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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

Celiac disease, an inflammatory disease of small bowel caused by sensitivity to dietary gluten and related protein, affects approximately 0.5-1% of the population in the Western world. Extra-intestinal symptoms and associated diseases are increasingly recognized including diabetes mellitus type 1, thyroid disease, dermatitis herpetiformis and ataxia. There have also been a number of reports of various types of renal involvement in patients with celiac disease including diabetes nephropathy, IgA nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis, nephrotic syndrome related to malabsorption, oxalate nephropathy, and associations of celiac disease with chronic kidney disease and end-stage kidney disease. This review aims to present the current literature on possible pathologic mechanisms underlying renal disease in patients with celiac disease.

ABSTRACT Diabetes mellitus is a major cause of morbidity and mortality and is the leading cause of end-stage renal disease worldwide. New onset diabetes post renal transplantation is associated with reduced graft function, decreased patient survival and increased risk of graft loss. The immunosuppressive regimes used and dosage of corticosteroid therapy appear to impact on the incidence of new onset diabetes post renal transplantation. The objectives of this study were: to ascertain the prevalence of new onset diabetes post transplantation; to determine the association between new onset diabetes with immunosuppressive regimens and ethnicity; and to assess outcomes in terms of morbidity and mortality. The study design consisted of a retrospective analysis of 398 patient files transplanted between 01/07/1994 and 30/06/2004. Information retrieved from the files consisted of patient demographics ( age, race, gender ), weight, date of onset of diabetes, immunosuppressive regimens used, infections, cardiovascular and overall morbidity and mortality. The diagnosis of diabetes was based on the American Diabetes Association (ADA) criteria or the requirement for anti-diabetic agents. Results obtained showed that 15.58% (62/398) of patients became diabetic. The mean time to onset of diabetes was 22.9 months ( range 1 week to 100 months ). 20.21% Black patients (p=0.100), 9.42% White, 12.5% Coloured and 12% Indian patients became diabetic. Treatment with Cyclosporine( CyA) had an incidence of diabetes of 14.44%, Tacrolimus 20.25% p = 0.228, Rapamune 11.36% and Mycophenolate Mofetil 11.97%. Infections occurred in 96.77% of diabetic patients, p = <0.0001. Cardiovascular morbidity and mortality was 11.29%, p = 0.82. Overall mortality was 79.3% in the diabetic group p = 0.237, HR 1.45. In conclusion, the incidence of new onset diabetes is significant as it confers a higher risk of infections and overall mortality. Black patients are more affected, with an increased risk for those treated with Tacrolimus.

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.

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Renal cell carcinoma (RCC), following prostate and bladder tumours, is the third most prevalent genitourinary malignancy. Clear cell renal cell carcinoma makes up the bulk of RCC cases (ccRCC). Despite the fact that ccRCC is the most aggressive type of RCC, our understanding of its pathophysiology is limited. Previous research in our laboratory revealed important oncogenic roles of contactin 1 (CNTN1), a neuronal cell adhesion protein, in prostate cancer. CNTN1 is involved in a number of signalling pathways that are often changed in cancer, including the VEGFC-VEGF receptor 3 (VEFGR3)/fms-related tyrosine kinase 4 (Flt4) axis, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) axis, and the Notch signalling system. Collectively, evidence suggests that CNTN1 facilitates ccRCC. To examine this possibility, I have established stable ccRCC 786-O and A498 cell lines expressing either empty vector (EV) or CNTN1. In comparison to the respective EV lines, ectopic expression of CNTN1 enhances colony formation and cell proliferation. In comparison to A498 EV cells, A498 CNTN1 cells seems to possess enhanced migration ability based on wound healing assay. Taken together, my research provides in vitro evidence supporting CNTN1 in facilitating ccRCC pathogenesis. Future research will be required to investigate this concept using in vivo systems and primary ccRCC tumor tissues. / Thesis / Master of Science (MSc)

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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.