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(Lastest Advances) Reconditioning Strategies in Solid Organ Transplantation: Linking Theory to Clinical Practice

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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 (30 June 2023) | Viewed by 16607

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Dr. Daniele Dondossola

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1. Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
2. Department of HPB Surgery, Università degli Studi, Milan, Italy
Interests: machine perfusion; liver transplantation; ischemia-reperfusion injury; preclinical research

Dr. Andrea Schlegel

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Department of Surgery and Transplantation, Swiss HPB Centre, University Hospital Zurich, Zurich, Switzerland
Interests: machine perfusion; liver transplantation; ischemia-reperfusion injury; role of mitochondria

Dr. Caterina Lonati

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Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
Interests: metabolomics; nutrition; hepatology; cell metabolism; personalized medicine; ischemia/reperfusion
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Special Issue Information

Dear Colleagues,

In our field, we are daily faced with the increasing number of patients waiting for solid organ transplantation and with a higher number of donors of impaired quality, based on the evolution of donor characteristics. One key issue today appears with the impaired utilization of our donor pool. The area of organ preservation is therefore currently shifting, and new technologies are not only tested in studies, but also implemented in routine clinical practice as new standard of care for such risky donors or to bridge difficult logistical situations. The most successful and widely used perfusion technique will be the approach, which enables the use of risky donors and maintain the good post-transplant outcomes we have achieved today.

Three main concepts are currently tested in clinical studies in different western countries, where a few concepts became recently commissioned for specific donors. From in-situ preservation and evaluation techniques (e.g. normothermic regional perfusion), we have learned that an early assessment of organs at the beginning of the preservation is beneficial and a useful selection tool. The ex-situ concepts appear most beneficial for risky grafts, when the cold ischemic times prior to perfusion are short and reduce the additional ischemic injury. In contrast, hypothermic oxygenated perfusion (HOPE/D-HOPE) have been identified to improve organ quality and reduce ischemia-reperfusion injury and related complications after transplantation. All techniques, and their combinations significantly contribute to the field and the task to identify the optimal technology, particularly for smaller centers who aim to start a new perfusion program, appears not easy. A thorough understanding of underlying mechanisms of protection and injury is therefore the key to provide the best preservation for our patients and to identify the next and most important trials required to move the entire field forward.

This special issue aims therefore to present articles, which explore and critically discuss new aspects of perfusion technology. Experimental and clinical studies that report innovative approaches will increase the knowledge, particularly as translational approaches when they may serve as a link between theory and clinical practice to trigger ideas for new clinical studies with a focus on the patient needs.

Dr. Daniele Dondossola
Dr. Andrea Schlegel
Dr. Caterina Lonati
Guest Editors

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Keywords

reconditioning
machine perfusion
extended criteria donor
translational study

Published Papers (10 papers)

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20 pages, 1781 KiB

Open AccessArticle

Long and Short-Term Effects of Hypothermic Machine Perfusion vs. Cold Storage on Transplanted Kidneys from Expanded Criteria Donors—A Matched Comparison Study

by Matthias Axelsson, Per Lindnér, Nils-Gunnar Pehrsson and Seema Baid-Agrawal

J. Clin. Med. 2023, 12(17), 5531; https://doi.org/10.3390/jcm12175531 - 25 Aug 2023

Cited by 1 | Viewed by 749

Abstract

Hypothermic machine perfusion (HMP) has been shown to reduce delayed graft function (DGF)-rates in kidneys from expanded criteria donors (ECD) and may increase graft survival compared with static cold storage (SCS). This single-center, retrospective observational study aimed to evaluate this effect. The primary endpoint was the DGF-rate, defined as the use of dialysis in the first postoperative week, excluding the first 24 h. The main secondary endpoint was graft survival at 5 years. Recipients of ECD-kidneys between 2013 and 2021 with ≤2 grafts were included (n = 438). The SCS-kidneys were marginal-matched by propensity score to the HMP-group for donor age, cold ischemia time, and graft number. Multivariable adjusted analysis for confounders in the unmatched cohort and caliper-based ID-matching constituted sensitivity analyses. HMP showed a trend to lower DGF-rate in the marginal-matched comparison (9.2% vs. 16.1%, p = 0.063). This was strengthened by a significant benefit observed for HMP in both the sensitivity analyses: an adjusted OR of 0.45 (95% CI: 0.24; 0.84; p = 0.012) in the multivariable analysis and DGF-rate of 8.7% vs. 17.4% (p = 0.024) after ID-matching. The 5-year graft survival rate was >90% in both groups, with no benefit using HMP (HR = 0.79; 95% CI:0.39–1.16; p = 0.52). Our results suggest that HMP may be effective in decreasing DGF-rates, however, without any significant benefit in graft survival. Full article

