Background. Native arteriovenous fistula (AVF) is the vascular access of choice and its use c.f. catheters is associated with sustained reduction in mortality. This may be due to factors beyond dialysis catheter associated sepsis. This study aims to investigate the impact of AVF formation on the spectrum of cardiovascular factors that might be important in the pathophysiology of cardiovascular diseases in CKD patients. Methods. We recruited 43 pre-dialysis patients who underwent AVF formation. Patients were studied two weeks prior to AVF operation, two weeks and three months postoperatively. Haemodynamic variables were measured using pulse wave analysis, carotid femoral pulse wave velocity (CF-PWV) by applanation tonometry and AVF blood flow by Doppler ultrasound. Bioimpedence analysis was performed and patients underwent serial transthoracic echocardiography. Laser Doppler Perfusion Imaging and iontophoresis were used to assess endothelial dependant (ED) and non-endothelial dependant (NED) vasodilatation. Results. AVF formation was successful in 30/43 patients. Two weeks postoperatively, total peripheral resistance decreased (-17 18%, p=0.001), stroke volume tended to rise (12 30ml, p=0.053) and both heart rate (4 8bpm, p=0.01) and cardiac output (1.1 1.5l/min, p=0.001) increased. Systolic and diastolic blood pressures reduced (-9 18mmHg; -9 10mmHg; ≤ p=0.006). CF-PWV reduced (-1.1 1.5m/sec, p=0.004). Left ventricular ejection fraction (LVEF) increased (6 8%, p<0.001). Patients with successful AVF formation had a significantly reduced ED vasodilatation in the fistula arm -36±46%, p<0.001. Only NED vasodilatation was significantly reduced in the non-fistula arm 23±40%, p=0.01. Patients who had unsuccessful AVF operation exhibited no recordable changes. All the observed haemodynamic changes were largely maintained after 3 months. No change in hydration status/body composition was observed. AVF formation resulted in a sustained reduction in arterial stiffness and BP as well as an increase in LVEF. Furthermore, there were significant changes in the local and systemic microcirculation. Overall, post AVF adaptations might be characterised as potentially beneficial in these patients and supports the widespread use of native vascular access, including older or cardiovascular compromised individuals.

The psychosocial challenges of living with prostate cancer have been well documented. Whilst information and support can help ameliorate these challenges, research points towards several barriers to obtaining support face-to-face. Recent research suggests that online support groups can help empower members to become active healthcare participants. Few studies, however, have examined the role of these groups in the context of prostate cancer. This research programme seeks to examine how, if at all, participation within prostate cancer online support groups empowers members. In Study 1, an analysis of 631 messages posted to prostate cancer online support groups was undertaken to explore the beneficial processes observed in members’ communication. In Study 2, open-ended surveys were employed to collect qualitative data from 147 members to explore their perception of empowering processes and outcomes within the groups. In Study 3, quantitative surveys (n=195) were employed to examine the extent to which members experience these processes and outcomes and the relationship between the two. The findings point towards the existence of several empowering processes, such as informational and emotional support exchange, encountering similar others and the ability to discuss sensitive issues. Empowering outcomes commonly experienced by the members included increased knowledge, the ability to participate in treatment-related decisions, an increased sense of community and enhanced communication with their medical practitioner. The processes significantly predicted the outcomes, with ‘information exchange’ consistently being the most significant predictor. This indicates that the processes, and particularly informational support in these groups, play an important role in empowering members. Although some negative processes have been identified, the positive aspects outweigh the negatives. These findings suggests that prostate cancer online support groups can be an effective and cost-efficient source of support and information for prostate cancer patients and their caregivers, and have a significant impact on their sense of empowerment.

