The increased risk of atherothrombosis in chronic kidney disease (CKD) has been under extensive examination for decades now. However, a treatment tailored for CKD patients is yet to be found. Current management plans can only tackle comorbidities and mostly fail. This thesis study examines the current literature related to CKD and thrombosis. The aim is to find a target suitable for therapeutic exploration. Normalizing the risk of thrombosis in CKD patients could curb a huge margin of their morbidity and mortality. In recent years, molecular biology studies attributed the extreme thrombogenicity in CKD to the retained uremic toxins. Indolic compounds are uremic toxins with a well described point of thrombotic activation. Of them, indoxyl sulfate is to be highlighted since it was shown to that it is one of the strongest pro-thrombotic uremic toxin. It is possible to therapeutically target this CKD specific cause of hyperthrombogenicity. Further research is very much needed in this area.

ASSOCIATION OF AGE, GENDER AND RACE IN CHRONIC KIDNEY DISEASE PATIENTS WITH AND WITHOUT DIALYSIS 1Busayo Adeyemi Onatolu, 2Hemang Panchal, 3Edward Francis Leinaar, 1*Shimin Zheng, 2Timir K. Paul 1Department of Biostatistics and Epidemiology, College of Public Health, ETSU, Johnson City, TN 37614 2Department of Internal Medicine, Quillen College of Medicine, ETSU, Johnson City, TN, 37614 3Department of Health Services Management and Policy, CPH, ETSU, Johnson City, TN 37614 *Sponsoring faculty Introduction: Studies have shown that chronic kidney disease (CKD) is common among adults in the United States. The Centers for Disease Control and Prevention (CDC) states that 30 million people, or 15% of US adults, are estimated to have CKD. Forty-eight percent of those with severely reduced kidney function are not aware of having CKD, and therefore do not receive hemodialysis (HD). Methods: A nationwide inpatient sample database from 2012-2014 was used to identify all patients admitted to the hospital using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes (n= 534,845). Patients with dialysis dependent CKD (n=8,100) and CKD without dialysis (n=51,285) were compared to non-CKD patients (n=475,460). Hierarchical logistic regression was performed and p Results: Of the 534,845 patients, 88.9% were without CKD and 9.59% had CKD without HD and 1.51% had CKD with HD. Among patients with CKD, 13.64% were on HD and 86.34% were non-HD patients. The result shows that a higher proportion of patients with CKD without HD in the ≥ 80 years age group (≥ 80 = 37.84%, 65-79 = 36.94%, 50-64 = 20.80%, 35-49 = 4.12% and 18-34 = 0.30%) and a higher proportion of patients with CKD with HD in the 65-79 years age (≥ 80 = 16.30%, 65-79 = 41.79%, 50-64 = 33.09%, 35-64 = 8.09% and 18-34 = 1.29%). The OR of age group 18-34 compared to ≥ 80 is 5.690, 95% CI: 4.202,7.705, OR 35-49 is 4.552, 95% CI: 4.552, 95% CI: 4.103, 5.050, OR of 50-64 is 3.693, 95% CI: 3.444, 3.961 and OR 65-79 is 2.626, 95% CI: 2.457, 2.807. Males had higher rates of CKD than females, without HD (Male= 63.12%, female= 36.88%, p Conclusion: From this study, males had higher rates of CKD with and without HD than females, the age group ≥ 80 years had higher proportion of CKD without HD and those between 65-79 years had higher number of CKD with HD. Whites had higher rates of CKD with and without HD than other races.

Background: Coronary artery calcification (CAC) is common in chronic kidney disease (CKD) patients, and is demonstrable in fifty percent of incident dialysis patients. Therefore, the process of CAC initiation likely occurs in the pre-dialysis period. Pre-dialysis CKD patients have been shown to have a substantially higher burden of CAC than age and sex matched controls from the general population. Consequently, the hypothesis that CKD itself is a risk factor for CAC occurrence is biologically plausible. Objective: 1) To quantify the relationship between CKD and CAC in stage three to five CKD patients without known cardiovascular disease. 2) To estimate the strengths of associations between traditional cardiovascular disease risk factors, non- traditional cardiovascular disease risk factors and CAC in this patient population. Methods: This cross-sectional study investigated one hundred and nineteen CKD patients (excluding dialysis) receiving care at a single hospital in Kingston, Ontario, Canada. For the primary objective, correlational analyses were performed to evaluate associations between a priori selected variables of kidney function and CAC scores, as well as other a priori chosen variables of interest. Results: Mean and median CAC scores were 566.5 SD: 1108 and 111 (inter-quartile range 2 to 631.5) respectively. CAC correlated with age (r = 0.44, p<0.001), body mass index (r = 0.28, p = 0.002), high density lipoprotein cholesterol (r = -0.23, p = 0.01), diabetes mellitus (r = 0.23, p = 0.01), and the cardiovascular risk score (r = 0.35; p < 0.001). By multivariable linear regression controlling for eGFR and diabetes, age (ß = 0.05, 95% CI 0.03-0.06; p<0.001), body mass index (ß = 0.04, 0.02 - 0.07; p=0.001), and serum calcium (ß = 0.9, 0.15 - 1.6; p=0.02), were risk factors for CAC. Results from multivariable logistic regression modeling demonstrated consistent findings. Limitations: Inadequate sample size and uncontrolled confounding are possible limitations, but are unlikely to have changed the main study findings. Conclusions: In this study, traditional cardiovascular disease risk factors and serum calcium were associated with coronary artery calcification. No association was demonstrated between CKD and CAC. Studies exploring potential protective mechanisms against coronary artery calcification are needed.

