A cistatina C sérica tem sido apontada como um marcador de filtração glomerular. Neste trabalho realizamos a validação de um método específico e automatizado, a imunonefelometria, mensurando os níveis séricos de cistatina C através do nefelômetro da empresa Behring (BN II). O ensaio perfaz o intervalo de referência de 0.23-7.25 mg/L, até sete vezes acima dos limites considerados normais. A imprecisão intra e interensaio foram de 8,73% and 5,38% , respectively. A recuperação analítica de cistatina C após adição de controle foi entre 86,7 % e 98% (média 92,3%). A estabilidade da cistatina C a temperatura ambiente, sob refrigeração e sob congelamento foi testada. A perda mais significativa foi encontrada nas amostras armazenadas sob temperatura ambiente, onde foi perdido até 10% da concentração inicial. Nós encontramos CV de 14,79 % para sensibilidade analítica. Durante todo o processo nós comparamos os resultados com o controle de qualidade e obtivemos bons resultados. Depois destes testes, nós comparamos as correlações em 3 grupos de pacientes transplantados renais sob diferentes esquemas de imunossupressão (n=197) [azatioprina (n=36), micofenolato mofetil (n=131) ou sirolimus (n=30)], entre as equações de estimativa de filtração glomerular( Cockroft Gault, Nankivell e MDRD) e cistatina C sérica ou creatinina sérica. Nós concluimos que o ensaio nefelométrico cistatina C pode perfeitamente ser adequado à nossa rotina laboratorial e as correlações entre creatinina sérica e as diferentes equações de estimativa de filtração glomerular são melhores do que quando comparamos as mesmas à cistatina C nos 3 grupos independentemente da terapia imunossupressora utilizada. / Serum cystatin C has been suggested as a marker of glomerular filtration rate (GFR). We describe a validation of an automated and rapid particle-enhanced nephelometric immunoassay (PENIA) for measuring serum cystatin C on the Behring nephelometer (BN II). The assay covers the range 0.23-7.25 mg/L, up to seven times the upper limit of normal. The intra- and interassay imprecision are 8,73% and 5,38% , respectively. The analytical recovery by cystatin C addition between 86,7% and 98% (mean 92,3%). The estability of cistatyn C room temperature, refrigerator temperature and frozen temperature was tested. The higher lost was when we stored sample in a room temperature, when we can lost until 10% of initial concentration. We found CV of 14,79 % for analytical sensibility. During all the process we compare the results with a quality control and we obtained good results. After this validation, we have compared the correlation, in 3 different patients groups after renal transplant (n=197) were using different imunossupressors [azatioprine (n=36), micophenolic acid (n=131) or sirolimus (n=30), between glomerular filtration equations (Cockroft Gault, Nankivell and MDRD) and cystatin C or creatinine serum levels. We concluded cystatin C assay may be perfectly used in our laboratory and the correlation between serum creatinine and glomerular filtration equations are better then cystatin C at the same groups independent of imunosupressor therapy.

A nicotina é o principal componente do tabaco e dos cigarros eletrônicos. A exposição crônica a nicotina, em quantidades semelhantes às atingidas pelo tabagismo humano, é responsável por piora da lesão renal aguda e da doença renal crônica. O gene klotho, predominantemente expresso no rim, foi descoberto após uma mutação insercional, com o surgimento de um fenótipo semelhante ao envelhecimento humano nos camundongos homozigotos para esse transgene. A proteína Klotho transmembrana tem ação de co-receptor do fator de crescimento fibroblástico 23 (FGF-23) e sua forma secretada atua em diversas vias intracelulares e em órgãos a distância. A deficiência de Klotho ocorre no envelhecimento, em situações que levam a lesão renal aguda e na doença renal crônica. A expressão reduzida de Klotho também agrava lesão renal aguda e participa da progressão da doença renal crônica, enquanto o seu aumento, ou a sua reposição, protegem dos processos inflamatórios e do estresse oxidativo. Neste estudo, objetivamos avaliar os efeitos renais, hemodinâmicos e sobre a expressão de Klotho da exposição crônica a nicotina e quais os efeitos dessa exposição nos animais haploinsuficientes para o transgene klotho (Kl+/-). Utilizamos para estas avaliações camundongos Kl+/- e seus controles wild type (Kl+/+), que foram expostos a nicotina (200 mcg/mL) ou veículo (sacarina 2%) diluídos em água por 28 dias. Ao final do estudo foram avaliados diurese, eletrólitos plasmáticos e urinários, ureia, aldosterona, ADH, FGF-23 e PTH intactos plasmáticos, expressão protéica renal de Klotho, alfa7-nAchR, NHE3, ENaC, NKCC2, AQP2, e-NOS, VEGF, MnSOD e renina, expressão genica renal de klotho, interleucinas, TBARS e GSH em tecido renal, taxa de filtração glomerular por FITC-inulina, pressão arterial e frequência cardíaca invasivas, sensibilidade baroreflexa e modulação autonômica cardíaca e periférica por análise espectral. Após a exposição a nicotina, os animais Kl+/+ apresentaram redução da expressão renal da proteína e do RNAm de Klotho e uma tendência a aumento dos níveis plasmáticos de FGF-23, associados a uma queda da diurese e da taxa de filtração