Introdução: A curcumina é um polifenol presente no rizoma da espécie Curcuma longa L. que tem sido usado há séculos como medicamento anti-inflamatório na medicina asiática. A síndrome nefrótica é classicamente tratada com corticosteroides, uma potente classe antiinflamatória e imunossupressora. O tratamento pode trazer sérios efeitos adversos. Objetivos: Este estudo foi desenhado para avaliar o efeito anti-inflamatório e antiproteinúrico da C. longa na forma de droga vegetal, na lesão renal induzida pela doxorrubicina. Desenho do estudo: Trata-se de um estudo experimental in vivo. Métodos: O efeito anti-inflamatório e anti-proteinúrico da C. longa foi avaliado utilizando-se 4 grupos de ratos Wistar: dois grupos com lesão renal induzida por doxorrubicina (3,5 mg/kg) em dose única endovenosa, sendo um alimentando-se de ração padrão e outro com ração misturada a C. longa (5 mg/g de ração). Outros dois grupos controles sem lesão renal foram alimentados, sendo um com ração padrão e outro com C. longa. Foram coletadas amostras de urina para dosagem de albuminúria a cada 2 semanas. Após 8 semanas os animais foram anestesiados e coletado sangue para dosagem no plasma de creatinina, albumina, sódio, potássio, colesterol e osmolalidade. Nas amostras de urina foram dosados albuminúria, sódio, potássio, osmolalidade e os mediadores inflamatórios proteína quimiotática para monócitos-1 e fator de transformação do crescimento beta urinário. Foi coletado tecido renal para realização de microscopia de luz e de imuno-histoquímica para desmina, vimentina e células ED-1 positivas. Resultados: Após a 8a semana de acompanhamento, o tratamento com C. longa atenuou o aumento do MCP-1 urinário, do TGF-? urinário, da imunomarcação para desmina, vimentina e células ED-1+ nos ratos com lesão renal induzida. Conclusão: Os resultados sugerem que o uso de C. longa em um modelo experimental de lesão renal por doxorrubicina, por 8 semanas, não reduz a albuminúria, mas leva a diminuição dos mediadores inflamatórios renais MCP-1 e TGF-? urinário, além de imunomarcação para desmina, vimentina e células ED-1+ no tecido renal. / Background: Curcumin is a polyphenol present in the rhizome of the species Curcuma longa L., which has been used for centuries as an anti-inflammatory remedy in Asian medicine. Nephrotic syndrome is classically treated with corticosteroids, a potent antiinflammatory and immunosuppressive class. The treatment can cause serious adverse effects. Objectives: This study was designed to evaluate the anti-inflammatory and antiproteinuric effects of C. longa, as powdered dried rhizomes, in renal injury induced by doxorubicin. Study design: This is an in vivo experimental study. Methods: The antiinflammatory and anti-proteinuric effects of C. longa were evaluated in four groups of Wistar rats: two groups with intravenous doxorubicin-induced kidney injury (3.5 mg/kg), one fed with standard food and another with standard food mixed with C. longa (5 mg/g food). Two other control groups without kidney injury were fed, one with standard and one with C. longa-mixed food. Urine samples were collected for albuminuria every 2 weeks. After 8 weeks, the animals were anesthetized and blood was collected for measurement of plasma creatinine, albumin, sodium, potassium, cholesterol and osmolality. In the urine samples, measurements of albuminuria, sodium, potassium, osmolality and inflammatory mediators as monocyte chemoattractant protein-1 and transforming growth factor beta were done. Renal tissue was collected for light microscopy and immunohistochemistry for desmin, vimentin and ED-1 positive cells. Results: After the 8th week of follow-up, treatment with C. longa attenuated the increase of urinary MCP-1, urinary TGF-?, and immunostaining for desmin, vimentin and ED-1+ cells in rats with doxorubicin-induced kidney injury. Conclusion: The results suggest that the use of C. longa in an experimental model of nephrotic syndrome for 8 weeks does not reduce albuminuria, but there is a decrease in the inflammatory mediators urinary MCP- 1, urinary TGF-?, and immunostaining for desmin, vimentin and ED-1+ cells.

