<p>BACKGROUND: The ontogeny of peanut allergy (PA) is poorly understood, and the treatment of its most severe manifestation, peanut-induced anaphylaxis (PIA), remains limited to rescue epinephrine. We argued that an untargeted metabolomic analysis would be a useful hypothesis-generating tool to identify novel biomarkers, mediators and possibly therapeutic targets in PA and PIA.</p> <p>METHODS: Models of PA and PIA used in this thesis involved either the oral administration of peanut along with cholera toxin or the topical application of peanut on tape-stripped skin. Liquid-chromatography mass-spectrometry (LC-MS) was performed to identify chemical changes in the serum of mice undergoing sensitization and anaphylaxis. Flow cytometry as well as <em>in vivo</em> gain-of-function and loss-of-function immunological studies were used to determine the biological significance of particular molecules in sensitization.</p> <p>RESULTS: LC-MS followed by multivariant analysis showed that the purine metabolism pathway was altered with elevated levels of uric acid (UA) in sensitized mice. UA depletion using allopurinol and uricase fully prevented the development of the allergic and anaphylactic phenotype. Conversely, administration of UA crystals, instead of cholera toxin or tape stripping along with peanut induced a typical allergic and anaphylactic phenotype. The effects of UA and UA crystals are likely a consequence of effects on the activation of resident dendritic cells. Post-challenge metabolic analysis also revealed a distinct metabolic signature in sensitized mice, highlighted by an increase in several metabolites such as histamine. Likewise, peanut allergic patients display a distinct metabolic profile after oral peanut challenge.</p> <p>CONCLUSION: We identified UA, released after damage to the mucosa and/or skin, as a critical alarmin that facilitates the development of Th2 immunity, specifically PA and PIA. Metabolomics analyses of either mice undergoing anaphylaxis or peanut allergic children subjected to a peanut oral challenge provided an extensive overview of metabolomic changes underlying these conditions. Further studies may lead to the identification of novel biomarkers and mediators.</p> / Master of Science in Medical Sciences (MSMS)

High sugar-sweetened beverage (SSB) intake and poor vitamin D status have both been associated with increased risk of elevated systolic blood pressure (SBP) in previous research. However, these associations have never been investigated in the same study population, leaving the question of a possible interaction uninvestigated. One potential mechanism for an interaction is that SSB intake may increase serum uric acid (UA) and UA may interfere with utilization of vitamin D. This study examined these relationships in a sample of men and women (n=2,875) aged 20-74 using data collected in the 2003-2006 NHANES survey. No statistically significant association was found between SSB intake and risk of elevated SBP (defined as SBP>120mmHg) in whole group analysis. In subgroup analysis by gender, women (n=1,550) showed a 68% (OR: 1.68, 95% CI: 1.12-2.50, p-value 0.011) increased risk of elevated SBP in the highest SSB intake quartile (mean intake of 3.27 servings/day) compared to the lowest (mean intake of 0.03 servings/day) after adjustment for age, race, BMI, alcohol use, physical activity, and smoking, but no association was found in men (n=1,325). A statistically significant association was found between 25(OH)D and SBP, with a 30% decrease in risk of elevated SBP (OR: 0.70, 95% CI: 0.55-0.90, p-value 0.005) for those in the highest serum 25(OH)D group (>75nmol/L) compared to the lowest (<50nmol/L) in the fully adjusted model. However, no association was found between SSB intake and serum UA. Assessing potential effect modification between SSB and vitamin D in their impact on blood pressure using a multiplicative term and stratified analysis did not provided evidence of an interaction effect.

