NORMOTHERMIC EX-VIVO KIDNEY PERFUSION PRESERVATION RELIABLY IMPROVES MARGINAL GRAFT FUNCTION COMPARED TO HYPOTHERMIC MACHINE PERFUSION

Ischemia-reperfusion injury (IRI) constitutes a significant source of morbidity and mortality after orthotopic liver transplantation (OLT). The allograft is metabolically impaired during warm and cold ischemia and is further damaged by a paradox reperfusion injury after revascularization and reoxygenation. Short-term and long-term complications including post-reperfusion syndrome, delayed graft function, and immune activation have been associated with IRI. Due to the current critical organ shortage, extended criteria grafts are increasingly considered for transplantation, however, with an elevated risk to develop significant features of IRI. In recent years, ex vivo machine perfusion (MP) of the donor liver has witnessed significant advancements. Here, we describe the concept of hypothermic (oxygenated) machine perfusion (HMP/HOPE) approaches and highlight which allografts may benefit from this technology. This review also summarizes clinical applications and the main aspects of ongoing randomized controlled trials on hypothermic perfusion. The mechanistic aspects of IRI and hypothermic MP—which include tissue energy replenishment, optimization of mitochondrial function, and the reduction of oxidative and inflammatory damage following reperfusion—will be comprehensively discussed within the context of current preclinical and clinical evidence. Finally, we highlight novel trends and future perspectives in the field of hypothermic MP in the context of recent findings of basic and translational research.

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High Oxygen Pressure during Continuous Hypothermic Machine Perfusion is Associated with a Better Ex Vivo Renal Blood Flow and Early Graft Function in a Porcine DCD Auto-Transplant Model

Transplantation Journal ◽

10.1097/01.tp.0000543661.39716.31 ◽

2018 ◽

Vol 102 ◽

pp. S701

Author(s):

Tom Darius ◽

Pierre Gianello ◽

Antoine Buemi ◽

Martine de Meyer ◽

Michel Mourad

Keyword(s):

Blood Flow ◽

Renal Blood Flow ◽

Oxygen Pressure ◽

Ex Vivo ◽

Graft Function ◽

Machine Perfusion ◽

Hypothermic Machine Perfusion ◽

High Oxygen Pressure ◽

Early Graft ◽

Transplant Model

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Normothermic Ex-vivo Kidney Perfusion in a Porcine Auto-Transplantation Model Preserves the Expression of Key Mitochondrial Proteins: An Unbiased Proteomics Analysis

10.1101/2020.08.17.253252 ◽

2020 ◽

Author(s):

Caitriona M. McEvoy ◽

Sergi Clotet-Freixas ◽

Tomas Tokar ◽

Chiara Pastrello ◽

Shelby Reid ◽

...

Keyword(s):

Molecular Mechanisms ◽

Ischemia Reperfusion Injury ◽

Ex Vivo ◽

Ischemia Reperfusion ◽

Graft Function ◽

Kidney Injury ◽

Tca Cycle ◽

Proteomics Analysis ◽

Beneficial Effects ◽

Kidney Perfusion

AbstractNormothermic ex-vivo kidney perfusion (NEVKP) results in significantly improved graft function in porcine auto-transplant models of DCD injury compared to static cold storage (SCS); however, the molecular mechanisms underlying these beneficial effects remain unclear. We performed an unbiased proteomics analysis of 28 kidney biopsies obtained at 3 time points from pig kidneys subjected to 30-minutes of warm ischemia, followed by 8 hours of NEVKP or SCS, and auto-transplantation. 70/6593 proteins quantified were differentially expressed between NEVKP and SCS groups (FDR<0.05). Proteins increased in NEVKP mediated key metabolic processes including fatty acid ß-oxidation, the TCA-cycle and oxidative phosphorylation. Comparison of our findings with external datasets of ischemia-reperfusion, and other models of kidney injury confirmed that 47 of our proteins represent a common signature of kidney injury reversed or attenuated by NEVKP. We validated key metabolic proteins (ETFB, CPT2) by immunoblotting. Transcription factor databases identified PPARGC1A, PPARA/G/D and RXRA/B as the upstream regulators of our dataset, and we confirmed their increased expression in NEVKP with RT-PCR. The proteome-level changes observed in NEVKP mediate critical metabolic pathways that may explain the improved graft function observed. These effects may be coordinated by PPAR-family transcription factors, and may represent novel therapeutic targets in ischemia-reperfusion injury.

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The Effects of Oxygenation on Ex Vivo Kidneys Undergoing Hypothermic Machine Perfusion

Transplantation Journal ◽

10.1097/tp.0000000000002542 ◽

2019 ◽

Vol 103 (2) ◽

pp. 314-322 ◽

Cited By ~ 17

Author(s):

Kamlesh Patel ◽

Thomas B. Smith ◽

Desley A.H. Neil ◽

Alpesh Thakker ◽

Yugo Tsuchiya ◽

...

