The current treatment for urolithiasis is mostly limited to removing stones rather than preventing their formation. This research investigated a range of bisphosphonates for their inhibitory properties on the crystallisation of calcium oxalate - the commonest constituent of urinary calculi. Calcium oxalate crystals were generated in a well-recognised artificial urine solution (Robertson WG et al. J. Urol 1986; 135:1322-1326) using the Mixed Suspension Mixed Product Removal system. This provided a reliable, reproducible environment closely comparable to urine within the pelvi-calyceal system of a stone-former. Five bisphosphonates were tested at different concentrations for their inhibitory properties on calcium oxalate crystallisation using a state of the art laser diffraction particle-sizer, the Mastersizer. The sizes of calcium oxalate crystals generated in the control experiments, after equilibrium, fell in a biphasic distribution peaking at 20 microns (single crystals) and 100 microns (crystal aggregates). After the addition of bisphosphonates, the group of aggregates diminished significantly and in some cases was completely obliterated. Of those bisphosphonates tested, disodium pamidronate was the most effective inhibitor and disodium clodronate, the least. Bisphosphonates are currently widely used in the treatment of bone disease and are excreted renally at concentrations shown here to be effective against calcium oxalate crystallisation. They therefore hold exciting potential in the prevention of urinary stone disease.

The purpose of this thesis was to investigate the contribution of the inflammatory mediators Nuclear factor κB and complement during the progression of renal diseases. The first two results chapters in this thesis demonstrated a novel role for complement component 3 (C3) during the progression of chronic renal disease in the murine model of unilateral ureteric obstruction (UUO) C3 gene up-regulation and complement activation persisted throughout the course of UUO in wild type (WT) mice. In situ hybridisation showed that renal tubular epithelial cells were the primary site of C3 gene expression during early ureteric obstruction in the renal cortices of WT mice. Gene expression for transforming growth factor-beta (TGF-β) and collagen I in obstructed C3 deficient (C3-/-) mouse kidneys was significantly reduced compared with obstructed kidneys from WT mice. The decrease in TGF-β and collagen I also coincided with a significant reduction in mRNA expression for alpha-smooth muscle actin (α-SMA) as well as a significant decrease in interstitial collagen deposition. In addition to these observations, the number of infiltrating CD8+ T cells and F4/80+ macrophages counted within the cortical tubulointerstitial compartment, was significantly higher in C3-/- mice. Gene expression for the membrane-bound complement regulatory proteins complement receptor-related protein-y (crry), CD59a and decay accelerating factor 1 (DAF1) decreased in WT and C3-/- mice during the course of UUO. In particular, crry, CD59a and DAF1 mRNA expression was found to be much lower in C3-/- mice. A transition from membrane to cytoplasmic expression of crry protein was also demonstrated in tubular epithelial cells of obstructed WT mouse kidneys. In contrast to this, factor H gene expression was markedly elevated in WT mice, but not in C3-/- mice. 13 In vitro stimulation of mouse proximal tubular cells using lipopolysaccharide (LPS) resulted in complement activation, C3 gene up-regulation and production of C3 protein, providing an in vitro model to use for future targeting of proximal tubular epithelial cell C3 gene expression. The final results chapter of this thesis demonstrated an important role for nuclear factor kappa-B (NF-κB) subunit nfκb1 during the progression of renal inflammation in the nephrotoxic serum nephritis model of acute renal injury. nfκb1 deficient mice developed significantly worse glomerular injury and proteinuria and displayed sustained up-regulation of interleukin-6 and S100 calcium binding proteins A8 and A9. Finally, in contrast to observations in the nephrotoxic serum model, fibrosis, immune cell infiltration and cytokine mRNA expression were all unchanged in nfκb1 deficient mice compared with WT mice after ten days of ureteric obstruction.

Introduction: Chronic kidney disease (CKD) common, particularly in the elderly, and is linked to an increased risk of cardiovascular disease (CVD). This is partly explained by joint risk factors such as hypertension and diabetes but novel risk factors such as arterial stiffness, arterial calcification and endothelial dysfunction may play a role. Our aims were 1) to prospectively investigate whether aortic stiffness was linked with rate of decline of renal dysfunction, 2) to investigate the associations of arterial stiffness in patients with moderate renal dysfunction, and 3) to investigate whether aortic stiffness was linked with adverse outcomes. Secondary aims were to explore the links between 24 hour ambulatory blood pressure (BP) monitoring (24h ABPM), aortic stiffness, and the novel CV risk factors asymmetric dimethylarginine (ADMA) and Fetuin-A. Methods: This is an observational study of 133 patients with CKD stages 3-4 (estimated GFR 15-60mUmin). At baseline subjects underwent full assessment of CV risk, measurement of arterial stiffness, Fetuin-A, ADMA, and 24h ABPM. Patients were then followed-up with repeat of arterial stiffness measurements 6- monthly. Change in renal function and clinical events were recorded. Major results: Renal function is a determinant of aortic stiffness independent of other well-described factors. Aortic stiffness is closely linked to deterioration in renal function and predicts cardiovascular events within this cohort. There is a high prevalence of ambulatory hypotension during 24h ABPM in older patients with CKD, and a large difference in BP between clinic and home measurements. The BP difference is associated with aortic stiffness, and is suggestive of a causal relationship. A rise in BP at night is associated with increased aortic stiffness, as is the related measure of postural hypotension. ADMA levels are related to change in renal function, while Fetuin-A is related to change in aortic stiffness. Conclusion: In this predominantly elderly cohort of patients with CKD stages 3 and 4, aortic stiffness is associated with baseline and change in renal fundion, CV risk and BP pattems. This highlights the close links between macro- and microvascular disease and suggests that knowledge of aortic stiffness may be crucial in further understanding the pathophysiology and treatment of renal disease.

Whilst there is research evidence on the consequences of involuntary childlessness in majority ethnic communities in the UK and other more developed societies, and also a growing literature on the experiences of infertile women in less well-resourced countries, there is a dearth of research exploring the potential impact of ethnicity and culture on the experience of infertility within Western societies.To begin to address this lacuna, this thesis was designed to exlore the social meanings of infertility in British South Asian communities, and the infertility experiences of individual South Asian women. The study used a qualitative, interpretive approach, and employed a multiple method design. The first phase of the study consisted of 13 single gender focus groups with a total of 87 participants of Indian, Pakistani and Bangladeshi ethnic origin, which explored public perceptions of involuntary childlessness and attitudes towards infertility treatments. The second phase of the study included in-depth interviews with 15 individuals of South Asian ethnic origin who had experience of infertility.

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