Veighey, KV; (2015) Ischaemia-reperfusion injury in chronic kidney disease. Doctoral thesis , UCL (University College London).

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Abstract

When an organ or tissue is rendered ischaemic, there is inevitable cell death and tissue injury, the extent of which can be limited by timely reperfusion. However, paradoxically, an additional injury occurs upon reperfusion that limits the amount of tissue that can be salvaged. This composite injury is termed ‘ischaemia-reperfusion (IR) injury’. Ischaemic preconditioning (IPC) is an innate protective phenomenon whereby brief non-lethal periods of ischaemia and reperfusion may protect against subsequent more sustained IR injury. IR injury was modelled in healthy volunteers and patients with chronic kidney disease (CKD) using an arterial model of endothelial function, flow-mediated dilatation (FMD). Healthy volunteers sustained a significant reduction in FMD following experimental IR injury. IPC and its systemic phenotype, remote ischaemic preconditioning (RIPC) failed to protect against IR injury. Patients with CKD sustained minimal IR injury in this model. The venodilatory response to bradykinin was demonstrated to be significantly reduced following IR injury. RIPC protected against IR injury in this model, as did preinfusion with sodium nitrite. The effect of nitrite was abolished by prior treatment with oral allopurinol, suggesting a role of xanthine oxoreductase in the reduction of nitrate to nitric oxide during ischaemia. Vitamin D deficiency has been associated with IR injury and endothelial dysfunction however a detrimental effect of deficiency on FMD or arterial IR injury could not be demonstrated in either CKD patients or controls. Additionally, vitamin D deficient CKD patients undergoing transplantation did not have increased graft fibrosis or worse kidney function at 1 year. Lastly a European multicentre randomised controlled trial, REnal Protection Against Ischaemia-Reperfusion in transplantation (REPAIR) demonstrated a trend towards increased 1-year iohexol glomerular filtration rate (GFR), and a statistically significant improvement in 1 year estimated GFR in patients who received RIPC immediately prior to live donor kidney transplantation.

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