glomerular, sem alteração dos níveis de ADH. Esses animais Kl+/+ também apresentaram aumento da sensibilidade barorreflexa em resposta ao nitroprussiato e um predomínio da modulação simpática cardíaca, com redução da expressão renal dos alfa7-nAchR. Os animais Kl+/- tiveram níveis renais ainda menores de Klotho após a exposição a nicotina, com aumento de TBARS, IL-6, uréia e aldosterona em relação aos Kl+/- não expostos. A diurese, a taxa de filtração glomerular e a expressão dos alfa7-nAchR não se reduziram e não houve aumento da sensibilidade barorreflexa após exposição a nicotina, com um predomínio da modulação parassimpática cardíaca, nesses animais Kl+/-. A ingesta hídrica, a pressão arterial e a frequência cardíaca foram semelhantes entre os 4 grupos. A proteinúria foi maior nos animais Kl+/- do que nos animais Kl+/+ após a exposição a nicotina. Podemos concluir que a exposição crônica à nicotina reduz a expressão renal de Klotho, estimula vias de inflamação, fibrose e estresse oxidativo renais e tem efeitos renais e sistêmicos diferentes de acordo com os níveis basais de Klotho / Nicotine is a major compound of tobacco and electronic cigarettes. Chronic exposure to nicotine concentrations that are similar to human smoke worsens acute kidney injury and chronic kidney disease. The klotho (Kl) gene is expressed predominantly by the kidney and was discovered after an unintentional insertional mutation that resulted, in transgenic homozygous mice, in a phenotype similar to human aging. Klotho transmembrane protein acts as a co-receptor to fibroblastic growth factor 23 (FGF-23) and the secreted form interacts in multiple intracellular pathways, with effects in distant organs. Klotho deficiency occurs in aging and in multiple acute kidney injury and chronic kidney disease etiologies, whereas klotho upregulation and replacement protect from inflammation and oxidative stress. Here, we investigated renal and hemodynamic effects of chronic nicotine exposure, its effects over renal expression of Kl, and compared wild type (Kl+/+) and Kl haploinsufficient mice (Kl+/-) in terms of the effects of that exposure. Kl+/- and Kl+/+ mice received nicotine (200 ?g/ml) or vehicle (saccharine 2%) in drinking water for 28 days. We evaluated diuresis, ions in serum and urine, urea, plasma and urinary levels of cotinine, aldosterone, plasma antidiuretic and parathyroid hormone, plasma FGF-23, protein expression of (immunoblotting for) Klotho and ?7 nicotinic acetylcholine receptor, NHE3, NKCC2, ENaC, aquaporin-2, e-NOS, VEGF and renin, klotho mRNA, kidney interleukines, TBARS and GSH, glomerular filtration rate by fluorescein isothiocyanate-inulin clearance, mean arterial pressure, heart rate, baroreflex sensitivity and autonomic cardiac and peripheral modulation by spectral analysis. After nicotine exposure, Kl+/+ mice showed decreased Klotho protein and mRNA and a tendency towards an elevation in plasma FGF-23, which were associated with both diuresis and glomerular filtration rate reductions, without modifications in ADH levels. Besides that, Kl+/+ animals increased baroreflex sensitivity after nitroprusside, a predominant sympathetic cardiac modulation and lower alfa7-nAchR kidney expression. Kl+/- mice reduced even more Klotho renal expression, with higher levels of TBARS, IL-6, urea and aldosterone. Diuresis, glomerular filtration rate, alfa7-nAchR expression and baroreflex sensitivity were the same of their controls. Cardiac parasympathetic modulation predominated in Kl+/- mice. Fluid intake, mean arterial pressure and heart rate were similar across the 4 groups. Renal protein excretion was higher in Kl+/- than in their controls after nicotine exposure. We can conclude that chronic nicotine exposure downregulates Klotho kidney expression induces inflammation and oxidative stress and stimulates fibrosis, with different renal and systemic responses according to basal Klotho levels

INTRODUÇÃO Pacientes com doença renal crônica sofrem alterações musculoesqueléticas nos estágios iniciais da doença associadas a fatores como alteração de substratos séricos, capacidade funcional, qualidade de vida e parâmetros nutricionais. O objetivo deste estudo foi avaliar o desempenho funcional, qualidade de vida, e parâmetros respiratórios em pacientes com doença renal crônica não dialítica segundo o estágio da doença renal. MÉTODOS Foram selecionados 26 indivíduos acompanhados pelo Serviço de Nefrologia do Instituto Central da Faculdade de Medicina da Universidade de São Paulo, com diagnóstico de doença renal crônica não dialíticos, e taxa de filtração glomerular abaixo de 45 mL/min, foram excluídos pacientes com doenças reumatológicas, respiratórias, neurológicas ou que apresentassem limitações para a execução dos testes funcionais. Foram aplicados os seguintes instrumentos: questionário de Qualidade de Vida (SF-36), o questionário Internacional de Nível de Atividade Física (IPAQ), foi realizado os seguintes testes: teste de Caminhada de Seis Minutos, teste de Sentar e Levantar, e o teste de Preensão Palmar, foram aferidas também as pressões máximas inspiratórias e expiratórias e volumes pulmonares através da manuvacuometria e exames laboratoriais de rotina. RESULTADOS Os dados do grupo geral foram comparados com os