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Machine Perfusion and Its Effects on Ischemia-Reperfusion Injury in the Era of Organ Shortage in Solid Organ Transplantation

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Gastroenterology & Hepatopancreatobiliary Medicine".

Deadline for manuscript submissions: closed (28 February 2020) | Viewed by 31374

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Dr. Georg Lurje

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Department of Surgery and Transplantation, University Hospital RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany
Interests: machine perfusion; solid organ transplantation; normothermic; hypothermic

Special Issue Information

Dear Colleagues,

In the face of a critical organ shortage in the Western world, various strategies are employed to expand the donor pool for orthotopic liver transplantation (OLT). Among them is the transplantation of organs from extended criteria donors, a valuable source of liver allografts, however, characterized by potential risks for post-OLT complications and inferior outcomes. In recent years, machine perfusion (MP) of the explanted donor liver as well as regional perfusion techniques has witnessed significant advancements. Here, we aim to discuss different modes of dynamic organ preservation in OLT. These include hypothermic and normothermic MP, hypothermic oxygenated machine perfusion (HOPE), controlled oxygenated rewarming as well as regional perfusion protocols. Over recent years, multiple feasibility trials have demonstrated the clinical prospects of MP. In the context of OLT using organs from extended criteria donors, MP has numerous advantages compared to conventional cold storage, some of which include the preservation and reconditioning of borderline transplantable organs and the viability assessment of high-risk donor allografts. This Special Issue aims to address the topic of liver allograft MP, highlighting particularly the current trends in clinical applications and future perspectives.

Dr. Georg Lurje
Guest Editor

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Keywords

Machine perfusion
Ischemia
Reperfusion
Organ shortage
Liver transplantation
Liver allograft

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Published Papers (6 papers)

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Research

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11 pages, 2420 KiB

Open AccessArticle

Split-Liver Ex Situ Machine Perfusion: A Novel Technique for Studying Organ Preservation and Therapeutic Interventions

by Viola Huang, Negin Karimian, Danielle Detelich, Siavash Raigani, Sharon Geerts, Irene Beijert, Fermin M. Fontan, Mohamed M. Aburawi, Sinan Ozer, Peony Banik, Florence Lin, Murat Karabacak, Ehab O.A. Hafiz, Robert J. Porte, Korkut Uygun, James F. Markmann and Heidi Yeh

J. Clin. Med. 2020, 9(1), 269; https://doi.org/10.3390/jcm9010269 - 18 Jan 2020

Cited by 20 | Viewed by 4221

Abstract

Ex situ machine perfusion is a promising technology to help improve organ viability prior to transplantation. However, preclinical studies using discarded human livers to evaluate therapeutic interventions and optimize perfusion conditions are limited by significant graft heterogeneity. In order to improve the efficacy and reproducibility of future studies, a split-liver perfusion model was developed to allow simultaneous perfusion of left and right lobes, allowing one lobe to serve as a control for the other. Eleven discarded livers were surgically split, and both lobes perfused simultaneously on separate perfusion devices for 3 h at subnormothermic temperatures. Lobar perfusion parameters were also compared with whole livers undergoing perfusion. Similar to whole-liver perfusions, each lobe in the split-liver model exhibited a progressive decrease in arterial resistance and lactate levels throughout perfusion, which were not significantly different between right and left lobes. Split liver lobes also demonstrated comparable energy charge ratios. Ex situ split-liver perfusion is a novel experimental model that allows each graft to act as its own control. This model is particularly well suited for preclinical studies by avoiding the need for large numbers of enrolled livers necessary due to the heterogenous nature of discarded human liver research. Full article

(This article belongs to the Special Issue Machine Perfusion and Its Effects on Ischemia-Reperfusion Injury in the Era of Organ Shortage in Solid Organ Transplantation)

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16 pages, 3318 KiB

Open AccessArticle

A Dual Protective Effect of Intestinal Remote Ischemic Conditioning in a Rat Model of Total Hepatic Ischemia

by Zoltan Czigany, Koichiro Hata, Wei Lai, Timo Schwandt, Yuzo Yamamoto, Shinji Uemoto and Rene H. Tolba