Patients on dialysis are subject to hugely elevated rates of cardiovascular mortality. This thesis describes research work focusing on the large scale haemodynamic changes that occur during dialysis and how they may negatively impact on the cardiovascular system. Our results show that the haemodynamic disturbances that occur during haemodialysis are of sufficient magnitude to cause left ventricular (LV) regional wall motion abnormalities, reflecting subclinical myocardial ischaemia (myocardial stunning). This is pertinent as in non-dialysis patients repeated episodes of myocardial stunning lead to chronic heart failure, and in dialysis patients the presence of LV dysfunction dramatically increases the risk of death. We also explore how the haemodynamic effects of dialysis and the genesis of LV regional wall motion abnormalities can be ameliorated by using various interventions comprising of biofeedback dialysis (Hemocontrol and Diacontrol), cooling the dialysate and acetate free paired haemodiafiltration (PHF). We also examine the haemodynamic and metabolic effects of peritoneal dialysis (both continuous ambulatory and automated peritoneal dialysis) and show that these are much greater than previously thought. We also investigate possible mechanisms underlying these changes, namely alterations in cardiac filling and systemic glucose absorption leading to hyperinsulinaemia, and go on to examine the differential effects of the commercially available peritoneal dialysis solutions. Finally, we examine whether regional LV function is affected by the haemodynamic changes of CAPD.

Chronic kidney disease (CKD) is a significant public health issue. The uraemic milieu is associated with profound alterations in body composition and function. Therapeutic interventions to preserve renal function and to provide adequate homeostasis to improve outcomes in all stages of chronic kidney disease may promote other unwanted functional adversities which with careful attention to individualised treatment may be modifiable. The aim of this thesis is to clearly document these disorders of body composition and function and investigate whether commonly practiced interventions can indeed have additional deleterious impact. Our work involved subjects with different levels of CKD and included: • Antihypertensive therapy and falls in older persons with CKD 3/4. • Assessment of dynamic bone function in ERF subjects treated with haemodialysis and consequences of phosphate binder medication. • Distinguishing the dominant cardiac functional abnormalities in ERF subjects treated with haemodialysis and determination of the effects of haemodialysis on camitine depletion and its functional consequences (skeletal and myocardial). Key results included: • Antihypertensive therapy in older subjects with CKD was associated with a reduction in muscle mass over time and reduced overall function but no significant falls risk was noted. • Commonly utilised measurements to determine bone turnover in ERF subjects treated with haemodialysis do not appear to correlate with dynamic collagen formation rates. • Dobutamine-atropine stress with non-invasive assessment of cardiac parameters can be used to identify the dominant functional abnormalities that predispose to intradialytic hypotension in ERF subjects. • Skeletal muscle total carnitine decreases over the first 12 months of dialysis. Change in muscle total carnitine correlated weakly with exercise capacity. Carnitine replacement did not confer any measurable cardiovascular benefit over the first 12 months of dialysis. Body composition is highly variable over time in CKD. This is seen both in subjects receiving haemodialysis and in pre-dialysis patients. The interplay of these common alterations with the effects of treatments is potentially underestimated but should always be considered in the individualisation of patient care.

