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.

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.

Background Chronic Kidney Disease (CKD) can be described as the loss of the kidney function over time. Symptoms usually develop slowly, and it may not appear in early stages. Lab tests can confirm a CKD diagnosis. The approximate number of incidents per year is more than 200,000 cases, and approximately 30 million people are living with CKD today in the United States. This long-standing disease ultimately leads to renal failure at the end. At this present time, there are no known cures for CKD, and the only treatment available is dialysis. Objectives The purpose of this study is to determine the association between CKD and further with hemodialysis (HD) and medical condition such as cardiac complications, cardiogenic shock, hemorrhage, anemia, vascular complication, postop respiratory failure, post op infarct hemorrhage, acute renal failure, new temporary pacemaker, new permanent pacemaker, pericardial complications, and death. Study design The study employed secondary data in a cross-sectional design. Methods A sample of 106,969 was drawn from the population. The outcome variables were a diagnosis of CKD and/or CKD with HD. The predictor variables were cardiac complications, cardiogenic shock, hemorrhage, anemia, vascular complication, postop respiratory failure, post op infarct hemorrhage, acute renal failure, new temporary pacemaker, new permanent pacemaker, pericardial complications and death. Logistic regression was conducted to analyze the relationship between outcome variable and each independent variable. Variables with a p-value Results Analysis shows that subjects with cardiac complications were 17% less likely to have CKD as compared to those who did not have cardiac complications (OR: 0.83, 95% CI: 0.78-0.88). CKD patients who had cardiac complications were 18% more likely to have HD than the subjects who did not have cardiac complications (OR: 1.18, 95% CI: 1.01-1.39). Patients with cardiogenic shock were 86% more likely to have CKD than the subjects who did not have cardiogenic shock (OR: 1.86, 95% CI: 1.82-1.91). CKD patients who had cardiogenic shock were also 18% more likely to have HD than the subjects who did not have cardiogenic shock (OR: 1.18, 95% CI: 1.11-1.25). We have similar results if a patient had other conditions. Conclusion Chronic kidney disease with hemodialysis is significantly associated by the other medical conditions such as cardiac complications cardiogenic shock, hemorrhage, anemia, vascular complication, postop respiratory failure, post op infarct hemorrhage, acute renal failure, new temporary pacemaker, new permanent pacemaker, pericardial complications and death in the United States. Further studies are needed to confirm the results and to understand the prognosis.

archives@tulane.edu / Background: Chronic kidney disease (CKD) is a disease that affects 13.6% of American adults. The prevalence of abnormal serum potassium levels and their downstream renal and cardiovascular effects in CKD are not clearly understood. Objective: The objective of this project is to determine the prevalence of abnormal serum potassium in the CKD population in the United States and to identify associations between abnormal serum potassium and renal and cardiovascular endpoints in CKD patients. Paper 1: At baseline, 4.07% of CRIC study participants had hypokalemia and 7.65% had hyperkalemia. Non-Hispanic Black participants had the highest prevalence of hypokalemia (5.67%), and Hispanic CKD patients had the highest prevalence of hyperkalemia (10.92%). Women, non-Hispanic Black individuals, and individuals who were non-diabetic and/or middle-aged at baseline were likelier to experience hypokalemia at some point during the CRIC study. Male gender, Hispanic ethnicity, diabetes at baseline, higher CKD stage at baseline, and younger age at baseline were found to be risk factors for ever experiencing hyperkalemia. Overall, over 40% of participants experienced an abnormal serum potassium level at some point during the study. Paper 2: Using time-updated serum potassium, hypokalemia was associated with increased risk of ESRD. Hyperkalemia was associated with increased risk of both ESRD and CKD progression. Baseline-only modeling of hypokalemia and hyperkalemia as exposures did not identify significant associations with renal outcomes. Paper 3: Using baseline-only serum potassium, hypokalemia was associated with both all-cause mortality [HR = 1.31; 95% CI: (1.01, 1.71)] and cardiovascular disease [HR = 1.49; 95% CI: (1.18, 1.89)]. However, marginal structural models with repeated potassium measures only identified elevated risk of cardiovascular disease associated with hypokalemia [HR = 1.36; 95% CI: (1.18, 1.89)]. Conclusion: The results of this project demonstrate that abnormal serum potassium is a prevalent problem in the United States CKD population. Very low and very high potassium levels are associated with severe renal and cardiovascular outcomes, and these associations are stronger in some subgroups compared to others, including older and Hispanic CKD patients. This information can help clinicians identify individuals at high risk for severe endpoints and intervene early to prevent these outcomes from occurring. Future research should focus on establishing causality, which could provide a new treatment target for preventing renal and cardiovascular outcomes in CKD patients. / 1 / Andrei Stefanescu

Cardiovascular disease is most deadly medical condition in the United States. Medial vascular calcification is a disease that often precedes other more serious cardiovascular diseases that have high mortality. In order to research new therapies for the treatment of medial vascular calcification, an in vitro cell culture model must be developed that mimics the process in vivo. This disease is shown to be an active, cell-mediated process where the vascular smooth muscle cells (VSMCs) in the arteries are differentiating into osteoblast-like cells and depositing hydroxyapatite mineral in the artery walls. By administering inorganic phosphate to cell culture medium, an osteogenic shift can initiated in VSMCs in vitro resulting in calcium deposition and an increase in bone related proteins. We propose to develop and characterize a model for vascular calcification and investigate the effects of magnesium supplementation on in vitro calcification and cellular phosphate uptake.

