| Summary: | Kidney transplantation is the most effective treatment for patients with end stage renal disease. One of the concerns in the transplant community is the persistent donor organ shortage and the lack of suitable organs for transplantation. Marginal kidneys from high- risk donors are increasingly accepted, however a large proportion are discarded due to their susceptibility to ischemia reperfusion injury (IRI) and the risk that the use of these organs may ultimately result in post-transplant complications. Normothermic machine perfusion (NMP) of the donor kidneys provides an opportunity to assess, potentially repair and therapeutically intervene on the organ ex vivo prior to transplantation - hereby transforming kidney transplantation by increasing utilisation of marginal organs. Mesenchymal stromal cells (MSCs) can exert regenerative and anti-inflammatory effects in organs and tissues during IRI. This thesis focused on the optimisation of donor kidney NMP conditions and studied the optimal duration of NMP needed to allow homing and initiation of biological effects of infused MSCs on the donor kidney during NMP. Through the work in this thesis we have developed a reproducible kidney NMP slaughterhouse model and demonstrated that stable kidney NMP with a red blood cell-albumin based solution can be performed for a minimum of seven hours. Furthermore, an oxygen carrier is necessary during NMP of healthy porcine kidneys. NMP of kidneys without an oxygen carrier led to significantly impaired renal function and high lactate and aspartate aminotransferase levels, indicating injury and anaerobic metabolism. Administration of MSCs to the donor kidney during NMP is safe and feasible as there were no adverse effects on perfusion characteristics and injury markers. After seven hours of NMP, MSCs were mainly localised in the glomeruli and the addition of MSCs resulted in secretion of prostaglandin E2, vascular endothelial growth factor A, angiopoietin 1 and interleukin 10 in the perfusate. Despite no improvement on early renal function of MSC therapy during NMP delivery prior to porcine auto-transplantation, MSC administration during NMP was successful, proving the feasibility of NMP as a method to deliver cellular therapies.
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