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The aim of this thesis is to investigate the mechanism of cisplatin nephrotoxicity and to examine the responses of rat and human proximal tubular cell cultures to platinum analogues for potential early markers of toxicity. Nephrotoxicity was induced in male Sprague Dawley rats (N = 4 +/- standard deviation) and male C57BL/6 mice (N = 6 +/- standard deviation) with doses of 6 milligrams per kilogram and 10 milligrams per kilogram cisplatin administered by intraperitoneal injection respectively. These doses increased blood urea nitrogen and serum creatinine significantly. Male Spraque Dawley rats and C57BL/6 mice had control blood urea nitrogen day 5 and day 4 values of 8 +/- 1 micromoles per millilitre and 7 +/- 0.7 micromoles per millilitre respectively compared with values post cisplatin treatment of 36 +/- 4 micromoles per millilitre and 31 +/- 11.6 micromoles per millilitre. Histological analysis revealed significant damage to the proximal tubules, including loss of brush border membrane, cellular vacuolation and loss of cell-cell adhesion. The inhibition of aminopeptidase N and renal dipeptidase in vivo in male Sprague Dawley rats (N = 4 +/- standard deviation) or in rat and human proximal tubule cell cultures did not alter the toxicity of cisplatin (N = 5 +/- standard deviation). These data show that the dipeptidase enzymes are not implicated in the nephrotoxicity of cisplatin and contradict the publications of Hanigan and Townsend (2002) and Townsend et al (2003b), which hypothesise that dipeptidase activity is an integral part of a cisplatin biotransformation, pathway that is responsible for cisplatin nephrotoxicity. The inhibition of cysteine S-conjugate b-lyase activity in male Sprague Dawley rats (N = 4 +/- standard deviation) and C57BL/6 mice (N = 6 +/- standard deviation) did not affect the level of cisplatin toxicity. The inhibition of cysteine S-conjugate b-lyase in vitro significantly increased cisplatin toxicity in rat and human proximal tubule cell cultures at 24 hours (N = 5 +/- standard deviation). These data contradict the published data of Hanigan and Townsend (2002) and Townsend et al (2003b) in which cysteine S-conjugate b-lyase inhibition prevented cisplatin nepthrotoxicity in C57BL/6 mice and reduced toxicity in LLC-PK1 cell cultures.

Extracellular nucleotides, such as ATP and UTP, are now widely accepted as regulators of diverse cellular functions including regulation of ion transport in epithelial tissues. They signal via multiple P2 receptor subtypes. Current evidence suggests that P2 receptors are expressed in kidney epithelia and that they may influence transport of ions and fluid. Consequently, alterations in the physiology of P2 receptor signalling may be involved in the development of renal diseases such as autosomal dominant polycystic kidney disease (ADPKD), an inherited kidney disease in which abnormal cell physiology is thought to contribute to disease progression. In this thesis, the expression and role of P2 receptors in the kidney and their possible influence on ADPKD cyst growth have been investigated. Several P2 receptor subtypes were identified on specific cells of the normal rat kidney. Mostly P2Y receptors were detected in the glomerulus and tubule epithelium, but also P2Xs receptors were found on collecting duct cells and P2X4 and P2X6 receptors were expressed at a low level throughout the nephron. The P2Y1,2,4,6 and the P2X5 and P2X7 subtypes were detected on the cyst lining cells of (cy/+) rat polycystic kidneys, and P2Y2,6 and P2X7 receptor mRNA was increased when compared to normal rat kidneys. P2X7 receptor expression was also increased in rodent models of glomerular injury. In vitro, inhibition of mostly P2Y receptor subtypes with antagonists or removal of ATP from the growth medium significantly reduced the growth of MDCK microcysts. This work has extended the current knowledge of P2 receptor expression in healthy and diseased kidney tissue. The pattem of P2 receptor expression in renal cysts indicate that these receptors may play a role in cyst formation and progression. Their influence is most likely via ATP-stimulated chloride secretion and accelerated proliferation of epithelial cells; both of which are key factors that affect ADPKD cyst growth. These findings support the hypothesis for a role of P2 receptors in renal cyst growth and enlargement. However, these initial observations require more study, since there are many P2 receptor subtypes, one of which might prove to be a therapeutic target to limit cyst growth and preserve renal function.

