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

Pacientes com diagnósticos oncológicos diversos sob terapia com agentes nefrotóxicos, foram avaliados através de procedimentos radioisotópicos, em três momentos diferentes. Os achados radioisotópicos foram comparados com as avaliações laboratoriais rotineiras. Não mostraram alterações estatisticamente significativas os seguintes parâmetros: uréia, creatinina, sedimentos anormais e índice de Crockoft-Gault. Concluiu-se que a avaliação da função renal com os métodos rotineiramente utilizados na prática oncológica não foram estatisticamente significativas. Dentre os estudos utilizando radionuclídeos, o DTPA-99mTc e DMSA-99mTc, evidenciaram alterações, enquanto o EC-99mTc, não as detectou / Patients with different oncologic diagnoses under treatment with nephrotoxic drugs were evaluated by radioisotopic agents at three different moments. Radioisotopic data were compared with biochemical routine tests. Concerning laboratorial parameters like serum creatinine, urea and Cockroft Gault index, no statistically significant changes were observed. Possible to conclude that renal function evaluation with methods routinely used in oncological practice did not reveal any statistically significant change. Radioisotopic studies using 99mTc-DTPA and 99mTc-DMSA showed considerable alterations, however with 99mTc-EC no significant changes were evidenced

Pacientes com diagnósticos oncológicos diversos sob terapia com agentes nefrotóxicos, foram avaliados através de procedimentos radioisotópicos, em três momentos diferentes. Os achados radioisotópicos foram comparados com as avaliações laboratoriais rotineiras. Não mostraram alterações estatisticamente significativas os seguintes parâmetros: uréia, creatinina, sedimentos anormais e índice de Crockoft-Gault. Concluiu-se que a avaliação da função renal com os métodos rotineiramente utilizados na prática oncológica não foram estatisticamente significativas. Dentre os estudos utilizando radionuclídeos, o DTPA-99mTc e DMSA-99mTc, evidenciaram alterações, enquanto o EC-99mTc, não as detectou / Patients with different oncologic diagnoses under treatment with nephrotoxic drugs were evaluated by radioisotopic agents at three different moments. Radioisotopic data were compared with biochemical routine tests. Concerning laboratorial parameters like serum creatinine, urea and Cockroft Gault index, no statistically significant changes were observed. Possible to conclude that renal function evaluation with methods routinely used in oncological practice did not reveal any statistically significant change. Radioisotopic studies using 99mTc-DTPA and 99mTc-DMSA showed considerable alterations, however with 99mTc-EC no significant changes were evidenced