Over the past few years the healthcare setting has seen a vast increase in the use of medical devices and whilst this may have improved clinical outcomes for patients their increase in use has given rise to an increase in medical - device associated infections. It has been reported that urinary tract infections (UTIs) account for up to 40% of all healthcare associated infections and about 80% of those are associated with catheter use [1]. Urinary catheters are hollow, flexible, tubular devices designed to drain urine when inserted into a patient‟s bladder. They are widely used both on patients requiring short - term urinary catheterisation e.g. during and after some types of surgical procedures or long - term urinary catheterisation e.g. due to urinary incontinence. For patients undergoing long - term indwelling urinary catheterisation (LTC) it is almost inevitable that their catheter will become colonised with bacteria and a biofilm (an accumulation of microorganisms and their extracellular products that form a functional, structured community on a surface) [2] develop which can result in a symptomatic or asymptomatic catheter associated urinary tract infection (CAUTI). Infections associated with biofilms are difficult to treat due to the bacteria within the biofilm being insusceptible to antibiotic treatment. Often to resolve the infection, removal and replacement of the catheter is required and antibiotic treatment if necessary. Certain patients may require their catheter to be changed frequently, often causing considerable distress and morbidity and giving rise to increased medical costs. Biomaterials used to produce long - term urinary catheters that are able to completely resist bacterial colonisation for significant periods, remain elusive. The development of antimicrobial urinary catheters has, however, shown some success in clinical trials but only in the short-term. This project proposes to modify a silicone urinary catheter used for LTC by impregnating it with a suitable combination and concentration of antimicrobial agents. The aim of the study is to develop an antimicrobial catheter that will provide protection from bacterial colonisation and subsequent biofilm development by the principle organisms involved in CAUTIs over a prolonged period (12 weeks). Silicone material was processed using an impregnation method. A variety of agents were assessed using drug screening tests to establish their potential duration of antimicrobial activity and ability to prevent bacterial colonisation. The combination of agents showing the most potential were selected and impregnated into the catheter material. They were: rifampicin, sparfloxacin and triclosan. Further testing involved the development of an in - vitro model designed to test the ability of the antimicrobial catheter to resist colonisation following repeated bacterial challenges. The emergence of bacterial resistance was also monitored during this time. In addition, the total antimicrobial content, drug release profiles and uniformity of drug distribution were elucidated using high performance liquid chromatography (HPLC) and time of flight secondary ion mass spectroscopy (ToF-SIMS) respectively. The effect impregnating antimicrobial agents into the catheter had on its surface properties and the impact on mechanical performance of the catheter shaft and balloons were also examined. Drug screening tests revealed a combination of rifampicin, sparfloxacin and triclosan had the potential to deliver a long duration of protective activity against principal uropathogens. In - vitro model results demonstrated the antimicrobial catheter was able to prevent colonisation by Escherichia coli and Meticillin Resistant Staphylococcus aureus for >12 weeks, Klebsiella pneumoniae and Proteus mirabilis for 8 weeks but only 8 days against Enterococcus faecalis. K.pneumoniae and P.mirabilis colonised catheters did, however, show an increase in the sparfloxacin and triclosan minimum inhibitory concentrations (MICs), highlighting that the development of bacterial resistance could be an issue. The catheter was found to contain (w/w) 0.006% rifampicin, 0.16% sparfloxacin and 0.17% triclosan of which 19.8% sparfloxacin and 29.9% triclosan were released by a diffusion process over the first 28 days. Rifampicin release was not detected possibly due to low concentrations. With the drug release trend suggesting a continued steady release of sparfloxacin and triclosan above the MIC and with 80.2% of sparfloxacin and 70.1% of triclosan remaining, this would suggest there should be sufficient drug to provide protection from bacterial colonisation over a 12 week duration. However, why the MICs increased as catheters became colonised with K.pneumoniae and P.mirabilis could be due to a number of factors. ToF-SIMS revealed the drugs which could be traced (sparfloxacin and triclosan) were mostly uniformly distributed on the catheter surface, with some drug localization being seen which may have added to the initial burst effect and could be important in the prevention of bacterial colonisation during catheter insertion. Surface analysis techniques also showed the incorporation of antimicrobial agents lead to an increase in the surface hydrophilicity but following exposure to an aqueous environment no difference was seen compared to control catheters. As drugs eluted from the catheter the surface topography marginally deteriorated but the impact of this in terms of bacterial colonisation is not thought to be of a clinical significance. No adverse affect to the mechanical performance of the antimicrobial catheter shaft or balloon compared to the conventional silicone Foley urinary catheter was shown, indicating that it would be as mechanically stable as the catheter in clinical use and therefore suitable if applied to clinical practice. Further work on the drug release concentrations and ratios are needed to help overcome the potential of bacterial resistance. The catheter could have a greater effect on reducing bacterial colonisation and potential for resistance development if drug concentrations were adjusted to release at higher concentrations and equal ratios and more data could be gathered if drug release studies were taken to the end point of 12 weeks rather than 28 days. In - vitro model challenges using urine as the perfusion medium and a larger array of microorganisms is required and investigations are also necessary to assess the antimicrobial catheters ability to prevent encrustation, a further complication of LTC. This preliminary study has shown with further work there is potential that the antimicrobial catheter could have a substantial effect on reducing/delaying colonisation by several of the main organisms involved in CAUTIs over a prolonged course. This in turn would help reduce CAUTI rates, reduce the frequency at which catheters need to be replaced and improve the quality of life for patients on LTC.