encontrados na literatura demonstrando menor capacidade funcional e respiratória do que indivíduos saudáveis de mesmo gênero e faixa etária. Os indivíduos avaliados também foram subdivididos em dois grupos através da estimativa da taxa de filtração glomerular pela formula CKD-EPI, o primeiro grupo com taxa de filtração glomerular menor que 30 mL/min e o segundo grupo com taxa de filtração glomerular maior ou igual a 30 mL/min. Foram encontradas diferenças significantes quanto a: pressão expiratória máxima (P=0.04) onde os pacientes com pior função renal apresentaram maior força muscular expiratória, paratormônio (P= 0.02), fosforo (P= 0.04) e ureia (P= 0.00) . CONCLUSÃO: Concluiu se que indivíduos com doença renal crônica apresentam diferenças em relação aos parâmetros respiratórios, exames séricos diferentes estágios da doença renal crônica antes da terapia renal substitutiva / INTRODUCTION Patients with chronic kidney disease (CKD) suffer musculoskeletal disorders in the early stages of the disease associated with factors such as change in serum substrates, functional capacity, quality of life and nutritional characteristics. The aim of this study was to evaluate the functional performance, quality of life, and respiratory parameters in patients with CKD not requiring dialysis according to the stage of kidney disease. METHODS We selected 26 individuals accompanied by the Nephrology Department of the Central Institute of the Faculty of Medicine, University of São Paulo, diagnosed with chronic kidney disease not on dialysis, and glomerular filtration rate below 45 mL / min, patients were excluded with rheumatic diseases, respiratory, neurological or who present limitations for the execution of functional tests. The following instruments were applied: Quality of Life questionnaire (SF-36), the International Physical Activity Questionnaire (IPAQ), was performed the following tests: the Six Minutes Walk test, Sitting and Rising test, and Hand Grip Strength test were also measured the maximum inspiratory and expiratory pressure and lung volumes through manuvacuometria and routine laboratory tests. RESULTS The results presented by the general group were compared with those found in the literature showing lower functional and respiratory capacity than healthy individuals of the same gender and age. The evaluated individuals were also subdivided into two groups by means of the glomerular filtration rate by the formula CKD-EPI, the first group of glomerular filtration rate lower than 30 ml / min and the second group with higher glomerular filtration rate or equal to 30 ml / min. Significant differences were found regarding: maximal expiratory pressure (P 0.04) where patients with poor kidney function had higher expiratory muscle strength, parathyroid hormone (P = 0.02) and phosphorus (P 0.04). CONCLUSION: We conclude that individuals with chronic kidney disease have differences from respiratory parameters, different blood tests stages of chronic kidney disease before renal replacement therapy

INTRODUÇÃO: A hipertensão renovascular (HRV) decorrente da estenose de artéria renal (EAR) é uma patologia potencialmente curável, mas os benefícios da revascularização não são alcançados por todos porque selecionar pacientes com base nos critérios clínicos ou angiográficos pode não ser suficiente para se obter o sucesso clínico. Existe um grande interesse em se desenvolver exames para detectar a presença de EAR e avaliar seu significado funcional. OBJETIVOS: avaliar se a redução da Taxa de Filtração Glomerular (TFG) medida com EDTA-51Cr após o uso de captopril consegue diferenciar pacientes hipertensos com EAR daqueles sem estenose da artéria e avaliar se existe correlação entre as variações da TFG e a evolução de pacientes submetidos a diferentes tratamentos. MÉTODOS: Foram estudados 41 pacientes com hipertensão arterial de difícil controle que foram divididos em dois grupos: GP: 21 pacientes com EAR e GH: 20 pacientes sem EAR. Os pacientes foram submetidos à medida de TFG com EDTA-51Cr pré e após a administração do captopril. Os pacientes do GP realizaram simultaneamente cintilografia com DMSA-99mTc para avaliação da função renal diferencial. Os pacientes com estenose de artéria renal foram subdivididos de acordo com o tratamento recebido: clínico (GP-CL) ou por intervenção (GP-I). As medidas das TFGs antes e após o captopril foram comparadas entre os grupos. Foi também, investigado se a relação pré/pós captopril tinha correlação com a resposta clínica dos pacientes. RESULTADOS: a média da TFG (ml/min./1,73m2) no total de pacientes estudados, foi de 56,7±26,5 na fase pré-captopril e 47,0±24,4 após o captopril. A modificação da TFG determinada pelo captopril,foi avaliada pela relação da filtração glomerular pré/pós-captopril. A média da relação TFG pré/pós-captopril foi 1,36 ±0,54 no grupo total de pacientes e quando foi feita a comparação entre a TFG pré e pós-captopril, houve uma redução significativa (p= 0,016). O GH mostrou relação média da TFG pré/pós-captopril de 1,13, valor significativamente menor que o GP que teve a relação média de 1,57 (p= 0,007). Quando foi avaliada a variação da TFG após o captopril nos dois grupos não foi observada diferença estatisticamente significativa no GH (p=0,68), mas observou-se