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Vascular calcification (VC) is accelerated in patients with chronic kidney disease (CKD), resulting in increased risk of cardiovascular disease and mortality. Although the consequences of VC are associated with elevated pulse wave velocity (PWV) and left ventricular hypertrophy (LVH), the temporal impact on blood pressure changes is unknown. Mineral imbalance in CKD greatly contributes to the development of VC, and elevated serum phosphate is a major risk factor. Magnesium, which plays an important role in bone regulation, has been recently shown to be a modifier of VC, but whether magnesium inhibits calcification in CKD is unknown. A modified adenine model of CKD was developed in rats, characterized by mineral imbalance and progressive VC. During the development of VC, pulse pressure increased, which was driven by a drop in diastolic blood pressure, rather than systolic hypertension. Continuous pressure recordings in conscious rats using radiotelemetry revealed a significant increase in systolic variability associated with development of VC. Regional VC was associated with regional changes in the hemodynamic profile of the CKD rats. For example, only thoracic aortic calcification was associated with elevated PWV and pulse pressure. In contrast, the presence of abdominal and thoracic calcification differentially affected proximal and distal arterial pressure wave forms. CKD animals exhibited LVH, which was further increased by the presence of VC. In addition, fibroblast growth factor 23, which regulates renal excretion of phosphate, was elevated in CKD animals at every time point and was associated with LVH independently from VC. Development of VC was characterized in an in vitro organ model. Phosphate elevation in vitro caused VC in aortas. In vitro, magnesium supplementation inhibited initiation and progression of VC. CKD animals given a magnesium diet also demonstrated attenuated development of VC. In patients with stage 3-5 CKD (excluding dialysis), dietary phosphate was associated with the progression of coronary artery calcification even after adjusting for use of phosphate binders, total dietary energy and total dietary protein. Given the serious negative outcomes associated with development of VC, these findings fill key gaps in knowledge regarding the detection, management, prevention and treatment of VC in CKD. / Thesis (Ph.D, Pharmacology & Toxicology) -- Queen's University, 2013-12-01 15:12:54.388

The surgical management of renal masses involves either radical nephrectomy (RN) or partial nephrectomy (PN). The relationship between treatment choice and definitive outcomes of CKD are lacking. Our aim was to examine whether PN is associated with a lower risk of end-stage renal disease (ESRD) requiring renal replacement therapy (RRT). We performed a population-based, retrospective cohort study with data from administrative databases in the province of Ontario, Canada. We included individuals with renal cell carcinoma diagnosed between 1995 and 2010. Cox proportional hazards, propensity score, and competing risks models were used to assess the impact of treatment. PN compared to RN reduces the risk of ESRD in a modern cohort of patients (2003-2010). PN is associated with a lower risk of CKD, reduced cardiac morbidity, and improved overall survival. We provide further evidence for the benefit of PN compared to RN, particularly related to definitive outcomes of renal failure.

The surgical management of renal masses involves either radical nephrectomy (RN) or partial nephrectomy (PN). The relationship between treatment choice and definitive outcomes of CKD are lacking. Our aim was to examine whether PN is associated with a lower risk of end-stage renal disease (ESRD) requiring renal replacement therapy (RRT). We performed a population-based, retrospective cohort study with data from administrative databases in the province of Ontario, Canada. We included individuals with renal cell carcinoma diagnosed between 1995 and 2010. Cox proportional hazards, propensity score, and competing risks models were used to assess the impact of treatment. PN compared to RN reduces the risk of ESRD in a modern cohort of patients (2003-2010). PN is associated with a lower risk of CKD, reduced cardiac morbidity, and improved overall survival. We provide further evidence for the benefit of PN compared to RN, particularly related to definitive outcomes of renal failure.

