Normothermic Machine Perfusion Protects Against Liver Ischemia-Reperfusion Injury During Reduced-Size Liver Transplantation in Pigs

Abstract Liver ischemia/reperfusion injury (IRI) is a dreadful vascular complication, which leads to liver damage. It is often associated with graft loss in liver transplantation and with a higher morbidity and mortality. IRI can have different causes, such as inflow clumping during surgical procedures in hepatic resection, liver transplantation, trauma, as well as during the stenosis of the vasculature caused by cancer. Here, we show a detailed IRI protocol in a porcine model.

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Liver transplantation without graft ischemia in humans

10.1101/2020.04.20.20065979 ◽

2020 ◽

Author(s):

Zhiyong Guo ◽

Qiang Zhao ◽

Shanzhou Huang ◽

Changjun Huang ◽

Jian Zhang ◽

...

Keyword(s):

Liver Transplantation ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Absolute Risk ◽

Ischemia Reperfusion ◽

Surgical Techniques ◽

Risk Difference ◽

Clinical Trial Registry ◽

Conventional Procedure ◽

Normothermic Machine Perfusion

ABSTRACTBACKGROUNDIschemia-reperfusion injury is considered an inevitable event that compromises posttransplant outcomes. Numerous treatments have been proposed to reduce its impact. However, most of them have had limited success, as none of them can completely avoid graft ischemia.METHODSIschemia-free liver transplantation (IFLT) comprises surgical techniques to enable continuous oxygenated blood supply to brain-dead donor livers during procurement, preservation and implantation using normothermic machine perfusion technology. In this nonrandomized study, 38 donor livers were transplanted using IFLT and were compared to 130 livers procured and transplanted using a conventional procedure (CLT).RESULTSOne patient (2.6%) suffered early allograft dysfunction in the IFLT group, compared with 43.8% of patients in the CLT group (absolute risk difference, 41.2 percentage points; 95% confidence interval, −31.3, −51.1). The median (range) peak aspartate aminotransferase levels within the first week (336, 149-4112 vs. 1445, 149-25083 U/L, P<0.001), and the median (range) total bilirubin levels on day 7 (2.11, 0.68-12.47 vs. 5.11, 0.56-51.97 mg/dL, P<0.001) posttransplantation were much lower in the IFLT than in the CLT group. The IFLT recipients had less need for renal replacement therapy (2.6% vs. 16.9%, P=0.02), shorter median (range) intensive care unit stay (34, 12-235 vs. 43.5, 7-936 hours, P=0.003), and higher one-year recipient survival (97.4% vs. 84.6%, P=0.02) and graft survival (94.7% vs. 83.8%, P=0.04) rates than the CLT recipients. The extended criteria donor livers in IFLT yielded faster posttransplant recovery than the standard criteria donor livers in CLT.CONCLUSIONSIFLT provides a new approach to minimize ischemia-reperfusion injury and improve post-transplant outcomes.Clinical trial registryThis trial is registered with http://www.chictr.org.cn, number ChiCTR-OPN-17012090.

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Cold Preflush of Porcine Kidney Grafts Prior to Normothermic Machine Perfusion Aggravates Ischemia Reperfusion Injury

Scientific Reports ◽

10.1038/s41598-019-50101-7 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Gregor Fabry ◽

Benedict M. Doorschodt ◽

Tim Grzanna ◽

Peter Boor ◽

Aaron Elliott ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Warm Ischemia ◽

Total Output ◽

Machine Perfusion ◽

Buffer Solution ◽

Preservation Method ◽

Fractional Excretion Of Sodium ◽

Normothermic Machine Perfusion

Abstract Normothermic machine perfusion (NMP) of kidney grafts is a promising new preservation method to improve graft quality and clinical outcome. Routinely, kidneys are washed out of blood remnants and cooled using organ preservation solutions prior to NMP. Here we assessed the effect of cold preflush compared to direct NMP. After 30 min of warm ischemia, porcine kidneys were either preflushed with cold histidine-tryptophan-ketoglutarate solution (PFNMP group) prior to NMP or directly subjected to NMP (DNMP group) using a blood/buffer solution. NMP was performed at a perfusion pressure of 75 mmHg for 6 h. Functional parameters were assessed as well as histopathological and biochemical analyses. Renal function as expressed by creatinine clearance, fractional excretion of sodium and total output of urine was inferior in PFNMP. Urine protein and neutrophil gelatinase-associated lipocalin (NGAL) concentrations as markers for kidney damage were significantly higher in the PFNMP group. Additionally, increased osmotic nephropathy was found after PFNMP. This study demonstrated that cold preflush prior to NMP aggravates ischemia reperfusion injury in comparison to direct NMP of warm ischemia-damaged kidney grafts. With increasing use of NMP systems for kidneys and other organs, further research into graft flushing during retrieval is warranted.

