A thesis submitted to the Faculty of Health Sciences, University of the Witwatersrand in fulfilment of the requirements for the degree of Doctor of Philosophy. Johannesburg, 2017. / Background Abnormalities of mineral bone disease have been consistently associated with adverse clinical outcomes in patients with chronic kidney disease (CKD). The consequences of these changes have also been shown to differ across races. However, in Africa the impact of derangements of CKD -mineral and bone disorder (CKD-MBD) on patients with CKD is largely unknown. In addition, studies from the USA have reported racial variations in markers of CKD and it remains unclear whether genetic factors may explain this discrepancy in the levels of biochemical markers of CKD-MBD across ethnic groups. Therefore, this study has been conducted to determine the existence of racial differences in the levels of fibroblast growth factor 23(FGF23) and traditional markers of mineral bone metabolism in a heterogeneous African CKD population, and to provide important insights into the pattern and genetic variability of CKD-MBD in sub-Saharan Africa. Methods This was a cross sectional multicenter study carried out from April 2015 to May 2016, involving two hundred and ninety three CKD patients from three renal units in Johannesburg, South Africa. The retrospective arm of this study involved two hundred and thirteen patients undergoing maintenance haemodialysis (MHD) from two dialysis centers in Johannesburg between January 2009 and March 2016. The first part of this study described the pattern of CKD-MBD in MHD patients using traditional markers of CKD-MBD. The second part of the study looked into the spectrum of CKD-MBD and racial variations in markers of CKD-MBD in pre dialysis and dialysis patients. This was followed by the genetic aspect of the study that examined the influence of vitamin D receptor polymorphisms on biochemical markers of mineral bone disorders. Lastly, the study also evaluated the association between markers of CKD-MBD and mortality in MHD patients. Results The prevalence of hyperparathyroidism (iPTH>150 pg/mL), hyperphosphataemia, hypocalcaemia and 25-hydroxyvitamin D deficiency (<30 ng/mL) was 73.4%, 57.0%, 20.3% and 80.7 % respectively in our MHD patients. The combination of markers of bone turnover (iPTH>150 pg/mL and total alkaline phosphatase > 112 U/L) suggestive of high turnover bone disease, was present in 47.3 % of the study population. The odds ratios for developing secondary hyperparathyroidism with hypocalcaemia and hyperphosphataemia were 5.32 (95% CI 1.10 - 25.9, P =0.03) and 3.06 (95 % CI 1.15 - 8.10, P =0.02) respectively. The 293 CKD patients (208 blacks, 85 whites) had an overall mean age of 51.1±13.6 years, and black patients were significantly younger than the white patients (48.4 ±.13.6 versus 57.1±15.5 years; p<0.001). In comparison to whites, blacks had higher median iPTH (498 [37-1084] versus 274[131-595] pg/ml; P=0.03), alkaline phosphatase (122[89-192] versus 103[74-144] U/L; P=0.03) and mean 25- hydroxyvitamin D (26.8±12.7 versus 22.7 ±12.2 ng/ml, P=0.01) levels, while their median FGF23 (100 [34-639] versus 233[80-1370] pg/ml; P=0.002) and mean serum phosphate (1.3±0.5 versus 1.5±0.5, P =0.001) levels were significantly lower. With the exception of vitamin D receptor (VDR) Taq I polymorphism, the distribution of the VDR polymorphisms differs significantly between blacks and whites. In hemodialysis patients, the BsmI Bb genotype was significantly associated with moderate secondary hyperparathyroidism (OR, 3.88; 95 CI 1.13-13.25, P=0.03) and severe hyperparathyroidism (OR, 2.54; 95 CI 1.08-5.96, P=0.03). Patients with high total alkaline phosphatase (TAP) had significantly higher risk of death compared to patients with TAP <112 U/L (hazard ratio, 2.50; 95% CI 1.24–5.01, P = 0.01). Similarly, serum calcium >2.75 mmol/L was associated with increased risk of death compared to patients within levels of 2.10–2.37 mmol/L (HR 6.34, 95% CI 1.40–28.76; P = 0.02). The HR for death in white patients compared to black patients was 6.88; 95% CI 1.82–25.88; P = 0.004. Conclusions Secondary hyperparathyroidism and 25–hydroxyvitamin D deficiency were common in our haemodialysis patients. The study also highlighted the existence of racial differences in the circulating markers of mineral bone disorders in our African CKD population. In addition, the study showed that both moderate and severe secondary hyperparathyroidism are predicted by the BsmI Bb genotype, and the over expression of this genotype in black patients may partly explain the ethnic variations in the severity of secondary hyperparathyroidism in the CKD population. High levels of serum alkaline phosphatase, hypercalcaemia, and white race are associated with increased risk of death in MHD patients. / LG2018