The investigation of renal pathophysiology and toxicology has traditionally been advanced by the development of increasingly defined and refined in vitro preparations. This study has sought to develop and evaluate various methods of producing pure samples of renal proximal tubules (PTs) from the Fischer rat. The introduction summarised the most common in vitro preparations together with the parameters used to monitor viability - particularly with regard to toxic events. The most prevalent isolation methods have involved the use of collagenase to produce dissociation of the cortex. However, the present study has shown that even the mildest collagenase treatment caused significant structural damage which resulted in a longevity of only 3hr in suspension. An alternative mechanical isolation technique has been developed in this study that consists of perfusion loading the renal glomeruli with Fe304 followed by disruption of the cortex by homogenisation and sequential sieving. The glomeruli are removed magnetically and the PTs then harvested by a 64μM sieve. PTs isolated in this way showed a vastly superior structural preservation over their collagenase isolated counterparts; also oxygen consumption and enzyme leakage measurements showed a longevity in excess of 6hr when incubated in a very basic medium. Attempts were then made to measure the cytosolic calcium levels in both mechanical and collagenase isolated PTs using the fluorescent calcium indicator Fura. However results were inconclusive due to significant binding of the Fura to the external PT surfaces. In conclusion, PTs prepared by the present mechanical isolation technique exhibit superior preservation and longevity compared with even the mildest collagenase isolation technique and hence appear to offer potential advantages over collagenase isolation as an in vitro renal system.

Chronic renal failure patients develop a coagulopathy primarily due to reversible platelet dysfunction. This coagulopathy makes certain anaesthetic techniques and procedures such as neuraxial anaesthesia and invasive line placement possibly contra-indicated or risky. There is no evidence to suggest that the degree of platelet dysfunction is proportional to the degree of renal dysfunction. In this research project the platelet function of 39 end stage renal failure patients, who received regular dialysis and who presented to theatre for vascular access, was assessed using the thromboelastogram. A bleeding time was also performed pre-operatively. A linear regression model was used to determine if the bleeding time, plasma urea, plasma creatinine or creatinine clearance could predict maximum amplitude (and therefore clot strength) on the thromboelastogram. No such regression could be found. The clinical implication of this result is that there exists no "safe" plasma urea or creatinine, below which it is safe to perform procedures which are contra-indicated in coagulopathies. The degree of renal dysfunction did not predict the degree of platelet dysfunction. Since dialysis reverses the platelet dysfunction, the question that should be asked before performing such a procedure is not "how severe is the renal dysfunction?" but rather "has the patient been receiving regular dialysis?"

Perceived benefits and burdens encountered by relatives caring for person on long-term haemodialysis in Johannesburg. This study examines the perceived benefits and burdens of family members caring for persons on long term Haemodialysis. The caregiver burden scale by Elmastahl, Malmeberg and Annerstedtl (1996) was used for the purposes of the study. The participants were selected by Census (total) sampling. The sample consisted of family caregivers who were 18 years and above who were selected from three haemodialysis units in Johannesburg. Permission to conduct the study was requested and granted from all relevant authorities. One hundred and fifty questionnaires were distributed amongst the three haemodialysis units of which seventy nine participants responded to the study. Data were analysed using the statistical package STATA version 12. Demographic data and the caregiver burden scale were analysed through frequency counts, percentages and graphs were constructed from the collected data and analysed. Cross tabulations, using Fisher’s exact test were performed to determine the relationship between the demographic information and factors of the caregiver burden scale. The results are presented in the form of tables and graphs. Semi structured questionnaire with an option for elaboration were analysed using content analysis to enumerate a deeper understanding of the perceived burdens and benefits of caring for a person on Haemodialysis. Findings from the study concluded that family caregivers have encountered both benefits and burdens when caring for a person on Haemodialysis. The following factors have emerged namely demographics which include age, gender, relation to patient, highest education level, employment, ethnicity and duration of care and the factors surrounding general strain, isolation, disappointment, emotional involvement and environment. The factors, whether good or poor, are not always a predictor of perceived benefits and burdens of caring for persons on long term haemodialysis. The overall caregiver burden score, inclusive of all factors, showed a median score of 46.59% of all family caregivers’ experienced burden in caring for their relative on haemodialysis. Health education and support for the family caregivers proved to be a need in improving and reducing the caregiver burden. Caregiver health is quickly becoming a public health care issue that requires a more focused attention from health professionals, policy makers and caregivers themselves to ensure the health and safety of those dedicating their lives to the care of their relatives on haemodialysis.

