Machine perfusion for abdominal organ preservation: a systematic review of kidney and liver human grafts

Introduction: To match the current organ demand with organ availability from the donor pool, there has been a shift towards acceptance of extended criteria donors (ECD), often associated with longer ischemic times. Novel dynamic preservation techniques as hypothermic or normothermic machine perfusion (MP) are increasingly adopted, particularly for organs from ECDs. In this study, we compared the viability and incidence of reperfusion injury in kidneys and livers preserved with MP versus Static Cold Storage (SCS). Methods: Systematic review and meta-analysis with a search performed between February and March 2019. MEDLINE, EMBASE and Transplant Library were searched via OvidSP. The Cochrane Library and The Cochrane Central Register of Controlled Trials (CENTRAL) were also searched. English language filter was applied. Results: the systematic search generated 10,585 studies, finally leading to a total of 30 papers for meta-analysis of kidneys and livers. Hypothermic MP (HMP) statistically significantly lowered the incidence of primary nonfunction (PMN, p = 0.003) and delayed graft function (DGF, p < 0.00001) in kidneys compared to SCS, but not its duration. No difference was also noted for serum creatinine or eGFR post-transplantation, but overall kidneys preserved with HMP had a significantly longer one-year graft survival (OR: 1.61 95% CI: 1.02 to 2.53, p = 0.04). Differently from kidneys where the graft survival was affected, there was no significant difference in primary non function (PNF) for livers stored using SCS for those preserved by HMP and NMP. Machine perfusion demonstrated superior outcomes in early allograft dysfunction and post transplantation AST levels compared to SCS, but however, only HMP was able to significantly decrease serum bilirubin and biliary stricture incidence compared to SCS. Conclusions: MP improves DGF and one-year graft survival in kidney transplantation; it appears to mitigate early allograft dysfunction in livers, but more studies are needed to prove its potential superiority in relation to PNF in livers

European Society for Organ Transplantation (ESOT) Consensus Statement on the Role of Pancreas Machine Perfusion to Increase the Donor Pool for Beta Cell Replacement Therapy

The advent of Machine Perfusion (MP) as a superior form of preservation and assessment for cold storage of both high-risk kidney’s and the liver presents opportunities in the field of beta-cell replacement. It is yet unknown whether such techniques, when applied to the pancreas, can increase the pool of suitable donor organs as well as ameliorating the effects of ischemia incurred during the retrieval process. Recent experimental models of pancreatic MP appear promising. Applications of MP to the pancreas, needs refinement regarding perfusion protocols and organ viability assessment criteria. To address the “Role of pancreas machine perfusion to increase the donor pool for beta cell replacement,” the European Society for Organ Transplantation (ESOT) assembled a dedicated working group comprising of experts to review literature pertaining to the role of MP as a method of improving donor pancreas quality as well as quantity available for transplant, and to develop guidelines founded on evidence-based reviews in experimental and clinical settings. These were subsequently refined during the Consensus Conference when this took place in Prague.</p

Combined hepatocyte‐islet transplantation: an allograft model

Abstract Experimental hepatocyte transplantation (Tx) has been shown to improve the survival rate of acute hepatic failure (AHF) in different models. Histological and biochemical data from some studies suggest more satisfactory function of hepatocytes after combined hepatocyte‐islet Tx. The aim of the present study was to compare the survival rate between two different sites of Tx (kidney subcapsular and spleen) of hepatocytes alone or combined with islets of Langerhans in rats with surgically induced AHF (90% hepatectomy) accross a major histocompatibility barrier (WAG to Lewis). Rats were divided into five groups (n= 6 in each group). Group 1 consisted of AHF without treatment, group 2, AHF followed by hepatocyte Tx into the spleen, group 3, AHF followed by hepatocyte Tx subcapsular into the kidney, group 4, AHF followed by combined hepatocyte islet Tx into the spleen, and group 5, AHF followed by combined hepatocyte islet Tx subcapsular into the kidney. The number of hepatocytes was 107 and the number of islets was 400. All rats received cyclosporin A (CsA) i.v. (20 mg/kg on days 0–4 and 10mg/kg on days 5–30). Hepatocytes were harvested using a modification of the portal vein collagenase perfusion (type V 1.3 mg/ml) and islets, with the collagenase digestive technique (type XI 1 mg/ml). All Tx took place 24 h after AHF. All rats in group 1 died within 48 h. In groups 2 and 3, the combined survival rate was 33% 1 month after Tx, while in groups 4 and 5, the combined survival rate was 50% at 1 month. All surviving animals were sacrificed and histological examination showed well‐preserved hepatocellular aggregates in the spleen and beneath the renal capsule, as well as islets around the clusters of hepatocytes. SGOT and SGPT values were also measured. We concluded that the copbined Tx in a rat experimental allo‐Tx model in casedof AHF improves the survival rate in comparison with hepatocyte Tx alone. The survival rate at the two different sites for combined Tx was similar. Copyright © 1994, Wiley Blackwell. All rights reserve