Diabetic kidney disease (DKD) is the leading cause of end stage renal disease worldwide and occurs in up to 40% of patients with diabetes. The standard of care for DKD treatment has not kept up with the current health epidemic, which has led to a heavy economic toll and substantial health burden. Targeting either cell surface (cs)GRP78, activated α2-macroglobulin (α2M*) or preventing their interaction may provide a novel anti-fibrotic therapeutic target for the treatment of DKD and potentially non-diabetic chronic kidney disease (CKD) as well. Previously our lab has shown that HG-induced csGRP78 is a mediator of PI3k/Akt signaling and downstream extracellular matrix (ECM) protein production in glomerular mesangial cells (MC). However, the ligand responsible for activating high glucose (HG)-induced csGRP78 had not yet been determined. We have shown thus far that α2M is endogenously produced, secreted, and activated (denoted α2M*) in HG by MC, which leads to its binding to and activation thereof csGRP78. Further, α2M knockdown or α2M* neutralization attenuated Akt activation, the production of the profibrotic cytokine connective growth tissue factor (CTGF) and ECM proteins fibronectin and collagen IV. We have also shown that integrin β1 (Intβ1), a transmembrane receptor, associated with csGRP78 under HG conditions and likely acts as a tether to present csGRP78 completely extracellularly on MC. Interestingly, Intβ1 activation, even in the absence of HG, was sufficient to induce csGRP78 translocation. Further, inhibition of either csGRP78 or Intβ1 prevented synthesis, secretion and signaling of TGFβ1. This data implicates a role for Intβ1 as a required signaling partner for csGRP78-mediated profibrotic signaling. To further our understanding of csGRP78/ α2M*’s role in DKD, we investigated their ability to mediate TGFβ1 signaling through its non-proteolytic activator thrombospondin-1 (TSP1). Here, HG-induced TSP1 expression, ECM deposition, and activation of TGFβ1 was regulated by the PI3k/Akt pathway via csGRP78/α2M* in MC. Furthermore, we assessed whether this csGRP78/ α2M* axis is relevant to promoting profibrotic signaling in other renal cell types, including proximal tubule epithelial cells (PTEC) and renal fibroblasts (RF), that contribute to the pathogenesis of both later stage DKD and non-diabetic CKD. We show evidence here that HG and direct treatment with TGFβ1, a key pathologic regulator of kidney fibrosis, induce GRP78 surface translocation as well as the endogenous production and activation of α2M in both PTEC and RF. Inhibition of either csGRP78 or α2M* prevented TGFβ1 signaling measured as Smad3 activation as well as downstream ECM production. Interestingly, inhibition of this pathway under direct TGFβ1 treatment did not prevent Smad3 activation, implicating a role for Smad-independent TGFβ1 signaling through this axis. We identified the known noncanonical TGFβ1 signaling partners, yes associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ), are mediated by csGRP78 and α2M*. Lastly, we evaluated the potential therapeutic benefit of inhibiting csGRP78/α2M* interaction in the kidney fibrosis model, unilateral ureteral obstruction (UUO). Here, we show evidence that inhibition of this signaling axis using an inhibitory peptide can prevent renal fibrosis. Whether this peptide also prevents fibrosis in DKD is currently being assessed. Together, these studies strongly implicate targeting csGRP78/α2M* interaction as a novel anti-fibrotic therapeutic intervention for early and late stage DKD, as well as a potential role in non-diabetic CKD. / Thesis / Doctor of Philosophy (Medical Science) / Diabetic kidney disease is the leading cause of kidney failure in developed nations. This progressive disease leads to the loss of kidney function due to an accumulation of scar proteins in the kidney over time. High glucose is a major factor that causes this to occur. Our lab studies specific kidney cells called mesangial cells, proximal tubule epithelial cells, and fibroblasts that produce scar proteins in the presence of high glucose. We have shown that when these cells are treated with high glucose, this causes the movement of a protein called GRP78 that normally resides inside the cell to move to the cell’s surface where it can interact with other proteins. My research has established that the proteins alpha 2-macroglobulin (ɑ2M), integrin β1 (Intβ1), and thrombospondin-1 (TSP1) can bind to GRP78 on the cell surface and cause cells to make scar proteins. Preventing ɑ2M or Intβ1 from binding to GRP78 or preventing TSP1 production prevents mesangial cells from making scar proteins when exposed to high glucose. In a mouse model that overproduces these scar proteins, we showed that preventing cell surface GRP78 and α2M interaction prevents scar protein production and is thus a novel potential treatment option for kidney disease.

