Surgery (Austin & Northern Health) - Theses
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ItemProtection of the kidney against Ischaemia-Reperfusion injury using zinc( 2019)Acute kidney injury (AKI) continues to be a major cause of morbidity and mortality worldwide. Septic shock, hypovolaemia, and renal ischaemia related to major surgeries are the primary contributors to AKI in hospitalised patients. AKI is associated with a four-fold increase in mortality in hospitalised patients, and a two-fold increase in the likelihood of discharge to a short- or long-term care facility. As a result, the estimated healthcare costs associated with AKI in hospitalised patients in the US alone exceeds US$10billion per year. Studies have also demonstrated that AKI resulting from ischaemia-reperfusion (IR) is a causative determinant in the development, and progression, of chronic kidney disease (CKD). Despite major medical advances to the current day, short of supportive measures there is still no definitive therapeutic option available to prevent AKI in these settings. Preconditioning (PC) against renal IR injury has been heralded as a promising solution to abrogate this major healthcare problem, and an extensive volume of research has amassed in this area. Preconditioning is a phenomenon whereby an innate tissue adaptation occurs in response to a sublethal stimulus, which leads to protection of an organ or tissue against a subsequent insult. PC was first discovered in the context of ischaemic PC (IPC), where brief sublethal periods of ischaemia led to protection against a subsequent more sustained period of ischaemia in the canine heart. Since the discovery of the IPC phenomenon in 1986, tissue protection against ischaemia by means of IPC has been demonstrated by a number of methods in a variety of tissues, including the heart, brain, liver, kidney, and striated smooth muscle. The promise of these findings has also prompted research into the use of alternative methods of tissue PC, and studies have since investigated the use of pharmaceutical agents to promote these tissue adaptations by pharmacological preconditioning (PPC). The race for a pharmaceutical agent capable of eliciting protective adaptations against tissue ischaemia has involved many classes of pharmaceutical compounds, endogenous proteins, and trace elements. Zinc (Zn) is a metal that is essential to many biological functions, including cell growth and survival. The omnipresence of Zn in cellular interactions, and its importance in so many biological processes has led to the investigation of augmenting Zn homeostasis as a means of protection against tissue ischaemia. This is the primary topic of this thesis. The promise of enabling organ protection against IR injury has major clinical implications, spanning many areas of medicine. However, despite the extensive volume of clinical and basic science research in this area, there is still currently no effective method of PC that will protect the human kidney against IR injury. The aims of this thesis are to investigate if parenteral Zn can be used as a therapeutic strategy to protect the kidney against IR injury. The body of research on the topic of tissue PC has highlighted some potential targets for PC agents, however to date a definitive mechanism has not been elucidated, and therefore a further aim of this thesis is to investigate the potential mechanisms through which Zn effects renal tubular and glomerular epithelial cell survival in the setting of renal IR.