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Background: The extent and the distribution of end stage kidney disease (ESKD) in Libya have not been reported despite provision of dialysis over 4 decades. The aim of this thesis is to develop the first comprehensive description of the epidemiology of dialysis-treated ESKD in adults in Libya as well as to assess the outcomes of this treatment. Methods: A structured interview regarding dialysis provision and infection control measures was conducted with the medical directors of all 40 dialysis centres and 28 centres were visited. In the same time demographic and clinical data were obtained regarding all adult patients treated at all maintenance dialysis facilities in Libya from May to August 2009. Additional information about the patterns of vascular access used for haemodialysis (HD) as well as prevalence and incidence of hepatitis Band/or C infection was collected and analysed. Subsequently data were collected prospectively from September 2009 to August 2010. Results: There were 40 functioning maintenance dialysis centres in Libya (one of them was serving children only). The total number of adult patients was 2417. The prevalence rate of ESKD treated by dialysis was 624 per million population. Most dialysis units were located in the northern part of the country and only 12.5% were free standing units. Only three centres offered peritoneal dialysis. There were 192 HD rooms. They hosted 713 functioning HD stations, giving a ratio of one machine to 3.4 patients. Nephrologist/internist to patient ratio was 1:40 and nurse to patient ratio was 1:3.7. There was wide variation in monitoring of dialysis patients with dialysis adequacy assessed only in a minority. 85% of prevalent patients were aged <65 years and 58% were male. The prevalence of ESKD varied considerably with age with a peak at 55-64 years (2475 pmp for males; 2197 pmp for females). The annual incidence rate was 282 pmp with some regional variation and a substantially higher rate in the South (617 pmp). The most common cause of ESKD among prevalent and incident patients was diabetes. Other important causes were glomerulonephritis, hypertensive nephropathy and congenital or hereditary diseases. During one year follow- up, 458 deaths occurred, (crude annual mortality rate of 21.2%). Of these, 3 1 % were due to ischaemic heart disease, 16% cerebrovascular accidents and 16% due to infection. Annual mortality rate was 0-70% in different dialysis centres. Best survival was in age group 25-34 years. Binary logistic regression analysis identified age at onset of dialysis, physical dependency, diabetes and predialysis urea as independent determinants of increased mortality. Of all dialysis- treated patients, 34.9% were sero-positive for HBV and/or HCV (anti-HCV positive 31.1%; HBsAg positive 2.6%; both positive \.2%). The prevalence of HBV±HCV infection varied widely between HD centres from 0% to 75.9%. Sero-positive patients were younger, had longer time on dialysis and more previous blood transfusions. Prospective follow-up revealed an incidence ofsero-conversion of7.7% during 1 year (7.1% HCV; 0.6% HBV). Wide variation in rates of newly acquired infections was observed between dialysis centres. Duration of dialysis, history of previous renal transplant and history of receiving HD in another centre in Libya were significantly associated with sero-conversion. The majority of HD- treated patients (91.9%; n=1573) were using permanent vascular access in the form of arteriovenous fistula or arteriovenous graft. Patients with permanent vascular access were more likely to be male and less likely to be diabetic. Most patients had commenced HD using a temporary central venous catheter (91.8%). Vascular access- related complications were: thrombosis (46.7%), aneurysm (22.6%), infection (11.5%) and haemorrhage (10.2%). Hospitalisation for VA related complications was reported by 31.4%. Conclusion: ESKD in Libya is a major health problem where the incidence rate is among the highest in the world. Despite rapid expansion of dialysis services throughout the country, this thesis has identified that many aspects of dialysis provision are suboptimal and that outcomes are relatively poor. We have identified several major challenges to improving the quality of dialysis provision including lack of dialysis practice guidelines, absence of auditing and quality control and limited access to kidney transplantation. As Libya reorganises its health services in the post-conflict period it is hoped that this study will be the first step in establishing a renal registry and that the areas of concern highlighted will prompt the implementation of national clinical practice guidelines for dialysis.

In the study, the incidence of haemodialysis catheter-associated infection was established with the Meditrend audit tool. This tool was used to assess the infection outcomes of catheter insertion and management procedures until the catheter was explanted. Introduction of a catheter management protocol decreased the incidence of catheter-related infection. Staphylococcal species recovered from episodes of haemodialysis catheter-associated infection and continuous ambulatory peritoneal dialysis (CAPD)-associated peritonitis were genotyped by determination of macrorestriction profiles with pulsed-field gel electrophoresis. This highlighted horizontal transfer of microorganisms between different patients and the environment. The phenotypic characteristics of these strains were also investigated to determine characteristics that could be used as markers for dialysis catheter-associated infection. The expression of elastase, lipase and esterase by CNS was significantly associated with infection. A rapid enzyme-linked immunosorbent assay incorporating a novel staphylococcal antigen (lipid S) was used to evaluate the early detection of anti-staphylococcal immunoglobulin gamma in patient sera. The comparison of culture positive and culture negative patients demonstrated a steady state of immune activation in both groups. However anti-lipid S serum antibody titres > 1000 were found to be a predictor of infection. The effect on faecal carriage of vancomycin resistant enterococci (VRE) and Clostridium difficile toxins in patients treated with CAPD when empiric cephalosporin therapy was substituted for piperacillin/tazobactam was investigated. The introduction of piperacillin/tazobactam demonstrated a decrease in the faecal carriage of VRE.