Síndrome nefrótica é definida pela presença simultânea de edema sistêmico, hipoalbuminemia e proteinúria intensa. Vários componentes da composição corporal, principalmente relacionados à água corporal, sofrem rápidas e frequentes alterações nessa síndrome. A espectroscopia por bioimpedância (BIS) é um método de fácil execução, baixo custo, que pode ser repetido e praticamente isento de riscos que permite avaliar água corporal, massa magra e gordura corporal e tem sido pouco utilizado na síndrome nefrótica. Objetivo. Avaliar as alterações da água e de outros componentes da composição corporal através da BIS em pacientes com síndrome nefrótica. Métodos. Pacientes foram avaliados na ocasião da biópsia renal e no desfecho com ou sem remissão do edema. Foram medidos o peso corporal, albumina sérica e proteinúria de 24 h e, pela BIS, variáveis relacionadas à água corporal e a outros parâmetros de composição corporal. Resultados. Foram estudados 17 pacientes (idade: 51,1 + 17,4 anos) com síndrome nefrótica. Dez pacientes obtiveram remissão do edema (grupo R), sendo que em nove ocorreu também remissão da síndrome nefrótica. Em sete pacientes o edema permaneceu presente, sem remissão (grupo SR). A variação entre a primeira e a segunda medida para a sobrecarga hídrica foi de -5,4 L (-8,5 L; -1,8 L) no grupo R e de 0,0 L (-1,1 L; 1,2 L) no grupo SR (p < 0,05). A água corporal total variou de -4,75 L (- 10,20 L; -2,50 L) e de 4,80 L (-1,30 L; 6,10 L) nos grupos R e SR, respectivamente (p < 0,05), e a água extracelular variou de -5,90 L (-10,10 L; -0,42 L) e de 1,20 L (-0,80 L; 2,70 L) nos mesmos grupos (p < 0,05). Não houve diferença estatisticamente significante na variação entre as duas avaliações nos grupos R e SR para a água intracelular, massa de tecido magro, massa de tecido adiposo, massa gorda total e massa celular corporal. A variação do ângulo de fase entre as avaliações foi de 1,55° (0,41°; 2,24°) no grupo R e 0,10° (-0,28°; 0,46°) no grupo SR (p < 0,05). Houve correlação estatisticamente significante entre cada variável definidora da síndrome nefrótica (peso corporal, proteinúria e albumina sérica) versus sobrecarga hídrica, água corporal total, água extracelular e ângulo de fase, mas não versus as demais medidas de composição corporal obtidas pela BIS. Conclusão. A espectroscopia por bioimpedância mostrou-se eficiente em detectar mudanças da água corporal e do ângulo de fase em pacientes com síndrome nefrótica, mas não para identificar variações relacionadas à massa de tecido magro, massa de tecido adiposo, massa gorda total e massa celular corporal. . / Nephrotic syndrome is established by the simultaneous presence of systemic edema, hypoalbuminemia, and severe proteinuria. Several components of the body composition, mainly related to the body fluid, undergo to rapid and frequent changes in this syndrome. Spectroscopy by bioimpedance (BIS) is a reliable, cost-effective and easy-to-perform method to evaluate body water, adipose tissue mass, and body cell mass. Despite these advantages, BIS has barely been used to evaluate patients with nephrotic syndrome. Aims. To evaluate body fluid variable changes and other components of the body composition in patients with nephrotic syndrome by bioimpedance spectroscopy. Methods. Patients were studied in two moments: at the occasion of the renal biopsy (1st evaluation), and at the end-point (2nd evaluation). Patients were grouped according to they reached remission (Group R) or remained without remission (Group WR) of the edema at the 2nd evaluation. Body weight, serum albumin and 24 hours proteinuria were measured at the two time-points, as well as other variables associated with body fluid and other components of the body composition obtained by the BIS. Results. Seventeen patients (age: 51,1 + 17,4 years-old) with nephrotic syndrome were studied. Ten patients reached remission of the edema while nine of them were also in remission of the nephrotic syndrome. Seven patients remained with edema at the end-point. The variation between the 1st and the 2nd measurement for the overhydration was of -5,4 L (-8,5L; -1,8L) at the group R and of 0,0 (-1,1 L; 1,2 L) at the group NR (p < 0,05). Total body water changes were of -4,75 L (-10,20 L; -2,50 L) and of 4,80 L (-1,30 L; 6,10 L) at the groups R and WR, respectively (p < 0,05), and the extracellular water changed of the -5,90 L (-10,10 L; -0,42 L) and of 1,20 L (-0,80 L; 2,70 L) at the same groups, respectively (p < 0,05). There was no statistically significant difference in the variation between the two evaluations for the groups R and NR for intracellular water, lean tissue mass, fat mass, adipose tissue mass, and body cell mass. The variation of the phase angle between the two evaluations was of the 1,55° (0,41°; 2,24°) at the group R and 0,10° (-0,28°; 0,46°) at the group WR (p < 0,05). There was a statistically significant correlation between each related nephrotic syndrome variable compared with overhydration, total body water, extracellular water, and phase angle, but no difference when compared with the other variables related to the body composition measured by the BIS. Conclusion. The spectroscopy by bioimpedance was efficient to measure body water changes and the phase angle in patients with nephrotic syndrome. However, the BIS could not detect changes related to the intracellular water, lean tissue mass, fat mass, adipose tissue mass, and body cell mass.

