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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.

DKD is the leading cause of kidney failure in Canada and its patients suffer the highest morbidity and mortality rates of any kidney failure patient group. Current interventions including strict glycemic control only delay DKD. Thus, there is a major need to identify new therapeutic targets. High glucose (HG) is identified as a major pathogenic factor, inducing the release of growth factors leading to kidney fibrosis. Although treatments have been developed to target these factors, their effectiveness is accompanied by adverse effects due to the lack of specificity. Recently, activins have been suggested to have a prominent role in promoting renal fibrosis and developing a specific anti-activin therapy can avoid potential side effects. Although there is evidence supporting an important role for activin A (ActA) in the induction of fibrosis in DKD, whether ActB also contributes is unknown. In this study, we aim to determine the potential contribution of ActB to promoting fibrosis. Our results show that ActA and ActB are upregulated in rodent and human DKD. We show that hyperglycemia leads to the secretion of ActA and ActB by mesangial cells (MC), whereas only ActB is secreted by renal fibroblasts (RF). Similar to HG, treatment with ActA or ActB leads to Smad2/3 activation and upregulation of extracellular matrix proteins, whereas specific inhibition of either ActA or ActB attenuates these effects. We show that ActA and ActB regulate HG-induced activation of MRTF-A/SRF in MC, leading to an activated phenotype characterized by increased α-SMA expression and ECM production. Lastly, we confirm the specificity and functionality of the activin propeptides in vitro, providing evidence for their effectiveness in vivo. This study will help further our knowledge of the role activins in DKD, potentially providing an alternative therapy. / Thesis / Master of Science (MSc) / As the leading cause of end stage renal disease, diabetic kidney disease (DKD) is described as the reduction in renal function due to chronic exposure to diabetes. This thesis is aimed to understand the pathways and mechanisms that contribute to the development and progression of DKD to help identify novel therapeutic options. This project identified activin B (ActB) as a contributor to the disease and gives evidence that blocking the actions of ActB can prevent profibrotic effects in cells, similar to the profibrotic effects seen in DKD. Furthermore, this thesis demonstrates preliminary evidence for the beneficial effects of anti-ActB therapy, providing a potential alternative therapeutic option for DKD patients.

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.

Introduction Podocytes are terminally differentiated, highly specialized glomerular cells that form the final barrier to protein loss. Podocyte injury is characterised by proteinuria. Proteinuria is an important prognostic marker in kidney diseases, and lowering proteinuria has become a principal clinical goal. Compelling evidence supports the notion that continuing loss of podocytes plays a major role in the initiation and progression of glomerular diseases. It is my hypothesis that interventions that reduce the disruption by rescuing susceptible podocytes next to injured ones are potential therapies to restore podocyte phenotype and filtration behaviour, thereby protecting the kidney from progressive deterioration. Prevention of this damage, or ways to aid its recovery, could therefore be important to improving the management of human kidney diseases. Methods Transgenic mice expressing the human diphtheria toxin receptor on podocytes had been previously generated in our laboratory. Characterization of two lines showed that graded specific podocyte injury could be induced by single intraperitoneal injection of diphtheria toxin. Eight-week intervention studies involved administration of oral drug in water or food from 24h after toxin injection. Two control groups received no drug or were non-transgenic (wild-type) littermates. Primary endpoints were glomerulosclerosis and kidney function (serum creatinine). Other readouts included blood pressure, albuminuria, serum albumin, podocyte quantification and collagen staining of kidney. The angiotensin converting enzyme inhibitor (ACEi) captopril was tested because of its proven protective effect on renal function in patients with proteinuria. Subsequently another proteinuria-reducing drug, the endothelin receptor A antagonist sitaxsentan was tested alone and in combination with captopril. Results Captopril reduced proteinuria and ameliorated scarring, with matrix accumulation and glomerulosclerosis falling almost to baseline. Podocyte counts were reduced after toxin administration and showed no significant recovery irrespective of captopril treatment. In the following sitaxsentan and captopril combined intervention study, glomerular scarring was significantly reduced in all drug-treated groups either alone or in combination, but only combination drug treatment reduced glomerular damage to levels comparable to wild-type controls, demonstrating a synergistic effect of the two agents. Similarly, serum creatinine was lowered further in combined but not single drug-treated groups. Blood pressure of all drug treated mice was lowered compared to the placebo group. Surprisingly in this second study there were no significant differences in proteinuria between treated and untreated groups. Conclusion These results support the hypothesis that continuing podocyte dysfunction is a key abnormality in proteinuric disease, and plays a major role in progressive glomerulosclerosis. Both captopril and sitaxsentan alone or in combination provided protection without substantial preservation or restoration of podocyte numbers at the degree of injury induced in these experiments. Combined therapy showed a synergistic effect in protecting the kidney from progressive damage. These results suggest that protection may be at least partly due to change in podocyte phenotype. The model is ideal for studying strategies to protect the kidney from progressive damage following specific podocyte injury. Further elucidations on the mechanism of action of the drugs may aid development of superior future therapeutic treatments in the field of renal diseases.

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.

Adult Polycystic Kidney Disease (APKD) is a genetic disease transmitted in an autosomal dominant fashion. There is no cure. Treatment is of the symptoms as they appear usually in adulthood. Patients affected by APKD may receive genetic counselling from renal physicians. The aims of genetic counselling can be described through paradigms which reflect the current understanding of genetics and knowledge of the illnesses. The availability of new diagnostic techniques creates a new paradigm concerned with the ethical issues of genetic testing and counselling. An investigation into patients' knowledge, perceptions and understanding of genetic counselling was undertaken at the Renal Unit of Glasgow Royal Infirmary, prior to the establishment of a screening and counselling service for those at risk for APKD. The main findings of the study were: the majority of patients had received some genetic counselling from renal physicians; the majority of patients had relatively good knowledge of the symptoms of and treatments for APKD; nevertheless patients believed that the two most important items to be included in genetic counselling were information about the symptoms and the treatment of APKD; patients did not fully understand the genetic inheritance of APKD; they described the risk of transmission of APKD (50-50) as a medium risk; almost all patients recommended that their at risk relatives and their children be tested for APKD; prior to the availability of prenatal diagnosis, patients thought that their children should be tested between the ages of 16 and 20. A secondary study, including spouses of those with APKD and also haemophiliacs and their spouses, found that respondents favoured prenatal testing without termination of pregnancy and that both diseases were rated as being of medium severity. These findings raise ethical issues for those giving genetic counselling, and have implications for the content of genetic counselling.

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