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A Novel and Sensitive Approach for the Evaluation of Liver Ischemia-Reperfusion Injury After Liver Transplantation

Investigative Radiology ◽

10.1097/rli.0000000000000220 ◽

2016 ◽

Vol 51 (3) ◽

pp. 170-176 ◽

Cited By ~ 5

Author(s):

Martina Brandlhuber ◽

Marco Armbruster ◽

Blaž Zupanc ◽

Paola Coan ◽

Emmanuel Brun ◽

...

Keyword(s):

Liver Transplantation ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Liver Ischemia

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Beneficial effects of end-ischemic oxygenated machine perfusion preservation for split-liver transplantation in recovering graft function and reducing ischemia–reperfusion injury

Scientific Reports ◽

10.1038/s41598-021-01467-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Daisuke Ishii ◽

Naoto Matsuno ◽

Mikako Gochi ◽

Hiroyoshi Iwata ◽

Tatsuya Shonaka ◽

...

Keyword(s):

Liver Transplantation ◽

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Autologous Blood ◽

Graft Function ◽

Machine Perfusion ◽

Perfusion System ◽

Split Liver Transplantation ◽

Split Liver

AbstractThis study examined the efficacy of end-ischemic hypothermic oxygenated machine perfusion preservation (HOPE) using an originally developed machine perfusion system for split-liver transplantation. Porcine split-liver grafts were created via 75% liver resection after 10 min of warm ischemia. In Group 1, grafts were preserved by simple cold storage (CS) for 8 h (CS group; n = 4). In Group 2, grafts were preserved by simple CS for 6 h and end-ischemic HOPE for 2 h (HOPE group; n = 5). All grafts were evaluated using an isolated ex vivo reperfusion model with autologous blood for 2 h. Biochemical markers (aspartate aminotransferase and lactate dehydrogenase levels) were significantly better immediately after reperfusion in the HOPE group than in the CS group. Furthermore, the HOPE group had a better histological score. The levels of inflammatory cytokines (tumor necrosis factor-α, interferon-γ, interleukin-1β, and interleukin-10) were significantly lower after reperfusion in the HOPE group. Therefore, we concluded that end-ischemic HOPE for split-liver transplantation can aid in recovering the graft function and reducing ischemia–reperfusion injury. HOPE, using our originally developed machine perfusion system, is safe and can improve graft function while attenuating liver injury due to preservation.

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Pharmacologic targeting of renal ischemia-reperfusion injury using a normothermic machine perfusion platform

Scientific Reports ◽

10.1038/s41598-020-63687-0 ◽

2020 ◽

Vol 10 (1) ◽

Cited By ~ 1

Author(s):

Ahmer M. Hameed ◽

David B. Lu ◽

Heather Burns ◽

Nicole Byrne ◽

Yi Vee Chew ◽

...

Keyword(s):

Reperfusion Injury ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Renal Ischemia ◽

Machine Perfusion ◽

Renal Ischemia Reperfusion Injury ◽

Normothermic Machine Perfusion

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Inflammasome-Mediated Inflammation in Liver Ischemia-Reperfusion Injury

Cells ◽

10.3390/cells8101131 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1131 ◽

Cited By ~ 13

Author(s):

Mónica B. Jiménez-Castro ◽

María Eugenia Cornide-Petronio ◽

Jordi Gracia-Sancho ◽

Carmen Peralta

Keyword(s):

Liver Transplantation ◽

Reperfusion Injury ◽

Molecular Mechanisms ◽

Ischemia Reperfusion Injury ◽

Current Knowledge ◽

Ischemia Reperfusion ◽

Therapeutic Strategies ◽

Experimental Models ◽

Inflammasome Activation ◽

Liver Ischemia

Ischemia-reperfusion injury is an important cause of liver damage occurring during surgical procedures including hepatic resection and liver transplantation, and represents the main underlying cause of graft dysfunction and liver failure post-transplantation. To date, ischemia-reperfusion injury is an unsolved problem in clinical practice. In this context, inflammasome activation, recently described during ischemia-reperfusion injury, might be a potential therapeutic target to mitigate the clinical problems associated with liver transplantation and hepatic resections. The present review aims to summarize the current knowledge in inflammasome-mediated inflammation, describing the experimental models used to understand the molecular mechanisms of inflammasome in liver ischemia-reperfusion injury. In addition, a clear distinction between steatotic and non-steatotic livers and between warm and cold ischemia-reperfusion injury will be discussed. Finally, the most updated therapeutic strategies, as well as some of the scientific controversies in the field will be described. Such information may be useful to guide the design of better experimental models, as well as the effective therapeutic strategies in liver surgery and transplantation that can succeed in achieving its clinical application.

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