Introdução: A curcumina é um polifenol presente no rizoma da espécie Curcuma longa L. que tem sido usado há séculos como medicamento anti-inflamatório na medicina asiática. A síndrome nefrótica é classicamente tratada com corticosteroides, uma potente classe antiinflamatória e imunossupressora. O tratamento pode trazer sérios efeitos adversos. Objetivos: Este estudo foi desenhado para avaliar o efeito anti-inflamatório e antiproteinúrico da C. longa na forma de droga vegetal, na lesão renal induzida pela doxorrubicina. Desenho do estudo: Trata-se de um estudo experimental in vivo. Métodos: O efeito anti-inflamatório e anti-proteinúrico da C. longa foi avaliado utilizando-se 4 grupos de ratos Wistar: dois grupos com lesão renal induzida por doxorrubicina (3,5 mg/kg) em dose única endovenosa, sendo um alimentando-se de ração padrão e outro com ração misturada a C. longa (5 mg/g de ração). Outros dois grupos controles sem lesão renal foram alimentados, sendo um com ração padrão e outro com C. longa. Foram coletadas amostras de urina para dosagem de albuminúria a cada 2 semanas. Após 8 semanas os animais foram anestesiados e coletado sangue para dosagem no plasma de creatinina, albumina, sódio, potássio, colesterol e osmolalidade. Nas amostras de urina foram dosados albuminúria, sódio, potássio, osmolalidade e os mediadores inflamatórios proteína quimiotática para monócitos-1 e fator de transformação do crescimento beta urinário. Foi coletado tecido renal para realização de microscopia de luz e de imuno-histoquímica para desmina, vimentina e células ED-1 positivas. Resultados: Após a 8a semana de acompanhamento, o tratamento com C. longa atenuou o aumento do MCP-1 urinário, do TGF-? urinário, da imunomarcação para desmina, vimentina e células ED-1+ nos ratos com lesão renal induzida. Conclusão: Os resultados sugerem que o uso de C. longa em um modelo experimental de lesão renal por doxorrubicina, por 8 semanas, não reduz a albuminúria, mas leva a diminuição dos mediadores inflamatórios renais MCP-1 e TGF-? urinário, além de imunomarcação para desmina, vimentina e células ED-1+ no tecido renal. / Background: Curcumin is a polyphenol present in the rhizome of the species Curcuma longa L., which has been used for centuries as an anti-inflammatory remedy in Asian medicine. Nephrotic syndrome is classically treated with corticosteroids, a potent antiinflammatory and immunosuppressive class. The treatment can cause serious adverse effects. Objectives: This study was designed to evaluate the anti-inflammatory and antiproteinuric effects of C. longa, as powdered dried rhizomes, in renal injury induced by doxorubicin. Study design: This is an in vivo experimental study. Methods: The antiinflammatory and anti-proteinuric effects of C. longa were evaluated in four groups of Wistar rats: two groups with intravenous doxorubicin-induced kidney injury (3.5 mg/kg), one fed with standard food and another with standard food mixed with C. longa (5 mg/g food). Two other control groups without kidney injury were fed, one with standard and one with C. longa-mixed food. Urine samples were collected for albuminuria every 2 weeks. After 8 weeks, the animals were anesthetized and blood was collected for measurement of plasma creatinine, albumin, sodium, potassium, cholesterol and osmolality. In the urine samples, measurements of albuminuria, sodium, potassium, osmolality and inflammatory mediators as monocyte chemoattractant protein-1 and transforming growth factor beta were done. Renal tissue was collected for light microscopy and immunohistochemistry for desmin, vimentin and ED-1 positive cells. Results: After the 8th week of follow-up, treatment with C. longa attenuated the increase of urinary MCP-1, urinary TGF-?, and immunostaining for desmin, vimentin and ED-1+ cells in rats with doxorubicin-induced kidney injury. Conclusion: The results suggest that the use of C. longa in an experimental model of nephrotic syndrome for 8 weeks does not reduce albuminuria, but there is a decrease in the inflammatory mediators urinary MCP- 1, urinary TGF-?, and immunostaining for desmin, vimentin and ED-1+ cells.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-10-18T11:17:00Z No. of bitstreams: 1 priscyllaaparecidavieiradocarmo.pdf: 1470676 bytes, checksum: fd5e83ad78ccfe4675fb74294a6ad3a6 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-10-25T12:06:50Z (GMT) No. of bitstreams: 1 priscyllaaparecidavieiradocarmo.pdf: 1470676 bytes, checksum: fd5e83ad78ccfe4675fb74294a6ad3a6 (MD5) / Made available in DSpace on 2016-10-25T12:06:50Z (GMT). No. of bitstreams: 1 priscyllaaparecidavieiradocarmo.pdf: 1470676 bytes, checksum: fd5e83ad78ccfe4675fb74294a6ad3a6 (MD5) Previous issue date: 2008-02-15 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / As glomerulopatias persistem entre as principais causas de doença renal crônica dialítica em nosso país. Traçar um perfil destas doenças assume importância não só como fonte para investigações clínicas e epidemiológicas, como também constitui-se em importante passo para o conhecimento da história natural das doenças glomerulares. O presente estudo avaliou o perfil das doenças glomerulares na Zona da Mata Mineira, estabelecendo a distribuição e freqüência dos tipos