Malnutrition is present in up to 48% of chronic kidney disease patients on the initiation of renal replacement therapy (dialysis)1. At this time, malnutrition is an independent and significant predictor of morbidity and mortality2. As a consequence of progressive deterioration in kidney function, symptoms of decreased appetite and reduced intake are common factors leading to the decline in nutritional status3. However, at present there is little evidence to inform nutrition assessment and intervention for pre-dialysis chronic kidney disease (CKD). The purpose of this study was to provide evidence for the nutritional management of CKD patients prior to dialysis with an aim to optimise nutritional status. To address this, an investigation comprising of two phases examining nutrition assessment and intervention in a sample of pre-dialysis Stage IV and V CKD patients was undertaken. Both phases of the study were conducted through Royal Brisbane and Women’s Hospital (RBWH) Department of Renal Medicine pre-dialysis clinic. Participants met the following criteria: adult (&gt18 years) Glomerular Filtration Rate (GFR) &lt30ml/min CKD, not previously seen by a dietitian for Stage IV CKD, absence of communication or intellectual impairment inhibiting their ability to undertake the intervention and an absence of malnutrition from a cause other than CKD. Phase I was a cross-sectional investigation into the performance of a range of tools assessing nutrition status, conducted at baseline of Phase II. Phase II was a randomisedcontrolled trial designed to determine if providing individual nutrition counselling with regular telephone follow-up resulted in improved body composition, nutritional status, dietary intake and quality of life, compared with standard care. A range of intermediate, clinical and patient-centred outcome measures were collected at baseline and twelve weeks. Body composition was measured by total body potassium counting (TBK), considered a gold-standard measure of body cell mass (BCM, the body’s functional metabolising tissue). Nutritional status was measured using Subjective Global Assessment (SGA) and a number of modified versions of SGA, 7-point SGA, Malnutrition Inflammation Score (MIS) and the scored Patient-Generated Subjective Global Assessment (PG-SGA). Dietary intake was measured using 3-day food records. Quality of life was measured by Kidney Disease Quality of Life Short Form version 1.3 (KDQOL-SFTM v1.3 © RAND University), combining the Short Form-36 (SF-36), with a kidney disease-specific module4. Statistical analysis was carried out using SPSS Version 13 (SPSS Inc, Chicago, IL, USA). Phase I analysis was based on descriptive and bi-variate statistics, including chi-square, t-test and ANOVA. For phase II, change variables (Week 12 – Week 0) were created for the outcome measures (BCM, SGA tools, dietary intake (energy and protein) and the 18 KDQOL-SFTM subscales). The assessment of change in outcome measures by treatment group was undertaken by ANCOVA, adjusting for baseline values. Further multivariate analysis (ANCOVA and MANCOVA models) were created for outcome variables when confounding variables were identified and adjusted for. In Phase I, 56 patients (Male n=34; age mean (±SD) 70.7 (±14.0); GFRMDRD 22.4 (±6.5) mL/min) underwent baseline assessment. In this population the prevalence of malnutrition was 19.6% (n=11, SGA B; no C ratings). Malnutrition was associated with lower body cell mass (mean BCM, 26.3 vs. 33.4 kg p=0.007), body weight (64.8 vs. 76.1 kg p=0.042), BMI (23.7 vs. 27.6 kg/m2 p=0.015) and greater weight loss over previous 6 months (-6.2 vs. -0.1 kg p=0.004). Body cell mass indexed for height (BCM-I kg/m3.5) had a relationship with MIS (r=-0.27 p=0.063) and scored PG-SGA (r=-0.27 p=0.060), but not with 7-point SGA (F(4) 2.24 p=0.080). PG-SGA best discriminated malnutrition based on a BCM-I cut-off of &lt5.25kg/ m3.5 of all the modified SGA tools. The scored PG-SGA including the global SGA rating is recommended for use in pre-dialysis CKD. In Phase II, 50 patients, (Male n=31 (62.0%); age 69.7 (±12.0) years; GFRMDRD 22.1 (±6.9) ml/min) completed the 12 week study period (intervention n=24; standard care n=26). At 12 weeks, there was a clinically significant improvement in all outcome measures in the intervention group. There was a 3.9% (95% CI, -1.0 to 8.7%) mean difference in change for Body Cell Mass between the treatment groups, represented by a significant decrease in the standard care group and maintenance in the intervention group. Nutritional status measured by SGA improved or was maintained (24/24) in the intervention group, however, decreased in 14% (4/26) of the standard care group. Energy intake significantly improved in the intervention group resulting in a mean difference in change of 17.7kJ/kg (8.2 to 27.2 kJ/kg). Quality of life improved significantly in 10 of the 18 sub-scales in the intervention group. Significant effect modification for gender was apparent for many of the outcome variables, with females responding most significantly to the intervention treatment. This study concluded that, overall, structured nutrition intervention limits the deterioration in nutritional status, improves dietary intake and quality of life in patients with CKD prior to the onset of renal replacement therapy. This thesis makes a significant contribution to the evidence base for nutritional management of pre-dialysis Stage IV CKD. The use of SGA for nutrition assessment and including PG-SGA to measure change is recommended for routine nutrition assessment of pre-dialysis CKD. The provision of individual nutrition counselling with regular follow-up, with a focus on promoting intake provides beneficial patient outcomes supporting optimal nutritional status in pre-dialysis CKD patients.