End-stage renal disease (ESRD), or kidney failure, is a serious illness with significant health consequences and high-cost treatment options. Since the early 1980s, the number of Canadians with ESRD has more than quadrupled (CIHI, 2001), leading to questions about the current and future impact of the disease on public health, quality of life, health spending, and patients’ productivity. Using an economic burden of illness approach, this thesis estimates ESRD’s “direct” health care costs and “indirect” costs, such as productivity losses due to premature death and short- and long-term disability. It also projects future results under various alternative assumptions using a multi-state discrete time Markov model. The analysis suggests that, although less than 0.1% of Canadians have ESRD, it generated direct health care costs of $1.3 billion in 2000 or $51,099 per person with ESRD. That compares to $3,183 per capita for Canadians overall (CIHI, 2002b). Adding indirect morbidity and mortality costs brings the total to $1.9 billion. Rising ESRD numbers suggest higher costs in the future. Further analysis explored the effect of various assumptions about drivers of past trends, such as population growth, changes in the age structure, and the prevalence of conditions known to cause ESRD (e.g. diabetes). Projections were most sensitive to assumptions about the rate at which new cases are diagnosed. If current trends continue, the total economic burden of the disease can be expected to reach $7.9 billion by 2015 (year 2000 dollars). On the other hand, if the rate of new cases in 2000 were maintained, the economic burden of illness would be $5.7 billion in 2015. Nevertheless, under this and many other assumptions, there is likely to be a significant gap between available organs for transplant and the demand for transplantation. The likely effects of various options for addressing this gap are also explored. / Thesis / Doctor of Philosophy (PhD)

Introdução: O perfil de morbidade e mortalidade no Brasil passou por uma transição demográfica, com o aumento da prevalência de doenças crônicas na população em geral, tais como diabetes mellitus (DM) e hipertensão arterial (HA), e como consequência, a doença renal crônica (DRC). Na última década, a DRC tem sido apresentada como um grande desafio para a saúde pública no Brasil e no mundo. Objetivo: O objetivo deste estudo foi identificar os fatores envolvidos na progressão da doença renal dos pacientes atendidos no Ambulatório de Uremia do HCFMRP-USP. Material e métodos: Trata-se de um estudo epidemiológico, transversal e retrospectivo de prontuários de pacientes do Ambulatório de Uremia, no período entre 2002 e 2012. Os dados foram extraídos dos registros médicos para a análise quantitativa e qualitativa. Resultados: A análise mostrou que 53% dos indivíduos eram do sexo masculino, com idade média de 61,21 anos. A mortalidade foi maior entre os idosos, que também apresentaram menor tempo de seguimento ambulatorial. A doença de base principal foi a HA (42,94%) e o tempo médio de seguimento foi de 11,23 meses. O encaminhamento para hemodiálise (44,48%) foi o desfecho clínico mais comum. Os principais fatores relacionados à progressão da DRC foram baixos níveis séricos de albumina, baixo valor de depuração da creatinina, pressão arterial não controlada e níveis séricos elevados de colesterol total. Discussão: A DRC tem aumentada progressivamente na população, especialmente entre os idosos, onde a taxa de mortalidade é maior e eles têm menos tempo de acompanhamento. As causas mais comuns das doenças de base foram HA e DM e vários fatores estavam envolvidos na progressão da doença renal. Aqueles indivíduos que tiveram DM como doença de base evoluíram mais rápido do que os outros para diálise. Conclusão: Os níveis séricos baixos de albumina, baixo valor de depuração da creatinina, pressão arterial não controlada e níveis séricos elevados de colesterol total são fatores envolvidos na progressão da doença renal, e são fatores modificáveis que através de intervenções multidisciplinares durante o tratamento conservador pode retardar a progressão da DRC para diálise. / Introduction: The profile of morbidity and mortality in Brazil has undergone a demographic transition, with increasing prevalence of chronic diseases in the general population, such as diabetes mellitus (DM) and hypertension (H), and as a consequence the chronic kidney disease (CKD). In the last decade the CKD has been presented as a major challenge for public health in Brazil and worldwide. Objective: This study aims was to identify the factors involved in the progression of renal disease of patients attending in the Outpatient Uremia of the HCFMRP-USP. Material and methods: This is an epidemiological, cross-sectional and retrospective analysis of medical records of patients of Outpatient Uremia in the period between 2002 and 2012. The data were extracted of medical records for quantitative and qualitative analysis. Results: The analysis showed that 53% of subjects were male, with a mean age of 61.21 years. Mortality was higher among the elderly, who also presented shorter time of outpatient follow-up. The main underlying disease was H (42.94%) and the mean time of follow-up was 11.23 months. The referral for hemodialysis (44.48%) was the clinical outcome more common. The main factors related to the progression of CKD were low serum albumin, low value of creatinine clearance, high blood pressure levels and high serum levels of total cholesterol. Discussion: The CKD has been progressively increasing in the population, especially among the elderly, where the mortality rate is higher and they have less time of follow-up. The most common causes of underlying disease were H and DM and several factors were involved in the progression of kidney disease. Those individuals who had DM like underlying disease evolved faster than the others to dialysis. Conclusion: Low serum levels of albumin, low value of creatinine clearance, high blood pressure levels and high serum levels of total cholesterol are factors involved in the progression of renal disease, and are modifiable factors that through multidisciplinary interventions during conservative treatment can slow the progression of CKD to dialysis.

Chronic kidney disease (CKD) is a non-communicable progressive disease that can lead to kidney failure or end-stage renal disease. In Nigeria, many people do not have access to health care due to extreme poverty, which means that those suffering from diabetes or high blood pressure, or both diseases, which have been identified as the 2 main risk factors, may not know their health status. The purpose of this phenomenological study was to explore the level of CKD awareness among Nigerians and if cultural beliefs affect individuals' health seeking behaviors because of the diverse nature of the Nigerian population. The protection motivation theory provided the framework for the study. Data were collected through semi-structured interviews with 14 participants, and data analysis included traditional coding. Findings indicated that CKD awareness in Nigeria is low. The social change implication is that the findings may be used to increase awareness of the CKD mortality and morbidity rate in Nigeria to facilitate the development and implementation of health policies that could lower the morbidity and mortality rate of CKD.