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.

Prostate cancer is the UK number one male cancer. Evidence from epidemiological studies suggests only age, race and family history as established risk factors. Other factors such as low dose diagnostic radiations and surrogate hormone markers such as baldness, finger length pattern and acne are hypothesized to have a potential role in the aetiology of prostate cancer. It is evident that genetics plays an important role in prostate cancer aetiology. This thesis focuses both environmental and genetic factors. The environmental factors include selected surrogate hormone markers, medical diagnostic radiation procedures and family history of prostate cancer. The genetic part explores genetic polymorphisms that could have implications for interactions with exposures studied. Single nucleotide polymorphisms (SNPs) involved in mechanistic pathways related to DNA repair genes and potential hormone marker genes were the main targets.

Despite the recent introduction of a number of new and more potent anti-rejection drugs, the incidence of rejection and long-term graft survival remain unchanged. There remains a significant difference in long-term graft survival depending on the source of the donor. The purpose of this study was to examine gene expression in the transplanted kidney using microarray technology to identify potential biomarkers that could be used to predict and monitor graft function so that appropriate interventions could be made in the event of graft dysfunction. Over a 5 year period RNA was extracted from 144 donor kidneys that were transplanted. The initial attempts at probe preparation and hybridization were unsuccessful. This led to the development of a new strategy which involved the use of state-of-the-art microarray technology which embraced the advances realised with the completion of the human genome project. Microarray data was analysed using J-Express and Pathway studio. Significance analysis of microarray, hierachical clustering, gene ontology mapping and pathway analysis was performed. The identification of potential biomarkers that had previously been described by other authors validated this approach. In addition novel genes were identified that may have a role as biomarkers of graft function. Other potential biomarkers were identified that represented cellular processes that could be modified by therapeutic intervention thus possibly changing the clinical outcome or allowing monitoring of the success of therapy. Confirmation of previously described biomarkers and the identification of novel potential biomarkers has confirmed that gene expression profiling has a valuable role in identifying processes that are indicative of disease processes including those involved in kidney transplantation. Furthermore with the development of minimally invasive tests to measure these biomarkers, we can potentially change the natural history of the disease process, and hence, preserve graft function and possibly prolong life.

The primary objective of this thesis was to determine any associations between herbal and dietary supplement (HDS) use and the fast progression of chronic kidney disease (CKD) in Thai outpatients with CKD. The secondary objectives were to determine any associations between HDS use and CKD complications, and the prevalence and reasons for HDS use. A survey recruited 421 outpatients with stages 3 to 5 CKD from two kidney clinics in Thailand, from January to June 2012. A prospective cohort study followed up these respondents, in particular noting their serum creatinine, as well as serum levels of potassium and phosphate, for 12 months. Such data were extracted from patients’ medical notes. Three hundred and fifty-seven respondents were followed up. The exposed group was defined as the current and regular users of HDS, and the primary outcome of the cohort study was defined as either a decline in the estimated glomerular filtration rate of at least 5 ml/min/1.73m2/year or the initiation of renal replacement therapy. Sixteen HDS users were recruited from the survey to be interviewed about their reasons for using HDS, using open-ended questions to elicit information in the qualitative study. Exclusion criteria were those with had received renal replacement therapy before recruitment. Univariate and multivariate analyses were performed to determine the associations using Chi-squared tests and multiple logistic regressions. Tests were 2-tailed and a p-value < 0.05 was considered statistically significant. The prevalence of HDS use during the previous year in Thai patients with CKD was 45% (95%CI 40%-50%). The most frequently reported influences on HDS use in the survey and the qualitative study were family members, friends and perception of benefits gained from using HDS. An association between HDS use and CKD progression was not found (adjusted OR 1.16, 95%CI 0.66 – 2.03). Two respondents (0.6%) had acute kidney injury, which may be related to the use of unknown Chinese herbal medicines or river spiderwort combined with diclofenac; issues which were reported by their doctor in their medical note. HDS use was associated with uncontrolled hyperphosphatemia (adjusted OR 3.53, 95%CI 1.20 – 10.43), possibly due to the HDS used in the cohort study which contained phosphate or vitamin D. Health care providers should closely monitor CKD patients using Chinese herbal medicine, river spiderwort or HDS containing phosphorus or vitamin D. Further studies need to examine renal adverse effects of specific herbal medicines, particularly in relation to acute kidney injury.

