: Safety and feasibility Intervention: DHOPE (dual hypothermic oxygenated perfusion) Inclusion: 10 consecutive DCD liver transplantations (2014) Controls: 20 previous DCD liver transplantations ( ) Matched: donor age, MELD score, and asystole time Slides courtesy of Prof. Robert Porte, used with permission Zurich Group: Dutkowski et al. End Ischemic HOPE for DCD livers HOPE: Liver Perfusion 2018: Dutkowski et al. from Zurich (personal communication) single center experience 70 DCD liver transplants performed (donors up to 90yrs) Minimum 2 hours of End ischemic HOPE after up to 8 hours of static CS PNF no different than CS controls No cases of Ischemic Cholangiopathy requiring re transplant See also Dutkowski et.al, Ann Surg 2015; 262:

6 Fig from: Quillin RC, Guarrera JV Liver Transplantation; 2018 Accepted Proof of Concept/ Feasibility study in 20 patients with NMP/ 40 Controls No significant differences in outcomes Reduction in post transplant peak transaminases 2016 Liver Machine Perfusion Normothermic machine perfusion: Clinical data now emerging Organ Ox Metra: Blood Based Normothermic Machine Perfusion Ravikumar et. al AJT 2016 Selzner et al. Toronto ILTS 2016 Korea: Abstract O 63, Edmonton NMP Data 10 NMP cases 1 graft discarded; 5/9 with EAD COPE Trial: Data being analyzed Over 200 patients Transmedics Trial 20 patients: on hold pending FDA review Subnormothermic machine perfusion (room Temperature, variable temps): still in preclinical animal model COPE Trial: 7 Centers, 220 pts Enrollment Complete Citations 4 groups Clinical Liver Machine Perfusion Citations Many groups Collaborative Only Columbia HMP 5 cases NMP: Preclinical 3 different US RCT multicenter clinical trials Organ Ox (Metra): NMP Transmedics (OCS): NMP Organ Recovery Systems : HMP 6

7 Why I think Liver MP will be widely adopted Nationally Organ Allocation: The sickest patients with the highest MELDS benefit the most from reduction of stress associated with I/R injury. If MP improves early function as evidence demonstrates then MP will improve early graft function and outcomes Redistricting: Livers may be moving over longer distances by air or ground. MP ameliorates the injuries associated with prolonged ischemia which may add a layer of buffer against the effects of increased distances livers may have to travel Why I think Liver MP will be widely adopted Nationally Liver MP shows the most promise in reducing the injuries associated with utilization of the most risky organs DCD: amelioration of ischemic cholangiopathy by utilizing MP for all DCDs would have a profound effect on the organ gap and reducing waiting time and increase organ availability Steatotic livers: Metabolic syndrome and liver steatosis is increasing in the population. Steatotic livers are very intolerant to Cold Ischemia. MP reduces the I/R hit associated with utilization of steatotic livers. Elderly Livers: The population is aging Older livers have poor tolerance to cold ischemia. This will become an issue that must be faced by all centers. MP will improve early function and outcomes when elderly donor livers are utilized. Added Complexity: Cannulation Logistics: Site of Perfusion Initiation (SPI) Donor Hospital vs Recipient Center 7

8 OrganOx Metra (NMP) PILOT Multicenter Trial Open Label RCT 140 subjects (70 HMP/ 70 CS controls) Under FDA IDE/ in support of de novo 510k application Collection of perfusate, sera, tissue for mechanistic analyses, elucidation of biomarkers Slides Courtesy of Markus Selzner, MD, Toronto General Hospital (used with permission) Centers: (10 Centers) Columbia Cornell NYU Montefiore University of Massachusetts University of Rochester University of Virginia University of Cincinnati Rutgers/ UH (Central Pathology and Biobank; possible enrolling center) Intermountain Health, Utah (requested admission) University of Colorado (requested admission) Important Considerations Cost Who is paying for this? Regulatory: Who is overseeing this? We may not want to think about this. UNOS, FDA, CMS, ASTS, AST Certification: what are the QAPI and training ramifications Additional Complexity Who is pumping the liver: Center Staff vs. OPO model Risk of device failure not a theoretical risk Reallocation of pumped liver: who will accept ADDITIONAL RISK OF DISCARD if original recipient is unsuitable Important Considerations Additional time for backtable work in donor hospital angry coordinators and delays at outside institution Viability testing: Perfusate Lactate/ AST/ Bile production TMI?: is it possible to have too much information? Ie, an erroneous value may trigger discard So Far the community is embracing perfusion and these obstacles appear to be surmountable 8

9 Organ Repair Center Concept Bioengineering of Repopulated Organ Scaffolds: The future of Transplant? Ex Vivo Defatting of Steatotic Collaboration with Prof. Yarmush s Group. Dept of Biomedical Engineering at Rutgers University, NJ What s Next In the last 10 years Ex Vivo Liver perfusion has entered a Renaissance period with intense interest worldwide and novel promising results in multiple models and clinical settings The optimal temperature, protocol, and perfusate are hot topics of debate and investigation these questions still remain to be fully answered in ongoing clinical trials Perfusion technology shows great promise in lengthening safe ex vivo time, and allowing more transplants from marginal donor livers with better outcomes and less complications There is a great deal of excitement and support throughout the transplant community which encourages my belief that we will be able to nationally adopted Ex vivo liver perfusion as a complimentary technique which will likely evolve into a standard of care modality 9