Introdução: O perfil de morbidade e mortalidade no Brasil passou por uma transição demográfica, com o aumento da prevalência de doenças crônicas na população em geral, tais como diabetes mellitus (DM) e hipertensão arterial (HA), e como consequência, a doença renal crônica (DRC). Na última década, a DRC tem sido apresentada como um grande desafio para a saúde pública no Brasil e no mundo. Objetivo: O objetivo deste estudo foi identificar os fatores envolvidos na progressão da doença renal dos pacientes atendidos no Ambulatório de Uremia do HCFMRP-USP. Material e métodos: Trata-se de um estudo epidemiológico, transversal e retrospectivo de prontuários de pacientes do Ambulatório de Uremia, no período entre 2002 e 2012. Os dados foram extraídos dos registros médicos para a análise quantitativa e qualitativa. Resultados: A análise mostrou que 53% dos indivíduos eram do sexo masculino, com idade média de 61,21 anos. A mortalidade foi maior entre os idosos, que também apresentaram menor tempo de seguimento ambulatorial. A doença de base principal foi a HA (42,94%) e o tempo médio de seguimento foi de 11,23 meses. O encaminhamento para hemodiálise (44,48%) foi o desfecho clínico mais comum. Os principais fatores relacionados à progressão da DRC foram baixos níveis séricos de albumina, baixo valor de depuração da creatinina, pressão arterial não controlada e níveis séricos elevados de colesterol total. Discussão: A DRC tem aumentada progressivamente na população, especialmente entre os idosos, onde a taxa de mortalidade é maior e eles têm menos tempo de acompanhamento. As causas mais comuns das doenças de base foram HA e DM e vários fatores estavam envolvidos na progressão da doença renal. Aqueles indivíduos que tiveram DM como doença de base evoluíram mais rápido do que os outros para diálise. Conclusão: Os níveis séricos baixos de albumina, baixo valor de depuração da creatinina, pressão arterial não controlada e níveis séricos elevados de colesterol total são fatores envolvidos na progressão da doença renal, e são fatores modificáveis que através de intervenções multidisciplinares durante o tratamento conservador pode retardar a progressão da DRC para diálise. / Introduction: The profile of morbidity and mortality in Brazil has undergone a demographic transition, with increasing prevalence of chronic diseases in the general population, such as diabetes mellitus (DM) and hypertension (H), and as a consequence the chronic kidney disease (CKD). In the last decade the CKD has been presented as a major challenge for public health in Brazil and worldwide. Objective: This study aims was to identify the factors involved in the progression of renal disease of patients attending in the Outpatient Uremia of the HCFMRP-USP. Material and methods: This is an epidemiological, cross-sectional and retrospective analysis of medical records of patients of Outpatient Uremia in the period between 2002 and 2012. The data were extracted of medical records for quantitative and qualitative analysis. Results: The analysis showed that 53% of subjects were male, with a mean age of 61.21 years. Mortality was higher among the elderly, who also presented shorter time of outpatient follow-up. The main underlying disease was H (42.94%) and the mean time of follow-up was 11.23 months. The referral for hemodialysis (44.48%) was the clinical outcome more common. The main factors related to the progression of CKD were low serum albumin, low value of creatinine clearance, high blood pressure levels and high serum levels of total cholesterol. Discussion: The CKD has been progressively increasing in the population, especially among the elderly, where the mortality rate is higher and they have less time of follow-up. The most common causes of underlying disease were H and DM and several factors were involved in the progression of kidney disease. Those individuals who had DM like underlying disease evolved faster than the others to dialysis. Conclusion: Low serum levels of albumin, low value of creatinine clearance, high blood pressure levels and high serum levels of total cholesterol are factors involved in the progression of renal disease, and are modifiable factors that through multidisciplinary interventions during conservative treatment can slow the progression of CKD to dialysis.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-05-06T17:58:43Z No. of bitstreams: 1 lucianadossantostirapani.pdf: 1416883 bytes, checksum: 1a79bea047bbedac18db6f9798555854 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-06-08T14:41:23Z (GMT) No. of bitstreams: 1 lucianadossantostirapani.pdf: 1416883 bytes, checksum: 1a79bea047bbedac18db6f9798555854 (MD5) / Made available in DSpace on 2016-06-08T14:41:23Z (GMT). No. of bitstreams: 1 lucianadossantostirapani.pdf: 1416883 bytes, checksum: 1a79bea047bbedac18db6f9798555854 (MD5) Previous issue date: 2013-08-02 / Introdução: O Serviço social entra oficialmente para o rol de profissões da saúde com a resolução do ministério da saúde nº 218/97. Esse reconhecimento da profissão perpassa um processo histórico, marcado pelas condições históricas nas quais a saúde pública se desenvolveu no Brasil e pelo reconhecimento social da profissão. Dentro da intervenção do Serviço Social na saúde, encontramos um novo campo de atuação que é o da nefrologia, uma atuação que, nos centros de Terapia Renal Substitutiva (TRS), possui um respaldo legal, sendo um reconhecimento da importância dos assistentes sociais na composição das equipes mínimas de atenção ao usuário com Doença Renal Crônica (DRC) em TRS. A associação entre fatores socioeconômicos e incidência e prevalência de DRC está bem determinada na literatura. Indubitavelmente, a etnia é o fator social mais estudado no que diz respeito à incidência e prevalência da DRC. Apenas recentemente, fatores educacionais têm sido abordados com relação à DRC, analisando a importância do autoconhecimento da patologia e a melhora dos desfechos. Um problema frequentemente abordado é a dificuldade de acesso aos serviços de saúde, tanto em países desenvolvidos, com modelos de sistemas de saúde que não são universais, como nos Estados