Machine perfusion preservation versus static cold storage for deceased donor kidney transplantation.

Ex vivo normothermic machine perfusion (NMP) of donor kidneys prior to transplantation provides a platform for direct delivery of cellular therapeutics to optimize organ quality prior to transplantation. Multipotent Adult Progenitor Cells (MAPC®) possess potent immunomodulatory properties that could minimize ischemia reperfusion injury. We investigated the potential capability of MAPC cells in kidney NMP. Pairs (5) of human kidneys, from the same donor, were simultaneously perfused for 7 hours. Kidneys were randomly allocated to receive MAPC treatment or control. Serial samples of perfusate, urine, and tissue biopsies were taken for comparison. MAPC‐treated kidneys demonstrated improved urine output (P = .009), decreased expression of injury biomarker NGAL (P = .012), improved microvascular perfusion on contrast‐enhanced ultrasound (cortex P = .019, medulla P = .001), downregulation of interleukin (IL)‐1β (P = .050), and upregulation of IL‐10 (P < .047) and Indolamine‐2, 3‐dioxygenase (P = .050). A chemotaxis model demonstrated decreased neutrophil recruitment when stimulated with perfusate from MAPC‐treated kidneys (P < .001). Immunofluorescence revealed prelabeled MAPC cells in the perivascular space of kidneys during NMP. We report the first successful delivery of cellular therapy to a human kidney during NMP. Kidneys treated with MAPC cells demonstrate improvement in clinically relevant parameters and injury biomarkers. This novel method of cell therapy delivery provides an exciting opportunity to recondition organs prior to transplantation.

Combining NAR and Ca19-9 into a prognostic score allows stratification of unresectable PDAC patients into groups with significantly different overall survival.

Normothermic machine perfusion (NMP) is a novel clinical approach to overcome the limitations of traditional hypothermic organ preservation. NMP can be used to assess and recondition organs prior to transplant and is the subject of clinical trials in solid organ transplantation. In addition, NMP provides an opportunity to deliver therapeutic agents directly to the organ, thus avoiding many limitations associated with systemic treatment of the recipient. We report the delivery of oligonucleotide‐based therapy to human kidneys during NMP, in this case to target microRNA function (antagomir). An antagomir targeting mir‐24‐3p localized to the endothelium and proximal tubular epithelium. Endosomal uptake during NMP conditions facilitated antagomir co‐localization with proteins involved in the RNA‐induced silencing complex (RISC) and demonstrated engagement of the miRNA target. This pattern of uptake was not seen during cold perfusion. Targeting mir‐24‐3p action increased expression of genes controlled by this microRNA, including heme oxygenase‐1 and sphingosine‐1‐phosphate receptor 1. The expression of genes not under the control of mir‐24‐3p was unchanged, indicating specificity of the antagomir effect. In summary, this is the first report of ex vivo gymnotic delivery of oligonucleotide to the human kidney and demonstrates that NMP provides the platform to bind and block detrimental microRNAs in donor kidneys prior to transplantation.

Background There remains a lack of consensus on the optimal storage method for deceased donor kidneys. This meta‐analysis compares storage with hypothermic machine perfusion (HMP) vs traditional static cold storage (SCS). Methods The Cochrane Kidney and Transplant Specialised Register was searched to identify (quasi‐) randomized controlled trials (RCTs) to include in our meta‐analysis. PRISMA guidelines were used to perform and write this review. Results There is high‐certainty evidence that HMP reduces the risk of delayed graft function (DGF) when compared to SCS (2138 participants from 14 studies, RR = 0.77; 0.67‐0.90, P = .0006). This benefit is significant in both donation following circulatory death (DCD; 772 patients from seven studies, RR = 0.75; 0.64‐0.87, P = .0002) and donation following brainstem death (DBD) grafts (971 patients from four studies, RR = 0.78; 0.65‐0.93, P = .006). The number of perfusions required to prevent one episode of DGF was 7.26 and 13.60 in DCD and DBD grafts, respectively. There is strong evidence that HMP also improves graft survival in both DBD and DCD grafts, at both 1 and 3 years. Economic analyses suggest HMP is cost‐saving at 1 year compared with SCS. Conclusion Hypothermic machine perfusion is superior to SCS in deceased donor renal transplantation. Direct comparisons with normothermic machine perfusion in RCTs are essential to identify optimal preservation methods in kidney transplantation.

