The innovation and clinical application of ischemia-free organ transplantation

The incidence rate of liver cancer is increasing year by year globally. Liver transplantation has become one of the therapeutic methods for patients with liver cancer. In the past, ischemia-reperfusion injury (IRI) was unavoidable in liver transplantation, compromising recipient and graft survival. At the same time, the imbalance between the supply and demand of organs limits the use of transplantation in patients with liver cancer. Recently, advances have been made in machine perfusion techniques to reduce graft IRI. However, none of the techniques can completely abrogate graft IRI. In 2017, the concept of ischemia-free organ transplantation (IFOT) was proposed, and our group conducted the first case of ischemia-free liver transplantation (IFLT). We then extended the concept of IFOT to kidney transplantation in 2018 and to heart transplantation in 2021. Here, we review the history, strengths, and weaknesses, and the future direction of IFOT, particularly in patients with liver cancers.

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Extracellular RNA, a Potential Drug Target for Alleviating Atherosclerosis, Ischemia/Reperfusion Injury and Organ Transplantation

Current Pharmaceutical Biotechnology ◽

10.2174/1389201020666190102150610 ◽

2019 ◽

Vol 19 (15) ◽

pp. 1189-1195 ◽

Cited By ~ 3

Author(s):

Anna-Kristina Kluever ◽

Elisabeth Deindl

Keyword(s):

Reperfusion Injury ◽

Organ Transplantation ◽

Drug Target ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Potential Drug Target ◽

Potential Drug ◽

Extracellular Rna

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Ischemic Preconditioning for Liver Transplantation: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Visceral Medicine ◽

10.1159/000516608 ◽

2021 ◽

pp. 1-8

Author(s):

Lina Jakubauskiene ◽

Matas Jakubauskas ◽

Philipp Stiegler ◽

Bettina Leber ◽

Peter Schemmer ◽

...

Keyword(s):

Liver Transplantation ◽

Mortality Rate ◽

Randomized Controlled Trials ◽

Ischemic Preconditioning ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Meta Analysis ◽

Graft Loss ◽

Controlled Trials ◽

Randomized Controlled

Background: In recent decades, liver transplantation (LTx) has increased the survival and quality of life of patients with end-stage organ failure. Unfortunately, LTx is limited due to the shortage of donors. A lot of effort is put into finding new ways to reduce ischemia-reperfusion injury (IRI) in liver grafts to increase the number of suitable organs procured from expanded-criteria donors (ECD). The aim of this study was to systematically review the literature reporting LTx outcomes when using ischemic preconditioning (IPC) or remote ischemic preconditioning (RIPC) to reduce IRI in liver grafts. Methods: A literature search was performed in the MEDLINE, Web of Science, and EMBASE databases. The following combination was used: “Liver” OR “Liver Transplantation” AND “Ischemic preconditioning” OR “occlusion” OR “clamping” OR “Pringle.” The following outcome data were retrieved: the rates of graft primary nonfunction (PNF), retransplantation, graft loss, and mortality; stay in hospital and the intensive care unit; and postoperative serum liver damage parameters. Results: The initial search retrieved 4,522 potentially relevant studies. After evaluating 17 full-text articles, a total of 9 randomized controlled trials (RCTs) were included (7 IPC and 2 RIPC studies) in the qualitative synthesis; the meta-analysis was only performed on the data from the IPC studies. RIPC studies had considerable methodological differences. The meta-analysis revealed the beneficial effect of IPC when comparing postoperative aspartate aminotransferase (AST) corresponding to a statistically lower mortality rate in the IPC group (odds ratio [OR] 0.51; 95% confidence interval [CI] 0.27–0.98; p = 0.04). Conclusion: IPC lowers postoperative AST levels and reduces the mortality rate; however, data on the benefits of RIPC are lacking.

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Impact of Three Methods of Ischemic Preconditioning on Ischemia-Reperfusion Injury in a Pig Model of Liver Transplantation

Journal of Investigative Surgery ◽

10.1080/08941939.2021.1933274 ◽

2021 ◽

pp. 1-10

Author(s):

Alessandro Rodrigo Belon ◽

Ana Cristina Aoun Tannuri ◽

Daniel de Albuquerque Rangel Moreira ◽

Jose Luiz Figueiredo ◽

Alessandra Matheus da Silva ◽

...

Keyword(s):

Liver Transplantation ◽

Reperfusion Injury ◽

Ischemic Preconditioning ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Pig Model

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Monocytic MDSC mobilization promotes tumor recurrence after liver transplantation via CXCL10/TLR4/MMP14 signaling

Cell Death and Disease ◽

10.1038/s41419-021-03788-4 ◽

2021 ◽

Vol 12 (5) ◽

Author(s):

Hui Liu ◽

Chang Chun Ling ◽

Wai Ho Oscar Yeung ◽

Li Pang ◽

Jiang Liu ◽

...