diferença significativa no GP (p<0,001). No total, 15 pacientes apresentaram melhora dos seus níveis pressóricos, sendo oito do grupo de intervenção e sete do grupo clinico, não havendo diferença estatisticamente significativa em relação à melhora clínica entre os dois grupos (p=0,36). Quando comparamos os pacientes com e sem melhora clínica não se observou diferença significativa na TFG basal (p=0,09) ou na relação TFG pré/pós-captopril (p=0,74). A função renal diferencial obtida pelo DMSA-99mTc pré e pós captopril não mostrou diferença estatisticamente significativa nos rins com e sem estenose, (p=0.09). CONCLUSÃO: O captopril acarreta uma redução significativa da TFG e esta redução é mais acentuada em pacientes com EAR, mas não houve correlação entre as mediadas da TFG e a evolução clínica dos pacientes / INTRODUCTION: Renovascular hypertension (RVH) resulting from renal artery stenosis (RAS) is a potential curable pathology, but the revascularization benefits are not reached among all patients because selecting patients on the basis of clinical and angiographic criteria may not be sufficient to achieve clinical success. There has been increasing interest in developing screening tests capable of accurately detecting the presence of RAS and also of evaluating its functional consequences PURPOSE: the purpose of this study was to evaluate if captopril induced changes in 51Cr-EDTA clearance could be used to differentiate between hypertensive patients with and without renal artery stenosis and to investigate if there was a correlation between these changes and patients clinical response to therapy. METHODS: 41 patients with poor-controlled severe hypertension were studied. Patients were divided into two groups: GP=patients with renal artery stenosis (n=21), and GH=patients without renal artery stenosis (n=20). They were submitted to a Glomerular Filtration Rate (GFR) measurement with EDTA-51Cr pre and post captopril administration. The GP patients were submitted simultaneously to 99mTc-DMSA scintigraphies to estimate individual renal function. GP patients were further subdivided according to the treatment strategy: optimization of clinical treatment (GP-Cl) and interventional procedures (GP-I). The GFRs before and after captopril administration were compared between the groups. It was also investigated if baseline to post-captopril GFR ratio had a correlation to clinical response of patients. RESULTS: The GFR average (ml/min./1,73m2) on the total patients, was 56,7±26,5 on pre-captopril phase and 47,0±24,4 post captopril. The GFR alteration determinated by captopril was evaluated by Baseline/post-captopril GFR ratio. Baseline/post-captopril GFR mean ratio was 1,36 in total patients and the GFR had a significant decrease after captopril administration (p value 0.016). Baseline/post-captopril GFR mean ratio in GH was 1.13, value significantly lower than the GP which had the average relation of 1,57 (p= 0,007). When GFR pre and post-captopril was compared among the two groups separately, there was no significantly difference on the GH (p=0,68), but a expressive difference was observed on GP (p<0,001). 15 patients had a clinical response to the treatment. Clinical response was observed in 8/10 patients from GP-I and 7/11 from GP-Cl and there was not observed a significantly difference between the two groups (p=0,36). Comparing the groups with or without clinical improvement there was not a significantly difference on the GRF baseline (p=0,09) or on or baseline/post-captopril ratio (p=0,74). When evaluating the differential renal function obtained by pre and post-captopril DMSA-99mTc, significantly difference was not observed (p=0.09) for the kidneys with or without stenosis. CONCLUSION: captopril induced a decrease in GFR of hypertensive patients and it is more pronounced in patients with renal artery stenosis, but no correlation was observed between captopril induced decrease in GFR and clinical response of patients submitted to interventional or clinical treatment

Hypertension artérielle résistante et maladie rénale chronique : Déterminants et risques associésL’hypertension résistante, définie par une pression artérielle au-dessus de la cible en dépit de la prise de trois antihypertenseurs à dose optimale dont un diurétique, est fréquemment associée à la maladie rénale chronique (MRC). Sa prévalence, ses déterminants et l’impact potentiel de la MRC sur son pronostic à long terme sont mal connus, notamment chez le sujet âgé. Dans l’étude des 3 cités, incluant 4262 personnes de plus de 65 ans traitées pour hypertension, la prévalence de l’hypertension apparemment résistante (HTAR) - la notion de traitement à dose optimale étant inconnue - était de 11,8% vs 5,2% chez ceux avec vs sans MRC (définie par une fonction rénale < 60 mL/min/1.73 m2). Nous avons montré que l’apparition d’une HTAR était plus fortement liée à la rapidité du déclin annuel de la fonction rénale qu’à son niveau, indépendamment des autres facteurs de risque : obésité, diabète, sexe masculin, antécédent cardiovasculaire. Comparé au groupe de référence (avec hypertension contrôlée et sans MRC), les personnes avec une HTAR et une MRC n’avaient pas de risque significativement plus élevé de mortalité toute cause, mais avaient deux