Unidos, quanto em países em desenvolvimento, com populações com baixo nível socioeconômico, como o Brasil. Fatores como o gênero também tem sido abordados em poucos estudos, com mulheres tendo maior incidência de DRC. Quando avaliamos a influência desses mesmos fatores na progressão da DRC, há apenas escassos e fragmentados estudos que avaliam a questão, e vemos claramente que os estudos que avaliam a progressão da DRC abordam prioritariamente fatores biológicos. O objetivo deste estudo foi caracterizar o perfil social dos usuários com doença renal crônica pré-dialítica nos estágios 3, 4 e 5, como também avaliar o impacto das variáveis socioeconômicas na progressão da DRC pré-dialítica nos estágios estudados. Usuários e Métodos: Foi feito um estudo de coorte retrospectivo, período de acompanhamento de janeiro de 2002 a dezembro de 2009. As variáveis analisadas foram sociodemográficas, clínicas e laboratoriais. Os critérios de inclusão: usuários com mais de 18 anos de idade, DRC estágios 3A, 3B, 4 e 5, acompanhados por mais de três meses. Análise Estatística: Os usuários foram divididos de acordo com a vulnerabilidade social (VS). Para calcular a VS, foram utilizadas três técnicas estatísticas em seqüência, análise fatorial, análise de cluster (Cluster) e análise discriminante. Os dados sociodemográficos, clínicos e laboratoriais foram avaliados para cada grupo de VS. Foi realizada uma análise descritiva dos dados, expressos em média ± desvio padrão, mediana ou percentagem, de acordo com a característica da variável. Para avaliar a normalidade, utilizamos o teste de Kolmogorov-Smirnov. Diferenças entre os grupos foram analisadas pelo teste t para amostras independentes ou o teste de Wilcoxon para as comparações não-paramétricas. Um teste de χ2 foi usado para variáveis categóricas. A sobrevida foi analisada com curvas de sobrevida de Kaplan-Meier. O desfecho foi mortalidade ou iniciar a terapia renal substitutiva (TRS), analisadas por uma regressão de Cox. Resultados: Foram avaliados 209 usuários, acompanhados por um período de 7 anos, 29,4% foram classificados como vulneráveis. Não observamos diferença na mortalidade entre os usuários vulneráveis e não vulneráveis (log rank: 0,23), o que também ocorreu quando o resultado foi TRS (log rank: 0,17). No modelo de regressão de Cox, risco relativo (RR) e intervalo de confiança (IC) para o impacto da VS sobre a mortalidade, não ajustado foi RR: 1,87 (IC: 0,64-5,41) e, após RR ajustado: 1,47 (C1: 0,35-6,0). Quando analisamos o impacto da VS em TRS, observamos o R RR não ajustado: 1,85 (IC: 0,71-4,8) e RR ajustado: 2,19 (CI :0.50-9 0,6). Conclusão: A VS não apresentou impacto nos desfechos óbito e TRS. O acesso aos cuidados de saúde, no Brasil, apesar de suas características universais, tem barreiras sociais no acesso ao tratamento especializado. Acreditamos que os usuários passaram pelas barreiras sociais impostas para o 7 acesso a cuidados especializados (viés de seleção). Nosso estudo apresenta limitações, já que não nos permite comprovar a eficácia de uma intervenção interdisciplinar, uma vez que o desenho do estudo adotado (coorte retorspectiva) não nos permite avaliar o impacto da aborgadem interdisciplinar, pois a coleta dos dados ocorreu após a intervenção da equipe.No entanto, o presente estudo é o primeiro a avaliar a VS em usuários com DRC em pré-diálise, por um período de acompanhameto de sete anos. / Introduction: The Social Work officially enter the ranks of health professions with the resolution of the Ministry of Health No. 218/97. This recognition of the profession goes through a historical process marked by the historical conditions in which public health was developed in Brazil and the social recognition of profession. Inside Social Service Health, found a new playing field that is nephrology, a performance that, in the centers of Renal Replacement Therapy (RRT), has a legal backing, and a recognition of the importance of social workers in the composition teams minimal attention to patient with Chronic Kidney Disease (CKD) in TRS. The association between socioeconomic factors and incidence and prevalence of CKD is well established in the literature. Undoubtedly, the ethnicity is the most studied social factor with regard to the incidence and prevalence of CKD. Only recently, educational factors have been addressed with respect to CKD, analyzing the importance of self-pathology and improves outcomes. An issue often discussed is the difficulty of access to health services, both in developed countries, with models of health systems that are not universal, as in the United States and in developing countries with populations with low socioeconomic status, as Brazil. Factors such as the genre has also been addressed in a few studies, with women having higher incidence of CKD. When we evaluated the influence of these same factors in the progression of CKD, there is only scarce and fragmented studies evaluating the issue, and we see clearly that studies evaluating the progression of CKD deal primarily biological. The aim of this study was to characterize the social profile of users with chronic kidney disease pre-dialysis stages 3, 4 and 5, as well as assess the impact of socioeconomic variables on the progression of CKD pre-dialysis stages studied. Patients and Methods:: We conducted a retrospective cohort study, follow-up period from January 2002 to December 2009. The variables were sociodemographic, clinical and laboratory. Inclusion criteria: users over 18 years of age, CKD stages 3A, 3B, 4 and 5, accompanied by more than three months. Statistical Analysis: The users were divided according to social vulnerability (SV). To calculate the VS, we used three statistical techniques in sequence, factor analysis, cluster analysis (Cluster) and discriminant analysis. The demographic data, clinical and laboratory data were evaluated for each group of VS. We performed a descriptive analysis of the data, expressed as mean ± standard deviation, median, or percentage, according to the characteristic of the variable. To assess normality, we used the Kolmogorov-Smirnov test. Differences between groups were