Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-06-19T11:21:12Z No. of bitstreams: 1 andersontavaresrodrigues.pdf: 12102128 bytes, checksum: ad04f5fdd01e1041a5459207d8137ad5 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-06-29T12:18:45Z (GMT) No. of bitstreams: 1 andersontavaresrodrigues.pdf: 12102128 bytes, checksum: ad04f5fdd01e1041a5459207d8137ad5 (MD5) / Made available in DSpace on 2017-06-29T12:18:45Z (GMT). No. of bitstreams: 1 andersontavaresrodrigues.pdf: 12102128 bytes, checksum: ad04f5fdd01e1041a5459207d8137ad5 (MD5) Previous issue date: 2015-03-20 / A doença renal crônica (DRC) é uma enfermidade de grande morbimortalidade. A hemodiálise periódica é o método mais amplamente utilizado na manutenção da sobrevida dos pacientes com DRC. No tratamento hemodialítico é necessário uma via de um acesso vascular, sendo o padrão-ouro é a fístula arteriovenosa (FAV). As principais complicações da FAV são a falência do acesso e consequente maior morbimortalidade. Os objetivos do trabalho são: 1) avaliar a taxa de sucesso nas FAV confeccionadas pelo nefrologista; e 2) identificar as variáveis clínicas, laboratoriais e demográficas que impactam na patência da FAV. Método: Estudo de coorte retrospectiva caracterizado pelo exame de prontuários de pacientes com DRC e que realizaram confecção de FAV pelo nefrologista. Foram incluídos os prontuários de 101 pacientes, totalizando 159 procedimentos entre junho de 2010 e junho de 2013. Resultados: Das FAV realizadas, 124 (78%) apresentaram patência imediata e 110 (62,9%) apresentaram patência tardia. Das variáveis estudadas somente a hemoglobina mostrou relação com a patência tardia da FAV (p=0,05). Pressão arterial elevada no momento da cirurgia se associou com redução do número de procedimentos por paciente com p=0,001. FAV distais se associaram a maior número de procedimentos por paciente com p=0,03. Adicionalmente, observou-se que o nosso índice de sucesso de patência da FAV apresentou índices compatíveis com os da literatura por outros nefrologistas e cirurgiões vasculares. Conclusão: Manutenção de hemoglobina nas faixas recomendadas impactam favoravelmente na patência tardia da FAV, pressão arterial elevada no momento da cirurgia associou-se com menor número de procedimentos a que o paciente é submetido. Os procedimentos distais se associaram a maior número de procedimentos por paciente, enquanto os proximais são mais frequentes em pacientes com 2 acessos, indicando sua utilização principalmente na falha dos acessos distais. / Chronic kidney disease (CKD) is an illness of high morbidity and mortality. The periodic hemodialysis is the most widely used method in maintaining the survival of patients with CKD. In hemodialysis is needed a vascular access, and the gold standard is the arteriovenous fistula (AVF). The main complications of AVF are the failure of access and consequent higher mortality. The objectives are: 1) to evaluate the success rate in AVF made by a nephrologist; and 2) to identify clinical, laboratory and demographic variables that impact the AVF patency. Method: Retrospective cohort study characterized the examination records of patients with CKD who underwent construction of AVF by a nephrologist. The medical records of 101 patients were included, totaling 159 procedures between June 2010 and June 2013. Results: Of AVF performed, 124 (78%) had immediate patency and 110 (62.9%) had late patency. Of the variables studied only hemoglobin was related to the late patency of AVF (p = 0.05). High blood pressure at the time of surgery was associated with fewer procedures per patient with p = 0.001. Distal AVF associated with a major number of procedures per patient with p = 0.03. Additionally, it was observed that our AVF patency success rate compatible with the indexes presented in the literature by other nephrologists and vascular surgeons. Conclusion: hemoglobin maintenance at the recommended tracks impact favorably on late patency of the AVF, high blood pressure at the time of surgery was associated with fewer procedures which the patient is submitted. The distal procedures associated with a major number of procedures per patient, while the proximal are more frequent in patients with 2 accesses, indicating its use mainly in the failure of distal access.