histológicos das glomerulopatias primárias e secundárias, relacionando-os com os achados clínico laboratoriais. Foram realizadas 261 biópsias, sendo que 126 delas correspondiam a rins nativos de adultos e foram consideradas para análise. A síndrome glomerular mais freqüente foi a nefrótica (55,2%), seguida da síndrome de anormalidades urinárias (28,8%). As glomerulopatias primárias e secundárias predominantes foram a glomeruloesclerose segmentar e focal (40,8%) e a nefrite lúpica (80,7%), respectivamente. Considerando-se toda a população, a GESF foi a glomerulopatia predominante (n=31; 24,6%), seguida pela nefrite lúpica (n=21; 16,6%) e pela nefropatia por IgA (n=16; 12,6%). Dentre as principais causas de síndrome nefrótica, a 10 GESF foi a glomerulopatia mais freqüentemente encontrada (27,5%), seguida pela nefrite lúpica (23,1%). Na síndrome de anormalidades urinárias, os diagnósticos mais freqüentes foram o rim normal (27,7%) e a nefropatia por IgA (22,2%). A maioria dos pacientes avaliados apresentavam algum grau de cronicidade à biópsia renal (56,3%), que se relacionou com menores valores de filtração glomerular. Este estudo forneceu informações importantes sobre as glomerulopatias na nossa região, contribuindo não só para uma adequada documentação da distribuição destas doenças entre nós, mas sobretudo para definição de melhores condutas visando terapêuticas cada vez mais específicas para diferentes tipos histológicos. / Glomerulopathies are still among the main causes of chronic kidney diseases requiring dialysis in our country. It is important to establish a profile of these diseases not only as a source for clinical and epidemiological investigations, but also because this is an important step for the knowledge of the natural history of glomerular diseases. This study assessed the profile of glomerular diseases in the Zona da Mata region of Minas Gerais, and established the distribution and frequency of the histological types of primary and secondary glomerulopathies, comparing them to clinical-laboratorial results. 261 biopsies were carried out, 126 of which were native adult kidneys and which were submitted to analysis. The most common glomerular syndrome was nephrotic syndrome (55.2%), followed by urinary abnormality syndrome (28.8%). The predominant primary and secondary glomerulopathies were focal segmental glomerulosclerosis (40.8%) and lupus nephritis (80.7%), respectively. Considering the whole population, FSGS was the predominant glomerulopathy (n=31; 24.6%), followed by lupus nephritis (n=21; 16.6%) and IgA nephropathy (n=16; 12.6%). Among the main causes of nephrotic syndrome, FSGS was the most frequently found glomerulopathy (27.5%), followed by lupus nephritis (23.1%). In the urinary abnormality syndrome, the most common diagnoses 12 were normal kidney (27.7%) and IgA nephropathy (22.2%). The majority of the patients presented some degree of chronicity at the renal biopsy (56,3%), which correlated with lower values of glomerular filtration rate. This study supplied important information about glomerulopathies in our region, contributing not only to suitable documentation on the distribution of these diseases among us, but particularly to a definition of more appropriate conduct, aiming at therapies that are more and more specific for different histological types.

La pathogénie du syndrome néphrotique idiopathique est inconnue, mais de nombreux arguments clinques et expérimentaux favorisent l’hypothèse d’une pathogénie dys-immunitaire à expression immunologique et rénale, au cours de laquelle on observerait une altération des lymphocytes T. Cependant, le mécanisme exact reste encore mal connu. Récemment, le Rituximab, un anticorps dirigé contre l’antigène CD20, a montré une efficacité à induire une rémission à moyen et long terme suggérant l’implication d’une dysfonction des lymphocytes B et/ou un défaut de coopération T-B. Notre laboratoire a isolé un nouveau gène C-MIP dont l’expression est induite dans certaines sous-populations lymphocytaires T et B, ainsi que dans les podocytes de patients atteints de SNI en phase de poussée mais quasiment indétectable chez les sujets sains.Dans ces travaux, ancillaires au PHRC NEPHRUTIX, nous avons étudié les perturbations lymphocytaires T, avant, au moment de la rechute et en période de rémission au cours de syndrome néphrotique à lésions glomérulaires minimes et l’effet du traitement par le Rituximab. Dans cette étude, nous avons mis en évidence que la rechute était associée à un effondrement des lymphocytes T régulateurs, une baisse profonde de l’interleukine-2 ainsi qu’à une surexpression significative de C-MIP, précédant la survenue de la rechute. Ces modifications se restaurent en rémission. Enfin, la rémission obtenue dans le bras Rituximab, entraîne une diminution des lymphocytes T folliculaires (Tfh), des iNKT et des cellules double-négatives DN-TCR Vα24, suggérant que le SNLGM implique un défaut des réponses immunitaires innées et adaptatives, qui peut être stabilisé par un traitement par Rituximab.Afin d’étudier le rôle de C-MIP, nous avons généré des souris transgéniques sur-exprimant ce gène dans les lymphocytes T matures périphériques. Cette surexpression est à l’origine d’un phénotype