Immunomodulatory properties of mesenchymal stromal cells can vary in genetically modified rats

Mesenchymal Stromal Cells (MSC) have been shown to exhibit immuno-modulatory and regenerative properties at sites of inflammation. In solid organ transplantation (SOT), administration of MSCs might lead to an alleviation of ischemia-reperfusion injury and a reduction of rejection episodes. Previous reports have suggested ‘MSC-preconditioning’ of macrophages to be partly responsible for the beneficial effects. Whether this results from direct cell-cell interactions (e.g., MSC trans-differentiation at sites of damage), or from paracrine mechanisms, remains unclear. Immunosuppressive capacities of MSCs from donors of different age and from genetically modified donor animals, often used for in-vivo experiments, have so far not been investigated. We conducted an in vitro study to compare paracrine effects of supernatants from MSCs extracted from young and old wild-type Wystar-Kyoto rats (WKY-wt), as well as young and old WKY donor rats positive for the expression of green fluorescent protein (WKY-GFP), on bone marrow derived macrophages (BMDM). Expression levels of Mannose receptor 1 (Mrc-1), Tumor necrosis factor α (TNFα), inducible NO synthase (iNos) and Interleukin-10 (IL-10) in BMDMs after treatment with different MSC supernatants were compared by performance of quantitative PCR. We observed different expression patterns of inflammatory markers within BMDMs, depending on age and genotype of origin for MSC supernatants. This must be taken into consideration for preclinical and clinical studies, for which MSCs will be used to treat transplant patients, aiming to mitigate inflammatory and allo-responses

Exercise, Telomeres, and Cancer: “The Exercise-Telomere Hypothesis”

Telomeres are genomic complex at the end of chromosomes that protects the DNA and telomere length (TL) is related to several age-related diseases, lifespan, and cancer. On the other hand, cancer is a multifactorial disease that is responsible for reduce the quality of life and kills millions of people every year. Both, shorter TL and cancer are related and could be treated or prevented depending of the lifestyle. In this review we discuss the possible role of exercise in the relationship between shorter telomeres, telomerase activity, and cancer. In summary, there is evidence that exercise leads to less telomere attrition and exercise also may diminish the risk of cancer, these two outcomes are possible intermediated by a reduction in oxidative stress, and chronic inflammation. Although, there is evidence that shorter TL are associated with cancer, the possible mechanisms that one may lead to the other remains to be clarified. We assume that humans under cancer treatment may suffer a great decrease in quality of life, which may increase sedentary behavior and lead to increased telomere attrition. And those humans with already shorter TL likely lived under a poor lifestyle and might have an increased risk to have cancer. © Copyright © 2018 Nomikos, Nikolaidis, Sousa, Papalois, Rosemann and Knechtle

Cold ischaemia time: is too long really too bad? studies using a porcine kidney ex-vivo reperfusion model

Introduction Post-ischaemic hypothermic machine perfusion (HMP) may be beneficial in recovery of marginal kidney grafts. The full capacity of conventional HMP (with passive oxygenation) to recondition an organ has not been realised. We investigated whether HMP can ameliorate ischemic damage caused by extremely prolonged static cold storage (SCS). Methods Porcine kidneys underwent 4-h (SCS4,n = 4) or 52-h (SCS52,n = 4) SCS, followed by 10 h of HMP and were then subjected to 2 h of isolated normothermic reperfusion (NRP). Results There was a post-SCS graft weight loss in SCS52 vs SCS4 kidneys. SCS52 kidneys showed viable perfusion dynamics during HMP, with significantly shorter times to reach viable parameters vs SCS4 kidneys (p < 0.027). During NRP SCS52 kidneys demonstrated similar trends in perfusion dynamics, renal function, oxygen consumptions, lactate production, and tubular injury to SCS4 kidneys. Conclusion Graft weight loss after SCS, reducing resistance to perfusion, may facilitate better HMP dynamics and graft reconditioning. Clinicians utilising HMP should be aware of this phenomenon when using HMP in kidneys exposed to extreme periods of SCS. HMP after an extended period of SCS can resuscitate kidneys to a level equitable of viability as those after a short period of SCS. Utilising passive oxygenation however may be limiting such recovery and interventions utilising active oxygenation may provide benefit in such organs