Submitted by Geandra Rodrigues (geandrar@gmail.com) on 2018-03-26T18:48:44Z No. of bitstreams: 0 / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-03-27T14:06:54Z (GMT) No. of bitstreams: 0 / Made available in DSpace on 2018-03-27T14:06:55Z (GMT). No. of bitstreams: 0 Previous issue date: 2017-10-26 / A Sarcopenia é uma condição crônica associada ao envelhecimento e caracterizada por redução da massa muscular, força e função. A prevalência de sarcopenia em pacientes com doença renal crônica (DRC) é aumentada e associa-se ao aumento da morbimortalidade. Além disso, a ocorrência concomitante de obesidade e perda muscular, condição definida por obesidade sarcopênica (OS), é comum na DRC, associando-se com pior sobrevida e função física. A tomografia computadorizada (TC) e a absorciometria com emissão de energia dupla (DXA) são consideradas para avaliação da massa muscular, entretanto, o custo e a dificuldade de acesso são fatores limitantes para o seu uso, tornando-se essencial a pesquisa de métodos mais acessíveis e de menor custo. A ultrassonografia (US) vem surgindo como um método promissor na avaliação da massa muscular em algumas populações com doenças crônicas, comparável à avaliação realizada pela TC. Objetivos: Avaliar a prevalência de sarcopenia e obesidade sarcopênica em pacientes com DRC prédialítica e suas associações com variáveis clínicas, laboratoriais, marcadores inflamatórios e medidas de obesidade visceral. Além disso, objetivamos investigar a validade e confiabilidade da medida da área transversa do reto femoral (ATRF) pela US comparado à TC, em pacientes com DRC pré-dialítica, além da associação entre estas medidas e o diagnóstico de sarcopenia. Métodos: Foram avaliados 100 pacientes com DRC pré-dialítica, de ambos os sexos e com mais de 65 anos. A sarcopenia foi definida pelos critérios do Grupo Europeu de Estudos em Sarcopenia em Idosos (EWGSOP) e do Projeto de Sarcopenia da Fundação do Instituto Nacional de Saúde (FNIH), utilizando a DXA para cálculo da massa muscular. Foram também avaliados dados sociodemográficos e clínicos, atividades de vida diária, capacidade funcional e nível de atividade física. A inflamação foi avaliada pela proteína C-reativa de alta sensibilidade (PCRus) e interleucinas (IL) 4 e 6. A obesidade foi definida de acordo com o Índice de Massa Corporal (IMC), Índice de Massa Gorda (IMG) e o Percentual de Gordura Corporal Total (PGCT). A obesidade visceral foi avaliada pelas medidas do tecido adiposo visceral (VAT) e gordura androide. Para comparação, os pacientes foram divididos em nãoobesos e não-sarcopênicos, obesos, sarcopênicos e obesos sarcopênicos. A ATRF foi avaliada usando US e TC. Resultados: A prevalência de sarcopenia foi de 11,9% e 28,7% utilizando os critérios do EWGSOP e do FNIH, respectivamente. A sarcopenia foi mais prevalente nos estágios mais avançados da DRC (34,5% nos estágios 2 e 3A e 65,5% nos estágios 3B, 4 e 5) e associada com pior desempenho nas atividades da vida diária (p=0,049), menor velocidade de caminhada (p<0,001) e maiores índices de massa corporal (IMC) (p=0,001) no modelo não ajustado. Além disso, os pacientes com sarcopenia apresentaram menor capacidade funcional (p=0,012) e maior prevalência de inatividade física (p=0,041) em comparação com pacientes sem sarcopenia. Após o ajuste para variáveis confundidoras, a sarcopenia manteve associação significante com a velocidade de caminhada (p=0,004) e IMC (p=0,002). Os níveis de PCRus foram inversamente correlacionados com a massa magra apendicular ajustada pelo IMC (p=0,007) e apresentaram uma correlação positiva com IMC (p=0,001). Os níveis de IL4 apresentaram correlação positiva com a velocidade de caminhada (p=0,007) e massa magra nos membros inferiores (p=0,022). A prevalência de obesidade foi de 19,8%, 37,6% e 48,5%, e de OS foi de 15,8%, 13,9% e 27,7%, quando utilizados os critérios do IMC, PGCT e IMG, respectivamente. Com relação ao perfil metabólico, observamos que o IMC, IMG, VAT e gordura androide (p<0,001) foram mais elevados nos obesos e obesos sarcopênicos, utilizando o critério de obesidade do IMC e IMG. Houve associação entre as medidas de obesidade visceral com o IMC, IMG e estágio 4 da DRC. A taxa de filtração glomerular (TFG) apresentou correlação positiva com VAT (r=0,311; p=0,002), gordura androide (r=0,414; p<0,001), IMC (r=0,348; p<0,001) e IMG (r=0,272, p=0,006). A diferença das médias da ATRF avaliada por US e TC foi de 3,97 mm, com uma forte correlação entre os métodos (p<0,001). O Bland-Altman mostrou uma boa concordância entre TC e US. Com base na definição de baixa massa muscular da ATRF pelo US, observou-se uma prevalência de sarcopenia de 12%. Conclusões: A sarcopenia foi comum em pacientes com DRC, particularmente nos estágios mais avançados da doença. Observamos uma associação entre os níveis de marcadores inflamatórios e massa magra apendicular, performance física e IMC. Além disso, a obesidade e a obesidade sarcopênica foram prevalentes nos pacientes com DRC, principalmente quando utilizada a definição de obesidade pelo IMG. Houve associação entre um pior perfil metabólico e medidas de obesidade visceral nos pacientes obesos e OS com a definição de obesidade pelo IMC e IMG. A TFG associou-se com obesidade visceral, principalmente no estágio 4 da DRC. Por fim, a US demonstrou ser um método válido e confiável para avaliar a ATRF em pacientes com DRC pré-dialítica. / Sarcopenia is a chronic condition associated with aging characterized by reduced muscle mass, strength and function. The prevalence of sarcopenia in patients with chronic kidney disease (CKD) is increased and is associated with increased morbidity and mortality. In addition, the concomitant occurrence of obesity and muscle loss, a