lymphocytaire altéré marqué par une accumulation de lymphocytes T naïfs, un effondrement des cytokines activatrices de type Th1 et Th2 et une accumulation des formes inactives des Src kinases. Ces résultats suggèrent que C-MIP, en inhibant les Src kinases, est un régulateur négatif de l’activation T impliqué dans la signalisation proximale et pourrait être impliqué dans l’hypo-réactivité lymphocytaire T observée chez les patients atteints de SNLGM actif. / The pathogenesis of minimal-change nephrotic syndrom (MCNS) is unknown, but, supported by many clinical and experimental arguments, it was suggested that MCNS is a dys-immune disorder with immunogical and renal expression, during which T-cell alteration would be observed. However, the exact mechanism remains unknown. Recently, Rituximab, a B-cell depleting agent, is effctive in inducing mid- and long-term remission suggesting involvement of B-cell dysfunction and/or lack of T-B cooperation. Our laboratory identified a new gene: C-MIP. We have shown that C-MIP abundance is increased in some T and B lymphocyte subpopulations, as well as in podocytes of MCNS patients during relapse phase but undetectable in healthy subjects.In this work, ancillary to the NEPHRUTIX PHRC, we studied T-cell disturbances before and during the relapse or during the remission time in MCNS and the effect of Rituximab therapy. In this study, we found that relapses were associated with significant decrease in regulatory T cell and interleukin-2 expression, while C-MIP abundance was significantly increased. These changes are restored during remission time. Finally, remission after Rituximab therapy leads to a decrease in follicular T cells (Tfh), iNKT and double-negative (CD4- CD8-) T cells expressing the invariant Vα24 chain, suggesting that MCNS involves a disorder of innate and adaptative immune response, which can be stabilized by Rituximab treatment.In order to study the C-MIP role, we generated transgenic mice overexpressing this gene in the peripheral mature T-cells. This overexpression leads to an altered lymphocyte phenotype with an accumulation of naive T lymphocytes, a significant decrease of Th1 and Th2 activating cytokines and accumulation of inactive Src kinases. These results suggest that, by inhibiting Src kinases, C-MIP is a negative regulator of activation T involved in proximal signalling and may be responsable of the lymphocyte T hypo-reactivity observed in patients with active MCNS.

Nephrotic syndrome (NS) is characterized by proteinuria, hypalbuminemia and edemas. It occurs during first and second glomerulopathies. This disease can be divided into two groups: primary (idiopathic) and secondary. The heredity of the familial nephrotic syndrome is autosomal dominant and autosomal recessive. There are four most important genes that condition the formation of hereditary nephrotic syndrome in adult patienst. These genes are ACTN4, CD2AP, NPHS2 and TRPC6. The gene ACTN4, which encodes protein α-actinin 4, is responsible for the autosomal dominant form of focal segmental glomerulosclerosis (FSGS). FSGS is included in first glomerulopathies. α-Actinin 4 was also researched for some types of carcinomas. There was performed the mutational analysis of the gene ACTN4 on the set of 48 patients with nephrotic syndrome in this diploma thesis. High resolution melting (HRM) analysis and sequencing selected samples were used during this mutation detection. During this process many published and unpublished SNPs and one unpublished candidate mutation that could have causal associations with FSGS were found.

Objetivos: Avaliar a estatura final, mineralização e marcadores de mineralização óssea de adultos com síndrome nefrótica (SN) idiopática corticossensível na infância e adolescência e analisar a influência da doença, suas comorbidades e do alvo de estatura no crescimento e mineralização destes pacientes. Casuística: Avaliamos a estatura final de 60 pacientes (41 masculinos e 19 femininos) com idade mínima de dezenove anos ou desenvolvimento genital P4G4 nos masculinos e menarca nos femininos portadores de SN corticossensível na infância e adolescência. Realizamos a densitometria óssea (DMO=g/cm2) em 26 destes pacientes e em 35 controles, com análise concomitante dos níveis séricos de 25 OH vitamina D3 (25(OH)D), Paratormônio (PTH), telopéptido carboxiterminal do colágeno tipo 1( (CTx), Propeptídeo Aminoterminal do Colágeno Tipo I (P1NP) e Osteocalcina (OC) Resultados: A idade média inicial dos 60 pacientes foi de 5a3m e final de 20a5m, com acompanhamento médio de 15a2m. A dose média de prednisona utilizada foi de 1264 mg/kg. O Zscore médio da estatura inicial (-0,60; SD: 1,0) e final (0,64; SD: 0,92), não diferiu significativamente (Teste T: p=0,72) entre si. O Zscore estatura na idade adulta se correlacionou significativamente apenas com o Zscore estatura inicial e com o Zscore alvo de estatura. Seis pacientes atingiram Zscore estatura < -2 na idade adulta e este achado demonstrou forte correlação com o Zscore estatura inicial e com o Zscore alvo de estatura. A DMO e Zscore DMO de L1L4, Cabeça do fêmur e do Fêmur total dos pacientes e controles não diferiram significativamente. 