INTRODUCTIONThe roles of non-medically trained practitioners within the NHS are expanding; they are now being employed by many specialties, including surgery, to relieve pressures on healthcare teams. AIMS To investigate the learning curve and competence of an orthopaedic surgical care practitioner (SCP) in performing hip aspirations. METHODS Data were retrospectively collected on 510 orthopaedic hip aspirations, of which 360 were completed by a single SCP and 150 were completed by surgeons before the SCP took over routine aspiration. The 360 aspirations completed by an SCP were separated into groups of 30 by date, so any trend in failure rate could be analysed. Ordinal 2 analysis was used to analyse this trend and Pearson 2 analysis was used to analyse differences in failure rates between professionals.

In fibrotic diseases, myofibroblasts derive from a range of cell types including endothelial-to-mesenchymal transition (EndMT). Increasing evidence suggests that miRNAs are key regulators in biological processes but their profile is relatively understudied in EndMT. In human umbilical vein endothelial cells (HUVEC), EndMT was induced by treatment with TGFβ2 and IL1β. A significant decrease in endothelial markers such as VE-cadherin, CD31 and an increase in mesenchymal markers such as fibronectin were observed. In parallel, miRNA profiling showed that miR-126-3p was down-regulated in HUVECs undergoing EndMT and over-expression of miR-126-3p prevented EndMT, maintaining CD31 and repressing fibronectin expression. EndMT was investigated using lineage tracing with transgenic Cdh5-Cre-ERT2; Rosa26R-stop-YFP mice in two established models of fibrosis: cardiac ischaemic injury and kidney ureteric occlusion. In both cardiac and kidney fibrosis, lineage tracing showed a significant subpopulation of endothelial-derived cells expressed mesenchymal markers, indicating they had undergone EndMT. In addition, miR-126-3p was restricted to endothelial cells and down-regulated in murine fibrotic kidney and heart tissue. These findings were confirmed in patient kidney biopsies. MiR-126-3p expression is restricted to endothelial cells and is down-regulated during EndMT. Over-expression of miR-126-3p reduces EndMT, therefore, it could be considered for miRNA-based therapeutics in fibrotic organs.

Background. In many transplant centers, a recipient body mass index (BMI) >30 kg/m 2 would be considered a contraindication for pancreas transplantation. This study aims to investigate the impact of recipient BMI on graft outcomes after pancreas transplantation. Methods. Retrospective data on all UK solid organ pancreas transplants from 1994 to 2016 were obtained from the National Health Service Blood and Transplant UK Transplant Registry, n = 2618. Cases missing BMI data were excluded, resulting in a final cohort of n = 1452. Graft and patient survival analysis were conducted using Kaplan-Meier plots and Cox regression models. Results. The mean recipient BMI was 24.8 kg/m 2 (±2.4). There were 507 overweight (BMI 25-29.9) and 146 obese (>30) recipients receiving pancreas transplants. Univariate analysis showed no statistically significant difference between overweight BMI categories compared with normal BMI (18.5-24.9 kg/m 2 ). Multivariate analysis revealed increasing recipient BMI had a significant impact on graft survival (P = 0.03, hazard ratio 1.04, 95% confidence interval, 1.00-1.08). Receiver operating characteristic curve analyses revealed no value of BMI that provided both specific and sensitive discrimination between death and survival of both grafts or patients. Recipients on dialysis with a BMI >30 kg/ m 2 had a statistically significant decrease in both graft (P = 0.002) and patient survival (P = 0.015). Conclusions. Analysis of available UK Pancreas data has shown recipient BMI is an independent risk factor for patient survival after transplantation. However, we have been unable to define a specific cutoff value above which patients have poorer outcomes. Obese patients on hemodialysis had the poorest graft survival, and preemptive transplantation may be beneficial in this cohort.