condition defined by sarcopenic obesity (SO), is common in CKD, associated with worse survival and physical function. Computed tomography (CT) and dual-energy x-Ray absorptiometry (DXA) are considered for evaluation of muscle mass, however, cost and difficulty of access are limiting factors for its use. Due to the population aging, it is essential to research new methods for assessing muscle mass, which are more affordable and less costly. Ultrasonography (US) has emerged as a promising method for assessing muscle mass in some populations with chronic diseases, comparable to the evaluation performed by CT. Objectives: To evaluate the prevalence of sarcopenia and sarcopenic obesity in patients with CKD not yet on dialysis, and its associations with clinical, laboratory, inflammatory markers and measures of visceral obesity. In addition, we aimed to investigate the validity and reliability of rectus femoris cross-sectional area (RFCSA) measurement compared to CT in CKD patients not yet on dialysis, and the association between these measurements and the diagnosis of sarcopenia. Methods: A total of 100 patients of both sexes and aged over 65 were evaluated. Sarcopenia was defined by the criteria of the European Working Group on Sarcopenia in Older People (EWGSOP) and of the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project, using DXA to calculate muscle mass. Sociodemographic and clinical data, activities of daily living, functional capacity and level of physical activity were also evaluated. Inflammation was assessed by high-sensitivity C-reactive protein (hsCRP) and interleukin (IL) 4 and 6. Obesity was defined according to the Body Mass Index (BMI), Fat Mass Index (FMI) and the Percentage of Total Body Fat (PTBF). Visceral obesity was evaluated by measures of visceral adipose tissue (VAT) and android fat. For comparison, the patients were divided into groups of non-obese and non-sarcopenic, obese, sarcopenic and obese sarcopenic. RFCSA was assessed using US and CT. Results: The prevalence of sarcopenia was 11.9% and 28.7% using the EWGSOP and FNIH criteria, respectively. Sarcopenia was more prevalent in the more advanced stages of CKD (34.5% in stages 2 and 3A and 65.5% in stages 3B, 4 and 5) and associated with worse performance in activities of daily living (p=0.049), lower walking speed (p<0.001) and higher BMI (p=0.001) in the nonadjusted model. In addition, patients with sarcopenia had lower functional capacity (p=0.012) and higher prevalence of physical inactivity (p=0.041) compared to patients without sarcopenia. After adjusting for confounding variables, sarcopenia was still significantly associated with walking speed (p=0.004) and BMI (p=0.002). HsCRP levels were inversely correlated with lean mass adjusted for BMI (p=0.007) and were also positively associated with BMI (p=0.001). IL4 levels were positively correlated with walking speed (p=0.007) and lean body mass in the lower limbs (p=0.022). The prevalence of obesity was 19.8%, 37.6% and 48.5%, and of SO was 15.8%, 13.9% and 27.7%, when the criteria of BMI, PTBF and FMI were used, respectively. Regarding the metabolic profile, we observed that BMI, FMI, VAT and android fat (p<0.001) were higher in obese and SO patients, using the BMI and FMI obesity criteria. There was an association between measures of visceral obesity with BMI, FMI and stage 4 of CKD. The glomerular filtration rate (GFR) showed a positive correlation with VAT (r=0.311, p=0.002), android fat (r=0.414, p<0.001), BMI (r=0.348, p<0.001) and FMI (r=0,272, p=0,006). The difference in mean RFCSA by US and CT was 3.97 mm, with a strong correlation between the methods (p<0.001). Bland-Altman showed good agreement between CT and US. Based on the definition of low muscle mass according to US of the RFCSA, a sarcopenia prevalence of 12% was observed. Conclusions: Sarcopenia was common in patients with CKD, particularly in the more advanced stages of the disease. We observed an association between levels of inflammatory markers and appendicular lean mass, physical performance and BMI. In addition, obesity and SO were prevalent in patients with CKD, mainly when the FMI obesity criteria was used. There was an association between a worse metabolic profile and visceral obesity measures in obese and SO patients when the BMI and FMI criteria for obesity were used. Regarding CKD, there was an association between GFR and visceral obesity, mainly in stage 4. Finally, US has proven to be a valid and reliable method for assessing RFCSA in patients with CKD not yet on dialysis.

Submitted by Geandra Rodrigues (geandrar@gmail.com) on 2018-04-27T11:55:53Z No. of bitstreams: 1 analuisasilveiravieiratollendal.pdf: 1031624 bytes, checksum: 2a4a0647b9d22be1da3f719765d6d470 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2018-04-27T12:09:21Z (GMT) No. of bitstreams: 1 analuisasilveiravieiratollendal.pdf: 1031624 bytes, checksum: 2a4a0647b9d22be1da3f719765d6d470 (MD5) / Made available in DSpace on 2018-04-27T12:09:21Z (GMT). No. of bitstreams: 1 analuisasilveiravieiratollendal.pdf: 1031624 bytes, checksum: 2a4a0647b9d22be1da3f719765d6d470 (MD5) Previous issue date: 2018-01-19 / Introdução: A doença renal crônica (DRC) se tornou uma preocupante questão de saúde pública em todo o mundo devido às suas crescentes incidência e prevalência e ao impacto em morbimortalidade por ela desencadeado. O tratamento da DRC se baseia na intervenção em seus fatores de risco. Entretanto, os fatores atualmente conhecidos e sua abordagem não têm sido suficientes para conter a doença. Por esse motivo, torna-se imprescindível a busca por outros fatores associados à sua patogênese. Nesse sentido, a hiperuricemia tem sido apontada, nas últimas décadas, como uma