analyzed by t test for independent samples or the Wilcoxon test for nonparametric comparisons. A χ2 test was used for categorical variables. Survival was analyzed with survival curves of Kaplan-Meier. Cox regression was performed to examine the impact of SV on the outcomes. Results. We evaluated 209 patients cared for a period of 7 years, 29.4% were classified as vulnerable. There were no differences in mortality among the vulnerable and non-vulnerable users (log rank: 0.23), which also occurred when the result was TRS (log rank: 0,17). In the Cox regression model, hazard ratio (HR) and confidence interval (CI) for the impact of VS on mortality was not adjusted HR: 1.87 (CI: 0.64 to 5.41) and after adjusted HR: 1.47 (C1: 0.35 to 6.0). When we analyze the impact of VS on TRS, observe the HR and CI, unadjusted HR: 1.85 (CI: 0.71 to 4.8) and adjusted HR: 2.19 (CI:0.50-9 0.6) . Conclusion: VS showed no impact on mortality outcomes and TRS. Access to health care in Brazil, despite its universal features, have social barriers in access to specialized treatment. We believe that users spent by social barriers imposed for access to specialized care (selection bias). Our study has limitations, as it does not allow us to prove the effectiveness of an interdisciplinary intervention, since the method adopted (retrospective cohort) did not allow us to evaluate the impact of an interdisciplinary approach, because data collection occurred 9 after the intervention team. However, the present study is the first to evaluate the VS in users with CKD pre-dialysis, for a follow-up period of seven years.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-08-09T14:18:47Z No. of bitstreams: 1 rosaliamarianuneshenriqueshuaira.pdf: 2338300 bytes, checksum: bcb856eb45dfa5fd1d7f3007ad320c2b (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-08-09T14:59:27Z (GMT) No. of bitstreams: 1 rosaliamarianuneshenriqueshuaira.pdf: 2338300 bytes, checksum: bcb856eb45dfa5fd1d7f3007ad320c2b (MD5) / Made available in DSpace on 2017-08-09T14:59:27Z (GMT). No. of bitstreams: 1 rosaliamarianuneshenriqueshuaira.pdf: 2338300 bytes, checksum: bcb856eb45dfa5fd1d7f3007ad320c2b (MD5) Previous issue date: 2017-04-20 / Introdução: As doenças crônicas são responsáveis pela maioria dos óbitos no Brasil. Entre estas se destacam a hipertensão arterial e diabetes mellitus que são as principais causas da doença renal crônica (DRC). A DRC na sua fase dialítica no Brasil representa um alto custo financeiro e impacta na qualidade de vida dos usuários, o que justifica a necessidade de um diagnóstico mais precoce e um controle na fase pré-dialítica. Em 2010 foi inaugurado o Centro Hiperdia Juiz de Fora (CHJF), que ampliou o atendimento fornecido anteriormente pelo Preverim. Este programa acompanhava apenas os doentes renais em fase pré-dialítica. Com a criação CHJF ampliou o atendimento a usuários hipertensos e diabéticos com controle metabólico inadequado. Para isso foi criado um registro eletrônico onde são gravados estes atendimentos. O uso de registros eletrônicos tem sido ampliado no mundo todo visando o acompanhamento de usuários na diálise, no entanto registros em pré-diálise são raros. O objetivo deste trabalho foi validar os dados deste registro para a utilização em pesquisas e na gestão do programa. E ao final fazer a caracterização clínica da coorte em relação ao perfil demográfico e também aos indicadores clínicos de qualidade destas três enfermidades. Material e Métodos: Inicialmente foi realizada a validação do registro. A validação de um registro eletrônico de saúde é um procedimento contínuo na programação de qualquer sistema de dados. Sabemos que podem haver ocorrências que não foram previamente definidas e que impactam na qualidade dos dados. Após realizada esta padronização, avaliamos a coorte. Trabalhamos com 63.146 registros de atendimentos de usuários do CHJF de agosto de 2010 a dezembro de 2014. Foram incluídos os usuários com mais de 18 anos com pelo menos duas consultas no ambulatório da DRC. Analisamos as seguintes variáveis: sócio-demográficos, doença de base, principais medicações, principais indicadores clínicos de controle da DRC, hipertensão arterial (HAS), Diabetes mellitus (DM). Resultados: Foram exportados, convertidos e validados dados de 1.977 usuários com tempo de acompanhamento médio de 21 meses. Destes, 51,4% eram homens, 58% tinham idade >64 anos e 81,6% estavam acima do peso. As principais medicações em uso foram: diuréticos (82,9%), Bloqueador do receptor da angiotensina (BRAT) (62%), Estatina (60,7%) e Inibidor da enzima conversora de angiotensina (IECA) (49,9%). O percentual de usuários com declínio da taxa de filtração glomerular foi de 33,7%. Em relação à hemoglobina glicada, os usuários com DRC e DM, 36% estavam dentro da meta inicial e 52,1% da final. Em relação à pressão arterial, os usuários estavam na meta na admissão em 34,3% e 49,8% ao final do acompanhamento. Conclusão: Concluímos que dados validados são de vital importância para gestores em saúde e para monitorização dos usuários. Nossa população é predominantemente idosa, obesa, usuária de polifarmácia, tem pouca escolaridade, é de baixa renda sendo, portanto, uma população vulnerável, necessitando de cuidados multiprofissionais intensivos para retardar a progressão da doença e diminuir a morbimortalidade. Ressaltamos que a taxa de filtração glomerular (TFG) apresentar-se com um delta positivo nos informa que estamos atingindo a principal meta que é retardar o início da terapia renal substitutiva e, com isto melhorar a qualidade de vida e diminuir os custos. / Introduction: Chronic diseases are responsible today for the majority of deaths in Brazil. Among these, hypertension and diabetes mellitus are the main causes of chronic kidney disease (CKD). The CKD in its dialytic phase in Brazil represents a high financial cost and impacts the quality of life of the users, which justifies the need for an earlier diagnosis and a control in the pre-dialytic phase. In 2010, the Centro Hiperdia Juiz de Fora (CHJF) was inaugurated in Juiz de Fora, MG, Brazil, which expanded the service previously provided by