First human liver transplantation using a marginal allograft resuscitated by normothermic machine perfusion

Perera, M Thamara P R; Mergental, Hynek; Stephenson, Barney; Roll, Garrett R.; Cilliers, Hentie; Liang, Richard; Angelico, Roberta; Hübscher, Stefan G.; Neil, Desley; Reynolds, Gary; Isaac, John; Adams, David H.; Afford, Simon C.; Mirza, Darius F.; Muiesan, Paolo

doi:10.1002/lt.24369

Cited by 100 publications

(84 citation statements)

References 4 publications

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“…(28,36,46) In fact, it has been shown that a constant reduction in perfusate glucose concentrations during NELP is accompanied by increased glycogen storage in the hepatocytes. (47) On the other hand, glucose decline during NELP is a good sign of liver functionality and shows that the glucose is constantly being picked up by the hepatocytes and is being stored as glycogen. Taken all together, with having biopsies, INR, and bile production, we believe that the observed glucose reduction is not an indicator of graft dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Development of a normothermic extracorporeal liver perfusion system toward improving viability and function of human extended criteria donor livers

Banan¹,

Watson²,

Xu³

et al. 2016

Liver Transpl

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Donor organ shortages have led to an increased interest in finding new approaches to recover organs from extended criteria donors (ECD). Normothermic extracorporeal liver perfusion (NELP) has been proposed as a superior preservation method to reduce ischemia/reperfusion injury (IRI), precondition suboptimal grafts, and treat ECD livers so that they can be successfully used for transplantation. The aim of this study was to investigate the beneficial effects of a modified NELP circuit on discarded human livers. Seven human livers that were rejected for transplantation were placed on a modified NELP circuit for 8 hours. Perfusate samples and needle core biopsies were obtained at hourly intervals. A defatting solution that contained exendin-4 (50 nM) and L-carnitine (10 mM) was added to the perfusate for 2 steatotic livers. NELP provided normal temperature, electrolytes, and pH and glucose levels in the perfusate along with physiological vascular flows and pressures. Functional, biochemical, and microscopic evaluation revealed no additional injuries to the grafts during NELP with an improved oxygen extraction ratio (>0.5) and stabilized markers of hepatic injury. All livers synthesized adequate amounts of bile and coagulation factors. We also demonstrated a mild reduction (10%) of macroglobular steatosis with the use of the defatting solution. Histology demonstrated normal parenchymal architecture and a minimal to complete lack of IRI at the end of NELP. In conclusion, a modified NELP circuit preserved hepatocyte architecture, recovered synthetic functions, and hepatobiliary parameters of ECD livers without additional injuries to the grafts. This approach has the potential to increase the donor pool for clinical transplantation. The major limiting factor of using extended criteria donor (ECD) grafts is their greater susceptibility to injury during cold preservation and lower tolerance for ischemia/reperfusion injury (IRI) upon reperfusion. Therefore, ECD grafts have been associated with a higher risk of posttransplant complications such as primary graft nonfunction and chronic cholangiopathy.(1-4) Machine perfusion has been investigated both as a preservation method to reduce IRI in ECD livers and as a method to assess the viability and function of suboptimal grafts prior to transplantation.(5-7)Currently, there are 3 variants of liver machine perfusion that are distinguished by the perfusate temperature: hypothermic, subnormothermic, and normothermic.

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Section: Discussionmentioning

confidence: 99%

Development of a normothermic extracorporeal liver perfusion system toward improving viability and function of human extended criteria donor livers

Banan¹,

Watson²,

Xu³

et al. 2016

Liver Transpl

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“…[1][2][3][4][5] (Dual) hypothermic oxygenated perfusion ([D]HOPE) can be applied to resuscitate the mitochondria and increase hepatic adenosine triphosphate (ATP) content, resulting in less cell injury, including less choliangiocyte injury. Machine perfusion, was recently introduced in clinical practice using two different temperature protocols: hypothermic (4-12°C) or normothermic (37°C) machine perfusion.…”

Section: Introductionmentioning

confidence: 99%

Pretransplant sequential hypo- and normothermic machine perfusion of suboptimal livers donated after circulatory death using a hemoglobin-based oxygen carrier perfusion solution

Vries

Matton

Nijsten

et al. 2019

American Journal of Transplantation

135

163

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Ex situ dual hypothermic oxygenated machine perfusion (DHOPE) and normothermic machine perfusion (NMP) of donor livers may have a complementary effect when applied sequentially. While DHOPE resuscitates the mitochondria and increases hepatic adenosine triphosphate (ATP) content, NMP enables hepatobiliary viability assessment prior to transplantation. In contrast to DHOPE, NMP requires a perfusion solution with an oxygen carrier, for which red blood cells (RBC) have been used in most series. RBC, however, have limitations and cannot be used cold. We, therefore, established a protocol of sequential DHOPE, controlled oxygenated rewarming (COR), and NMP using a new hemoglobin‐based oxygen carrier (HBOC)‐based perfusion fluid (DHOPE‐COR‐NMP trial, NTR5972). Seven livers from donation after circulatory death (DCD) donors, which were initially declined for transplantation nationwide, underwent DHOPE‐COR‐NMP. Livers were considered transplantable if perfusate pH and lactate normalized, bile production was ≥10 mL and biliary pH > 7.45 within 150 minutes of NMP. Based on these criteria five livers were transplanted. The primary endpoint, 3‐month graft survival, was a 100%. In conclusion, sequential DHOPE‐COR‐NMP using an HBOC‐based perfusion fluid offers a novel method of liver machine perfusion for combined resuscitation and viability testing of suboptimal livers prior to transplantation.

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“…Small series of clinical transplantation of suboptimal liver grafts after resuscitation by NMP resulting in better than expected outcomes compared to historic experience are also suggestive [27, 28]. Similarly, an experimental study of NMP on DCD rat hearts demonstrated beneficial effects on recovery of electrical activity and contractility of the myocardial tissue [29].…”

Section: Machine Perfusion: a Platform For Organ Treatmentmentioning

confidence: 99%

Opportunities for Therapeutic Intervention During Machine Perfusion

Karimian

Yeh

2017

Curr Transpl Rep

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Purpose of review There is a vast discrepancy between the number of patients waiting for organ transplantation and the available donor organs. Ex vivo machine perfusion (MP) has emerged in an effort to expand the donor pool, by improving organ preservation, providing diagnostic information, and more recently, acting as a platform for organ improvement. This article reviews the current status of MP with a focus on its role in organ preconditioning and therapeutic interventions prior to transplantation. Recent findings MP has allowed longer organ preservation compared to conventional static cold storage and allowed the use of organs that might otherwise have been discarded. Moreover, experimental studies have investigated the role of MP in reducing ischemia reperfusion injury of lungs, kidneys and livers by applying mesenchymal stem cells (MSCs), anti-inflammatory agents, cytotopic anticoagulants, and defatting cocktails. Summary MP has opened a new era in the field of organ transplantation and tissue medication.

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First human liver transplantation using a marginal allograft resuscitated by normothermic machine perfusion

Cited by 100 publications

References 4 publications

Development of a normothermic extracorporeal liver perfusion system toward improving viability and function of human extended criteria donor livers

Development of a normothermic extracorporeal liver perfusion system toward improving viability and function of human extended criteria donor livers

Pretransplant sequential hypo- and normothermic machine perfusion of suboptimal livers donated after circulatory death using a hemoglobin-based oxygen carrier perfusion solution

Opportunities for Therapeutic Intervention During Machine Perfusion

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