Chronic Kidney Disease (CKD) is common and is associated with increased risk of progression to end stage renal disease, cardiovascular disease and death. CKD is a heterogeneous condition and accurately predicting an individual’s risk for adverse outcomes remains a challenge. Over the past decade there has been a focus on the identification of novel biomarkers that may help improve risk stratification and the prediction of clinical endpoints in this population. The overall aim of this research project was to investigate a series of novel biomarkers in patients from the Chronic Renal Insufficiency Standards Implementation Study (CRISIS), a prospective observational study of outcome in all cause non-dialysis dependent CKD 3-5. The biomarkers selected for this project were Anti-Apolipoprotein A-1 (Anti-apoA-1 IgG), fetuin-A, fibroblast growth factor-23 (FGF23), high sensitivity cardiac troponin T (HS-cTnT), kidney injury molecule-1 (KIM-1), N-terminal pro-brain natriuretic peptide (NT-proBNP), neutrophil gelatinase associated lipocalin (NGAL) and osteoprotegerin (OPG). These biomarkers were chosen to address the three clinical endpoints of progression, cardiovascular disease and death with biomarkers considered both individually and as groups of related markers. The first aim of this project was to examine associations between the novel biomarkers and the clinical characteristics of the CRISIS population. The second aim was to investigate the associations between novel biomarkers and the study endpoints. In the case of FGF23 longitudinal measurements were analysed and in all other cases associations between baseline levels of the markers and clinical outcomes were considered. The third aim was to consider whether the biomarkers investigated in this project actually improve parameters of risk stratification and model discrimination, thereby demonstrating a potential to improve the prediction of outcome events in the CKD population. Many of the biomarkers were independently associated with one or all of the clinical outcomes considered. Despite these associations, it was more difficult to demonstrate clear improvement in risk classification or the prediction of clinical endpoints. Baseline models of standard biochemical and clinical parameters performed very well so even biomarkers that were strongly associated with clinical outcomes resulted in only small incremental improvements in the prediction of outcome events. It is now important to focus on defining how biomarkers may fit into clinical decision pathways.