Prevenrim. This program was only used for pre-dialytic renal patients. With the creation of CHJF, care was added to hypertensive and diabetic users with inadequate metabolic control. For this, an electronic record was created where these visits are recorded. The use of electronic records has been expanded worldwide to track dialysis users, however pre-dialysis registries are rare. The objective of this study was to validate the data from this registry for use in research and program management. Finally, the clinical characterization of the cohort in relation to the demographic profile and clinical quality indicators of these three diseases was done. Material and Methods: The registry was validated initially. The validation of an electronic health record is a continuous procedure in the programming of any data system. We know that there may be occurrences that have not been previously defined and that impact on data quality. After this standardization, we evaluated the cohort. We worked with 63,146 records of CHJF users' consultations from August 2010 to December 2014. Users 18 years old or older with at least two visits in the CKD outpatient clinic was included. We analyzed the following variables: sociodemographic, cause of kidney disease, main medications, main clinical indicators of CKD, systemic arterial hypertension (SAH), Diabetes mellitus (DM). Results: Data from 1,977 users with mean of follow-up time of 21 months were exported, converted and validated. Of these, 51.4% were men, 58% were> 64 years of age and 81.6% were overweight. The main medications used were diuretics (82.9%), angiotensin receptor blocker (ARB) (62%), Statin (60.7%) and ACE inhibitors (49.9%). The percentage of users with a decline in the glomerular filtration rate was 33.7%. Regarding glycated hemoglobin, users with CKD and DM, 36% were within the initial goal and 52.1% of the final. Regarding blood pressure, users were on target at admission at 34.3% and 49.8% at the end of follow-up. Conclusion: We conclude that the validated data is of vital importance for health managers to monitor users. We observed that our population is predominantly elderly, obese, polypharmacy patient, has a low level of education, is low income and therefore a vulnerable population, requiring intensive multi-professional care to delay the progression of the disease and reduce morbidity and mortality. It is important to highlight that since the glomerular filtration rate (GFR) presents a positive delta, it then indicates that we are achieving the main goal: to delay the onset of renal replacement therapy, thereby improving quality of life and lowering costs.

Indiana University-Purdue University Indianapolis (IUPUI) / Polycystic kidney diseases (PKD) are genetic disorders characterized by fluid filled cysts in the kidney tubules and liver bile ducts. There are two forms of PKD, autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). The focus of the studies in this thesis has been on ADPKD. The disease progresses slowly and the fluid-filled cysts grow in size due to increased rates of cell proliferation and fluid secretion into the cyst lumen. The expanding cysts compromise the normal kidney function and result in a decrease of renal function to the point of end-stage renal failure in midlife. Cyst enlargement is due, at least in part, to chloride secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Currently therapy is limited to renal cyst aspiration, dialysis, and eventually renal transplantation after organ failure, thus it has critical to determine possible drug therapies for the treatment of PKD. Previous studies showed that cyst fluid caused a secretory response in cells lining the cysts. We hypothesized that once the cyst have expanded and become so large that they burst or leak, which could also occur due to renal injury or aging, the cyst fluid may stimulate additional cyst growth. Lysophosphatidic Acid (LPA) was determined to be the active component of human cyst fluid, and we investigated the LPA stimulated signaling pathway. Our data suggest that the LPA stimulates chloride and fluid secretion by a combination of CFTR and Calcium-Activated chloride channels (CaCC) and that the two channels may functionally be linked to each other. The secretion is not occurring through a cAMP stimulated pathway, and it is possible that TMEM16A, a CaCC, plays a larger role than previously expected. Previous studies demonstrated that PPARγ agonists, insulin sensitizing drugs used to treat diabetes, inhibit chloride secretion by the collecting duct principal cells by decreasing CFTR synthesis. It was logical therefore to considered PPARγ agonists as long-term treatment for PKD. The first preclinical studied showed that high (20 mg/kg BW) dose pioglitazone, a PPARγ agonist, inhibited cyst growth in the PCK rat model, a slow progressing model, of PKD. To continue to look at the effects of the PPARγ agonists another preclinical study was completed, which tested if there was a class action of PPARγ agonists and if a lower dose was effective in treating the cystic burden. Using the PCK rat model, and another PPARγ agonist, rosiglitazone, a 24 week study was completed using 3 doses (4, 0.4, and 0.04 mg/kg BW). 4 mg/kg BW rosiglitazone is analogous to 20 mg/kg BW pioglitazone. The data indicated that the rosiglitazone is effective in lowering the cystic burden, and importantly the low dose proved to be effective. An additional rat model, the W-WPK rapidly progressing model was used to determine efficacy across multiple models, and to determine if there was a way to track the progress of the disease in a manner analogous to that used in human patients. The animals were treated with pioglitazone using 2 doses (2 and 20 mg/kg BW), and were imaged using CT scans to track the progress of the disease. The data suggest that pioglitazone was not as effective in the W-WPK rat model as it was the PCK rat model. There was a trend however, that low dose PPARγ agonist was as effective ad high dose. Even more important, the CT scans proved to be an effective way to track the progress of the disease in animal models.