Indivíduos com hemoglobina glicada (HbA1c) &#8805;6,5% e níveis normais de glicemia têm maior risco de complicações relacionadas ao diabetes, em médio e longo prazo. Estas evidências foram importantes na recomendação de que HbA1c &#8805;6,5% fosse aceita como critério diagnóstico de diabetes. Diferenças raciais/ étnicas tem sido encontradas quanto aos níveis de HbA1c. Níveis elevados de HbA1c em indivíduos sem diabetes e com níveis normais de glicemia em jejum tem sido associados a alterações micro e macrovasculares, entre elas alterações da filtração glomerular. Diversos marcadores inflamatórios, em especial a MCP-1 (proteína quimiotática de macrófagos-1), estão envolvidos no mecanismo de lesão glomerular descrito em casos de nefropatia diabética No entanto, a HbA1C ainda não foi amplamente incorporada a rotina de diagnóstico e de acompanhamento na atenção primária brasileira. O objetivo deste estudo foi o de investigar a associação entre a alteração da HbA1c e da glicemia e fatores étnicos/ raciais e de risco cardiovascular e renal em adultos assistidos pelo Programa Médico de Família de Niterói, sem diagnóstico prévio de diabetes. Trata-se de um estudo transversal, onde foram reunidas informações de participantes do Estudo Cardio Metabólico Renal (CAMELIA), colhidas entre os meses de julho de 2006 a dezembro de 2007. Observou-se que o perfil de risco cardiovascular foi mais acentuado em indivíduos com alterações simultâneas da glicemia e da HbA1c. A alteração isolada da glicemia indicou ser condição de maior risco que a alteração isolada da HbA1c. Indivíduos com HbA1c &#8805; 6,5% eram em sua maioria mulheres de pele preta e apresentavam maiores níveis de LDL e creatinina sérica. Verificamos associação independente entre a alteração da HbA1c (&#8805; 5,7 e < 6,5% versus < 5,7%) e diminuição da taxa de filtração glomerular estimada. A HbA1c mostrou ser um marcador subclinico de alterações metabólicas em pacientes nao diabéticos e com glicemia de jejum < 126 mg/dL, em especial na população de mulheres e de indivíduos com a cor da pele preta. Os resultados apontam para a possibilidade de se utilizar a HbA1c como marcador de risco cardiovascular e renal visando propor estratégias de intervenção precoce e assim promover a prevenção de condições de agravos relacionados as alterações do metabolismo da glicose. / Individuals with glycated hemoglobin (HbA1c) &#8805; 6.5% and normal levels of blood glucose are at increased risk of complications related to diabetes. This evidence led to the American Diabetes Association (ADA) to recommend HbA1c &#8805; 6.5% as a criterion for the diagnosis of diabetes. Racial / ethnic differences have been found regarding HbA1c levels. Elevated HbA1c levels in individuals without diabetes and with normal fasting glucose levels have been associated with microvascular and macrovascular complications, including changes in glomerular filtration. Inflammatory markers, in particular MCP -1 ( macrophage chemotactic protein -1), are involved in the glomerular lesions described in cases of diabetic nephropathy mechanism However, this test has not been widely incorporated as a routine examination in primary care in Brazil. The objective os this study was to describe and analyse the association between changes in HbA1c and blood glucose, racial / ethnic factors and cardiovascular and renal risk in adults in adults assisted by the Family Doctor Program of Niteroi, with no previous medical diagnosis of diabetes. It is a cross sectional study, with information of CAMELIA Studys participants. Data was collected from July 2006 to December 2007. It was noted that the cardiovascular risk profile was more pronounced in individuals with concurrent changes in blood glucose and HbA1c. The cardiovascular risk of individuals with high levels of glycemia and normal HbA1c was greater than the risk of individuals with HbA1c&#8805;6,5% alone. Individuals with HbA1c &#8805; 6.5%, mostly women and black skin persons, had higher LDL and creatinine levels. Independent association between changes in HbA1c ( &#8805; 5.7 and < 6.5% versus < 5.7 % ) and decreased estimated glomerular filtration rate . HbA1c showed to be a subclinical marker of metabolic disorders in diabetic patients and not with fasting glucose < 126 mg / dL, especially in the population of women and individuals with black skin color. HbA1c showed to be a subclinical marker of metabolic disorders in diabetic patients and not with fasting glucose < 126 mg / dL , especially in the population of women and individuals with black skin color. The results point to the possibility of using HbA1c as a marker of cardiovascular and renal risk aiming to propose strategies for early intervention and thus promote the prevention of diseases and conditions related changes in glucose metabolism.