Chronic kidney disease (CKD) is an important independent risk factor in the development of cardiovascular disease (CVD). Indeed, patients with CKD are far more likely to die from CVD than reach end stage renal disease. Conventional cardiovascular risk factors and co-morbidity contribute to this increased risk of CVD. However, emerging evidence suggests other novel factors including inflammation, oxidative stress, and a shift in the balance of the vasodilator nitric oxide and vasoconstrictor endothelin system, are also important contributors. Despite increasing evidence that the endothelin system plays an important role in the development of CKD and CVD, there has been little research examining possible therapeutic benefits of its modification in patients with CKD. The overall aims of the work presented within this thesis were to examine CVD risk in patients with renal impairment and then to see what impact chronic inhibition of the endothelin system would have on risk factors for CVD and CKD progression. In the first two studies I examined markers of arterial stiffness (AS) and endothelial function in a cohort of patients with immune-mediated renal disease. I was able to show in the acute setting that improvement in renal function following treatment for these conditions leads to significant improvements in AS. Interestingly, in patients who were in remission from their renal disease, only classical cardiovascular risk factors appear to be linked to AS. In the next study I was able to prove that sitaxsentan, a selective oral ETA antagonist, did not cause functional blockade of the ETB receptor in man. This was the first study of its kind to confirm that a “selective” endothelin antagonist truly is selective in vivo: a finding that will allow more accurate mechanistic investigation of the ET system. In the final studies, I showed that in subjects with stable non-diabetic proteinuric CKD, chronic selective ETA receptor antagonism reduces blood pressure and AS, and that these systemic benefits are associated with an increase in renal blood flow and reduction in proteinuria. The reduction in proteinuria is most likely haemodynamic and linked to a fall in GFR and filtration fraction, similar to what is seen with ACE inhibitors. Importantly, these benefits were seen in patients already taking maximally tolerated renin-angiotensin aldosterone system blockade, suggesting that chronic endothelin antagonism could be an important future therapy in the management of CKD. In summary, I have shown that renal impairment can directly affect markers of arterial function and by inference increase the risk of CVD. Chronic antagonism of the endothelin system with ETA receptor blockers would appear to improve many of these biomarkers, including reductions in BP, AS and proteinuria. There were no adverse effects reported in these studies, suggesting that selective ETA antagonism may be safe enough for clinical development in CKD patients. Further larger clinical trials are warranted.

No description available.

Background and objectives: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is a systemic condition defined by an increase in cardiovascular calcifications and bone fragility. The condition is diagnosed by abnormal serum concentrations of calcium, phosphorus, parathyroid hormone and vitamin D. These biochemical abnormalities have been linked to abnormal bone metabolism as well as cardiovascular calcifications if left untreated. Phosphate binders are known to cause phosphate reduction through mechanisms involve the gastrointestinal route. Their relative effects remain uncertain. Controversy arises because of concerns related to systematic effects, tolerability, costs and impact on patient important outcomes. The objective of Chapters 2 and 3 was to explore the relative effectiveness of phosphate binders on patient-important outcomes and laboratory outcomes in patients with CKD-MBD using the frequentist and Bayesian approaches, respectively. The purpose of Chapter 4 was to critically appraise clinical practice guidelines addressing CKD-MBD. Methods and results Chapter 2: We performed network meta-analyses for all cause-mortality for individual agents (seven-node analysis) and conventional meta-analysis of calcium vs. non-calcium based phosphate binders (NCBPB) for all-cause mortality, cardiovascular mortality and hospitalization. Our results suggested higher mortality with calcium than either sevelamer in our network meta-analysis or NCBPB in our conventional meta-analysis. Conventional meta-analysis suggested no statistically difference in cardiovascular mortality between calcium and NCBPBs. Chapter 3: We performed Bayesian network meta-analyses to calculate the effect estimates (mean differences) and 95% credible intervals for serum levels of phosphate, calcium and parathyroid hormone. Moderate-quality evidence suggests superior effect of active treatment categories as compared to placebo for reducing serum phosphate. Our NMA results did not find statistically significant difference between active treatment categories in lowering serum phosphate. Chapter 4: We performed a systematic survey to critically appraise clinical practice guidelines addressing CKD-MBD. Most guidelines assessing CKD-MBD suffer from serious shortcomings using the Advancing Guideline Development, Reporting and Evaluation in Health Care instrument II (AGREE) criteria; a minority, however, fulfill the criteria. Limitations with respect to AGREE criteria do not, however, necessarily lead to inappropriate recommendations. Conclusion: Given the likely mortality reduction with sevelamer versus calcium, the results suggest that higher calcium levels associated with calcium based phosphate binders may contribute to the mortality differential. We found that most clinical practice guidelines related to CKD-MBD were not satisfactory with major problems with rigor, update and implementation. Recommendations were consistent and thus unassociated with guideline quality. In other instances, however, this may not be the case, and ensuring trustworthiness of guidelines will require adherence to methodological standards. / Thesis / Doctor of Philosophy (PhD)