condição associada à DRC, porém sem que ainda tenha sido estabelecida uma associação causal entre ambas. Objetivos: 1. Avaliar as evidências sobre o impacto da hiperuricemia na incidência e progressão da DRC, através de revisão sistemática da literatura; 2. Avaliar o impacto dos níveis séricos de ácido úrico (AU) sobre o declínio da taxa de filtração glomerular (TFG) em uma população de pacientes com DRC. Métodos: Primeiramente, realizou-se revisão sistemática da literatura com busca por artigos publicados no período entre Janeiro de 2005 e Dezembro de 2016, utilizando-se a combinação de palavraschave “chronic renal insufficiency AND hyperuricemia AND uric acid” nos bancos de dados Lilacs e Pubmed. Os resumos dos artigos foram avaliados por dois pesquisadores, de acordo com os critérios de inclusão e exclusão estabelecidos. Na segunda fase do estudo, 788 pacientes incidentes no ambulatório de DRC do Centro Hiperdia Minas/Juiz de Fora tiveram seus registros eletrônicos analisados e o impacto dos níveis de AU na progressão da DRC foi avaliado. Resultados: Relativamente à revisão sistemática, foram encontrados 150 estudos envolvendo seres humanos, dos quais 22 foram elegíveis, 13 estudos avaliaram incidência e 11 avaliaram progressão da DRC (aumento de creatinina, variação da taxa de filtração glomerular, início de terapia renal substitutiva); dois avaliaram ambos os desfechos. Todos os treze artigos que avaliaram associação entre hiperuricemia e incidência de DRC mostraram associação positiva entre ambas. Uma metanálise avaliou impacto da hiperuricemia em 190.718 indivíduos e encontrou relação causal independente para incidência de DRC. Em relação à progressão da DRC, os estudos longitudinais apresentaram resultados conflitantes e três estudos randomizados controlados foram identificados, comparando um grupo tratado com alopurinol e um grupo controle, todos com melhora dos desfechos renais no grupo tratado. Os resultados da análise do banco de dados do Centro HIPERDIA mostraram que pacientes admitidos com hiperuricemia, ou seja, AU maior do que 6,8mg/dL, apresentaram risco quase duas vezes maior (IRR=1,91 95% IC: 1,21-3,00, p=0,005) de progressão rápida da DRC (TFG>5mL/min/ano). Além disso, para cada 1 mg/dL de aumento nos níveis basais de AU houve risco anual 48% maior de progressão rápida (IRR=1,48 95% IC:1,16-1,88, p=0,001). Conclusão: A revisão sistemática sugeriu que hiperuricemia se associa de forma independente com incidência de DRC, porém seu papel na progressão da doença ainda é controverso. Entre os pacientes com DRC do Centro Hiperdia Minas/Juiz de Fora, os níveis séricos aumentados de AU associaramse a maior risco de progressão rápida da doença renal crônica. / Introduction: Chronic kidney disease (CKD) has become a worrisome public health problem worldwide due to its increasing incidence and prevalence as well as its impact on morbidity and mortality. Treatment of CKD is based on risk factor intervention. However, currently known factors and their approach are insufficient to stop the disease. For this reason, it is imperative to search for other factors associated with its pathogenesis. Hyperuricemia has been identified as a condition associated with CKD, but causal association between them has not yet been proved. Objectives: 1. To evaluate the impact of hyperuricemia on the incidence and progression of CKD through a systematic review of the literature; 2. To evaluate the impact of serum uric acid levels on the decline of the glomerular filtration rate (GFR) in a population of chronic renal patients. Methods: Initially a systematic review of the literature was carried out between January 2005 and December 2016. The combination of keywords "chronic renal insufficiency AND hyperuricemia AND uric acid" was used to search in the Lilacs and Pubmed databases. The articles’ abstracts were evaluated by two researchers according to established inclusion and exclusion criteria. Secondly, the electronic records of 788 patients of the CKD outpatient clinic of the Hiperdia Minas/Juiz de Fora Center were analyzed and the impact of uric acid levels on the progression of CKD was evaluated. Results: A total of 150 studies involving humans were found. Twenty two were eligible; 13 studies evaluated incidence and 11 evaluated progression of CKD (increase in creatinine, variation of glomerular filtration rate, initiation of renal replacement therapy); two of the articles evaluated both outcomes. All thirteen articles that assessed the association between hyperuricemia and incidence of CKD showed a positive association between both. A further meta-analysis of 190,718 individuals evaluated the impact of hyperuricemia on the incidence of CKD and found an independent causal relationship. Regarding the progression of CKD, longitudinal studies presented conflicting results; three randomized controlled trials compared a group treated with allopurinol and a control group, all with improvement of the renal outcomes within the treated group. The Hiperdia Center database analysis results showed that patients admitted with hyperuricemia, that is, uric acid higher than 6.8mg/dL, presented almost twice the risk (IRR = 1.91 95% CI: 1, 21-3.00, p = 0.005) of rapid progression of CKD (TFG> 5mL/min/year). In addition, for each 1 mg/dL increase in the uric acid levels baseline, there was an additional 48% annual risk of progression (IRR = 1.48 95% CI: 1.16-1.88, p = 0.001). Conclusion: The systematic review suggested that hyperuricemia is independently related to the incidence of CKD, however, its role in disease progression is still controversial. Among patients with CKD, increased serum uric acid levels were associated with an increased progression of chronic kidney disease.