fois plus de risque d’accident vasculaire cérébral (AVC), létal ou non, et de récurrence d’un AVC ou d’un événement coronaire, et trois fois plus de décès coronaire. Cependant, l’’hypothèse d’un effet aggravant de la MRC sur le pronostic de l’HTAR n’a pas été confirmé (interaction non significative).Dans la cohorte CKD-REIN, incluant plus de 3000 patients avec une MRC modérée ou avancée suivis en néphrologie (âge moyen, 70 ans, 60% d’hommes), nos résultats préliminaires montrent une prévalence élevée d’HTAR, 36,7%, et plusieurs facteurs de risque potentiellement modifiables : adhérence médiocre au traitement, absence de diurétique, consommation de sel en excès, obésité.Dans l’ensemble, ces travaux montrent l’importance de la MRC dans le développement de l’HTAR et des risques cardiovasculaires associés, et suggère des moyens de prévention au-delà des traitements médicamenteux. / Resistant hypertension and chronic kidney disease: Determinants and outcomesResistant hypertension defined as blood pressure above goal despite simultaneous use of 3 antihypertensive classes at optimal doses including a diuretic, is commonly associated with chronic kidney disease (CKD). Resistant hypertension prevalence and determinants, and the impact of CKD on its long term outcomes are poorly known, particularly in the elderly population.In the 3 Cities cohort, including 4262 community-dwelling elderly individuals, aged 65 years or older treated for hypertension, the prevalence of apparent treatment resistant hypertension (aTRH) – because of lack of information on optimal treatment dose – was 11.8% vs 5.2% in those with vs without CKD (defined as estimated glomerular filtration rate < 60 mL/min/1.73 m2). We showed that new-onset aTRH was more strongly related to the speed of kidney function decline than kidney function level itself, independent of other risk factors: male sex, obesity, diabetes, and history of cardiovascular disease. Compared to the reference group (with controlled hypertension and no CKD), participants with aTRH and CKD had no significantly higher risk of all-cause mortality, but had a risk of fatal or non-fatal stroke and of recurrent stroke or coronary events more than twice as high, and of coronary death more than three times higher. However, the hypothesis that CKD may worsen the prognosis of aTRH was not confirmed (no significant interaction).In the CKDREIN cohort, which included more than 3000 nephrology outpatients with moderate or severe CKD (mean age, 70 years, 60% of men), our preliminary results showed a high prevalence of aTRH, 36,7% and several potentially modifiable risk factors : poor treatment adherence, lack of diuretic use, excess salt intake and obesity.Overall, this work shows the importance of CKD in the development of aTRH and associated cardiovascular outcomes, and suggests means for prevention beyond drug therapy.

La biosurveillance humaine permet aujourd’hui d’évaluer notre exposition aux produits chimiques par la mesure soit des substances elles-mêmes, soit de leurs métabolites ou marqueurs d'effets sur la santé, à partir des fluides corporels ou des tissus. Les informations recueillies dans le cadre d’enquêtes épidémiologiques renseignent sur l'exposition humaine et constituent des bases précieuses dans la recherche des relations exposition-réponse chez les humains. Les travaux de cette thèse s’inscrivent dans le cadre de l’enquête transversale IMePoGe conduite entre 2008-2010 dans la région Nord–Pas-de-Calais (au nord de la France), incluant 2000 résidents adultes âgés de 20 à 59 ans, et visant à quantifier les niveaux d’imprégnation de la population à 14 métaux et métalloïdes (aluminium, antimoine, arsenic total, béryllium, cadmium, cobalt, chrome, mercure, manganèse, nickel, plomb, thallium, vanadium, zinc) choisis pour leurs effets toxiques et la fréquence de l’exposition professionnelle et environnementale. Les objectifs spécifiques de cette thèse étaient, tout en portant une attention particulière au plomb et au cadmium, deux métaux néphrotoxiques connus dans la littérature : i) d’établir la distribution de l’imprégnation aux métaux et métalloïdes dans la population du Nord de la France et de comparer le niveau régional d’imprégnation avec les données nationales et internationales ; ii) d’identifier les facteurs majeurs de variation de l’imprégnation et les sources d’exposition au plomb et au cadmium dans la population générale ; iii) d’étudier la relation entre la variation du débit de filtration glomérulaire et les niveaux d’imprégnation aux métaux. Globalement, les concentrations sanguines et urinaires de la plupart des métaux et métalloïdes étaient plus élevées que celles rapportées dans l’enquête nationale nutrition santé conduite sur la même période dans la population française, à l’exception du vanadium urinaire et du plomb sanguin. La plombémie moyenne régionale (moyenne géométrique) était de 18,8 μg/L. De nombreuses sources d’exposition au plomb existaient dans la population et étaient à la fois d’origine professionnelle, environnementale et alimentaire. Pour ce qui est du cadmium, le tabagisme se présentait comme la principale source d’exposition récente ou chronique au métal : la cadmiémie moyenne, reflet de l’exposition récente, était de 0,39 μg/L et