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Whilst kidney transplantation is accepted as a cost effective treabnent ofend stage renal failure, the shortage in the kidney donor pool has recently become critical. Historical series ofNHBD renal transplants have been associated with high rates ofallograft failure and dysfunction due to prolonged warm and cold ischaemia. Machine preservation of NHBD kidneys provides a useful tool to test viability pre-transplant and this PhD thesis was directed at improving the existing Newcastle NHBD programme. Newcastle machine preservation is described in which viability criteria is used to reduced primary non function and discard rates. The sequential allograft failures were critically reviewed to develop the new 'IO-point' criteria. Case failures have become a necesSary painful learning experience that allowed improvements in the selection and screening criteria. The long term function ofNHBD renal transplants are presented to illustrate how the function is affected by warm ischaemic injury and delayed graft function. The early dysfunction ofNHBD kidney transplants was found to be temporary and improved with time. Kidney perfusate GST evaluation is an established criteria in the assessment of viability ofNHBD kidneys. In the search for novel biomarkers, perfusate Ala-AP and FABP have been assessed in relation to GST. The novel biomarkers measured a different aspect of allograft injury and comparable results to GST suggest that these could be developed as an adjunct to perfusate GST. The introduction ofstreptokinase pre-flush of the NHBD is illustrated in a porcine and a subsequent human clinical model. The effect on procurement, machine preservation and transplantation has been evaluated. Thrombolytic therapy ofNHB donor facilitated the clearing ofpremorbid intravascular thrombus, thereby improving the preservation and thus the viability of the NHBD kidneys. Allograft dysfunction is a standard feature of ischaemia reperfusion injury. A clinical model ofkidney transplantation is described to illustrate the biochemical and clinical effects of ischaemia reperfusion. An exaggerated response was observed in NHBD kidney transplants that could be attributed to the warm ischaemia insult at time of cardiac arrest.

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The use ofCPB is associated with significant lung dysfunction. Apart from factors such as, hypothermia, systemic heparinisation, and the artificial circuit itself, lung injury can result from pulmonary IR. The lungs have a unique trimodal oxygen supply for lung tissue oxygenation; bronchial arteries, pulmonary arteries, and oxygen from alveolar ventilation. During CPB, only a compromised low pressure bronchial artery perfusion to the lupgs is maintained, therefore a certain degree of lung ischemia is inevitable. Pulmonary ischemia and subsequent reperfusion injury causes a k>cal and systemic inflammatory response, and lung cellular necrosis and apoptosis, resulting in lung dysfunction. The significance of stopping ventilation during clinical CPB in the development of lung IR and inflammation is unknown. Furthermore, apoptosis ofthe lung tissue following IR involves a complex network of interacting enzyme pathways, which over the past decade, are becoming clearer. However, the early and upstream intracellular molecules which promote the expression of these apoptotic enzymes remain to be elucidated. Microarray is a powerful tool which has been used in lung tissue to detect gene expression changes following various insults, including ventilator induced lung injury and ischemia reperfusion. The previous studies of lung IR have focus on microarray gene expression changes following lung transplant in a rodent model, and also pulmonary artery occlusion for 4 to 72 hours in a murine model. Although they are in themselves invaluable to the understanding ofgene expression changes following lung IR, nevertheless those studies do not reflect conditions oflung IR. encountered during the more common procedures ofcoronary artery bypass grafting or valve replacement when lung ischemia times are much shorter. The murine model maintains nonnal ventilation and bronchial artery blood flow to ischemic lung, which is different from lung ischemia encountered during clinical CPB when ventilation is stopped and bronchial blood flow and pressure is reduced. In the first part ofthe study, the effects ofshort durations of lung ischaemia and reperfusion (without ventilation, and with low/no bronchial artery flow), which closely reflect conditions encountered during routine clinical coronary artery bypass graft and valve surgery, on early gene expression changes in the lungs involved in pulmonary apoptosis and inflammation is investigated using an experimental rodent model oflung IR. injury. It is hoped that important insight is gained into the early mechanisms oflung IR following CPB in clinical cardiac surgery. The second part is a clinical randomized prospective study, investigating the effects ofrestoring a source ofoxygenation by maintaining ventilation to the lung during clinical CPB, and how it may affect the degree ofischemia and subsequent reperfusion injury, associated pulmonary and systemic inflammatory and cytokine responses, and cardiovascular-pulmonary function following open heart surgery. The study will improve. our understanding ofthe mechanisms behind, and the relative contribution ofstopping ventilation during CPB towards postoperative pulmonary dysfunction.

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