A doença renal crônica é uma das maiores causas de enfermidade e óbito de gatos geriátricos e carreia o declínio da função renal. A forma crônica é caracterizada por persistir um período prolongado de tempo e de prognóstico reservado. Atualmente, a reposição hídrica, a hemodiálise e o transplante são as opções de terapia. Como a terapia com células-tronco tem sido extensivamente estudada nos últimos anos devido a sua capacidade de melhorar a função de órgão lesionados, inclusive os rins, este estudo teve como objetivo avaliar o efeito do transplante de células-tronco de tecido adiposo de gatos, bem como estudar a contribuição de exames complementares laboratoriais e de imagem na evolução terapêutica dos animais. As células provenientes deste tecido apresentaram morfologia fibroblastóide; aderência ao plástico; diferenciaram em osteócitos, condrócitos e adipócitos e expressaram marcadores de superfície característicos de células-tronco mesenquimais. Além disso, quando injetadas em camundongos imunossuprimidos nude não apresentaram formações tumorais. Para triar os animais com a doença renal crônica para este estudo foram realizados exames de sangue, urina e ultrassonografia de 97 animais, destes, sete animais tiveram o perfil escolhido e foram incluídos. Neste estudo os animais foram divididos em 3 grupos: placebo (A); terapia celular (B) e terapia celular associada a reposição hídrica (C). Os resultados demonstram que não houve diferença significativa entre os grupos, mas isso se deve ao tamanho de nossa amostra. Entretanto verificamos que 2 animais apresentaram discreta redução da creatinina sérica. Considerando o perfil das citocinas séricas, constatamos aumento significativo da IL6 dentro do grupo A; a IL10 se comportou de maneira diferente entre os grupos, havendo um discreto aumento no grupo B e significativa redução do grupo A e a TNF&alpha; não alterou ao longo do tempo. Sendo assim, a inoculação endovenosa de células-tronco do tecido adiposo pode prevenir a progressão da doença de forma sutil. / Chronic kidney disease (CKD) is one of the most commom causes of illness and death in geriatric cats and leads to a loss of kidney function. The chronic form is characterized by persisting an extended period of time and it has a poor prognosis. Currently, fluid replacement, hemodialysis and kidney transplantation are the treatment options. As the stem cell therapy has been extensively studied in recent years due to its ability to improve the function of organ injured, including the kidneys, this study aimed to evaluate the effect of transplantation of stem cell derived from adipose tissue of cats as also study the contribution of laboratory exams and imaging in therapeutic evolution. Cells from adipose tissue showed fibroblastoid morphology, adherence to plastic; differentiated into osteocytes, adipocytes and chondrocytes and expressed surface markers characteristic of mesenchymal stem cells. Furthermore, when injected into immunocompromised nude mice showed no tumor formation. To screen animals with chronic kidney disease for this study were performed blood tests, ultrasound and urine of 97 animals, these seven animals had chosen profile and were included. In this study the animals were divided into three groups: placebo (A); cell therapy (B) and cell therapy associated with hydration (C). The results show that no significant difference between the groups, but this is due to our sample size. However two cats with CKD of group B experienced modest decrease in serum creatinine. Regarding serum cytokine expression profile, we found a significant increase of IL-6 in the group A; the IL10 behaved differently among the groups, with a slight increase in group B while group A presented significant reduction and TNF&alpha; and did not change over time. Thus, the intravenous injection of stem cells from adipose tissue may prevent the progression of disease in a subtle way.

Chronic Kidney Disease-Mineral Bone Disorder (CKD-MBD) is a systemic disorder which includes abnormal bone chemistry, vascular or soft tissue calcification, and abnormal bone formation. Many of the parameters of CKD-MBD have been associated with an increased mortality risk in renal patients. There were three main facets to this research project. The first aim of this research was to perform two different studies using the Chronic Renal Insufficiency Standards Implementation Study (CRISIS) data. This prospective epidemiological study is designed to identify factors associated with renal progression and survival in the pre-dialysis CKD population. We have shown that for each 0.323mmol/L (1mg/dL) increase in serum phosphate there was a significant stepwise increased risk of death. (HR1.3 (1.1, 1.5) P=0.01). The association of baseline phenotypic data against vascular stiffness measurements was also investigated. Augmentation index measured at the radial artery was associated with a raised systolic blood pressure but no association with biochemical abnormalities was found.We hypothesised that the phosphate effect on survival was related to the effects within the CKD-MBD spectrum and therefore control of secondary hyperparathyroidism would improve bone and cardiovascular parameters. Therefore for the second part of this research we performed a randomised controlled trial to examine the effects of cinacalcet with standard therapy compared to standard therapy alone on bone and cardiovascular parameters in haemodialysis patients with uncontrolled hyperparathyroidism. The change of biochemical parameters and cardiovascular markers were also further explored in secondary analyses alongside survival data. The primary end point of change in vascular calcification at 52 weeks showed no significant difference between arms. As equivalent control of phosphate and iPTH was achieved in both arms secondary analyses were performed. This showed a significant regression of left ventricular hypertrophy and carotid intima-media thickness associated with phosphate but not iPTH reduction. Patients whose phosphate reduced during the study had a survival advantage when followed for 5 years (HR=10.2 (1.1, 104.5) P=0.049). The third part of this research was to investigate iPTH assay variability. We explored the variation in iPTH assays across the North West and paired this with regional audit data. This study showed that despite there being significant variation among iPTH assays across the region the variation in clinical management was still accounting for some variation in achieving PTH targets.In conclusion, serum phosphate, within the normal laboratory range, is associated with an increased mortality in CKD patients. Haemodialysis patients may have improvement of cardiovascular outcomes with tight control of secondary hyperparathyroidism, by whichever therapeutic means. Intact PTH assays variation may alter our clinical management but variation in practice still affects guideline achievement.

The worldwide population of patients with chronic kidney disease (CKD) is growing, with estimated prevalence at 12-15% of adults. Of particular concern are those with late stage CKD, defined as an estimated glomerular filtration rate (eGFR)of less than 30 ml/min/1.73m2, as they are susceptible to the highest risk of adverse outcomes such as progression to end stage kidney disease (ESKD), cardiovascular disease and all-cause mortality (1, 2). As such, late stage CKD patients are often managed in specialized clinics with set clinical targets, standardized education and multi-disciplinary care(3). A key clinical target for therapeutic intervention and prevention of the progression of CKD is blood pressure (BP) reduction(4). Yet, multiple relevant questions remain regarding the strength and nature of association of BP with clinical outcomes in late stage CKD. As the risks of hypotension-related complications are high in late stage CKD, it remains unclear whether strict BP control delays CKD progression in a real world clinic population(5). Furthermore, it is unclear how to appropriately specify the nature of the longitudinal association between BP and clinical outcomes of ESKD and mortality. The overall objective of this thesis is to examine the longitudinal association of BP and adverse clinical outcomes in a cohort of 1203 patients (mean eGFR 17.8 ml/min/1.73m2; mean of 6.7 BP measures per patient) with late stage CKD. In our first paper we examined the association of repeat measures of BP with CKD progression, defined as a decline in eGFR. When modeling eGFR using longitudinal linear regression, we found that its over-time trajectory was non-linear and that this trajectory was modified by BP; thus, we found a significant time-dependant association between BP and eGFR. When modeling time to eGFR decline ≥ 30% using Cox proportional hazards regression with categorized BP specified as a time-dependent exposure, BP was significantly associated with risk of eGFR decline; in particular, extremes of low and high systolic blood pressure (SBP) and high diastolic blood pressure (DBP) significantly increased the risk of eGFR decline. In our second paper, we examined different methods of modelling longitudinal BP and its association with time to mortality and ESKD. We found that elevations in SBP and DBP, in particular, when expressed as current (most recent visit), lag (previous visit), and cumulative exposure were significantly associated with increased risk of ESKD while low SBP (current, lag and cumulative exposure) was significantly associated with increased risk of mortality. Baseline BP measures were not statistically significantly associated with any outcomes. In patients with more moderate ranges of SBP (121-140) or DBP (60-85) at baseline, a subsequent rise to >160 or > 85 respectively, was associated with an increased risk of ESKD. Thus, longitudinal BP measures in late-stage CKD are significantly associated with adverse outcomes and convey important information beyond baseline BP measures.