J. Clin. Med. 2019, 8(10), 1546; https://doi.org/10.3390/jcm8101546 - 26 Sep 2019

Cited by 13 | Viewed by 3386

Abstract

The present study aimed to investigate the effects of intestinal remote ischemic preconditioning (iRIC) on ischemia-reperfusion injury (IRI) and gut barrier integrity in a rat model of total hepatic ischemia (THI). Male Wistar rats (n = 50; 250–300 g) were randomly allocated into two experimental groups: RIC/Control. Thirty minutes of THI was induced by clamping the hepatoduodenal ligament. iRIC was applied as 4-min of ischemia followed by 11-min of reperfusion by clamping the superior mesenteric artery. Animals were sacrificed at 1, 2, 6, 24 h post-reperfusion (n = 5/group/timepoint). RIC of the gut significantly improved microcirculation of the ileum and the liver. Tissue ATP-levels were higher following iRIC (Liver: 1.34 ± 0.12 vs. 0.97 ± 0.20 μmol/g, p = 0.04) and hepatocellular injury was reduced significantly (ALT: 2409 ± 447 vs. 6613 ± 1117 IU/L, p = 0.003). Systemic- and portal venous IL-6 and TNF-alpha levels were markedly lower following iRIC, demonstrating a reduced inflammatory response. iRIC led to a structural and functional preservation of the intestinal barrier. These results suggest that iRIC might confer a potent protection against the detrimental effects of THI in rats via reducing IRI and systemic inflammatory responses and at the same time by mitigating the dramatic consequences of severe intestinal congestion and bacterial translocation. Full article

(This article belongs to the Special Issue Machine Perfusion and Its Effects on Ischemia-Reperfusion Injury in the Era of Organ Shortage in Solid Organ Transplantation)

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Review

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15 pages, 1103 KiB

Open AccessReview

Normothermic Machine Perfusion (NMP) of the Liver as a Platform for Therapeutic Interventions during Ex-Vivo Liver Preservation: A Review

by Fungai Dengu, Syed Hussain Abbas, Georg Ebeling and David Nasralla

J. Clin. Med. 2020, 9(4), 1046; https://doi.org/10.3390/jcm9041046 - 7 Apr 2020

Cited by 52 | Viewed by 5765

Abstract

Liver transplantation is increasingly dependent on the use of extended criteria donors (ECD) to increase the organ donor pool and address rising demand. This has necessitated the adoption of innovative technologies and strategies to protect these higher-risk grafts from the deleterious effects of traditional preservation and ischaemia reperfusion injury (IRI). The advent of normothermic machine perfusion (NMP) and rapid growth in the clinical adoption of this technology has accelerated efforts to utilise NMP as a platform for therapeutic intervention to optimise donor livers. In this review we will explore the emerging preclinical data related to ameliorating the effects of IRI, protecting the microcirculation and reducing the immunogenicity of donor organs during NMP. Exploiting the window of opportunity afforded by NMP, whereby the liver can be continuously supported and functionally assessed while therapies are directly delivered during the preservation period, has clear logistical and theoretical advantages over current preservation methods. The clinical translation of many of the therapeutic agents and strategies we will describe is becoming more feasible with widespread adaptation of NMP devices and rapid advances in molecular biology and gene therapy, which have substantially improved the performance of these agents. The delivery of novel therapeutics during NMP represents one of the new frontiers in transplantation research and offers real potential for successfully tackling fundamental challenges in transplantation such as IRI. Full article

(This article belongs to the Special Issue Machine Perfusion and Its Effects on Ischemia-Reperfusion Injury in the Era of Organ Shortage in Solid Organ Transplantation)

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19 pages, 529 KiB

Open AccessReview

Kidney Perfusion as an Organ Quality Assessment Tool—Are We Counting Our Chickens Before They Have Hatched?