Chronic kidney disease (CKD) is a major cause of morbidity and mortality, affecting more than 10% of the world’s population. CKD is associated with excessive renal fibrosis, which leads to declining kidney function and eventual kidney failure. In CKD, glomerular mesangial cells (MC), resident fibroblasts and tubular epithelial cells undergo phenotypic activation and transition in response to profibrotic and proinflammatory cytokines such as transforming growth factor β1 (TGFβ1). These activated renal cells excessively produce extracellular matrix (ECM) proteins that replace functional renal tissue and lead to renal fibrosis. Caveolae are small omega-shaped invaginations of the plasma membrane that mediate signaling transduction events. Formation of caveolae require the protein caveolin-1 (cav-1). We have previously shown that the ability of MC to produce matrix proteins is dependent on cav-1 expression. Unfortunately, clinically targeting cav-1 within the kidneys, specifically within MC, is technically challenging and as of yet unfeasible. Thus, to better understand how cav-1 deletion is protective, we carried out a microarray screen comparing cav-1 wild-type (WT) and knockout (KO) MC. Here, we discovered significant up-regulation of a TGFβ superfamily inhibitory protein, follistatin (FST). FST specifically targets and neutralizes activin A (ActA) but not TGFβ1. TGFβ1 and ActA both belong to the TGFβ superfamily of cytokines and growth factors. While TGFβ1 itself is a known key mediator of renal fibrosis, therapies aimed at directly inhibiting TGFβ1 in kidney diseases have not been successful due to opposing profibrotic and anti-inflammatory effects. ActA has been shown to act as a strong profibrotic and proinflammatory agent in various organs, including the lungs and liver. We along with others have observed elevated levels of ActA within the kidneys and serum of mice and humans with CKD. Functionally, ActA has been shown to contribute to ECM production in the kidneys. Hence, we hypothesized that ActA inhibition through FST could prove beneficial in CKD. In this thesis, our first study elucidated a novel molecular pathway by which cav-1 regulates expression of the FST in MC. Our results indicate that FST is negatively regulated by cav-1 through a PI3K/PKC zeta/Sp1 transcriptional pathway. Our second study expands on these findings and tests whether exogenous FST administration protects against the progression of CKD in a surgical mouse model of CKD. Here, we discovered that FST acts as a reactive oxygen species (ROS) scavenger and that exogenous administration of FST protects against the development of CKD through the inhibition of renal fibrosis and oxidative stress. Lastly, our third study determined whether microRNAs (miRNAs) are implicated in post-transcriptionally regulating FST through cav-1 and whether these FST-targeting miRNAs can be utilized therapeutically to protect against the development and progression of CKD. Here, we determined that a FST-targeting miRNA, microRNA299a-5p, is significantly downregulated in cav-1 deficient MC, upregulated in vivo in a mouse model of CKD and that its inhibition, in vitro and in vivo protects against the accumulation of ECM proteins and renal fibrosis. These studies collectively suggest that FST is an effective therapeutic option for the management of CKD. / Thesis / Doctor of Philosophy (PhD) / Chronic kidney disease results from excessive fibrosis (scarring) within the kidneys. The goal of this thesis is to understand the molecular mechanisms involving the regulation of an antifibrotic protein, follistatin, in glomerular mesangial cells and to identify its therapeutic potential in chronic kidney disease. This thesis has identified that follistatin, an endogenous inhibitor of the profibrotic cytokine activin A, is regulated transcriptionally by Sp1 and post-transcriptionally by microRNA299a-5p. Furthermore, this thesis has demonstrated that exogenous recombinant follistatin administration protects against the progression of chronic kidney disease and that microRNA299a-5p targeting may be an alternative approach to block renal fibrosis. These studies collectively show that follistatin is an effective treatment for the management of chronic kidney disease.

Chronic kidney disease (CKD) is a multifaceted health problem with both physical and psychological manifestations. Increased symptom burden is associated with higher risk of mortality, decreased treatment adherence, and impaired quality of life. Despite the recognition of the importance of symptoms, the symptoms and mental health of individuals with CKD remain poorly understood in terms of their measurement, epidemiology and associated service use. The chapters in this dissertation aim to inform these knowledge gaps. Chapter 2 focusses on the symptom burden of patients receiving maintenance hemodialysis treatment and uses exploratory analyses to identify intra-dialytic symptom clusters associated with prolonged dialysis treatment recovery time. Chapters 3 and 4 are population-based studies examining mental health and addictions service utilization in patients with CKD using administrative data in Ontario, Canada. Chapter 3 is a cross-sectional study evaluating the prevalence of individuals with a history of mental health and addiction service use by levels of kidney function. Chapter 4 is a retrospective cohort study evaluating the rates of mental health and addiction service use over time in patients with CKD. Together, these chapters provide further understanding of how symptoms of dialysis and mental health and addiction service use may be measured in this patient population. They also inform considerations for the design of future symptom management and system-level mental health strategies in CKD. / Thesis / Doctor of Philosophy (PhD)