Impacts of the COVID-19 Pandemic on a Human Research Islet Program

Designated a pandemic in March 2020, the spread of severe acute respiratory syndrome virus 2 (SARS-CoV2), the virus responsible for coronavirus disease 2019 (COVID-19), led to new guidelines and restrictions being implemented for individuals, businesses, and societies in efforts to limit the impacts of COVID-19 on personal health and healthcare systems. Here we report the impacts of the COVID-19 pandemic on pancreas processing and islet isolation/distribution outcomes at the Alberta Diabetes Institute IsletCore, a facility specialising in the processing and distribution of human pancreatic islets for research. While the number of organs processed was significantly reduced, organ quality and the function of cellular outputs were minimally impacted during the pandemic when compared to an equivalent period immediately prior. Despite the maintained quality of isolated islets, recipient groups reported poorer feedback regarding the samples. Our findings suggest this is likely due to disrupted distribution which led to increased transit times to recipient labs, particularly those overseas. Thus, to improve overall outcomes in a climate of limited research islet supply, prioritization of tissue recipients based on likely tissue transit times may be needed.

Advances in Hypothermic and Normothermic Perfusion in Kidney Transplantation

Hypothermic and normothermic machine perfusion in kidney transplantation are purported to exert a beneficial effect on post-transplant outcomes compared to the traditionally used method of static cold storage. Kidney perfusion techniques provide a window for organ reconditioning and quality assessment. However, how best to deliver these preservation methods or improve organ quality has not yet been conclusively defined. This review summarises the promising advances in machine perfusion science in recent years, which have the potential to further improve early graft function and prolong graft survival.

Effect of Aprotinin on Liver Injury after Transplantation of Extended Criteria Donor Grafts in Humans: A Retrospective Propensity Score Matched Cohort Analysis

The number of patients awaiting liver transplantation still widely exceeds the number of donated organs available. Patients receiving extended criteria donor (ECD) organs are especially prone to an aggravated ischemia reperfusion syndrome during liver transplantation leading to massive hemodynamic stress and possible impairment in organ function. Previous studies have demonstrated aprotinin to ameliorate reperfusion injury and early graft survival. In this single center retrospective analysis of 84 propensity score matched patients out of 274 liver transplantation patients between 2010 and 2014 (OLT), we describe the association of aprotinin with postreperfusion syndrome (PRS), early allograft dysfunction (EAD: INR 1,6, AST/ALT > 2000 within 7–10 days) and recipient survival. The incidence of PRS (52.4% vs. 47.6%) and 30-day mortality did not differ (4.8 vs. 0%; p = 0.152) but patients treated with aprotinin suffered more often from EAD (64.3% vs. 40.5%, p = 0.029) compared to controls. Acceptable or poor (OR = 3.3, p = 0.035; OR = 9.5, p = 0.003) organ quality were independent predictors of EAD. Our data do not support the notion that aprotinin prevents nor attenuates PRS, EAD or mortality.

Machine Perfusion in Liver Transplantation: A Systematic Review and Meta-Analysis

<b><i>Background:</i></b> Liver transplantation (LTx) is the only treatment option for patients with end-stage liver disease. Novel organ preservation techniques such as hypothermic machine perfusion (HMP) or normothermic machine perfusion (NMP) are under investigation in order to improve organ quality from extended criteria donors and donors after circulatory death. The aim of this study was to systematically review the literature reporting LTx outcomes using NMP or HMP compared to static cold storage (SCS). <b><i>Methods:</i></b> The following data were retrieved: graft primary nonfunction rate, early allograft dysfunction (EAD) rate, biliary complication rate, and 12-month graft and patient survival. A total of 15 studies were included (6 NMP and 9 HMP studies), and meta-analysis was performed only for HMP studies because NMP had considerable differences. <b><i>Results:</i></b> The systematic review showed the potential of NMP to reduce graft injury and lower the liver graft discard rate. The performed quantitative analyses showed that the use of HMP reduces the rate of EAD (odds ratio [OR] 0.51; 95% confidence interval [CI] 0.34–0.76; <i>p</i> = 0.001; <i>I</i>² = 0%) and non-anastomotic biliary strictures (OR 0.34; 95% CI 0.17–0.67; <i>p</i> = 0.002; <i>I</i>² = 0%) compared to SCS. <b><i>Conclusion:</i></b> Our systematic review and meta-analysis revealed that the use of HMP reduces the rate of EAD and non-anastomotic biliary strictures compared to SCS.