Keyword(s):

Liver Transplantation ◽

Tumor Recurrence ◽

Ischemia Reperfusion Injury ◽

Therapeutic Potential ◽

Ischemia Reperfusion ◽

Weight Ratio ◽

Liver Graft ◽

Mouse Tumor ◽

Hepatic Ischemia ◽

Tlr4 Signaling

AbstractTumor recurrence is the major obstacle for pushing the envelope of liver transplantation for hepatocellular carcinoma (HCC) patients. The inflammatory cascades activated by acute liver graft injury promote tumor recurrence. We aimed to explore the role and mechanism of myeloid-derived suppressor cell (MDSC) mobilization induced by liver graft injury on tumor recurrence. By analyzing 331 HCC patients who received liver transplantation, the patients with graft weight ratio (GWR, the weight of liver graft divided by the estimated standard liver weight of recipient) <60% had higher tumor recurrence than GWR ≥60% ones. MDSCs and CXCL10/TLR4 levels were significantly increased in patients with GWR <60% or tumor recurrence. These findings were further validated in our rat orthotopic liver transplantation model. In CXCL10−/− and TLR4−/− mice of hepatic ischemia/reperfusion injury plus major hepatectomy (IRH) model, monocytic MDSCs, instead of granulocytic MDSCs, were significantly decreased. Importantly, CXCL10 deficiency reduced the accumulation of TLR4+ monocytic MDSCs, and CXCL10 increased MDSC mobilization in the presence of TLR4. Moreover, MMP14 was identified as the key molecule bridging CXCL10/TLR4 signaling and MDSC mobilization. Knockout or inhibition of CXCL10/TLR4 signaling significantly reduced the tumor growth with decreased monocytic MDSCs and MMP14 in the mouse tumor recurrent model. Our data indicated that monocytic MDSCs were mobilized and recruited to liver graft during acute phase injury, and to promote HCC recurrence after transplantation. Targeting MDSC mobilization via CXCL10/TLR4/MMP14 signaling may represent the therapeutic potential in decreasing post-transplant liver tumor recurrence.

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Carbon monoxide protects the kidney through the central circadian clock and CD39

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1716747115 ◽

2018 ◽

Vol 115 (10) ◽

pp. E2302-E2310 ◽

Cited By ~ 18

Author(s):

Matheus Correa-Costa ◽

David Gallo ◽

Eva Csizmadia ◽

Edward Gomperts ◽

Judith-Lisa Lieberum ◽

...

Keyword(s):

Carbon Monoxide ◽

Circadian Rhythm ◽

Organ Transplantation ◽

Ischemia Reperfusion Injury ◽

Purinergic Signaling ◽

Ischemia Reperfusion ◽

Neutralizing Antibody ◽

Fold Increase ◽

Signaling Mechanism ◽

Tissue Recovery

Ischemia reperfusion injury (IRI) is the predominant tissue insult associated with organ transplantation. Treatment with carbon monoxide (CO) modulates the innate immune response associated with IRI and accelerates tissue recovery. The mechanism has been primarily descriptive and ascribed to the ability of CO to influence inflammation, cell death, and repair. In a model of bilateral kidney IRI in mice, we elucidate an intricate relationship between CO and purinergic signaling involving increased CD39 ectonucleotidase expression, decreased expression of Adora1, with concomitant increased expression of Adora2a/2b. This response is linked to a >20-fold increase in expression of the circadian rhythm protein Period 2 (Per2) and a fivefold increase in serum erythropoietin (EPO), both of which contribute to abrogation of kidney IRI. CO is ineffective against IRI in Cd39−/− and Per2−/− mice or in the presence of a neutralizing antibody to EPO. Collectively, these data elucidate a cellular signaling mechanism whereby CO modulates purinergic responses and circadian rhythm to protect against injury. Moreover, these effects involve CD39- and adenosinergic-dependent stabilization of Per2. As CO also increases serum EPO levels in human volunteers, these findings continue to support therapeutic use of CO to treat IRI in association with organ transplantation, stroke, and myocardial infarction.

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Potential benefits of melatonin in organ transplantation: a review

Journal of Endocrinology ◽

10.1530/joe-16-0117 ◽

2016 ◽

Vol 229 (3) ◽

pp. R129-R146 ◽

Cited By ~ 16

Author(s):

Eduardo Esteban-Zubero ◽

Francisco Agustín García-Gil ◽

Laura López-Pingarrón ◽

Moisés Alejandro Alatorre-Jiménez ◽

Pablo Iñigo-Gil ◽

...

Keyword(s):

Free Radical ◽

Organ Transplantation ◽

Graft Rejection ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Antioxidant Defense System ◽

Free Radical Scavenger ◽

Radical Scavenger ◽

Therapeutic Tool ◽

Term Survival

Organ transplantation is a useful therapeutic tool for patients with end-stage organ failure; however, graft rejection is a major obstacle in terms of a successful treatment. Rejection is usually a consequence of a complex immunological and nonimmunological antigen-independent cascade of events, including free radical-mediated ischemia-reperfusion injury (IRI). To reduce the frequency of this outcome, continuing improvements in the efficacy of antirejection drugs are a top priority to enhance the long-term survival of transplant recipients. Melatonin (N-acetyl-5-methoxytryptamine) is a powerful antioxidant and ant-inflammatory agent synthesized from the essential amino acid l-tryptophan; it is produced by the pineal gland as well as by many other organs including ovary, testes, bone marrow, gut, placenta, and liver. Melatonin has proven to be a potentially useful therapeutic tool in the reduction of graft rejection. Its benefits are based on its direct actions as a free radical scavenger as well as its indirect antioxidative actions in the stimulation of the cellular antioxidant defense system. Moreover, it has significant anti-inflammatory activity. Melatonin has been found to improve the beneficial effects of preservation fluids when they are enriched with the indoleamine. This article reviews the experimental evidence that melatonin is useful in reducing graft failure, especially in cardiac, bone, otolaryngology, ovarian, testicular, lung, pancreas, kidney, and liver transplantation.

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