Keyword(s):

Ex Vivo ◽

Machine Perfusion ◽

Hypothermic Machine Perfusion

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An ex vivo comparison of adenosine and lidocaine solution and University of Wisconsin solution for hypothermic machine perfusion of porcine kidneys: potential for development

Journal of Surgical Research ◽

10.1016/j.jss.2016.08.068 ◽

2017 ◽

Vol 208 ◽

pp. 219-229 ◽

Cited By ~ 5

Author(s):

Karim Hamaoui ◽

Adeel Aftab ◽

Sally Gowers ◽

Martyn Boutelle ◽

Terry Cook ◽

...

Keyword(s):

Ex Vivo ◽

Machine Perfusion ◽

University Of Wisconsin Solution ◽

University Of Wisconsin ◽

Hypothermic Machine Perfusion ◽

Lidocaine Solution ◽

Wisconsin Solution

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Restoring Mitochondrial Function While Avoiding Redox Stress: The Key to Preventing Ischemia/Reperfusion Injury in Machine Perfused Liver Grafts?

International Journal of Molecular Sciences ◽

10.3390/ijms21093132 ◽

2020 ◽

Vol 21 (9) ◽

pp. 3132 ◽

Cited By ~ 3

Author(s):

Julia Hofmann ◽

Giorgi Otarashvili ◽

Andras Meszaros ◽

Susanne Ebner ◽

Annemarie Weissenbacher ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ex Vivo ◽

Ischemia Reperfusion ◽

Graft Function ◽

Ros Production ◽

Machine Perfusion ◽

Redox Stress ◽

Molecular Events ◽

Regulate Cell Death

Mitochondria sense changes resulting from the ischemia and subsequent reperfusion of an organ and mitochondrial reactive oxygen species (ROS) production initiates a series of events, which over time result in the development of full-fledged ischemia-reperfusion injury (IRI), severely affecting graft function and survival after transplantation. ROS activate the innate immune system, regulate cell death, impair mitochondrial and cellular performance and hence organ function. Arresting the development of IRI before the onset of ROS production is currently not feasible and clinicians are faced with limiting the consequences. Ex vivo machine perfusion has opened the possibility to ameliorate or antagonize the development of IRI and may be particularly beneficial for extended criteria donor organs. The molecular events occurring during machine perfusion remain incompletely understood. Accumulation of succinate and depletion of adenosine triphosphate (ATP) have been considered key mechanisms in the initiation; however, a plethora of molecular events contribute to the final tissue damage. Here we discuss how understanding mitochondrial dysfunction linked to IRI may help to develop novel strategies for the prevention of ROS-initiated damage in the evolving era of machine perfusion.

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Hypothermic Machine Perfusion Reduces Delayed Graft Function and Improves One-Year Graft Survival of Kidneys from Expanded Criteria Donors: A Meta-Analysis

PLoS ONE ◽

10.1371/journal.pone.0081826 ◽

2013 ◽

Vol 8 (12) ◽

pp. e81826 ◽

Cited By ~ 43

Author(s):

Baoping Jiao ◽

Shurong Liu ◽

Hao Liu ◽

Donghua Cheng ◽

Ying Cheng ◽

...

Keyword(s):

Graft Survival ◽

Meta Analysis ◽

Graft Function ◽

Delayed Graft Function ◽

Machine Perfusion ◽

Hypothermic Machine Perfusion ◽

Expanded Criteria ◽

Expanded Criteria Donors ◽

One Year

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Hypothermic Machine Perfusion in DCD Kidney Transplantation: A Single Center Experience

Urologia Internationalis ◽

10.1159/000431025 ◽

2015 ◽

Vol 96 (2) ◽

pp. 148-151 ◽

Cited By ~ 5

Author(s):

Liyu Yao ◽

Honglan Zhou ◽

Yuantao Wang ◽

Gang Wang ◽

Weigang Wang ◽

...

Keyword(s):

Kidney Transplantation ◽

Graft Function ◽

Postoperative Recovery ◽

Donation After Cardiac Death ◽

Machine Perfusion ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Single Center Experience ◽

Hypothermic Machine Perfusion ◽

Significant Difference

Introduction: Donation after cardiac death (DCD) began in 2011 after the program hosted by the First Affiliated Hospital of Sun Yat-sen University in China. The aim of this study is to report on our experience regarding the method of preserving donated kidneys for DCD kidney transplantation. Material and Methods: A total of 37 donors and 73 primary kidney transplant recipients during the period 2011-2014 in the Urology Center of the First Hospital of Jilin University were enrolled in the study. Recipients were assigned to traditional static cold storage (SCS) group and hypothermic machine perfusion (HMP) group based on the preservation environment of donated kidneys after organ harvest. Clinical data were collected for each group. Result: The HMP group had a lower rate of delayed graft function (DGF), better postoperative recovery and kidney function compared with that of SCS group. There is no significant difference in postoperative rejection incidence between the 2 groups. Conclusions: DCD kidneys stored by hypothermic machine contribute to a lower rate of DGF and promoted the rehabilitation progress.

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