Hypothermic oxygenated perfusion in extended criteria donor liver transplantation—A randomized clinical trial

Hypothermic machine perfusion (HMP) has become the new gold standard in clinical donor kidney preservation and a promising novel strategy in higher risk donor livers in several countries. As shown by meta-analysis for the kidney, HMP decreases the risk of delayed graft function (DGF) and improves graft survival. For the liver, HMP immediately prior to transplantation may reduce the chance of early allograft dysfunction (EAD) and reduce ischemic sequelae in the biliary tract. Ischemia-reperfusion injury (IRI), unavoidable during transplantation, can lead to massive cell death and is one of the main causes for DGF, EAD or longer term impact. Molecular mechanisms that are affected in IRI include levels of hypoxia inducible factor (HIF), induction of cell death, endothelial dysfunction and immune responses. In this review we have summarized and discussed mechanisms on how HMP can ameliorate IRI. Better insight into how HMP influences IRI in kidney and liver transplantation may lead to new therapies and improved transplant outcomes.

/pdf/the-effect-of-hypothermic-machine-perfusion-to-ameliorate-2ww3m0jy.pdf

The Effect of Hypothermic Machine Perfusion to Ameliorate Ischemia-Reperfusion Injury in Donor Organs

Long-time ischemia worsening transplant outcomes in vascularized composite allotransplantation (VCA) is often neglected. Ischemia-reperfusion injury (IRI) is an inevitable event that follows reperfusion after a period of cold static storage. The pathophysiological mechanism activates local inflammation, which is a barrier to allograft long-term immune tolerance. The previous publications have not clearly described the relationship between the tissue damage and ischemia time, nor the rejection grade. In this review, we found that the rejection episodes and rejection grade are usually related to the ischemia time, both in clinical and experimental aspects. Moreover, we summarized the potential therapeutic measures to mitigate the ischemia-reperfusion injury. Compare to static preservation, machine perfusion is a promising method that can keep VCA tissue viability and extend preservation time, which is especially beneficial for the expansion of the donor pool and better MHC-matching.

https://www.frontiersin.org/articles/10.3389/fimmu.2022.998952/pdf

Improving the ischemia-reperfusion injury in vascularized composite allotransplantation: Clinical experience and experimental implications

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.

/pdf/outcomes-of-kidney-perfusion-techniques-in-transplantation-2udhfvab.pdf

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

The use of high-risk renal grafts for transplantation requires optimization of pretransplant preservation and assessment strategies to improve clinical outcomes as well as to decrease organ discard rate. With oxygenation proposed as a resuscitative measure during hypothermic machine preservation, this review provides a critical overview of the fundamentals of active oxygenation during hypothermic machine perfusion, as well as the current preclinical and clinical evidence and suggests different strategies for clinical implementation.

https://www.mdpi.com/2227-9059/9/8/993/pdf

Simply Adding Oxygen during Hypothermic Machine Perfusion to Combat the Negative Effects of Ischemia-Reperfusion Injury: Fundamentals and Current Evidence for Kidneys

Importance Continuous hypothermic machine perfusion during organ preservation has a beneficial effect on graft function and survival in kidney transplant when compared with static cold storage (SCS). Objective To compare the effect of short-term oxygenated hypothermic machine perfusion preservation (end-HMPo2) after SCS vs SCS alone on 1-year graft survival in expanded criteria donor kidneys from donors who are brain dead. Design, Setting, and Participants In a prospective, randomized, multicenter trial, kidneys from expanded criteria donors were randomized to either SCS alone or SCS followed by end-HMPo2prior to implantation with a minimum machine perfusion time of 120 minutes. Kidneys were randomized between January 2015 and May 2018, and analysis began May 2019. Analysis was intention to treat. Interventions On randomization and before implantation, deceased donor kidneys were either kept on SCS or placed on HMPo2. Main Outcome and Measures Primary end point was 1-year graft survival, with delayed graft function, primary nonfunction, acute rejection, estimated glomerular filtration rate, and patient survival as secondary end points. Results Centers in 5 European countries randomized 305 kidneys (median [range] donor age, 64 [50-84] years), of which 262 kidneys (127 [48.5%] in the end-HMPo2group vs 135 [51.5%] in the SCS group) were successfully transplanted. Median (range) cold ischemia time was 13.2 (5.1-28.7) hours in the end-HMPo2group and 12.9 (4-29.2) hours in the SCS group; median (range) duration in the end-HMPo2group was 4.7 (0.8-17.1) hours. One-year graft survival was 92.1% (n = 117) in the end-HMPo2group vs 93.3% (n = 126) in the SCS group (95% CI, −7.5 to 5.1;P = .71). The secondary end point analysis showed no significant between-group differences for delayed graft function, primary nonfunction, estimated glomerular filtration rate, and acute rejection. Conclusions and Relevance Reconditioning of expanded criteria donor kidneys from donors who are brain dead using end-HMPo2after SCS does not improve graft survival or function compared with SCS alone. This study is underpowered owing to the high overall graft survival rate, limiting interpretation. Trial Registration isrctn.org Identifier:ISRCTN63852508

/pdf/oxygenated-end-hypothermic-machine-perfusion-in-expanded-1biqm8srm3.pdf

Oxygenated End-Hypothermic Machine Perfusion in Expanded Criteria Donor Kidney Transplant: A Randomized Clinical Trial

Steroid pretreatment of deceased donors and liver allograft function - Ten years follow-up of a blinded randomized placebo controlled trial.

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Oxygenated End-Hypothermic Machine Perfusion in Expanded Criteria Donor Kidney Transplant: A Randomized Clinical Trial

Steroid pretreatment of deceased donors and liver allograft function - Ten years follow-up of a blinded randomized placebo controlled trial.