Submitted by Nadir Basilio (nadirsb@uninove.br) on 2016-05-17T20:42:43Z No. of bitstreams: 1 Gabriela Gomes Cardoso Rodrigues.pdf: 623885 bytes, checksum: 3da3d1230fd77beffc9c12f00be889bb (MD5) / Made available in DSpace on 2016-05-17T20:42:43Z (GMT). No. of bitstreams: 1 Gabriela Gomes Cardoso Rodrigues.pdf: 623885 bytes, checksum: 3da3d1230fd77beffc9c12f00be889bb (MD5) Previous issue date: 2015-02-04 / Chronic kidney disease (CKD) is characterized by progressive and irreversible loss of renal function and often progresses with a muscular weakness, whose set of signs and symptoms is generally referred to as uremic myopathy. Possible risk factors for the uremic myopathy are the uremic toxins. Among uremic toxins, indoxyl sulfate (IS) is a derivative of tryptophan metabolism by intestinal bacteria. Because skeletal muscle tissue undergo constant remodeling due differentiation of myoblasts in myotubes, it is possible that uremic toxins have a deleterious effect to influence this process, exacerbating the uremic myopathy. Low level laser therapy (LLLT) is regarded as a growth promoter feature widely used in the treatment of chronic diseases and has shown positive effects on the modulation of skeletal muscle repair process and also in the process of inflammation. However, in the context of CKD, the LLLT has not yet been explored. The aim of this study was to evaluate the effects of the IS on cell viability and on oxidative stress on cellular differentiation in cultured C2C12 myoblasts. In addition, to verify the action of the LLLT as a protective alternative to the cells. The C2C12 myoblasts were cultured in DMEM culture medium containing 10% fetal bovine serum and were induced to differentiation process by adding 2% horse serum. Three different IS concentrations were used to mimic the plasma concentrations of normal individual, CKD patients with moderate uremia and CKD patients with advanced uremia (0.6 mg/l and 53 mg/l and 236 mg/l, respectively), at different times of incubation (24 h, 48 h and 72 h). Subsequently, the cells were subjected to treatment with LLLT GaAlAs 780 nm (output power 10 mW, 20 seconds application time and energy density of 0.5 J / cm2). In terms of analysis, we used MTT method to assess the viability of the cells, flow cytometry to assess the viability/cell death and oxidative stress, nitrite dosing to evaluate nitric oxide production and real-time PCR to analyze IL-6, myogenin and MyoD expression (inflammation and cell differentiation markers). The results demonstrate that the IS at the maximum concentration was toxic to C2C12 cells, because it significantly decreased cell viability by MTT and by flow cytometry and by increasing the percentage of necrosis. This effect was present throughout the three incubation periods. With respect to oxidative stress, was not any conclusion, probably by the time the samples, but do not rule out the possibility of IS induce this type of stress. Although the IS has induced death to C2C12 cells, the remaining had no change in cell differentiation markers. Treatment with BPL the IS sensitized cells, reducing cell viability. We conclude that the IS acts directly on C2C12 myoblasts with toxic effect and may be the one factor responsible for uremic myopathy. Treatment with LLLT was not effective in protecting the cells. / A doença renal crônica (DRC) é caracterizada pela perda progressiva e irreversível da função renal e que frequentemente cursa com um quadro de fraqueza muscular, cujo conjunto de sinais e sintomas é globalmente designado como miopatia urêmica. Possíveis fatores predisponentes para a miopatia urêmica são as toxinas urêmicas. Dentre as toxinas urêmicas, o indoxil sulfato (IS) é uma derivada do metabolismo do triptofano presente em bactérias intestinais. Devido ao fato do tecido muscular esquelético sofrer constante remodelação graças à diferenciação de mioblastos em miotubos, é possível que toxinas urêmicas tenham um efeito deletério por influenciar este processo, agravando a miopatia urêmica. A terapia a laser de baixa potência (LBP) é considerada como um recurso bioestimulante amplamente utilizado no tratamento de doenças crônicas e tem demonstrado efeitos positivos sobre a modulação do processo de reparo muscular esquelético e também no processo da inflamação. Entretanto, no contexto de DRC, o LBP não foi ainda explorado. O objetivo do presente estudo foi avaliar dos efeitos do IS sobre a viabilidade celular, sobre o estresse oxidativo e sobre a diferenciação celular em cultura de mioblastos C2C12. Além disso, verificar a ação do LBP como forma de proteção às células. Os mioblastos C2C12 foram cultivados em meio de cultura de DMEM, contendo 10% de soro fetal bovino e foram induzidos ao processo de diferenciação por meio da adição de 2% soro de cavalo. Três diferentes concentrações de IS foram usadas para mimetizar as concentrações plasmáticas de indivíduo normal, paciente DRC com uremia moderada e paciente DRC com uremia avançada (0,6 mg/l; 53 mg/l e 236 mg/l, respectivamente), em diferentes períodos de incubação (24 h, 48 h e 72 h). Posteriormente, as células foram submetidas ao tratamento com laser de baixa potência AsGaAl 780 nm (potência de saída de 10 mW, tempo de aplicação de 20 segundos e densidade de energia de 0,5 J/cm2). Como análise, foi utilizado o método MTT para acessar a viabilidade das células, citometria de fluxo para avaliar a viabilidade/mortalidade das células, bem como o estresse oxidativo, dosagem de nitrito para avaliar a produção de óxido nítrico e PCR em tempo real para analisar a expressão de IL-6, miogenina e MyoD (marcadores de inflamação e diferenciação celular). Os resultados demonstram que o IS na concentração máxima foi tóxico para as células C2C12, pois diminuiu significativamente a viabilidade das células, tanto por MTT como por citometria de fluxo, aumentando a porcentagem de necrose. Este efeito foi presente nos três períodos de incubação. Com relação ao estresse oxidativo, não foi possível nenhuma conclusão, provavelmente pelo tempo das amostras , porém não descartamos a possibilidade do IS induzir este tipo de estresse. Embora o IS tenha induzido morte às células C2C12, as remanescentes não tiveram alteração dos marcadores de diferenciação celular. O tratamento com LBP sensibilizou as células ao IS, diminuindo a viabilidade das células. Concluímos que o IS age diretamente sobre mioblastos C2C12 com efeito tóxico, podendo ser um dos responsáveis pela miopatia urêmica. O tratamento com LBP não foi eficiente na indução de proteção às células.

