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A dissertation submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of requirements for the degree of Master of Science in the School of Molecular and Cell Biology. Johannesburg, 2016. / Telomeres play significant roles in maintaining genome stability, regulating cell proliferation and apoptosis. The role of telomere biology and telomerase reactivation has been studied extensively in cancers. Telomerase has been previously associated with driving chronic kidney disease (CKD) advancement and most frequently due to HIV infection. However, the mechanism by which telomerase activation contributes towards disease progression beyond its canonical function of telomere maintenance is poorly understood. Telomerase is a ribonucleoprotein whose main function is telomere maintenance. Telomerase activity is dependent on expression of the rate-limiting human telomerase reverse transcriptase (hTERT) component. In addition to telomere maintenance, hTERT is implicated in other non-telomere related functions that promote cellular proliferation. Expression of hTERT is predominantly regulated at the transcription level where variation in promoter and minisatellite (MNS16A) sequences alter its expression. This variation has been implicated to confer susceptibility to diseases such as cancer and ageing disorders in non-African populations. Data on variation and pathogenicity of telomere-associated genes in African populations is limited and warrants further research. Thus bioinformatics analysis was performed to elucidate variation within the human TERT gene and promoter in different populations. The promoter, MNS16A and relative telomere length (RTL) were also evaluated in 159 African study participants with and without CKD. TERT common variants are equally distributed across populations with limited data on connection to the effects of the variants in African populations. Further bioinformatics analyses revealed significant difference (p<0.0001) in distribution of promoter variant rs2853669 between African and non-African populations. No common promoter mutations were identified in our study population. Interestingly, the long MNS16A variant suggested to increase TERT expression was significantly overrepresented in individuals with CKD regardless of HIV status. For the first time, a strong association of the long MNS16A variant with CKD regardless of HIV status is reported, implicating MNS16A as a potential risk factor in CKD.

No description available.

Acute kidney injury (AKI) is serious and complicates up to 1 in 7 hospital admissions. It is usually diagnosed from rapidly deteriorating blood tests. Much of the focus of clinical research into AKI has been on strategies to improve recognition and timely intervention. However, emerging evidence suggests that even when people survive AKI, they remain at an elevated risk of poor long-term outcomes. The aim of this thesis was to determine which people with AKI have an ongoing increased risk of poor outcomes (mortality, kidney failure, recurrent illness episodes) after hospital discharge. The design was a population-based data-linkage cohort study involving the Grampian Laboratory Outcomes Morbidity and Mortality Study (GLOMMS-II). Data linkages included population biochemistry, hospital episode data, mortality records, intensive care records and renal registry data from 1999-2013. A cohort of 17,630 people hospitalised in 2003 were followed through to 2013. Outcomes were mortality, progression of kidney disease and unplanned hospital readmission episodes. There have been several novel research outputs. I evaluated and adapted international AKI criteria for use in large population biochemistry datasets. I developed a clinical risk prediction model for unplanned readmissions after hospital discharge, for which AKI was a strong independent predictor. I described long-term survival after AKI, showing that people with AKI (vs no AKI) have a substantially higher risk of death in the first year, but diminishing excess risk thereafter. Finally, I conducted a novel analysis of renal prognosis after AKI, showing that mortality and non-recovery are more common than subsequent renal progression after AKI, but that renal progression is nevertheless increased after AKI. Overall, AKI is a serious condition and marker of people who have a long lasting poorer prognosis. The first year after discharge is a period of particularly heightened risk that could potentially be targeted with initiatives to improve care.

Abstract Cisplatin is one of the most effective chemotherapeutic agents used in treatment of a variety of human solid tumors. The most common adverse side effect limiting the use of Cisplatin is nephrotoxicity. Recent studies indicate that inflammatory and oxidative signaling play critical role in pathogenesis of Cisplatin related nephrotoxicity. Cisplatin-induced nephrotoxicity is associated with lipid peroxidation and the superoxide anion and hydroxyl radical scavenger could prevent acute renal failure through both attenuation of tubular damage and enhanced regenerative response of the damaged tubular cells. It has been shown that green tea polyphenols with antioxidant properties inhibit inflammatory and oxidative responses in mice. However, the evidence indicating the protective effect of epigallocatechin gallate (EGCG), the major polyphenol found in green tea, on Cisplatin-induced nephrotoxicity is lacking. The present study is to evaluate the effect of EGCG injection on Cisplatin-induced nephrotoxicity in rats. The male rats were divided into four groups (n = 6 each); control group, Cisplatin group, EGCG group and Cisplatin + EGCG group. The control group received only intraperitoneal normal saline injection. Cisplatin (6 mg/kg) was given single dose intraperitoneally at day 0, EGCG (10 mg/time) was given subcutaneously at day 4, day 2 and day 0 before Cisplatin challenge and day 2 and day 4 after Cisplatin injection. Nephrotoxicity was evaluated by biochemical analysis of blood and histopathological observations of rat kidney. Nuclear factor-kappa B (NF-£eB) activation, inducible nitric oxide synthase (iNOS) expression and malonyldialdehyde (MDA) content were also determined in rat kidney. Cisplatin injection induced an increase in serum blood urea nitrogen, creatinine and tubular necrosis, and upregulation of NF-£eB and iNOS expression and MDA content in kidney. All the increases were significantly inhibited by EGCG treatment. The results suggest that EGCG may attenuate Cisplatin induced nephrotoxicity through the anti-inflammatory/oxidative effects.

Thesis (Ph. D.)--University of Texas at Austin, 2000. / Vita. Includes bibliographical references (leaves 242-253). Available also in a digital version from Dissertation Abstracts.

Thesis--M.D., University of Hong Kong. / Typewritten.

Thesis (M.D.)--University of Hong Kong, 1987.