Persufflation—Current State of Play

With the ever-increasing disparity between the number of patients waiting for organ transplants and the number organs available, some patients are unable to receive life-saving transplantation in time. The present, widely-used form of preservation is proving to be incapable of maintaining organ quality during long periods of preservation and meeting the needs of an ever-changing legislative and transplantation landscape. This has led to the need for improved preservation techniques. One such technique that has been extensively researched is gaseous oxygen perfusion or Persufflation (PSF). This method discovered in the early 20th century has shown promise in providing both longer term preservation and organ reconditioning capabilities for multiple organs including the liver, kidneys, and pancreas. PSF utilises the organs own vascular network to provide oxygen to the organ tissue and maintain metabolism during preservation to avoid hypoxic damage. This review delves into the history of this technique, its multiple different approaches and uses, as well as in-depth discussion of work published in the past 15 years. Finally, we discuss exciting commercial developments which may help unlock the potential for this technique to be applied at scale.

Lung Transplantation, Pulmonary Endothelial Inflammation, and Ex-Situ Lung Perfusion: A Review

Lung transplantation (LTx) is the gold standard treatment for end-stage lung disease; however, waitlist mortality remains high due to a shortage of suitable donor lungs. Organ quality can be compromised by lung ischemic reperfusion injury (LIRI). LIRI causes pulmonary endothelial inflammation and may lead to primary graft dysfunction (PGD). PGD is a significant cause of morbidity and mortality post-LTx. Research into preservation strategies that decrease the risk of LIRI and PGD is needed, and ex-situ lung perfusion (ESLP) is the foremost technological advancement in this field. This review addresses three major topics in the field of LTx: first, we review the clinical manifestation of LIRI post-LTx; second, we discuss the pathophysiology of LIRI that leads to pulmonary endothelial inflammation and PGD; and third, we present the role of ESLP as a therapeutic vehicle to mitigate this physiologic insult, increase the rates of donor organ utilization, and improve patient outcomes.

Ex Vivo Mesenchymal Stem Cell Therapy to Regenerate Machine Perfused Organs

Transplantation represents the treatment of choice for many end-stage diseases but is limited by the shortage of healthy donor organs. Ex situ normothermic machine perfusion (NMP) has the potential to extend the donor pool by facilitating the use of marginal quality organs such as those from donors after cardiac death (DCD) and extended criteria donors (ECD). NMP provides a platform for organ quality assessment but also offers the opportunity to treat and eventually regenerate organs during the perfusion process prior to transplantation. Due to their anti-inflammatory, immunomodulatory and regenerative capacity, mesenchymal stem cells (MSCs) are considered as an interesting tool in this model system. Only a limited number of studies have reported on the use of MSCs during ex situ machine perfusion so far with a focus on feasibility and safety aspects. At this point, no clinical benefits have been conclusively demonstrated, and studies with controlled transplantation set-ups are urgently warranted to elucidate favorable effects of MSCs in order to improve organs during ex situ machine perfusion.

High Throughput Proteomic Exploration of Hypothermic Preservation Reveals Active Processes within the Cell Associated with Cold Ischemia Kinetic

The demand for organs to be transplanted increases pressure on procurement centers, to the detriment of organ quality, increasing complications. New preservation protocols are urgently needed, requiring an in-depth understanding of ischemia-reperfusion mechanisms. We performed a proteomic analysis using LC-MS/MS-TOF data analyzed through R software and Cytoscape’s ClueGO application, comparing the proteome of kidney endothelial cells, key cell type, subjected to 3, 6, 12, 19, and 24 h of cold ischemia and 6 h reperfusion. Critical pathways such as energy metabolism, cytoskeleton structure/transport system, and gene transcription/translation were modulated. Important time windows were revealed: a—during the first 3 h, central proteins were upregulated within these pathways; b—the majority of these upregulations were maintained until 12 h cold ischemia time (CIT); c—after that time, the overall decrease in protein expression was observed; d—at reperfusion, proteins expressed in response to cold ischemia were all downregulated. This shows that cold ischemia is not a simple slowing down of metabolism, as deep changes take place within the proteome on major pathways. Time-sensitive expression of key protein reveals possible quality biomarkers as well as potential targets for new strategies to maintain or optimize organ quality.