Indivíduos com hemoglobina glicada (HbA1c) &#8805;6,5% e níveis normais de glicemia têm maior risco de complicações relacionadas ao diabetes, em médio e longo prazo. Estas evidências foram importantes na recomendação de que HbA1c &#8805;6,5% fosse aceita como critério diagnóstico de diabetes. Diferenças raciais/ étnicas tem sido encontradas quanto aos níveis de HbA1c. Níveis elevados de HbA1c em indivíduos sem diabetes e com níveis normais de glicemia em jejum tem sido associados a alterações micro e macrovasculares, entre elas alterações da filtração glomerular. Diversos marcadores inflamatórios, em especial a MCP-1 (proteína quimiotática de macrófagos-1), estão envolvidos no mecanismo de lesão glomerular descrito em casos de nefropatia diabética No entanto, a HbA1C ainda não foi amplamente incorporada a rotina de diagnóstico e de acompanhamento na atenção primária brasileira. O objetivo deste estudo foi o de investigar a associação entre a alteração da HbA1c e da glicemia e fatores étnicos/ raciais e de risco cardiovascular e renal em adultos assistidos pelo Programa Médico de Família de Niterói, sem diagnóstico prévio de diabetes. Trata-se de um estudo transversal, onde foram reunidas informações de participantes do Estudo Cardio Metabólico Renal (CAMELIA), colhidas entre os meses de julho de 2006 a dezembro de 2007. Observou-se que o perfil de risco cardiovascular foi mais acentuado em indivíduos com alterações simultâneas da glicemia e da HbA1c. A alteração isolada da glicemia indicou ser condição de maior risco que a alteração isolada da HbA1c. Indivíduos com HbA1c &#8805; 6,5% eram em sua maioria mulheres de pele preta e apresentavam maiores níveis de LDL e creatinina sérica. Verificamos associação independente entre a alteração da HbA1c (&#8805; 5,7 e < 6,5% versus < 5,7%) e diminuição da taxa de filtração glomerular estimada. A HbA1c mostrou ser um marcador subclinico de alterações metabólicas em pacientes nao diabéticos e com glicemia de jejum < 126 mg/dL, em especial na população de mulheres e de indivíduos com a cor da pele preta. Os resultados apontam para a possibilidade de se utilizar a HbA1c como marcador de risco cardiovascular e renal visando propor estratégias de intervenção precoce e assim promover a prevenção de condições de agravos relacionados as alterações do metabolismo da glicose. / Individuals with glycated hemoglobin (HbA1c) &#8805; 6.5% and normal levels of blood glucose are at increased risk of complications related to diabetes. This evidence led to the American Diabetes Association (ADA) to recommend HbA1c &#8805; 6.5% as a criterion for the diagnosis of diabetes. Racial / ethnic differences have been found regarding HbA1c levels. Elevated HbA1c levels in individuals without diabetes and with normal fasting glucose levels have been associated with microvascular and macrovascular complications, including changes in glomerular filtration. Inflammatory markers, in particular MCP -1 ( macrophage chemotactic protein -1), are involved in the glomerular lesions described in cases of diabetic nephropathy mechanism However, this test has not been widely incorporated as a routine examination in primary care in Brazil. The objective os this study was to describe and analyse the association between changes in HbA1c and blood glucose, racial / ethnic factors and cardiovascular and renal risk in adults in adults assisted by the Family Doctor Program of Niteroi, with no previous medical diagnosis of diabetes. It is a cross sectional study, with information of CAMELIA Studys participants. Data was collected from July 2006 to December 2007. It was noted that the cardiovascular risk profile was more pronounced in individuals with concurrent changes in blood glucose and HbA1c. The cardiovascular risk of individuals with high levels of glycemia and normal HbA1c was greater than the risk of individuals with HbA1c&#8805;6,5% alone. Individuals with HbA1c &#8805; 6.5%, mostly women and black skin persons, had higher LDL and creatinine levels. Independent association between changes in HbA1c ( &#8805; 5.7 and < 6.5% versus < 5.7 % ) and decreased estimated glomerular filtration rate . HbA1c showed to be a subclinical marker of metabolic disorders in diabetic patients and not with fasting glucose < 126 mg / dL, especially in the population of women and individuals with black skin color. HbA1c showed to be a subclinical marker of metabolic disorders in diabetic patients and not with fasting glucose < 126 mg / dL , especially in the population of women and individuals with black skin color. The results point to the possibility of using HbA1c as a marker of cardiovascular and renal risk aiming to propose strategies for early intervention and thus promote the prevention of diseases and conditions related changes in glucose metabolism.

The aim of this dissertation thesis was to study the factors affecting drug distribution and elimination and to use these factors to individualize dosing. The work consists of three thematic areas: estimation of the volume of distribution and subsequent dosing of selected drugs (vancomycin, amikacin, phenobarbital) using body size descriptors; estimation of clearance and subsequent dosing of selected drugs (vancomycin, amikacin, phenobarbital, perindopril) using renal function status markers; and the impact of drug interactions on the distribution and elimination of phenobarbital. The thesis summarizes original papers on these topics. Individual pharmacokinetic parameters were calculated for each patient based on their demographic and clinical characteristics, dosing records and measured serum drug levels. The relationships between distribution volume/drug clearance and body size descriptors/renal functional status markers were examined by regression analysis. Vancomycin volume of distribution was best predicted by the total body weight. Loading dose of 10.7 mg/kg of total body weight was optimal in patients taking continuous vancomycin and would lead to reducing of median time to reach target concentrations from 17 to 1 hour. On the contrary, amikacin volume of distribution was most associated...

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

Cette thèse avait pour but d'illustrer l'intérêt de méthodes statistiques avancées lorsqu'on s'in­ téresse aux associations entre différents facteurs et la progression de la maladie rénale chronique (MRC). Dans un premier temps, une revue de la littérature a été effectuée alin d'identifier les méthodes classiquement utilisées pour étudier les facteurs de progression de la MRC ; leurs limites et des méthodes permettant de mieux prendre en compte ces limites ont été discutées. Notre second travail s'est concentré sur les analyses de données de survie et la prise en compte de la censure par intervalle, qui survient lorsque l'évènement d'intérêt est la progression vers un stade spécifique de la MRC, et le risque compétitif avec le décès. Une comparaison entre des modèles de survie standards et le modêle illness-death pour données censurées par intervalle nous a permis d'illustrer l'impact de la modélisation choisie sur les estimations à la fois des effets des facteurs de risque et des probabilités d'évènements, à partir des données de la cohorte NephroTest. Les autres travaux ont porté sur les analyses de données longitudinales de la fonction rénale. Nous avons illustré l'intérêt du modèle linéaire mixte dans ce contexte et présenté son extension pour la prise en compte de sous-populations de trajectoires de la fonction rénale différentes. Nous avons ainsi identifier cinq classes, dont une avec un déclin très rapide et une autre avec une amélioration de la fonction rénale au cours du temps. Des perspectives de travaux liés à la prédiction permettent enfin de lier les deux types d'analyses présentées dans la thèse. / The objective of this thesis was to illustrate the benefit of using advanced statistical methods to study associations between risk factors and chrouic kidney disease (CKD) progression. In a first time, we conducted a literature review of statistical methods used to investigate risk factors of CKD progression, identified important methodological issues, and discussed solutions. In our sec­ ond work, we focused on survival analyses and issues with interval-censoring, which occurs when the event of interest is the progression to a specifie CKD stage, and competing risk with death. A comparison between standard survival models and the illness-death mode! for interval-censored data allowed us to illustrate the impact of modeling on the estimates of both the effects of risk factors and the probabilities of events, using data from the NephroTest cohort. Other works fo­ cused on analysis of longitudinal data on renal function. We illustrated the interest of linear mixed mode! in this context and presented its extension to account for sub-populations with different trajectories of renal function. We identified five classes, including one with a strong decline and one with an improvement of renal function over time. Severa! perspectives on predictions bind the two types of analyses presented in this thesis.