(This article belongs to the Special Issue (Lastest Advances) Reconditioning Strategies in Solid Organ Transplantation: Linking Theory to Clinical Practice )

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12 pages, 744 KiB

Open AccessArticle

Impact of T Lymphocytes Isolated from Liver Perfusate of Deceased Brain Donors on Kidney Transplantation: Preliminary Evidence and Future Directions

by Duilio Pagano, Ester Badami, Giovanni Zito, Pier Giulio Conaldi, Ivan Vella, Barbara Buscemi, Giandomenico Amico, Rosalia Busà, Paola Salis, Sergio Li Petri, Fabrizio di Francesco, Sergio Calamia, Pasquale Bonsignore, Alessandro Tropea, Caterina Accardo, Salvatore Piazza and Salvatore Gruttadauria

J. Clin. Med. 2023, 12(14), 4786; https://doi.org/10.3390/jcm12144786 - 20 Jul 2023

Viewed by 1174

Abstract

Background: Ischemia/reperfusion injury (IRI), acute rejection (AR), and delayed graft function (DGF) might occur as major complications following kidney transplantation. Thus, the identification of biomarkers for the IRI, AR, and/or DGF development becomes crucial as it may help to guide post-transplant management. Natural killer (NK) cells, hepatic interstitial T-lymphocytes (T-Li), and NK-T cells are crucial in both innate and adaptive immunity after abdominal solid organ transplantation. Hence, the aim of this study was to evaluate the impact of the immune system after graft reperfusion during KT in adults in order to identify predictive biomarkers. Methods: The NK, T-Li, and NK-T phenotypes and concentrations were retrospectively analyzed in a consecutive series of liver perfusates obtained after organ procurement flushing the abdominal cavity recovered from deceased brain donors (DBDs). Their percentage was compared with the renal transplant recipients’ characteristics with kidneys taken from the same DCDs. The hepatic perfusate cells were purified by density gradient centrifugation. Flow cytometric investigation was used to determine their phenotype with the following immunological markers in order to determine the relative percentage of T-Li, NK-T, and NK cells: CD3, CD4, CD8, and CD56. Results: 42 DBDs’ liver perfusates were analyzed. The related clinical outcomes of kidney transplant recipients from 2010 to 2020 performed at our Institute were evaluated. Time in days of delayed functional recovery of transplanted kidneys (DGF) (p = 0.02) and the onset of secondary infection from a cytomegalovirus (p = 0.03) were significantly associated with the T-Li percentage. An increased relative risk (HR) of organ survival was significantly associated with the percent cell concentration of T-Li and time to DGF, on COX analysis, were (HR = 1.038, p = 0.04; and HR = 1.029, p = 0.01, respectively). None relevant clinical outcomes in kidney transplant patients were associated with the specificity of the NK and NK-T cell proportions. Conclusions: A new potential role of T-Li cells was detected in the context of hepatic perfusate from DBDs. It could detect potential impacts in organ allocation, surgical procuring techniques, and in the analysis of IRI pathophysiological events. Full article

(This article belongs to the Special Issue (Lastest Advances) Reconditioning Strategies in Solid Organ Transplantation: Linking Theory to Clinical Practice )

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16 pages, 1605 KiB

Open AccessArticle

Trends and Obstacles to Implement Dynamic Perfusion Concepts for Clinical Liver Transplantation: Results from a Global Web-Based Survey

by Alessandro Parente, Mauricio Flores Carvalho, Rebecca Panconesi, Yuri L. Boteon, Riccardo De Carlis, Philipp Dutkowski, Paolo Muiesan, Daniele Dondossola and Andrea Schlegel