Introdução: O trato gastrointestinal humano é composto por uma comunidade microbiana diversificada que atua no controle da saúde. Estudos recentes demonstraram que o equilíbrio da microbiota intestinal é afetado na doença renal crônica (DRC), ocasionando o quadro de disbiose intestinal. Estes estudos sugeriram uma associação da disbiose intestinal com complicações metabólicas como acúmulo de toxinas urêmicas, progressão da DRC, inflamação e risco cardiovascular. Diante disso, medidas com o objetivo de restaurar o equilíbrio da microbiota intestinal são sugeridas, tais como a ingestão oral de probióticos, mas poucos estudos têm abordado o efeito destes suplementos na progressão da DRC e no risco cardiovascular destes pacientes. Objetivo: Avaliar o efeito do consumo de probióticos em fatores associados com progressão da DRC e risco cardiovascular de pacientes com DRC. Material e métodos: Trata-se de um estudo clínico controlado por placebo registrado no Clinical Trials NCT03400228. O estudo incluiu 30 pacientes adultos com DRC nos estágios 3 a 5 não em diálise, com função renal estável e proteinúria igual ou superior a 500 mg. A coleta de dados ocorreu entre novembro de 2015 até dezembro de 2017. O protocolo do estudo constou de período de washout de 4 semanas e randomização dos pacientes para o grupo de intervenção (GI, suplemento com probiótico) ou para o grupo controle (GC, maltodextrina). Foi realizado avaliação basal e após 24 semanas de consumo de probiótico ou placebo. Todos os pacientes receberam a orientação de consumir 2 sachês por dia do probiótico ou do placebo (maltodextrina). Foram avaliadas variáveis demográficas, clínicas, nutricionais, hábito intestinal e exames laboratoriais com amostras sanguíneas e urinárias. Resultados: Dos 30 pacientes incluídos, 20 completaram as 24 semanas do estudo, sendo 10 no grupo intervenção e 10 no grupo placebo. Após o uso de probiótico houve aumento na taxa de filtração glomerular estimada (p<0,001) e diminuição nos níveis séricos de creatinina (p<0,001), ureia (p=0,015), proteína C reativa (p=0,03), hormônio da paratireóide (p=0,03) e potássio (p=0,012), em comparação ao grupo placebo. Os efeitos positivos do probiótico na taxa de filtração glomerular estimada e na diminuição dos níveis séricos de creatinina e ureia permaneceram após análise de regressão multivariada. Não houveram diferenças significativas nos parâmetros urinários entre os grupos. Sintomas de constipação (p<0,001) e consistência fecal (p=0,016) apresentaram melhora no grupo intervenção versus placebo. Conclusão: A suplementação de probióticos melhorou os marcadores de função renal e reduziu inflamação, além de auxiliar na melhora dos sintomas de constipação intestinal em pacientes com DRC. / Introduction: The human gastrointestinal tract is colonized by a diversified microbial community that acts in control of health. Recent studies have shown that intestinal microbiota balance is affected in chronic kidney disease (CKD) leading to intestinal dysbiosis. These studies have suggested association of intestinal dysbiosis with several metabolic disorders such as accumulation of uremic toxins, progression of CKD, inflammation and cardiovascular risk. Therefore, interventional measurement that improve intestinal microbiota balance are suggested such as supplementation of probiotics, however few studies evaluated the effect of these supplements on the progression of CKD and cardiovascular risk in CKD patients. Aim: The purpose of the study was to evaluate the effects of probiotic supplementation on the factors associated with progression of CKD and cardiovascular risk in patients with CKD. Desing and Methods: This was a randomized, double-blind, placebo-controlled study. Thirty patients with CKD stages 3 to 5 not on dialysis, with stable renal function and protein-creatinine ratio > 0.50 were included. Data collection was between November 2015 and December 2017. Study protocol was 4-week washout period, patients randomized to intervention group (IG, probiotic supplement) or control group (CG, maltodextrin), and follow for 24 weeks. Renal function, C-reactive protein (CRP), bone and mineral metabolism, nutritional, and lipid profile markers and intestinal habit were measured at baseline and 24 weeks of study. Results: From 30 patients included in this study, 20 completed the 24 study weeks, 10 in the TG and 10 in PG. After probiotic supplementation, there was increase in estimated glomerular filtration rate (p<0.001) and decrease in serum creatinine 8 (p<0.001), urea (p=0.015), C-reactive protein (p=0.030), parathyroid hormone (p=0.03), and potassium (p=0.012) levels compared to CG. The beneficials effects of probiotics on estimated glomerular filtration rate and serum creatinine, urea, and Creactive protein remained after multivariate linear regression. There were no significant differences in the urinary parameters between the two groups. Symptoms of constipation (p<0.001) and stool consistency (p=0.016) improved in IG compared to CG. Conclusion: Probiotic supplementation improved markers of renal function and reduced inflammation. In addition, it improved the symptoms of intestinal constipation in patients with CKD.

