Master of Science / Department of Clinical Sciences / Gregory F. Grauer / Hyperthyroidism is the most common endocrinopathy of geriatric cats and has physiologic effects on almost every organ in the body. It specifically affects the kidneys by increasing renal blood flow and glomerular filtration rate. In addition, activation of the renin angiotensin aldosterone system (RAAS) is increased and ultimately leads to efferent glomerular arteriole constriction and potentially glomerular hypertension. The classic treatment modalities for feline hyperthyroidism (anti-thyroid medication, radioiodine or surgery) have been evaluated for their overall effects on renal function. Studies have demonstrated that glomerular filtration rate (GFR) declines and serum creatinine increases with hyperthyroid treatment independent of the treatment modality. Hill’s® Prescription Diet® y/d® Feline, a relatively new dietary treatment modality for feline hyperthyroidism with controlled iodine concentrations, reduced phosphorus and protein, and increased omega-3 fatty acids, has been shown to significantly decrease thyroid hormone levels. The research provided in this report is the first evaluating the posttreatment effects of y/d® Feline on renal function. In agreement with previous studies, our research found that y/d® Feline resulted in a significant decrease in thyroid hormone levels. However, in contrast to other treatment modalities, y/d® Feline did not result in a significant decline in GFR, and it did result in a significant decline in mean serum creatinine concentration. These data indicate that y/d® Feline, as a treatment for feline hyperthyroidism, does not have a negative effect on renal function.

published_or_final_version / Pathology / Master / Master of Philosophy

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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

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.

The incidence rate of Chronic Kidney Disease¡]CKD¡^ in Taiwan is the highest among the world. This burden of disease is paralleled by enormous healthcare spending and society¡¦s pressure. Healthy People 2010 started to promote education program for the prevention of chronic kidney disease. A program has started in Taiwan since 2003 in order to control CKD progresses to end stage renal disease¡]ESRD¡^. However, few studies evaluated the effects of such program. This research will focus on the importance and outcome for the intervention of CKD education program and the impact on frequency for nephrology outpatient follow-up visit. Methods: 299 CKD patients were collected for their personal information, history of disease, and clinical values from hospitals in southern part of Taiwan. Results: The result indicated that early intervention for CKD had reduced the execration of clinical value. CKD patients with comorbidities have higher disease severity and inpatient utilization compare with those who without comorbidities. Although CKD education intervention has no significant difference on the change of clinical value, it is significant on the frequency of nephrology outpatient follow-up visit. Conclusion: Early intervention for patient with CKD has great impact on the progression of kidney failure. Effective CKD education program will increase nephrology follow-up visit so that patient could update the education plan and meet individual needs for the decrease of kidney function.

The treatment of end-stage renal disease (ESRD) by dialysis and transplantation (renal replacement therapy - RRT) imposes major social and economic burdens on the patient, the family and society. Data obtained from 2 Scottish and 4 European renal units indicate that non-renal comorbid illness significantly increased patient mortality. Furthermore, application of a simple risk stratification method based on age and comorbidity divided patients into groups which carried different survival rates. Multivariate analysis showed that even after adjustment for comorbidity and age, an apparent "centre effect" persisted which ranked the centres. A further study examined factors influencing early mortality on RRT. The method of risk stratification described can be used for comparative survival studies by national and international registries. The generic health status questionnaire (the SF-36) which has been validated in the UK was administered to patients receiving all 3 modalities of RRT and their health status compared with a large sample of the general population. Patients' quality of life was influenced by mode of treatment and like survival was also shown to relate to comorbidity. Further studies of the incidence and prevalence of chronic renal failure in Grampian showed that advancing age and comorbidity significantly influenced the decision by non-nephrologists to refer a patient to the renal service. The results of this study have manifest resource implications for the provision of renal services. A protocol for the use of erythroprotein in the Aberdeen renal unit was developed and implemented. Its efficacy was monitored by studying defined outcome measures. This study showed that formal implementation of the protocol led to an increase in the proportion of patients with haemoglobin concentrations in the acceptable range and a fall in the number of blood transfusions.