by Julie De Beule and Ina Jochmans

J. Clin. Med. 2020, 9(3), 879; https://doi.org/10.3390/jcm9030879 - 23 Mar 2020

Cited by 40 | Viewed by 5073

Abstract

The final decision to accept an organ for transplantation remains a subjective one. With “poor organ quality” commonly cited as a major reason for kidney discard, accurate, objective, and reliable quality assessment is essential. In an era of increasingly higher-risk deceased donor kidneys, the catch is to accept those where the risk–benefit scale will tip in the right direction. Currently available assessment tools, such as risk-scores predicting outcome and zero-time biopsy, perform unsatisfactory, and assessment options during static cold storage are limited. Kidney perfusion technologies are finding their way into clinical practice, and they bring a new opportunity to assess kidney graft viability and quality, both in hypothermic and normothermic conditions. We give an overview of the current understanding of kidney viability assessment during ex situ kidney perfusion. A pragmatic framework to approach viability assessment is proposed as an interplay of three different compartments: the nephron, the vascular compartment, and the immune compartment. Although many interesting ways to assess kidney injury and function during perfusion have been proposed, none have reached the stage where they can reliably predict posttransplant outcome. Larger well-designed studies and validation cohorts are needed to provide better guidance. Full article

(This article belongs to the Special Issue Machine Perfusion and Its Effects on Ischemia-Reperfusion Injury in the Era of Organ Shortage in Solid Organ Transplantation)

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18 pages, 2132 KiB

Open AccessReview

Ischemia-Reperfusion Injury in Marginal Liver Grafts and the Role of Hypothermic Machine Perfusion: Molecular Mechanisms and Clinical Implications

by Zoltan Czigany, Isabella Lurje, Moritz Schmelzle, Wenzel Schöning, Robert Öllinger, Nathanael Raschzok, Igor M. Sauer, Frank Tacke, Pavel Strnad, Christian Trautwein, Ulf Peter Neumann, Jiri Fronek, Arianeb Mehrabi, Johann Pratschke, Andrea Schlegel and Georg Lurje

J. Clin. Med. 2020, 9(3), 846; https://doi.org/10.3390/jcm9030846 - 20 Mar 2020

Cited by 84 | Viewed by 7097

Abstract

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. Full article

(This article belongs to the Special Issue Machine Perfusion and Its Effects on Ischemia-Reperfusion Injury in the Era of Organ Shortage in Solid Organ Transplantation)

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25 pages, 1182 KiB

Open AccessReview

The Effect of Preservation Temperature on Liver, Kidney, and Pancreas Tissue ATP in Animal and Preclinical Human Models

by Maria Irene Bellini, Janice Yiu, Mikhail Nozdrin and Vassilios Papalois

J. Clin. Med. 2019, 8(9), 1421; https://doi.org/10.3390/jcm8091421 - 9 Sep 2019

Cited by 35 | Viewed by 5108

Abstract

The recent advances in machine perfusion (MP) technology involve settings ranging between hypothermic, subnormothermic, and normothermic temperatures. Tissue level adenosine triphosphate (ATP) is a long-established marker of viability and functionality and is universal for all organs. In the midst of a growing number of complex clinical parameters for the quality assessment of graft prior to transplantation, a revisit of ATP may shed light on the underlying reconditioning mechanisms of different perfusion temperatures in the form of restoration of metabolic and energy status. This article aims to review and critically analyse animal and preclinical human studies (discarded grafts) during MP of three abdominal organs (liver, kidney, and pancreas) in which ATP was a primary endpoint. A selective review of recent novel reconditioning approaches relevant to mitigation of graft ischaemia-reperfusion injury via MP and for different perfusion temperatures was also conducted. With a current reiterated interest for oxygenation during MP, a re-introduction of tissue ATP levels may be valuable for graft viability assessment prior to transplantation. Further studies may help delineate the benefits of selective perfusion temperatures on organs viability. Full article

(This article belongs to the Special Issue Machine Perfusion and Its Effects on Ischemia-Reperfusion Injury in the Era of Organ Shortage in Solid Organ Transplantation)

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