Physiological parameters involved in formed urate pellet excretion by the wood cockroach, <i>Parcoblatta fulvescens</i> were investigated. Uric acid excretion by last instar juvenile <i>P. fulvescens</i> was studied first. Food consumption, urate and non-urate pellet excretion patterns show a skewed distribution with peak feeding occurring on day six and peak voiding of both pellet types on day seven of a 17.0 ± 2.0 (SD) day ecdysial cycle. The amount of urates excreted is determined by the level of dietary protein (p<0.0001) and is linearly related to protein consumption. Selective feeding on protein, carbohydrate and cellulose diets by reproductive female <i>P. fulvescens</i> was investigated. Separate consumption patterns exist for each diet. These females did not excrete uric acid. Urate pellet consumption by reproductive female <i>P. fulvescens</i> was examined in relation to dietary protein and carbohydrate. Urate pellet consumption increases with decreasing protein and increasing carbohydrate levels. Females that consume urate pellets do not excrete uric acid. These results suggest that urate-containing pellets serve to transfer nitrogen reserves among individuals. Urate spherules were enzymatically and histochemically identified in the middle and proximal regions of the Malpighian tubules of <i>P. fulvescens</i>, <i>Shawella couloniana</i> and <i>Symploce hospes</i>. These spherules are discharged into the hindgut in sufficient quantities to obscure the presence of food residues. The significance of formed urate pellet excretion is discussed in relation to the nitrogen economy of <i>Parcoblatta fulvescens</i>. / Master of Science / incomplete_metadata

Orientador: Luis Cuadrado Martin / Resumo: Fundamentação: É crescente o número de trabalhos revelando a associação de hiperuricemia assintomática com hipertensão, síndrome metabólica, doenças cardiovasculares e doença renal crônica. Alguns estudos revelam que o tratamento da hiperuricemia assintomática reduz o número de desfechos renais e cardiovasculares. Tal premissa, no entanto, ainda não foi avaliada em uma subpopulação brasileira. Objetivos: Avaliar a associação entre tratamento com alopurinol e ocorrência de desfechos definitivos em portadores de doença renal crônica com hiperuricemia assintomática. Materiais e métodos: Foram avaliados, de forma retrospectiva, pacientes hiperuricêmicos e portadores de doença renal crônica não dialítica, em tratamento no HC-FMB – UNESP, os quais iniciaram acompanhamento no ambulatório de Insuficiência Renal Crônica ou de Nefrologia Geral do HC-UNESP desde janeiro 2002 a dezembro 2017. Com o intuito de avaliar a associação do uso do alopurinol sobre desfechos definitivos (entrada em terapia renal substitutiva, duplicação da creatinina ou morte). Resultados: Foram avaliados 109 pacientes sendo 53 do sexo feminino, cuja média de idade foi de 68 ± 11 anos. Destes, 95 eram brancos, 13 afrodescendentes e um asiático. Vinte e seis pacientes apresentaram o desfecho estudado no período; entre todos os 36 pacientes que iniciaram o uso de alopurinol no primeiro ano seguimento, ocorreram oito desfechos (22%). A proteinúria em 24 h associou-se aos desfechos avaliados Hazzard Ratio de 1,301 (I... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Rationale: There is increasing number of studies revealing an association of hyperuricemia with hypertension, metabolic syndrome, cardiovascular diseases and chronic kidney disease. Some studies have shown that treatment of asymptomatic hyperuricemia reduces the number of renal and cardiovascular outcomes. This premise, however, has not yet been evaluated in a Brazilian subpopulation. Objectives: To evaluate the association between treatment with allopurinol and the occurrence of definitive outcomes in patients with chronic kidney disease with asymptomatic hyperuricemia. Materials and methods: Hyperuricemic patients with chronic non-dialytic kidney disease under treatment at HC-FMB - UNESP who began follow-up at the Chronic Kidney Insufficiency or General Nephrology outpatient clinic at HC-UNESP, were retrospectively evaluated, from January 2002 to December 2017. In order to evaluate the association of the use of allopurinol on definitive outcomes (renal replacement therapy, creatinine doubling or death). Results: A total of 109 patients were evaluated, of which 53 were females, whose mean age was 68 ± 11 years. Of these, 95 were white, 13 Afro-descendants and one Asian. Twenty-six patients presented the outcome studied in the period; among all 36 patients who started using allopurinol in the first year of follow-up, eight outcomes (22%) occurred. Proteinuria at 24 h was associated with the Hazzard Ratio of 1.301 (95% CI: 1.122 -1.508), p: 0.011. In univariate analysis, phosp... (Complete abstract click electronic access below) / Mestre