Diabetic vasculopathy (DV) is the most important consequence of chronic hyperglycemia in patients with diabetes mellitus (DM). This thesis explores the interaction of blood, bone and kidney in the pathogenesis of DV by i) reviewing the current understanding of pathogenesis of macrovascular and microvascular diseases in DM to identify gaps in literature and generate hypotheses relating to various facets of DV ii) undertaking a series of prospective studies to examine these hypotheses iii) analysing the findings and integrating any new information obtained from the clinical studies into the current knowledge base and iv) generating hypotheses upon which future work might be based. The literature search was carried out with the aim of understanding current concepts of pathogenesis of DV and its potential modulators. The original reviews resulting from this process are presented in chapters 2 to 4. A series of pilot studies reported in chapters 7 to 11, were then carried out to interrogate hypotheses originating from this process. The first study was carried out in healthy individuals to define the biological variation of potential modulators of DV, namely erythropoietin (EPO), parathyroid hormone, 25 hydroxyvitamin D and 1, 25-dihydroxyvitamin D to facilitate the design and interpretation of subsequent studies. It revealed a wide biological variation of these modulators in the healthy population thus,emphasizing the need to have a control group in the subsequent study population. To examine whether tubulointerstitial dysfunction occurs before the onset of microalbuminuria, a measurement of the above mentioned parameters was carried out along with markers of tubulointerstitial injury in patients with type 1 and type 2 DM without microalbuminuria and in non-diabetic controls. It was found that tubulointerstitial dysfunction with low levels of EPO and 1, 25-dihydroxyvitamin D and higher excretion of tubular injury markers, occurs before the onset of microalbuminuria. Subsequently, diabetic and nondiabetic chronic kidney disease (CKD) patients with EPO deficiency anaemia were examined to study the effects of EPO therapy on the excretion of tubular injury markers. However, in these patient groups, we were unable to demonstrate an effect of EPO therapy on the markers of tubular injury in spite of a beneficial haematological response. To examine whether vascular calcification (VC) and bone mineral density (BMD) were linked in patients with diabetes mellitus and to explore their relationship to modulators of DV, an assessment of VC and BMD was undertaken in patients with type 2 DM with different degrees of proteinuria and normoalbuminuria. VC was assessed by CT scan and BMD by a DEXA scan. Modulators of DV were measured including serum Osteoprotegerin (OPG) and receptor activator of nuclear factor kappa-b-ligand (RANKL). The findings were i) a high prevalence of VC and osteopenia in normoalbuminuric type 2 DM patients with normal serum creatinine ii) a weak inverse relationship between VC and osteopenia iii) proteinuric patients had worse VC but not osteopenia iv) weak relationships between OPG levels and both VC and osteopenia, masked by age in multivariate analysis. The final study examined the relationship between modulators of DV, including OPG and RANKL, and the degree of CKD. It was found that abnormalities of OPG and RANKL occur before the onset of microalbuminuria and progress with deterioration of renal function. Compared to nondiabetics, DM patients have higher OPG levels in the predialysis phase and lower levels in haemodialysis phase, a phenomenon that might indicate endothelial exhaustion in dialysis patients with DM. The derangements associated with DV seem to occur earlier than previously thought. Further work is required to untangle these complexities and to define the contribution of factors such as the adverse blood milieu, the vasculature, abnormal bone and mineral metabolism, and early tubulointerstitial damage. The findings from the studies reported here may help in the formulation of new hypotheses, which might contribute to future work in this area.