The intake of sodium, potassium, and phosphorus has important implications for chronic disease risk. Excess sodium intake is shown to be associated with elevated blood pressure, which in turn is a risk factor for cardiovascular disease (CVD) and chronic kidney disease (CKD). Potassium intake, on the other hand, is shown to be beneficial for lowering blood pressure and reducing the risk of CVD and CKD. Once an individual develops CKD, they experience alterations in mineral metabolism, especially phosphorus, and must closely monitor mineral intake and biochemical laboratory values in order to avoid complications. Thus, monitoring mineral intake is important in both healthy and CKD individuals in both research as well as clinical practice settings. It is therefore also important to have a method for estimating mineral intake that is both accurate as well as easy to administer. Two commonly used methods are self-report and 24-hour urinary mineral excretion. however, both methods have pros and cons. An alternative option that has been explored for all three minerals of interest is to collect a spot urine sample, then use one of several published equations to calculate an estimate of 24-hour urinary mineral excretion. While this method is relatively easy to administer, much remains unexplored regarding the accuracy of estimated 24-hour mineral excretion. My aim for my dissertation was to explore how estimated 24-hour sodium (e24hUNa), potassium (e24hUK) and phosphorus (e24hUP) compared to true mineral intake in healthy participants as well as those with CKD. We conducted secondary analyses from two controlled feeding studies, in which true mineral intake was known. Our results show that e24hUNa and e24hUK are not reliable indicators of true sodium and potassium intake, respectively, in healthy participants nor those with CKD, and e24hUP is not a reliable indicator of phosphorus intake in CKD participants. Though these findings should be confirmed by larger studies, these findings suggest that currently available equations may need to be revised and estimated 24-hour mineral excretion from spot urine samples should be interpreted with caution.

Orientador: Marina Nogueira Berbel Bufarah / Resumo: INTRODUÇÃO: A Doença Renal Crônica (DRC) apresenta alta prevalência global, sendo a doença cardiovascular (DCV) sua principal causa de morbidade e mortalidade. A dislipidemia e a inflamação são importantes fatores de risco cardiovascular nessa população, que podem ser atenuados com o aumento da ingestão de fibras alimentares. OBJETIVOS: Avaliar o efeito da suplementação de fibra alimentar na inflamação e dislipidemia de pacientes com doença renal crônica pré dialítica, bem como em outros parâmetros laboratoriais e nutricionais. MÉTODOS: Foi realizado ensaio clínico randomizado controlado com os pacientes maiores de dezoito anos atendidos no Ambulatório de Pré-Diálise do Hospital das Clínicas da Faculdade de Medicina de Botucatu. Os que não preencheram os critérios de exclusão foram agrupados em grupo controle (GC) e grupo intervenção (GI) por meio de sorteio. O GC recebeu 10g de módulo de carboidrato como placebo e o GI recebeu 10g de pó correspondendo a 8,6 gramas de fibras (goma guar e inulina), para serem ambos diluídos em 150mL de água filtrada 1 vez ao dia pela manhã durante 60 dias consecutivos. O protocolo de avaliação foi composto por dados clínicos, nutricionais e laboratoriais, aplicado antes da intervenção e após 60 dias. Os resultados foram apresentados como frequências e porcentagens ou média ± desvio padrão, conforme característica de cada variável. Para comparar as variáveis explanatórias no tempo foi ajustado um Modelo Misto em medidas repetidas. Considerou-se... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: INTRODUCTION: Chronic Kidney Disease (CKD) has a high global prevalence, being cardiovascular disease (CVD) its main cause of morbidity and mortality. Dyslipidemia and inflammation are important cardiovascular risk factors in this population, which can be attenuate by increasing dietary fiber intake. OBJECTIVE: To evaluate the effect of dietary fiber supplementation on inflammation and dyslipidemia in patients with pre-dialytic chronic kidney disease, as well as on other laboratory and nutritional parameters. METHODS: A randomized controlled trial was conducted with patients adults attending at the Pre-Dialysis Outpatient Clinic Hospital of Faculty of Medicine of Botucatu. Patients that did not meet the exclusion criteria were grouped into a control group (CG) and intervention group (GI). The CG received 10g of carbohydrate modulus as placebo and the GI received 10g of intervention powder corresponding to 8.6 grams of fiber (guar gum and inulin), both of which were diluted in 150mL of filtered water once a day in the morning during 60 consecutive days. Results were presented as frequencies and percentages or mean ± standard deviation, according to the characteristics of each variable. To compare the explanatory variables over time a mixed model was fitted in repeated measures. It was considered a 5% level of significance. RESULTS: Twenty-four patients were evaluated, 13 in GI and 11 in CG. The patients had a mean age of 57,5±12,6 years old, being 70,8% male, with an average g... (Complete abstract click electronic access below) / Mestre