6 pacientes e 2 controles apresentaram Zscore DMO < -2 (massa óssea reduzida) enquanto 2 pacientes e 1 controle demonstraram , Zscore DMO < -2,5 (osteoporose). Pacientes com massa óssea reduzida receberam 2189 mg/kg de prednisona durante 13 anos e aqueles com osteoporose, 2510 mg/kg durante 14 anos. Estes valores, comparados com aqueles de pacientes com massa óssea normal, mostraram significância estatística (p=0,01). Não houve correlação significativa entre as demais variáveis analisadas e a DMO. Os marcadores 25(OH)D, PTH, CTx, P1NP e OC dos pacientes e controles não diferiram significativamente. Quando analisados em relação à doença e suas comorbidades, DMO e estatura final não apresentaram significação estatística. Conclusões: 1. Os valores de Zscore estatura inicial e final se correlacionaram fortemente com o alvo de estatura. 2. Não houve associação entre as características clinicas da doença e a aquisição do alvo de estatura, neste grupo de pacientes. 3. A massa óssea e os marcadores de mineralização dos pacientes não diferiram quando comparados aos controles. 4. Os 6 pacientes com massa óssea reduzida (2 com osteoporose) utilizaram dose total e tempo de uso da prednisona significativamente maior que aqueles com massa óssea adequada 5. Não houve correlação entre os níveis séricos dos marcadores de mineralização óssea e a doença e suas comorbidades, a estatura final e a DMO dos pacientes adultos com SN na infância e adolescência / Objectives: The aim of the present study was to evaluate the final height, bone mineral density (BMD) and bone mineralization markers of adults with steroid responsive Idiopathic Nephrotic Syndrome (NS) in childhood and adolescence and to examine the influence of the disease, its co-morbidities and the patients\' target height in the final height and mineralization results. Patients and Methods: We have analyzed initial and final anthropometric data of 60 patients (41 male and 19 females) and / or their records, with a minimum age of nineteen years or fully developed pubertal status (P4G4 in males and menarche in females). BMD (g/cm2) was evaluated in 26 patients and in 35 controls, with a concomitant analysis, of serum levels of 25-OH Vitamin D (25(OH)D), Parathyroid Hormone (PTH); C-terminal telopeptide of type I collagen (CTx) and aminoterminal propeptide of type 1 procollagen (P1NP) and Osteocalcin (OC) Results: Mean age at first consultation was 5.3 years (SD: 2.4 yrs) and at last consultation was 20.4 yrs (SD: 3.0 yrs). The mean cumulative dose of prednisone was 1254 mg/kg (SD: 831.39 mg/kg). The mean initial height SDS was -0.60; (SD: 1.0) the final height SDS was -0.64; (SD: 0.92), (t-test: p=0.72). The final height SDS showed correlated significantly only with the initial height SDS and the target height SDS. Six patients achieved a final height SDS <-2 and this finding showed a strong correlation to the initial height SDS and to the target height SDS in the male patients. The patients\' and control subjects L1L4 head of the femur and the total femur BMD and BMD SDS did not differ significantly. 6 patients and 2 control subjects showed a BMD SDS <-2 (low bone mass) while 2 patients and 1 control subjects showed a BMD SDS <-2.5 (osteoporosis). Patients with BMD SDS <-2 received 2189 mg / kg of prednisone over 13 years while those with a BMD SDS <-2.5 received 2510 mg / kg prednisone for 14 years (p = 0.01 vs BMD SDS -2 ). No other studied variable correlated significantly with BMD. The studied bone biomarkers showed similar results in patients and control subjects without a significant correlation with disease activity, co-morbidities, and BMD or height parameters. Conclusion: 1. the initial and final height SDS were strongly correlated to the height target. 2. INS and its co-morbidities did not prevent the patients to reach their target height 3. The patients\' BMD and bone mineralization markers did not differ when compared to controls. 4. The 6 patients with low bone mass (2 with osteoporosis) used a total dose of prednisone for a longer period of time in relation to those with an adequate BMD 5. There was no correlation between bone mineralization markers, disease activity and its co-morbidities, final height and BMD of adult patients with INS in childhood and adolescence

Objetivos: Avaliar a estatura final, mineralização e marcadores de mineralização óssea de adultos com síndrome nefrótica (SN) idiopática corticossensível na infância e adolescência e analisar a influência da doença, suas comorbidades e do alvo de estatura no crescimento e mineralização destes pacientes. Casuística: Avaliamos a estatura final de 60 pacientes (41 masculinos e 19 femininos) com idade mínima de dezenove anos ou desenvolvimento genital P4G4 nos masculinos e menarca nos femininos portadores de SN corticossensível na infância e adolescência. Realizamos a densitometria óssea (DMO=g/cm2) em 26 destes pacientes e em 35 controles, com análise concomitante dos níveis séricos de 25 OH vitamina D3 (25(OH)D), Paratormônio (PTH), telopéptido carboxiterminal do colágeno tipo 1( (CTx), Propeptídeo Aminoterminal do Colágeno Tipo I (P1NP) e Osteocalcina (OC) Resultados: A idade média inicial dos 60 pacientes foi de 5a3m e final de 20a5m, com acompanhamento médio de 15a2m. A dose média de prednisona utilizada foi de 1264 mg/kg. O Zscore médio da estatura inicial (-0,60; SD: 1,0) e final (0,64; SD: 0,92), não diferiu significativamente (Teste T: p=0,72) entre si. O Zscore estatura na idade adulta se correlacionou significativamente apenas com o Zscore estatura inicial e com o Zscore alvo de estatura. Seis pacientes atingiram Zscore estatura < -2 na idade adulta e este achado demonstrou forte correlação com o Zscore estatura inicial e com o Zscore alvo de estatura. A DMO e Zscore DMO de L1L4, Cabeça do fêmur e do Fêmur total dos pacientes e controles não diferiram significativamente. 