Thesis (PhD)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: Despite the high prevalence of chronic kidney disease, renal narratives are under-reported. Much of what is written on kidney failure is written by health care professionals for health care professionals and about patients. While medical experts and health care practitioners have one type of knowledge, their patients have another type of knowledge acquired through their experience of their own condition. From within the disability and patients’ rights movements urgent calls have been made for the authentic voices of disabled people and patients to be heard without the mediation of professional lenses. In response to this my dissertation combines personal and academic writing to explore my own experience of end-stage renal disease, dialysis, transplantation and the life after transplant. I have used autoethnography as a methodology. Autoethnography is a relatively new, somewhat postmodern form of inquiry that developed from the reflexive turn in anthropology and narrative studies in the latter part of the twentieth century. It is very useful in writing about the experience of illness and reflecting on illness narratives because, in autoethnographic writing, the observer and observed, the narrator and narrated, insider and outsider are the same person. This allows scope for exploring the problematics of representation and for finding alternatives to already existing ways of telling certain stories. Engaging with autoethnography’s postmodern aspects has allowed me to conceptualize experiences that, until I undertook this research, I have never been able to articulate, because the traditional (static) illness narrative forms did not speak to my experience or my understanding of my condition. The central issue in my dissertation lies in the question: How do I tell the story of chronic illness once I have had an organ transplant? Flowing from this are a number of sub-issues: Can my story change? How do I describe myself: The well, the ill, the impaired, the disabled, the afflicted? Do I describe myself living in no man’s land? In my narrative, do I oscillate between being well and ill, or do I occupy another territory entirely? And if I do, what is it? My study shows that writing the story (or stories) of chronic kidney disease is complex, nuanced and dynamic and that, far from being an extended liminal experience, kidney disease is littoral. This distinction is important in coming to narrative terms with an identity that is not damaged so much as different. Through this I hope to demonstrate to both outsiders and insiders, who often submit to narratives that are forced on them, that more satisfying alternatives can be found. / AFRIKAANSE OPSOMMING: Ondanks die hoë voorkomssyfer van chroniese nierkwale word nierverhale nie genoeg aangemeld nie. Die meerderheid van dit wat oor nierversaking geskryf word, word deur gesondheidsorgdeskundiges vir gesondheidsorgdeskundiges en oor pasiënte geskryf. Terwyl mediese deskundiges en gesondheidsorgpraktisyns een soort kennis het, het hulle pasiënte ’n ander soort kennis op grond van hulle ervaring van hulle eie toestande. Van binne die gestremdheid en pasiënteregte-bewegings het ’n dringende oproep weerklink vir die outentieke stemme van mense met gestremdhede en pasiënte om gehoor te word sonder die tussenkoms van professionele perspektiewe. In reaksie hierop kombineer my verhandeling persoonlike en akademiese beskrywings om my eie ervaring van eindstadium- nierkwale, dialise, oorplanting en die lewe na oorplanting te verken. Ek het outo-etnografie as metodologie gebruik. Outo-etnografie is ’n relatief nuwe, ietwat postmoderne vorm van ondersoek wat in die tweede deel van die twintigste eeu uit die refleksiewe wending in antropologie en narratiewe studies ontwikkel het. Dit is baie bruikbaar wanneer oor die belewenis van siekte en besinning oor siekte-narratiewe geskryf word aangesien die waarnemer en die waargeneemde, die verteller en dit wat vertel word, die ingewyde en die buitestander in outo-etnografiese skryfwerk dieselfde persoon is. Dit laat meer ruimte vir verkenning van die problematiek van voorstelling en vir die opspoor van alternatiewe vir reeds bestaande wyses om sekere stories te vertel. My bemoeienis met postmoderne aspekte van outo-etnografie het dit vir my moontlik gemaak om ervaringe wat ek tot en met hierdie navorsing nooit kon artikuleer nie, te konseptualiseer, aangesien die tradisionele (statiese) vorme van siekte-narratiewe nie tot my ervaring of my begrip van my toestand gespreek het nie. ‘Hoe vertel ek die storie van chroniese siekte nadat ek ’n orgaanoorplanting gehad het?’ is ’n sentrale vraagstuk in my verhandeling. Hieruit spruit ’n aantal newevraagstukke voort: Kan my storie verander? Hoe beskryf ek myself: Die gesonde persoon, die sieke, die verswakte, die gestremde, die aangetaste? Hoe beskryf ek myself wat in ’n niemandsland woon? Fluktueer ek in my narratief tussen gesond wees en siek wees of betrek ek ’n geheel ander gebied? En indien wel, wat is dit? My studie toon dat, om die storie (of stories) van chroniese niersiekte te skryf, kompleks, genuanseerd en dinamies is en dat niersiekte glad nie ’n uitgebreide liminale ervaring is nie, maar eerder littoraal is. Dit is belangrik wanneer daar tot ’n narratiewe verstandhouding gekom moet word met ’n identiteit wat nie soseer beskadig is nie, maar eerder anders. Hierdeur hoop ek om aan beide buitestanders en ingewydes, wat dikwels voor narratiewe wat op hulle afgedwing word, moet buig, te wys dat daar meer bevredigende alternatiewe gekry kan word.