Background: International guidelines provide recommendations for early chronic kidney disease care. This thesis was completed to 1) measure the quality of chronic kidney disease care and identify gaps, 2) identify reasons why patients do not receive recommended care, and 3) determine if these guideline-recommended practices are associated with better patient outcomes. Methods: Population-based cohort studies were conducted for studies 1, 3 and 4. Using consensus-based indicators, study 1 quantified the quality of care for patients with early chronic kidney disease. Study 2 was a qualitative descriptive study eliciting primary care physicians’ perceived enablers and barriers to follow-up laboratory testing to confirm chronic kidney disease. Study 3 assessed the association between non-steroidal anti-inflammatory drug (NSAID) use versus non-use and adverse clinical outcomes among older adults. Study 4 assessed whether routine serum creatinine and potassium monitoring (versus no monitoring) following angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) initiation among older adults associated with better outcomes. Results: In study 1, most recommendations were being followed; however, some care gaps were identified. For example, half of the patients with initial abnormal kidney test results did not receive follow-up tests. This finding prompted study 2, where enablers and barriers to this practice were identified. Providers were aware that they should be ordering follow-up tests and had the resources to do so. However, some providers perceived this practice as low priority. In study 3, NSAID use was associated with a higher risk of complications. In study 4, routine ACEi / ARB monitoring did not prevent adverse outcomes. Conclusions: This thesis provides a better understanding of care gaps for patients with early chronic kidney disease in Ontario, and reasons for one of these care gaps. This research also provides evidence to help strengthen guideline recommendations (NSAID avoidance) or refute them (ACEi / ARB monitoring). / Thesis / Doctor of Philosophy (PhD) / Chronic kidney disease is a medical condition where a person’s kidney function is permanently reduced. Family doctors are responsible for the care of patients with early chronic kidney disease. However, many patients may not be receiving the right treatments from their family doctors to keep their kidneys healthy. This research used Ontario healthcare data to identify care gaps for patients with early chronic kidney disease. Interviews were then done with family doctors to identify reasons for one of these care gaps; specifically, why doctors do not always repeat blood and urine tests to confirm if patients have chronic kidney disease. Finally, this research looked at whether providing certain treatments led to better patient outcomes. This information can be used to update current guidelines and to inform strategies which help patients with chronic kidney disease receive the best possible care.

Background Chronic kidney disease (CKD) is a condition characterized by gradual loss of kidney function over time. Millions of adults have CKD and those who have diabetes, hypertension, and family history of kidney failure are at highest risk of its development. Patients may develop comorbidities, such as cardiovascular disease, anemia, mineral and bone disorders, and peripheral nervous system diseases. Those with kidney failure require dialysis or kidney transplantation, as well as medications, diet therapy, restriction of fluid intake, and lifestyle modifications. The cost for such treatment represents an enormous burden on healthcare systems worldwide, costing about 8% of the Medicare budget in the U.S. Literature review findings Chronic kidney disease is now described based on internationally accepted definitions and diagnosed, when structural or functional abnormalities of the kidneys persist for more than 3 months. End-stage kidney disease is the last stage of chronic kidney disease and is associated with a decreased quality of life and life expectancy. This comprehensive literature review focuses on the effectiveness of dietary therapy in delaying the progression of CKD to end stage kidney disease (ESKD). Current evidence provides guidelines to manage ESRD with the general population. However, despite this, many clinicians do not know how to use diet as part of clinical management. Proposed methods Given the broad spectrum of different dietary therapies to decelerate progression of CKD, many providers do not utilize this information in clinical practice. A workshop hosted by registered dieticians, summarizing the most up-to-date literature on the topic of dietary interventions to slow down CKD progression would be beneficial. The workshop will measure mid-level and high-level practitioner’s knowledge on dietary therapy for CKD and assess this post-workshop. The goal is to expand the knowledge of providers and equip them with the resources necessary to educate patients on healthy dietary modifications, in order to minimize progressive CKD. Conclusions Despite the availability of dialysis and recent advancements in post-transplant care, there is a benefit to lifestyle modification. There is promising evidence that a diet low in protein, potassium, or salt and following certain diets, such as the Mediterranean diet, is beneficial in the deceleration of CKD to end stage renal disease (ESRD). A diet containing processed foods, high protein, high salt, and high potassium content has been associated with an increased risk of transition from late-stage CKD to ESRD. It is possible that these dietary recommendations may apply to prevention of CKD or ESRD. The workshop will present the most up-to-date knowledge in the area of dietary therapies for CKD. A curriculum for mid- and advanced-level health care providers will provide them with the tools necessary to provide their patients with nutrition and lifestyle management.

Context: Albuminuria, a clinical indicator of chronic kidney disease, has a high prevalence among the US population where approximately half of the people with this condition are women. In the US, most participants in food based government assistance programs are women who have food insecurity. Research indicates that obesity and diabetes, known risk factors for chronic kidney disease, are consequences of food insecurity. Aim: The aim of this study is to examine racial-ethnic differences in the relationship between food insecurity and albuminuria in women who participated in the 2011-2012 NHANES. Methods: Odds ratios from racial-ethnic specific multivariate logistic regression were used to determine the associations between food insecurity and albuminuria. Results: Among all participants, black women had the highest rate of food insecurity at 36%. From multivariate analysis, it was determined that among non-Hispanic blacks that having albuminuria was associated (OR= 3.73 95% CI 1.47-9.44) with food insecurity. However, there was no statistically significant association between food insecurity and albuminuria (OR= 1.46 95% CI .501-4.261) for non-Hispanic whites. Discussion: Significant racial-ethnic differences in the association between food insecurity and albuminuria were identified in Non-Hispanic black women. It is recommended that further studies be done to evaluate the biological basis of the relationship between albuminuria and food insecurity in black women. A public health intervention to improve food insecurity may help reduce the risk of albuminuria in black women.