Urea production during normothermic machine perfusion: Price of success?

Reiling, Janske; Lockwood, David; Simpson, Andrew H.; Campbell, Catherine; Bridle, Kim R.; Santrampurwala, Nishreen; Britton, L.; Crawford, Darrell H. G.; Dejong, C.H.C.; Fawcett, Jonathan

doi:10.1002/lt.24094

Cited by 25 publications

(40 citation statements)

References 5 publications

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“…Urea is produced by the liver and results from an enzymatic reaction involving carbon dioxide and the ammonia derived from the deamination of proteins in the liver. The increased level of urea suggests increased urea synthesis in defatted livers . Our previously published viability criteria assert that lactate levels <2.5 mmol/L within 4 hours is a major criterion for safe transplantation of ECD donor livers.…”

Section: Discussionmentioning

confidence: 99%

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Manipulation of Lipid Metabolism During Normothermic Machine Perfusion: Effect of Defatting Therapies on Donor Liver Functional Recovery

et al. 2019

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Strategies to increase the use of steatotic donor livers are required to tackle the mortality on the transplant waiting list. We aimed to test the efficacy of pharmacological enhancement of the lipid metabolism of human livers during ex situ normothermic machine perfusion to promote defatting and improve the functional recovery of the organs. Because of steatosis, 10 livers were discarded and were allocated either to a defatting group that had the perfusate supplemented with a combination of drugs to enhance lipid metabolism or to a control group that received perfusion fluid with vehicle only. Steatosis was assessed using tissue homogenate and histological analyses. Markers for lipid oxidation and solubilization, oxidative injury, inflammation, and biliary function were evaluated by enzyme‐linked immunosorbent assay, immunohistochemistry, and in‐gel protein detection. Treatment reduced tissue triglycerides by 38% and macrovesicular steatosis by 40% over 6 hours. This effect was driven by increased solubility of the triglycerides ( P = 0.04), and mitochondrial oxidation as assessed by increased ketogenesis ( P = 0.008) and adenosine triphosphate synthesis ( P = 0.01) were associated with increased levels of the enzymes acyl‐coenzyme A oxidase 1, carnitine palmitoyltransferase 1A, and acetyl‐coenzyme A synthetase. Concomitantly, defatted livers exhibited enhanced metabolic functional parameters such as urea production ( P = 0.03), lower vascular resistance, lower release of alanine aminotransferase ( P = 0.049), and higher bile production ( P = 0.008) with a higher bile pH ( P = 0.03). The treatment down‐regulated the expression of markers for oxidative injury as well as activation of immune cells (CD14; CD11b) and reduced the release of inflammatory cytokines in the perfusate (tumor necrosis factor α; interleukin 1β). In conclusion, pharmacological enhancement of intracellular lipid metabolism during normothermic machine perfusion decreased the lipid content of human livers within 6 hours. It also improved the intracellular metabolic support to the organs, leading to successful functional recovery and decreased expression of markers of reperfusion injury.

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Section: Discussionmentioning

confidence: 99%

“…The increased level of urea suggests increased urea synthesis in defatted livers. (19,26) Our previously published viability criteria assert that lactate levels <2.5 mmol/L within 4 hours is a major criterion for safe transplantation of ECD donor livers. However, it also considers other parameters of liver metabolism.…”

Section: Discussionmentioning

confidence: 99%

Manipulation of Lipid Metabolism During Normothermic Machine Perfusion: Effect of Defatting Therapies on Donor Liver Functional Recovery

et al. 2019

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“…Indeed, the majority of published studies about ex vivo perfusion of discarded human livers have reported using more or less the same number of livers. (18,28,35,36) Moreover, due to facing various challenges with using discarded human livers, in the majority of these publications, the authors have preferred to report a review of their data and to describe the outcomes of their study rather than designing a full control-versus-treatment-like project. Therefore, although we believe that this project would certainly benefit from incorporating a higher number of livers, unfortunately, logistics of organ allocation for research purposes and practical challenges of ex vivo perfusion models have limited us to do so.…”

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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“…NELP systems that have not used a dialyzer have experienced significant increases in the urea levels accompanied by steady rise in the osmolarity of the perfusate and very high glucose levels unresponsive to insulin. 18 We also faced similar problems before adding the dialyzer to the circuit. These concerns are even more relevant when using DCD livers that have been insulted to long warm ischemia times.…”

Section: Surgery J 2015mentioning

confidence: 97%

Normothermic extracorporeal liver perfusion for donation after cardiac death (DCD) livers

Banan

Chung

Xiao

et al. 2015

Surgery

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Urea production during normothermic machine perfusion: Price of success?

Cited by 25 publications

References 5 publications

Manipulation of Lipid Metabolism During Normothermic Machine Perfusion: Effect of Defatting Therapies on Donor Liver Functional Recovery

Manipulation of Lipid Metabolism During Normothermic Machine Perfusion: Effect of Defatting Therapies on Donor Liver Functional Recovery

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

Normothermic extracorporeal liver perfusion for donation after cardiac death (DCD) livers

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