6 pacientes e 2 controles apresentaram Zscore DMO < -2 (massa óssea reduzida) enquanto 2 pacientes e 1 controle demonstraram , Zscore DMO < -2,5 (osteoporose). Pacientes com massa óssea reduzida receberam 2189 mg/kg de prednisona durante 13 anos e aqueles com osteoporose, 2510 mg/kg durante 14 anos. Estes valores, comparados com aqueles de pacientes com massa óssea normal, mostraram significância estatística (p=0,01). Não houve correlação significativa entre as demais variáveis analisadas e a DMO. Os marcadores 25(OH)D, PTH, CTx, P1NP e OC dos pacientes e controles não diferiram significativamente. Quando analisados em relação à doença e suas comorbidades, DMO e estatura final não apresentaram significação estatística. Conclusões: 1. Os valores de Zscore estatura inicial e final se correlacionaram fortemente com o alvo de estatura. 2. Não houve associação entre as características clinicas da doença e a aquisição do alvo de estatura, neste grupo de pacientes. 3. A massa óssea e os marcadores de mineralização dos pacientes não diferiram quando comparados aos controles. 4. Os 6 pacientes com massa óssea reduzida (2 com osteoporose) utilizaram dose total e tempo de uso da prednisona significativamente maior que aqueles com massa óssea adequada 5. Não houve correlação entre os níveis séricos dos marcadores de mineralização óssea e a doença e suas comorbidades, a estatura final e a DMO dos pacientes adultos com SN na infância e adolescência / Objectives: The aim of the present study was to evaluate the final height, bone mineral density (BMD) and bone mineralization markers of adults with steroid responsive Idiopathic Nephrotic Syndrome (NS) in childhood and adolescence and to examine the influence of the disease, its co-morbidities and the patients\' target height in the final height and mineralization results. Patients and Methods: We have analyzed initial and final anthropometric data of 60 patients (41 male and 19 females) and / or their records, with a minimum age of nineteen years or fully developed pubertal status (P4G4 in males and menarche in females). BMD (g/cm2) was evaluated in 26 patients and in 35 controls, with a concomitant analysis, of serum levels of 25-OH Vitamin D (25(OH)D), Parathyroid Hormone (PTH); C-terminal telopeptide of type I collagen (CTx) and aminoterminal propeptide of type 1 procollagen (P1NP) and Osteocalcin (OC) Results: Mean age at first consultation was 5.3 years (SD: 2.4 yrs) and at last consultation was 20.4 yrs (SD: 3.0 yrs). The mean cumulative dose of prednisone was 1254 mg/kg (SD: 831.39 mg/kg). The mean initial height SDS was -0.60; (SD: 1.0) the final height SDS was -0.64; (SD: 0.92), (t-test: p=0.72). The final height SDS showed correlated significantly only with the initial height SDS and the target height SDS. Six patients achieved a final height SDS <-2 and this finding showed a strong correlation to the initial height SDS and to the target height SDS in the male patients. The patients\' and control subjects L1L4 head of the femur and the total femur BMD and BMD SDS did not differ significantly. 6 patients and 2 control subjects showed a BMD SDS <-2 (low bone mass) while 2 patients and 1 control subjects showed a BMD SDS <-2.5 (osteoporosis). Patients with BMD SDS <-2 received 2189 mg / kg of prednisone over 13 years while those with a BMD SDS <-2.5 received 2510 mg / kg prednisone for 14 years (p = 0.01 vs BMD SDS -2 ). No other studied variable correlated significantly with BMD. The studied bone biomarkers showed similar results in patients and control subjects without a significant correlation with disease activity, co-morbidities, and BMD or height parameters. Conclusion: 1. the initial and final height SDS were strongly correlated to the height target. 2. INS and its co-morbidities did not prevent the patients to reach their target height 3. The patients\' BMD and bone mineralization markers did not differ when compared to controls. 4. The 6 patients with low bone mass (2 with osteoporosis) used a total dose of prednisone for a longer period of time in relation to those with an adequate BMD 5. There was no correlation between bone mineralization markers, disease activity and its co-morbidities, final height and BMD of adult patients with INS in childhood and adolescence