A doença renal crônica é uma doença mediada pelo sistema imune e caracterizada por fibrose. Camundongos deficientes em TLR2, TLR4, MyD88 e NLRP3 se mostraram protegidos frente ao dano renal e à deposição de colágeno após serem submetidos à obstrução unilateral do ureter (UUO). Além disso, os camundongos protegidos exibiram menor produção de citocinas relacionadas com um perfil imune Th2 e apresentaram menor acúmulo de macrófagos do subtipo M2. Inicialmente, creditamos aos macrófagos M2 o papel de macrófagos formadores de fibrose uma vez que tal subpopulação é encontrada em maior número aos sete dias após a UUO em animais WT, porém, vimos que os personagens centrais no desenvolvimento da fibrose são macrófagos M1, encontrados no início da lesão renal. Também vimos que o ácido úrico é a molécula capaz de induzir a troca de fenótipo de M1 para M2 ao longo da UUO, além de ser capaz de ativar a via do inflamassoma. O ácido úrico solúvel é liberado em um contexto de hipóxia e ativa o complexo do inflamassoma NLRP3 por mecanismos diferentes, mas complementares. / Chronic kidney disease is an immune mediated disease characterized by fibrosis development. The damaged tissue releases molecules such as soluble uric acid resulting from the degradation of extracellular matrix or dead cells, which activate TLR and NLR, leading to the translocation of MyD88 in many cell types. This modulation of the immune system interferes with the activation of different subtypes of macrophages and activity of CD4+ T cells, with the Th1/Th2 paradigm as a possible effector mechanism of fibrosis. TLR2, TLR4, MyD88, and NLRP3 deficient mice are protected against renal damage and collagen deposition after being submitted to unilateral ureteral obstruction (UUO), when compared to wild type animals. Moreover, protected mice exhibited less production of Th2 related cytokines and reduced accumulation of M2 macrophages. Initially, we hypothesized M2 macrophages are responsible for fibrosis formation since this subset is found in greater numbers seven days after UUO in WT mice, however, we observed the central characters on the development of fibrosis are M1 macrophages found in the onset of renal injury. These data were confirmed by the injection of Stat6 KO M1 macrophages into Rag deficient mice previously depleted of macrophages and subjected to UUO, in which we observed higher proteinuria and increased collagen deposition. We also observed that uric acid is able to induce the exchange of phenotype from M1 to M2 along the UUO, besides being able to activate the inflammasome pathway. The soluble uric acid is released in the context of hypoxia and activates the NLRP3 inflammasome complex by different, but complementary mechanisms. Therefore, the renal damage releases soluble uric acid, which signals via innate immune receptors, and the damage brings as a consequence the deposition of proteins in the renal interstitium, culminating in fibrosis.

Submitted by PRISCILA VIEIRA DA SILVA null (privieira.odonto@gmail.com) on 2016-05-16T16:04:00Z No. of bitstreams: 1 Dissertação Priscila Vieira da Silva.pdf: 1090391 bytes, checksum: 41dc10fe589d791d5b3020f707074cbe (MD5) / Approved for entry into archive by Ana Paula Grisoto (grisotoana@reitoria.unesp.br) on 2016-05-17T14:57:14Z (GMT) No. of bitstreams: 1 silva_pv_me_araca.pdf: 1090391 bytes, checksum: 41dc10fe589d791d5b3020f707074cbe (MD5) / Made available in DSpace on 2016-05-17T14:57:14Z (GMT). No. of bitstreams: 1 silva_pv_me_araca.pdf: 1090391 bytes, checksum: 41dc10fe589d791d5b3020f707074cbe (MD5) Previous issue date: 2016-03-31 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / O estresse oxidativo é atribuído a um desequilíbrio entre a ação de sistemas antioxidantes com a produção exacerbada de radicais livres, como espécies reativas de oxigênio. A atividade dos sistemas antioxidantes enzimáticos e não enzimáticos, são uma poderosa defesa do corpo contra danos causados pelos radicais livres. Biomarcadores do estresse oxidativo podem ser observados na saliva de adultos e crianças. O objetivo deste trabalho foi avaliar os níveis de estresse oxidativo e a atividade de sistema antioxidante enzimático, como a superóxido dismutase (SOD) e não-enzimático como o ácido úrico (AU) na saliva de crianças na primeira infância (0-3 anos de idade) que apresentaram cárie precoce severa da infância (S-ECC do inglês, severe early childhood caries). Amostras de saliva não estimuladas foram coletadas pela manhã, durante 5 minutos, usando o Salivette® em crianças de 0-3 anos de idade, com cárie precoce severa na infância (n = 30) e em crianças livres de cárie (n = 30) de escolas públicas de Araçatuba – SP. Foram feitas as avaliações de estresse oxidativo (EO), pela medida da peroxidação lipídica, da capacidade antioxidante total (CAT), pelo método FRAP, bem como de sistema antioxidante enzimático, avaliando a atividade