There is much observational evidence to suggest that patients with chronic kidney disease are biologically 'older' than their unaffected peers. This is most obviously seen with cardiovascular disease: young patients on haemodialysis have a relative risk of cardiovascular mortality similar to that of people over 50 years their senior in the general population. Moreover, there are striking analogies between the effects of physiological ageing and uraemia on the structure and function of the heart and vasculature. Despite this, little work has been published looking at whether these similarities are reflected at a molecular and cellular level. Two processes implicated in ageing are autophagy and senescence. There is much inferred evidence that these processes are affected by chronic kidney disease. The aim of this work was to investigate whether autophagy and senescence are indeed altered in the uraemic heart, whether these processes might be linked, and whether the findings of these enquiries might suggest their involvement in the pathogenesis of the prematurely aged cardiac phenotype. An in vitro model of the uraemic myocardium was created using rat cardiac myoblast cells exposed to the uraemic toxin indoxyl sulphate, and in vivo models using adenine-diet and subtotal (5/6) nephrectomy rodents. Autophagy was assayed using immunoblotting, PCR array, immunohistochemistry and fluorescence microscopy, and senescence by immunoblotting and as part of an ageing-dedicated PCR array. Though not achieving statistical significance, markers of autophagy activity appeared to be increased in rat cardiac myoblast cells exposed to indoxyl sulfate, and in cardiac tissue from adenine-diet rats. Interestingly markers of autophagy activity were significantly increased in hepatic tissue from subtotal nephrectomy rats. PCR of RNA purified from cardiac tissue from adenine-diet rats demonstrated an expression of ageing-related genes analogous to that in physiological ageing. Though limited by numbers, these findings present evidence to suggest that autophagy may be upregulated as a protective mechanism in the progeroid uraemic heart, a situation possibly comparable to that in physiological ageing. Changes in cardiac autophagy and ageing in uraemia present new avenues for translational research into pathological ageing in chronic kidney disease.

Renal blood flow and micropuncture studies were conducted in late gestation fetal sheep (gestational age 134 - 141 days; term 150 days) and neonatal lambs (8 - 18 days after birth) to study the forces involved in glomerular filtration (GFR) and characterize the tubuloglomerular feedback (TGF) system during development. These studies required the kidney to be immobilized so stable models in acutely prepared anaesthetized animals were developed. Fetuses were studied in a heated water bath exteriorized from the uterus but with an intact umbilical circulation. The lower GFR in fetuses than lambs was found to be due to both lower net filtration pressures (P<0.001) and a lower ultrafiltration coefficient (P<0.001). TGF was present at both ages, but in fetuses the sensitivity was higher (P<0.001) and reactivity was lower (P<0.001). The reduction in TGF sensitivity between fetal and neonatal life may facilitate the increase in renal blood flow and GFR which occurs at this time. In both fetuses and lambs the sensitivity of the TGF curve was reduced by volume expansion (P<0.001, P<0.05) and reactivity was reduced in lambs (P<0.001). Furosemide abolished TGF at both ages. In both fetuses and lambs, TGF reactivity was increased by inhibition of neuronal nitric oxide synthase (nNOS; P<0.01, P<0.001) and in lambs, TGF sensitivity was increased (P<0.01). This indicates that nitric oxide produced by the macula densa modulates TGF during development. In offspring destined to become hypertensive due to maternal dexamethasone treatment in early gestation TGF sensitivity tended to be enhanced in fetal life and was enhanced in lambs (P<0.01). Increased TGF sensitivity may contribute to the development of hypertension in this model of developmental programming. The effects of nNOS inhibition were attenuated in these animals, suggesting that they have low tonic production of nitric oxide by the macula densa. In fetuses whose mothers had been subtotally nephrectomized prior to mating to induce maternal mild renal impairment, GFR was increased (P<0.01) but net filtration pressure was reduced (P<0.001) so the ultrafiltration coefficient was increased (P<0.001). TGF sensitivity was normal and the effects of nNOS inhibition were similar to normal fetuses.

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