J. Clin. Med. 2023, 12(11), 3765; https://doi.org/10.3390/jcm12113765 - 30 May 2023

Cited by 2 | Viewed by 1245

Abstract

Background: Organ perfusion technology is increasingly used in many countries, with a focus, however, on the Western world. This study investigates the current international trends and obstacles to the broader routine implementation of dynamic perfusion concepts in liver transplantation. Methods: A web-based anonymous survey was launched in 2021. Experts of all involved specializations from 70 centers in 34 countries were contacted, based on the published literature and experience in the field of abdominal organ perfusion. Results: Overall, 143 participants from 23 countries completed the survey. Most respondents were male (67.8%) and transplant surgeons (64.3%) working at university hospitals (67.9%). The majority had experience with organ perfusion (82%), applying mainly hypothermic machine perfusion (HMP; 38%) and other concepts. While most (94.4%) expect a higher utilization of marginal organs with machine perfusion, the majority considers HMP the best technique to reduce liver discard-rates. While most respondents (90%) believed machine perfusion should be fully commissioned, the lack of funding (34%) and knowledge (16%) as well as limited staff (19%) were the three main obstacles to a routine clinical implementation. Conclusion: Although dynamic preservation concepts are increasingly used in clinical practice, significant challenges remain. Specific financial pathways, uniform regulations, and tight collaborations among involved experts are needed to achieve wider global clinical use. Full article

(This article belongs to the Special Issue (Lastest Advances) Reconditioning Strategies in Solid Organ Transplantation: Linking Theory to Clinical Practice )

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18 pages, 21046 KiB

Open AccessArticle

Intermittent Surface Oxygenation Results in Similar Mitochondrial Protection and Maintenance of Aerobic Metabolism as Compared to Continuous Oxygenation during Hypothermic Machine Kidney Machine Perfusion

by Tom Darius, Martial Vergauwen, Louis Maistriaux, Robin Evrard, Andrea Schlegel, Matteo Mueller, Donna O’Neil, Andrew Southam, Selda Aydin, Arnaud Devresse, Martine De Meyer, Pierre Gianello, Christian Ludwig, Philipp Dutkowski and Michel Mourad

J. Clin. Med. 2023, 12(11), 3731; https://doi.org/10.3390/jcm12113731 - 29 May 2023

Cited by 2 | Viewed by 1119

Abstract

Short bubble and subsequent surface oxygenation is an innovative oxygenation technique and alternative for membrane oxygenation during hypothermic machine perfusion (HMP). The metabolic effect of the interruption of surface oxygenation for 4 h (mimicking organ transport) during HMP was compared to continuous surface and membrane oxygenation in a pig kidney ex situ preservation model. After 30 min of warm ischemia by vascular clamping, a kidney of a ±40 kg pig was procured and subsequently preserved according to one of the following groups: (1) 22-h HMP + intermittent surface oxygenation (n = 12); (2) 22-h HMP + continuous membrane oxygenation (n = 6); and (3) 22-h HMP + continuous surface oxygenation (n = 7). Brief perfusate O₂ uploading before kidney perfusion was either obtained by direct bubble (groups 1, 3) or by membrane (group 2) oxygenation. Bubble oxygenation during minimum 15 min was as efficient as membrane oxygenation in achieving supraphysiological perfusate pO₂ levels before kidney perfusion. Metabolic tissue analysis (i.e., lactate, succinate, ATP, NADH, and FMN) during and at the end of the preservation period demonstrated similar mitochondrial protection between all study groups. Short bubble and subsequent intermittent surface oxygenation of the perfusate of an HMP-kidney might be an effective and cheap preservation strategy to protect mitochondria, eliminating the need/costs of a membrane oxygenator and oxygen source during transport. Full article

(This article belongs to the Special Issue (Lastest Advances) Reconditioning Strategies in Solid Organ Transplantation: Linking Theory to Clinical Practice )

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Review

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26 pages, 2920 KiB

Open AccessReview

How to Preserve Steatotic Liver Grafts for Transplantation

by Damiano Patrono, Nicola De Stefano, Elena Vissio, Ana Lavinia Apostu, Nicoletta Petronio, Giovanni Vitelli, Giorgia Catalano, Giorgia Rizza, Silvia Catalano, Fabio Colli, Luigi Chiusa and Renato Romagnoli

J. Clin. Med. 2023, 12(12), 3982; https://doi.org/10.3390/jcm12123982 - 12 Jun 2023

Cited by 2 | Viewed by 1394

Abstract

Liver allograft steatosis is a significant risk factor for postoperative graft dysfunction and has been associated with inferior patient and graft survival, particularly in the case of moderate or severe macrovesicular steatosis. In recent years, the increasing incidence of obesity and fatty liver disease in the population has led to a higher proportion of steatotic liver grafts being used for transplantation, making the optimization of their preservation an urgent necessity. This review discusses the mechanisms behind the increased susceptibility of fatty livers to ischemia-reperfusion injury and provides an overview of the available strategies to improve their utilization for transplantation, with a focus on preclinical and clinical evidence supporting donor interventions, novel preservation solutions, and machine perfusion techniques. Full article