Haemodialysis patients experience elevated levels of cardiovascular morbidity and mortality that has a profound effect on not only their survival and quality of life but also increases the already high social and economic cost of dialysis. It is increasingly appreciated that the circulatory stress caused by dialysis is a significant contributing factor and helps to accelerate the end organ damage this group of patients is known to experience. In particular the cumulative ischaemic insult suffered by the heart during haemodialysis sessions has been suggested as one of the principal drivers of heart failure and sudden cardiac death – the two principal causes of death in this population. The importance of dialysis induced haemodynamic instability was reinforced as we explored the relationship between cardiac function and the measure of intra-dialytic hypotension most clearly associated with mortality (a blood pressure below 90mmHg) and found that the severity of dialysis induced cardiac injury was experienced across the whole range of dialysis induced hypotension. A nadir blood pressure below 90mmHg was strongly associated with established reduction in systolic contractile function. We then tested two separate interventions designed to mitigate dialysis-induced injury. The first was Remote Ischaemic Preconditioning, a technique that in pre-clinical models and numerous small clinical studies protects against the effect of the ischaemia-reperfusion injury. We found that a single application of RIPC significantly reduces dialysis induced cardiac injury for up to 28 days. The second intervention was the stepwise reduction of dialysate sodium to reduce intra-dialytic fluid accumulation and the need for aggressive ultrafiltration. We found this to be well tolerated and an effective way to reduce inter-dialytic weight gain. This intervention did not have any adverse cardiac consequences and may have resulted in a modest improvement in cardiac tolerability while still being delivered within the context of a conventional 4-hour haemodialysis treatment. Finally, to investigate if transplantation is capable of reversing any of the factors predisposing dialysis patients to increased cardiovascular events, we chose to investigate one of the risk factors that contributes to the abnormalities of the vasculature and leave patients vulnerable to dialysis induced cardiac injury. We measured the deposition of advanced glycation end-products (via the method of skin autofluorescence) in patients who had undergone renal transplantation and compared this to existing cohorts of dialysis and chronic kidney disease patients. We found that following transplantation these markers of metabolic stress regressed to levels comparable to those seen in chronic kidney disease and much lower than seen in dialysis. This finding may suggest that the dialysis procedure itself is responsible for a great deal of metabolic stress and helps to accelerate the process by which the vasculature becomes stiff and non-compliant. In conclusion, we tested two interventions that showed potential to reduce the cardiac stress dialysis patients are subject to. Remote ischaemic preconditioning directly reduces the severity of cardiac injury and the stepwise reduction of dialysate sodium decreases inter-dialytic fluid gains and produces a modest improvement in cardiac tolerability. We also confirmed that transplantation reverses advanced glycation end-product deposition, one of the key non-traditional risk factors for cardiovascular disease in dialysis patients, giving us further insight into the ways in which transplantation improves cardiovascular outcome.