da SOD e não enzimático pela avaliação do UA, salivares. Os dados foram analisados por programa estatístico Graph Pad Prism, versão 5.0 e comparados pelo teste t de Student (p <0,05). Níveis de proteína elevados foram observados na saliva de crianças S-ECC quando comparados ao grupo livre de cárie. O dano oxidativo foi menor na saliva de S-ECC, enquanto a CAT salivar, atividade da SOD e ácido úrico salivares foram mais elevados em S-ECC quando comparados ao grupo livre de cárie. Nosso estudo demonstrou que o menor dano oxidativo observado na saliva de S-ECC estaria associado ao aumento da atividade de sistemas antioxidantes enzimático e não enzimático. / Oxidative stress is attributed to an imbalance between the antioxidant systems activity and the increased production of free radicals such as reactive oxygen species. The activity of enzymatic and non-enzymatic antioxidant systems are a powerful defense of the body against damage caused by free radicals. Oxidative stress biomarkers can be observed in the saliva of adults and children. The objective of this study was to evaluate the levels of oxidative stress and antioxidant enzyme system activity, such as superoxide dismutase (SOD) and nonenzymatic as uric acid (UA) in the saliva of toddlers (0-3 years old) with severe early childhood caries (S-ECC). Unstimulated saliva samples were collected in the morning during 5 minutes using Salivette® in S-ECC children (n = 30) and in caries-free children (n = 30) of public schools in Araçatuba - SP. We evaluated the salivary protein level by Lowry method, and the oxidative stress (OS) by lipid peroxidation. The total antioxidant capacity (TAC) was analyzed by FRAP method. The activity of salivary SOD and salivary UA were assessed as enzymatic and non-enzymatic antioxidant systems, respectively. Data were analyzed by statistical program Graphpad Prism version 5.0 and the results were compared between groups by Student's t test (p <0.05). High protein levels were observed in the saliva of S-ECC children when compared to caries-free group. Oxidative damage was lower in S-ECC group, while the salivary TAC, SOD activity and salivary UA were higher in S-ECC when compared to the caries-free group. This study demonstrated that decreased oxidative damage was associated with the increased activities of the enzymatic and non-enzymatic antioxidant systems in S-ECC saliva.

Submitted by (edna.saturno@ufrpe.br) on 2016-07-21T15:16:08Z No. of bitstreams: 1 Gyl Everson de Souza Maciel.pdf: 1066870 bytes, checksum: 5d3e6cb058a19d66e3669721aeb1a30a (MD5) / Made available in DSpace on 2016-07-21T15:16:08Z (GMT). No. of bitstreams: 1 Gyl Everson de Souza Maciel.pdf: 1066870 bytes, checksum: 5d3e6cb058a19d66e3669721aeb1a30a (MD5) Previous issue date: 2013-02-26 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Pomacea lineata (Spix, 1827) during the dry season buries itself in the ground and survives thanks to its ability to aestivation. Studies have shown that during aestivation levels of carbohydrates and uric acid, may provide more accurate information about the activity of the gonads in response to environmental stress. Thus, we tested the hypothesis that variations in the levels of uric acid and carbohydrate during aestivation induced, can affect gonadal histology and gametogenesis in P. lineata. The snails underwent aestivation of three, five and 10 months. Testes and ovaries were collected and processed for histological analysis. The results showed significant increase in the levels of uric acid and carbohydrates in proportion to the period of aestivation, and histological changes in the gonads. Thus, we conclude that the metabolism of proteins is proportional to the period of aestivation for carbohydrate synthesis and excretion of uric acid, thereby ensuring the integrity of the reproductive tract. / Pomacea lineata (Spix, 1827)durante a época de estiagem se enterra no solo e sobrevive graças a sua capacidade de estivação. Estudos têm mostrado que durante a estivação os níveis de carboidratos e ácido úrico, podem fornecer informações mais precisas sobre a atividade das gônadas em resposta ao estresse ambiental. Assim, testou-se a hipótese de que as variações nos níveis de carboidratos e acido úrico, durante a estivação induzida, pode afetar a histologia gonadal e gametogênese em P. lineata. Os caramujos foram submetidos à estivação por três, cinco e 10 meses. Testículos e ovários foram coletados e processados para análises histológicas. Os resultados mostraram aumento significativo dos níveis de carboidratos e ácido úrico proporcionalmente ao período de estivação, além de alterações histológicas nas gônadas. Assim, concluímos que a metabolização de proteínas é proporcional ao período de estivação, para síntese de carboidratos e excreção de ácido úrico, garantindo assim, a integridade do aparelho reprodutor.