(This article belongs to the Special Issue (Lastest Advances) Reconditioning Strategies in Solid Organ Transplantation: Linking Theory to Clinical Practice )

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18 pages, 762 KiB

Open AccessReview

Current Evidence and Future Perspectives to Implement Continuous and End-Ischemic Use of Normothermic and Oxygenated Hypothermic Machine Perfusion in Clinical Practice

by Maxime Foguenne, Serena MacMillan, Philipp Kron, Jay Nath, Arnaud Devresse, Martine De Meyer, Mourad Michel, Sarah Hosgood and Tom Darius

J. Clin. Med. 2023, 12(9), 3207; https://doi.org/10.3390/jcm12093207 - 29 Apr 2023

Cited by 2 | Viewed by 1222

Abstract

The use of high-risk renal grafts for transplantation requires the optimization of pretransplant assessment and preservation reconditioning strategies to decrease the organ discard rate and to improve short- and long-term clinical outcomes. Active oxygenation is increasingly recognized to play a central role in dynamic preservation strategies, independent of preservation temperature, to recondition mitochondria and to restore the cellular energy profile. The oxygen-related decrease in mitochondrial succinate accumulation ameliorates the harmful effects of ischemia-reperfusion injury. The differences between normothermic and hypothermic machine perfusion with regard to organ assessment, preservation, and reconditioning, as well as the logistic and economic implications, are factors to take into consideration for implementation at a local level. Therefore, these different techniques should be considered complementary to the perfusion strategy selected depending on functional intention and resource availability. This review provides an overview of the current clinical evidence of normothermic and oxygenated hypothermic machine perfusion, either as a continuous or end-ischemic preservation strategy, and future perspectives. Full article

(This article belongs to the Special Issue (Lastest Advances) Reconditioning Strategies in Solid Organ Transplantation: Linking Theory to Clinical Practice )

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15 pages, 718 KiB

Open AccessReview

How Can Machine Perfusion Change the Paradigm of Liver Transplantation for Patients with Perihilar Cholangiocarcinoma?

by Damiano Patrono, Fabio Colli, Matteo Colangelo, Nicola De Stefano, Ana Lavinia Apostu, Elena Mazza, Silvia Catalano, Giorgia Rizza, Stefano Mirabella and Renato Romagnoli

J. Clin. Med. 2023, 12(5), 2026; https://doi.org/10.3390/jcm12052026 - 03 Mar 2023

Cited by 1 | Viewed by 1817

Abstract

Perihilar cholangiocarcinomas (pCCA) are rare yet aggressive tumors originating from the bile ducts. While surgery remains the mainstay of treatment, only a minority of patients are amenable to curative resection, and the prognosis of unresectable patients is dismal. The introduction of liver transplantation (LT) after neoadjuvant chemoradiation for unresectable pCCA in 1993 represented a major breakthrough, and it has been associated with 5-year survival rates consistently >50%. Despite these encouraging results, pCCA has remained a niche indication for LT, which is most likely due to the need for stringent candidate selection and the challenges in preoperative and surgical management. Machine perfusion (MP) has recently been reintroduced as an alternative to static cold storage to improve liver preservation from extended criteria donors. Aside from being associated with superior graft preservation, MP technology allows for the safe extension of preservation time and the testing of liver viability prior to implantation, which are characteristics that may be especially useful in the setting of LT for pCCA. This review summarizes current surgical strategies for pCCA treatment, with a focus on unmet needs that have contributed to the limited spread of LT for pCCA and how MP could be used in this setting, with a particular emphasis on the possibility of expanding the donor pool and improving transplant logistics. Full article

(This article belongs to the Special Issue (Lastest Advances) Reconditioning Strategies in Solid Organ Transplantation: Linking Theory to Clinical Practice )

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39 pages, 2765 KiB

Open AccessReview

How to Best Protect Kidneys for Transplantation—Mechanistic Target

by Sara Akalay and Sarah A. Hosgood

J. Clin. Med. 2023, 12(5), 1787; https://doi.org/10.3390/jcm12051787 - 23 Feb 2023

Cited by 2 | Viewed by 1964

Abstract

The increasing number of patients on the kidney transplant waiting list underlines the need to expand the donor pool and improve kidney graft utilization. By protecting kidney grafts adequately from the initial ischemic and subsequent reperfusion injury occurring during transplantation, both the number and quality of kidney grafts could be improved. The last few years have seen the emergence of many new technologies to abrogate ischemia–reperfusion (I/R) injury, including dynamic organ preservation through machine perfusion and organ reconditioning therapies. Although machine perfusion is gradually making the transition to clinical practice, reconditioning therapies have not yet progressed from the experimental setting, pointing towards a translational gap. In this review, we discuss the current knowledge on the biological processes implicated in I/R injury and explore the strategies and interventions that are being proposed to either prevent I/R injury, treat its deleterious consequences, or support the reparative response of the kidney. Prospects to improve the clinical translation of these therapies are discussed with a particular focus on the need to address multiple aspects of I/R injury to achieve robust and long-lasting protective effects on the kidney graft. Full article