passait de 0,26 μg/L chez les non-fumeurs à 0,84 μg/L chez les fumeurs ; la cadmiurie moyenne, reflet de l’exposition chronique, était de 0,37 μg/L (0,33 μg/g créatinine) et passait de 0,33 μg/L (0,29 μg/g créatinine) chez les non-fumeurs à 0,46 μg/L (0.37 μg/g créatinine) chez les fumeurs. Enfin, dans le cadre de l’étude de la relation entre l’imprégnation aux métaux et le débit de filtration glomérulaire, notre étude a montré que la prise en compte de la co-exposition à d’autres métaux et métalloïdes potentiellement néphrotoxiques bouleversait considérablement les associations antérieures jusqu’ici rapportées spécifiquement avec le plomb et le cadmium, dans le cadre de faibles niveaux d’imprégnation en population générale. / Human Biomonitoring allows us to evaluate our exposure to chemicals by measuring substances themselves or their metabolites or markers of health effects, from body fluids or tissues. The information collected through epidemiological surveys provide information on human exposure and are valuable databases in the research of exposure-response relationships in humans. This thesis is part of the cross-sectional IMePoGe survey conducted between 2008-2010 in the Nord–Pas-de-Calais region (in northern France), including 2,000 adult residents aged 20 to 59 years old, and aimed to quantify the impregnation levels of the population to 14 metals and metalloids (aluminum, antimony, total arsenic, beryllium, cadmium, cobalt, chromium, mercury, manganese, nickel, lead, thallium, vanadium, zinc) chosen for their toxic effects and the frequency of occupational and environmental exposure. The specific objectives of this thesis were, which a special interest for lead and cadmium, two nephrotoxic metals known in the literature: i) to establish the distribution of impregnation metals into the northern population of France and compare the exposure regional level to metals and metalloids with the national and international data; ii) to identify the major factors of variation of the impregnation and the sources of exposure to lead and cadmium in the general population; iii) to study the relationship between the change in glomerular filtration rate and the impregnation levels to metals. Overall, blood and urinary concentrations of most metals and metalloids were higher than those found in the national nutritional health survey conducted during the same period in the French population, with the exception of urinary vanadium and blood lead. The regional mean of blood lead level (geometric mean) was 18.8 μg/L. Several sources of lead exposure existed in the population and were link to the occupational, environmental and consumption parameters. Regarding cadmium, smoking was the main source of recent or chronic exposure to metal: the geometric mean of blood cadmium, reflecting a recent exposure, was 0.39 μg/L and increased from 0.26 μg/L in non-smokers to 0.84 μg/L in smokers; the geometric mean of urinary cadmium, reflecting the chronic exposure, was 0.37 μg/L (0.33 μg/g creatinine) and increased from 0.33 μg/L (0.29 μg/g creatinine) in non-smokers to 0.46 μg/L (0.37 μg/g creatinine) in smokers. Finally, as part of the study of the relationship between the metal levels and the glomerular filtration rate, our study showed that taking into account the multiple exposure to the other potentially nephrotoxic metals and metalloids upset considerably the previous associations specifically reported with lead and cadmium, in the context of low levels exposure in the general population.

Health literacy is widespread, but its potential is not recognized. By not recognizing health literacy, patients have the burden of coping with diabetes with renal complications without full knowledge of their responsibility to their health. The focus of the project was to assess participants with diabetes with low health literacy and low mean glomerular filtration rate (eGFR). The project goal was achieved by the assessment of the participants' health literacy and eGFR before and after education for their diabetes, then assessed to determine if teaching the participants would improve their health literacy, lab values, and overall health. Participants were recruited by being patients of the designated clinic and screened for diabetes and low eGFR, for a total of 30 participants. The Brief Health Literacy Screen was used to measure health literacy. The health of the participants was appraised by the laboratory values of eGFR and fasting glucose. The project methodology was an observational design using correlation and 2-sample t analysis with the variables eGFR, fasting glucose, and health literacy. The variables were compared before and after the participants' education. Results showed health literacy with patient education was associated with greater patient self-efficacy and improved fasting glucose numbers, eGFR flows, and health literacy scores. The current health climate shows value in different types of health providers. Social change was defined by the project launching a nurse practitioner as the leader for advancing the treatment plans of chronic kidney disease. This project impacts social change by showing patients in the process of improved health and empowering the patients to be advocates of their own health.