In this work we developed an electrochemical sensor modified with multi-walled carbon nanotubes and 5-nitroindole (5-NI) for the simultaneous determination of ascorbic (AA) and uric (UA) acids in urine and serum samples and a biosensor based on dsDNA for determination of 3-nitro-L-tyrosine ethyl ester (3NO2TEE), as a biomarker of biological peroxynitration. The polymer of 5-NI was electrogenerated in situ on the carbon nanotubes deposited on glassy carbon electrode (GCE). Thereafter, the aromatic nitro group, present in the molecule, was reduced, generating a hydroxylamine/nitroso redox couple, then used for detection and quantification of the analytes in the biological samples. The electrochemical behavior of the modified electrodes were studied using cyclic voltammetry, differential pulse voltammetry and chronoamperometry, which were used for the detection of the analytes and to obtain the kinetic parameters and the analytical characterization of the platforms. The chronoamperometric studies were performed in order to obtain more information about the redox processes between AA and the sensor, since it proved to be an electrocatalytic process. Thus, by means of graphs and Cottrell equations, it was possible to obtain values for the diffusion coefficient (DAA) and the catalytic constant (kcat) for the AA electrocatalytic oxidation. The values for DAA and kcat, determined for AA were 4.2 x10-6 cm-2 s-1 and 1.1 x 106 M-1 s-1, respectively. The platform for the detection of AA e AU showed good sensitivity and stability in urine and serum samples, with LOD of 1.9 mol L-1 for AA and 2.1 mol L-1 for UA. The analytical performance obtained for the nanostructured platform GCE/MWCNT/poly-5-NID justifies its use as a sensor for the simultaneous determination of AA and UA. Studies of 3NO2TEE in protic media (pH 4.5 acetate buffer and pH 7.4 and 10.0, in phosphate buffer) and in aprotic media (DMF/TBAPF6, 0.1 mol L-1), using Pt and glassy carbon electrodes, were necessary before the construction of the CT-DNA biosensor. The spectrolectrochemistry of 3NO2TEE, held in aprotic media was useful for rationalizing the electrochemical behavior of 3NO2TEE and intermediates generated during the reduction. For the biosensor construction, the amount of dsDNA, the conditioning time for reduction of the analyte, the pH value, on GCE, were optimized. The developed biosensor was used to determine the concentration of 3NO2TEE and showed a linear range from 60 to 320 nmol L-1 and LOD and LOQ of 58 nmol L-1 and 200 nmol L-1, respectively. These results indicate that the prepared sensor and biosensor were effective for the detection of substances with biological interest. (P.S.: some expressions out of formatting) / Conselho Nacional de Desenvolvimento Científico e Tecnológico / Neste trabalho foram desenvolvidos um sensor eletroquímico modificado com nanotubos de carbono de paredes múltiplas (MWCNT) e 5-nitroindol (5-NI) para determinação simultânea dos ácidos ascórbico (AA) e úrico (AU), em amostras de urina e soro, e um biossensor à base de dsDNA para determinação do éster etílico da 3-nitro-L-tirosina (3NO2TEE), como biomarcador de peroxinitração biológica. O trímero do 5-nitroindol foi eletrogerado in situ sobre os nanotubos de carbono depositados em eletrodo de carbono vítreo (ECV). Após esse processo, o grupo nitro aromático, presente na molécula foi reduzido gerando o par redox hidroxilamina/nitroso, utilizado para detecção e quantificação dos analitos presentes nas amostras biológicas. Os comportamentos eletroquímicos dos eletrodos modificados foram estudados, empregando as técnicas de voltametria cíclica, voltametria de pulso diferencial e cronoamperometria, as quais foram utilizadas para a detecção dos analitos e para obtenção dos parâmetros cinéticos e caracterização analítica da plataforma. Os estudos cronoamperométricos foram realizados com o objetivo de obter maiores informações dos processos redox entre AA e o sensor, uma vez que este demonstrou ser um processo eletrocatalítico. Assim, por meio de gráficos e equações de Cottrell, foi possível obter os valores para o coeficiente de difusão (DAA) e a constante catalítica (kcat) da reação para o AA. Os valores do DAA e de kcat, determinados para AA, foram de 4,2 x10-6 cm-2 s-1 e 1,1 x 106 M-1 s-1, respectivamente. O método desenvolvido de detecção de AA e AU apresentou