(This article belongs to the Special Issue (Lastest Advances) Reconditioning Strategies in Solid Organ Transplantation: Linking Theory to Clinical Practice )

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10 pages, 1491 KiB

Open AccessEditor’s ChoiceReview

Introducing Machine Perfusion into Routine Clinical Practice for Liver Transplantation in the United States: The Moment Has Finally Come

by Kristopher P. Croome

J. Clin. Med. 2023, 12(3), 909; https://doi.org/10.3390/jcm12030909 - 23 Jan 2023

Cited by 11 | Viewed by 3388

Abstract

While adoption of machine perfusion technologies into clinical practice in the United States has been much slower than in Europe, recent changes in the transplant landscape as well as device availability following FDA approval have paved the way for rapid growth. Machine perfusion may provide one mechanism to maximize the utilization of potential donor liver grafts. Indeed, multiple studies have shown increased organ utilization with the implementation of technologies such as ex-situ normothermic machine perfusion (NMP), ex-situ hypothermic machine perfusion (HMP) and in-situ normothermic regional perfusion (NRP). The current review describes the history and development of machine perfusion utilization in the Unites States along with future directions. It also describes the differences in landscape between Europe and the United States and how this has shaped clinical application of these technologies. Full article

(This article belongs to the Special Issue (Lastest Advances) Reconditioning Strategies in Solid Organ Transplantation: Linking Theory to Clinical Practice )

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Other

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18 pages, 3657 KiB

Open AccessSystematic Review

Outcomes of Kidney Perfusion Techniques in Transplantation from Deceased Donors: A Systematic Review and Meta-Analysis

by Ahmed S. Ghoneima, Richard X. Sousa Da Silva, Martina A. Gosteli, Adam D. Barlow and Philipp Kron

J. Clin. Med. 2023, 12(12), 3871; https://doi.org/10.3390/jcm12123871 - 06 Jun 2023

Cited by 4 | Viewed by 1446

Abstract

The high demand for organs in kidney transplantation and the expansion of the donor pool have led to the widespread implementation of machine perfusion technologies. In this study, we aim to provide an up-to-date systematic review of the developments in this expanding field over the past 10 years, with the aim of answering the question: “which perfusion technique is the most promising technique in kidney transplantation?” A systematic review of the literature related to machine perfusion in kidney transplantation was performed. The primary outcome measure was delayed graft function (DGF), and secondary outcomes included rates of rejection, graft survival, and patient survival rates after 1 year. Based on the available data, a meta-analysis was performed. The results were compared with data from static cold storage, which is still the standard of care in many centers worldwide. A total of 56 studies conducted in humans were included, and 43 studies reported outcomes of hypothermic machine perfusion (HMP), with a DGF rate of 26.4%. A meta-analysis of 16 studies showed significantly lower DGF rates in the HMP group compared to those of static cold storage (SCS). Five studies reported outcomes of hypothermic machine perfusion + O₂, with an overall DGF rate of 29.7%. Two studies explored normothermic machine perfusion (NMP). These were pilot studies, designed to assess the feasibility of this perfusion approach in the clinical setting. Six studies reported outcomes of normothermic regional perfusion (NRP). The overall incidence of DGF was 71.5%, as it was primarily used in uncontrolled DCD (Maastricht category I-II). Three studies comparing NRP to in situ cold perfusion showed a significantly lower rate of DGF with NRP. The systematic review and meta-analysis provide evidence that dynamic preservation strategies can improve outcomes following kidney transplantation. More recent approaches such as normothermic machine perfusion and hypothermic machine perfusion + O₂ do show promising results but need further results from the clinical setting. This study shows that the implementation of perfusion strategies could play an important role in safely expanding the donor pool. Full article

(This article belongs to the Special Issue (Lastest Advances) Reconditioning Strategies in Solid Organ Transplantation: Linking Theory to Clinical Practice )

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