Vários estudos mostram que na doença renal policística autossômica dominante os cistos surgem a partir de um mecanismo de "dois-golpes". A patogênese das manifestações não-císticas, contudo, é pouco compreendida. Neste estudo usamos uma linhagem de camundongos endogâmica com uma mutação nula em Pkd1, onde animais heterozigotos apresentam formação cística renal mínima até 40 semanas de idade. O clearance de inulina e o número de glomérulos foram menores em machos Pkd1+/- que Pkd1+/+, enquanto o volume glomerular médio foi maior em heterozigotos. A excreção urinária de NO2/NO3 não diferiu significantemente entre os dois grupos. Avaliamos a osmolalidade urinária máxima em machos e fêmeas Pkd1+/- and Pkd1+/+, porém não foi detectada diferença significante entre os grupos heterozigoto e selvagem. Nossos resultados oferecem evidência direta de que a haploinsuficiência de Pkd1 resulta em anormalidades anatômicas e funcionais renais e sugerem que o estado haploinsuficiente de Pkd1 possa resultar na redução do número de néfrons por diminuir a ramificação tubular renal durante a nefrogênese / Several studies show that in autosomal dominant polycystic kidney disease cysts arise through a "two-hit" mechanism. The pathogenesis of non-cystic features, however, is poorly understood. In this study we used an inbred mouse line with a null mutation of Pkd1, where heterozygotes had minimal renal cyst formation up to 40 weeks of age. Inulin clearance and the number of glomeruli were lower in Pkd1+/- than in Pkd1+/+ males, while a higher average glomerular volume was observed in heterozygotes. The urinary excretion of NO2/NO3 did not significantly differ between the two groups. Maximal urinary osmolality was evaluated in Pkd1+/- and Pkd1+/+ males and females, but no significant difference was detected between the heterozygous and the wild type groups. Our results provide direct evidence that haploinsufficiency for Pkd1 results in anatomic and functional abnormalities of the kidney and suggest that Pkd1 haploinsufficiency may result in a reduced number of nephrons by diminishing renal tubule branching during nephrogenesis

INTRODUÇÃO: Em pacientes transplantados renais, a paratireoidectomia está associada à piora aguda da função renal. Os efeitos agudos e crônicos da paratireoidectomia sobre a filtração glomerular foram pouco estudados em Hiperparatireoidismo Primário (HPTP). MÉTODO E CASUÍSTICA: Neste estudo retrospectivo de coorte, foram estudados 494 pacientes submetidos a paratireoidectomia por HPTP, entre os anos de 2007 e 2016. Variações agudas da creatinina foram aferidas diariamente na internação, até o 4o pós-operatório, sendo classificados conforme os critérios de KDIGO para IRA. Dados bioquímicos incluíram dosagem sérica de creatinina, cálcio iônico e total, paratormônio (PTH) e 25-OH vitamina D. A taxa de filtração glomerular foi estimada a partir da equação CKD-EPI. Foram comparados dados de função renal pré e pós-operatórios até 5 anos de seguimento. RESULTADOS: Dos 494 pacientes, 391 (79,1%) eram mulheres e 422 (85,4%) de cor branca. A causa mais comum de HPTP foi adenoma de paratireóide (351, 71,1%) e a mediana de idade foi de 58 anos. As medianas (Q1-Q3) de creatinina, PTH e cálcio total séricos foram de: 0,81 mg/dL (0,68-1,01), 154,5 pg/mL (106-238,5) e 10,9 mg/dL (10,3-11,5) respectivamente. A mediana de eGFR préoperatória foi de 86 mL/min x 1,73m2. No período agudo, houve redução mediana de 26 mL/min x 1,73m2 na eGFR (p < 0,0001), que representou -27,44% (±19,12%) de variação aguda da eGFR. De acordo com os critérios de IRA, 41,1% dos pacientes tiveram IRA estágio 1, 5,9% estágio 2 e 1,8% estágio 3. Outros 223 pacientes (45,1%) tiveram elevação da creatinina porém não preencheram critérios de IRA. Na análise univariada foram observadas correlações fracas, porém significativas, entre o percentual de variação aguda de eGFR e os seguintes fatores pré-operatórios: idade, PTH, cálcio e creatinina. Uma redução definitiva da eGFR foi observada em 60,7% dos pacientes, após 12 meses de seguimento. CONCLUSÃO: Houve significativa redução aguda da função renal após paratireoidectomia por HPTP, sendo que quase metade dos pacientes preencheram critérios de IRA. Observou-se importante recuperação da eGFR no primeiro mês de pós-operatório, podendo ocorrer algum grau de perda definitva de função renal / INTRODUCTION: In kidney transplant patients, parathyroidectomy is associated with acute decrease in renal function. Acute and chronic effects of parathyroidectomy on renal function have not been as extensively studied in primary hyperparathyroidism (PHPT). PATIENTS AND METHODS: Retrospective cohort study of 494 patients undergoing parathyroidectomy for PHPT. Acute renal changes were evaluated daily until day 4 post parathyroidectomy, and stratified according to acute kidney injury (AKI) criteria. Biochemical assessment included serum creatinine, total and ionized calcium, PTH, and 25-hydroxyvitamin D (25OHD). EGFR were calculated using the CKD-EPI equation. We compared preoperative and postoperative renal function up to 5 years of follow-up. RESULTS: 391 (79.1%) patients were female and 422 (85.4%) were non-African American. Median age was 58 years old. Median (interquartile range) preoperative serum creatinine, PTH and total calcium were 0.81 mg/dL (0.68- 1.01), 154.5 pg/mL (106-238.5), and 10.9 mg/dL (10.3-11.5) respectively. Median (interquartile range) preoperative eGFR was 86 mL/min/1.73m2 (65-101.3). After surgery the median acute decrease in eGFR was 26 mL/min/1.73m2 (p < 0.0001). Acutely, 41.1% patients developed AKI stage 1, 5.9% AKI stage 2 and 1.8% AKI stage 3. Acute eGFR decrease (%) correlated with age, PTH, calcium and preoperative creatinine, in univariate analysis. Permanent reduction in eGFR occurred in 60.7 % of the patients, after acute episode. CONCLUSION: There is a significant acute impairment in renal function after parathyroidectomy for PHPT and almost half of patients meet the criteria for AKI. Significant eGFR recovery was observed during first month after surgery, but a small permanent reduction may occur