boa sensibilidade e estabilidade em amostras de urina e soro, com limite de detecção (LD) de 1,9 mol L-1 para AA e 2,1 mol L-1 para AU. A partir do desempenho analítico obtido da plataforma nanoestruturada ECV/MWCNT/poli-5-NID, justifica-se a sua utilização deste como sensor para a determinação simultânea de AA e AU. Antes da construção do biossensor de DNA, para nitroaromáticos de importância biológica, foi necessária a realização dos estudos da 3NO2TEE, em meios prótico: tampão acetato pH 4,5 e tampão fosfato pH 7,4 e 10,0 e, em meio aprótico (DMF/ TBAPF6, 0,1 mol L-1), utilizando eletrodo de Pt e carbono vítreo, como eletrodos de trabalho. A espectroeletroquímica de 3NO2TEE, realizada em meio aprótico, foi útil para racionalizar o comportamento eletroquímico de 3NO2TEE e de seus intermediários gerados durante a redução. Para a construção do biossensor, sobre o eletrodo de carbono vítreo, foram otimizados: concentração de dsDNA, tempo de condicionamento para a redução do nitrocomposto, valor de pH. O biossensor ECV/dsDNA apresentou faixa linear de 60 - 320 nmol L-1 e LD e LQ (limite de quantificação) encontrados foram 58 nmol L-1 e 200 nmol L-1. Estes resultados indicaram que o sensor e o biossensor foram produzidos e aplicados de forma eficaz para detecção de substâncias de interesse biológico. (obs.: algumas expressões fora da formatação)

A doença renal crônica é uma doença mediada pelo sistema imune e caracterizada por fibrose. Camundongos deficientes em TLR2, TLR4, MyD88 e NLRP3 se mostraram protegidos frente ao dano renal e à deposição de colágeno após serem submetidos à obstrução unilateral do ureter (UUO). Além disso, os camundongos protegidos exibiram menor produção de citocinas relacionadas com um perfil imune Th2 e apresentaram menor acúmulo de macrófagos do subtipo M2. Inicialmente, creditamos aos macrófagos M2 o papel de macrófagos formadores de fibrose uma vez que tal subpopulação é encontrada em maior número aos sete dias após a UUO em animais WT, porém, vimos que os personagens centrais no desenvolvimento da fibrose são macrófagos M1, encontrados no início da lesão renal. Também vimos que o ácido úrico é a molécula capaz de induzir a troca de fenótipo de M1 para M2 ao longo da UUO, além de ser capaz de ativar a via do inflamassoma. O ácido úrico solúvel é liberado em um contexto de hipóxia e ativa o complexo do inflamassoma NLRP3 por mecanismos diferentes, mas complementares. / Chronic kidney disease is an immune mediated disease characterized by fibrosis development. The damaged tissue releases molecules such as soluble uric acid resulting from the degradation of extracellular matrix or dead cells, which activate TLR and NLR, leading to the translocation of MyD88 in many cell types. This modulation of the immune system interferes with the activation of different subtypes of macrophages and activity of CD4+ T cells, with the Th1/Th2 paradigm as a possible effector mechanism of fibrosis. TLR2, TLR4, MyD88, and NLRP3 deficient mice are protected against renal damage and collagen deposition after being submitted to unilateral ureteral obstruction (UUO), when compared to wild type animals. Moreover, protected mice exhibited less production of Th2 related cytokines and reduced accumulation of M2 macrophages. Initially, we hypothesized M2 macrophages are responsible for fibrosis formation since this subset is found in greater numbers seven days after UUO in WT mice, however, we observed the central characters on the development of fibrosis are M1 macrophages found in the onset of renal injury. These data were confirmed by the injection of Stat6 KO M1 macrophages into Rag deficient mice previously depleted of macrophages and subjected to UUO, in which we observed higher proteinuria and increased collagen deposition. We also observed that uric acid is able to induce the exchange of phenotype from M1 to M2 along the UUO, besides being able to activate the inflammasome pathway. The soluble uric acid is released in the context of hypoxia and activates the NLRP3 inflammasome complex by different, but complementary mechanisms. Therefore, the renal damage releases soluble uric acid, which signals via innate immune receptors, and the damage brings as a consequence the deposition of proteins in the renal interstitium, culminating in fibrosis.

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.