Foi estudado o ritmo de filtração glomerular (RFG) de pacientes com câncer bem diferenciado da tireoide submetidos à radioiodoterapia (RIT). O estudo avaliou o RFG durante estímulo do hormônio estimulador da tireoide (TSH) por suspensão da reposição hormonal tireoidiana (RHT) ou no uso do hormônio estimulador da tireoide recombinante humano (TSHrh), correlacionou o RFG com o perfil hormonal tireoidiano, avaliou o RFG durante e na semana após a RIT, avaliou o RFG e a dose efetiva de radiação para corpo inteiro e correlacionou métodos de estimativa de RFG. Vinte e oito pacientes incluídos em estudo clínico randomizado não cego foram divididos em dois grupos de 14 pacientes, sendo o grupo A (GA) submetido à suspensão da RHT e o grupo B (GB) ao uso do TSHrh. Os pacientes tiveram antes e após o estímulo do TSH a determinação do RFG por 51Cr-EDTA e coletas séricas do perfil hormonal tireoidiano e creatinina, albumina e ureia, e, após a RIT, colheram exames séricos de creatinina, albumina e ureia, e tiveram estimadas suas doses efetivas de corpo inteiro. Os exames de creatinina, albumina e ureia foram utilizados para estimar o RFG pelas equações de creatinina sérica, Modified Diet in Renal Disease (MDRD), e Cockcroft-Gault. O GA apresentou, pelo 51Cr-EDTA, variação de -18,5% do RFG de 94,4±18,6 mL/min antes da suspensão da RHT para 76,2±15,7 mL/min (p=0,0002) e o GB apresentou pelo 51Cr-EDTA variação de 4% do RFG de 90,8±18,4 mL/min antes do TSHrh para 92,6±15,2 mL/min (p=0,64). O RFG variou significativamente só no GA, sem apresentar proporcionalidade entre as variações do hormônio tireoidiano e do RFG. Não houve correlação do RFG com elevação do TSH. Por equações baseadas em creatinina, houve, no GA, queda do RFG durante toda a suspensão da RHT e estabilidade após o retorno da RHT, e, no GB, houve estabilidade do RFG durante todo o estudo. A dose efetiva de corpo inteiro não apresentou diferenças significativas entre os grupos (p=0,76). Na comparação entre o 51Cr-EDTA e as equações para estimativa de RFG, a correlação de Pearson foi de 0,78 para creatinina sérica, 0,79 para MDRD e 0,66 para CockcroftGault, e a comparação das variações do RFG observadas no GA entre o 51Cr-EDTA e a equação por creatinina sérica foram estatisticamente diferentes. Concluiu-se que o RFG apresenta redução na suspensão da RHT, relacionado ao hipotireoidismo e não à elevação de TSH, voltando a estabilizar após retorno da RHT, e que não varia no uso do TSHrh, que a dose efetiva de corpo inteiro não varia entre os grupos proporcionalmente ao RFG, e que a melhor correlação foi do 51Cr-EDTA com a equação MDRD / Glomerular filtration rate (GFR) was studied in well differentiated thyroid cancer patients referred for radioiodine therapy (RIT). The study evaluated GFR during thyroid stimulating hormone (TSH) stimulation after thyroid hormone withdrawal (THW) or after recombinant human thyroid stimulating hormone (rhTSH), correlated GFR with thyroid hormone profile, evaluated GFR during and in the week after RIT, evaluated GFR and whole body radiation effective dose, and correlated different methods for GFR determination. 28 patients were included in a non-blinded randomized clinical trial and divided in two groups of 14 patients, being group A (GA) stimulated by THW and group B (GB) stimulated by rhTSH. Patients had GFR determined by 51Cr-EDTA, as well as serum thyroid hormone profile, creatinine, albumin and urea before and after TSH stimulation, and after RIT had determined their serum creatinine, albumin and urea and whole body radiation effective dose. Creatinine, albumin and urea were used to estimate GFR by serum creatinine, Modified Diet in Renal Disease (MDRD), and Cockcroft-Gault equations. GA presented a -18,5% GFR variation by 51CrEDTA varying from 94,4 ± 18,6 mL/min before THW to 76,2±15,7 mL/min after THW (p=0,0002) while GB presented a 4% GFR variation by 51Cr-EDTA varying from 90,8 ± 18,4 mL/min before TSHrh to 92,6 ± 15,2 mL/min after rhTSH (p=0,64). GFR significantly varied only in GA without presenting proportionality with thyroid hormone variation. There was no correlation between rise in TSH levels and GFR. Creatinine equations demonstrated a sustained reduction in GFR during THW and GFR stability after thyroid hormone reposition, while GB presented stable GFR during the whole study. Whole body radiation effective dose didn\'t present significant differences between the two groups (p=0,76). Comparing 51Cr-EDTA and GFR estimative equations presented Pearson correlation score of 0,78 for serum creatinine, 0,79 for MDRD and 0,66 for Cockcroft-Gault, while comparison between variances in GA between 51Cr-EDTA e serum creatinine equation was significantly different. In conclusion GFR presents a reduction during THW related to hypothyroidism and not to TSH rise and stabilizing after thyroid hormone therapy, GFR does not vary during rhTSH, whole body radiation effective dose does not vary between the two groups proportionally to GFR, and that MDRD equation had the best correlation with 51Cr-EDTA