Le syndrome néphrotique idiopathique (SNI) est une néphropathie glomérulaire définie par une protéinurie massive associée à une hypoalbuminémie, sans lésions inflammatoires rénales, ni dépôts de complexes immuns circulants. Les travaux réalisés au cours de ma thèse concernent l’étude du rôle potentiel du gène c-mip dans la physiopathologie du SNI.Dans un premier temps, nous avons étudié la physiopathologie moléculaire de l’association maladie de Hodgkin et SNI. Nous avons démontré que cette association était liée à une forte induction de c-mip à la fois dans les cellules de Reed Sternberg (dont la présence signe le lymphome hodgkinien) et les podocytes qui sont des cellules spécialisées du glomérule rénal (Audard, et al. 2010). Nous avons montré que l’induction de c-mip résultait d’un défaut quantitatif et/ou qualitatif du gène Fyn, à la fois chez les patients et dans un modèle de souris déficiente en Fyn. Nous avons trouvé que c-mip était fortement induit dans les podocytes au cours du SNI ainsi que dans la glomérulopathie extramemenbraneuse (GEM). La surexpression de c-mip par transgénèse chez la souris déclenche une protéinurie néphrotique dont le mécanisme implique une rupture, médiée par c-mip, de la voie de signalisation de la néphrine (Science Signaling, 2010 co-auteur). L’étude de la néphrite de Heyman, le modèle expérimental de la GEM humaine, a permis de montrer que l’induction de c-mip coincidait avec l’apparition de la protéinurie et était associée à l’inhibition de l’activité RhoA, à une perte de la synaptopodine, à une diminution du VEGF tandis que l’expression de la DAPK (death-associated protein kinase) est fortement augmentée (Audard et al, manuscrit soumis 1). Nous avons recherché si l’hypogammaglobulinémie au cours du SNI était associée à des anomalies fonctionnelles des lymphocytes B (LB). Nous avons trouvé que c-mip interagit avec la sous unité régulatrice de la PI3 kinase et empêche la dissociation de la sous unité catalytique, p110, nécessaire à l’activation de la PI3 kinase. Enfin, l’expression de l’IL 21, une cytokine–clé secrétée par les lymphocytes T et intervenant dans la commutation isotypique, était fortement réduite dans le SNI (Audard et al, manuscrit en préparation 2). Ces résultats donnent un éclairage nouveau sur la physiopathologie moléculaire du SNI et suggèrent un rôle crucial de c-mip dans les anomalies lymphocytaires et podocytaires observées chez les patients / Idiopathic nephrotic syndrome comprises several podocyte diseases of unknown origin, affecting the glomerular podocyte, which plays a key role in controlling the permeability of the kidney filter to proteins. It is characterized by massive proteinuria and hypoalbuminemia, with no inflammatory lesions or cell infiltration. This works focused on the potential role of c-mip in the pathogenesis of INS. We showed that occurrence of minimal change nephrotic syndrome in the course of Hodgkin lymphoma (cHL-MCNS) is closely related to the induction of c-mip in both Hodgkin-Reed Sternberg cells and podocytes (Audard, et al. 2010), which is caused by a qualitative and/or quantitative defect in Fyn in both HRS and podocytes cells. We found that c-mip is upregulated in podocytes of patients with membranous nephropathy (MN). Transgenic mice overproducing c-mip in the podocytes developed heavy proteinuria without morphological alterations, inflammatory lesions or cell infiltrations. We showed that c-mip turned off podocyte proximal signaling by preventing the interaction between Fyn and nephrin, resulting in the inhibition of nephrin signaling pathway (Science signaling, 2010 coauthor). Moreover, the induction of c-mip in passive type Heymann nephritis (the experimental model of MN) was concomitant to proteinuria occurrence and is associated with reduction of RhoA activity, downregulation of synaptopodin and VEGF expression whereas DAPK expression is significantly increased (Audard et al manuscript submitted 1).We demonstrated that hypogammaglobulinemia, a common feature in INS patients, may result from a defect in B lymphocytes. We found that c-mip interacts with p85 regulatory subunit and prevent its dissociation from p110 catalytic subunit, resulting in inactivation of PI3 kinase. Finally, the expression of IL21, a key cytokine involved in class switching recombination, is repressed in active phases of INS, which may contribute for immunoglobulin disorders commonly observed in these patients (Audard et al manuscript in progress 2).Altogether, these results suggest that c-mip is a major player of lymphocyte and podocytes dysfunction observed in patients with INS

O objetivo deste estudo foi analisar o metabolismo ósseo de pacientes com proteinúria glomerular sem uso prévio de drogas que afetassem esse metabolismo. Dezessete pacientes foram estudados com biópsia óssea para análise histomorfométrica e fragmentos ósseos foram obtidos para cultura de célula (n=13) na qual nós avaliamos proliferação de osteoblasto. A comparação dos achados histomorfométricos a controles de literatura demonstrou uma diminuição da remodelação óssea e comprometimento de sua microarquitetura. Corroborando com esse resultado houve diminuição da proliferação dos osteoblastos dos pacientes quando comparados a controles (n=5) doadores de órgãos. Análise bioquímica revelou correlação negativa da 25(OH)D3 com a proteinúria e positiva com a proliferação dos osteoblastos em cultura / The objective of this study was to analyze bone metabolism in proteinuria glomerular patients not having previously used drugs affecting bone metabolism. Seventeen patients were studied with histomorphometric analysis of bone biopsies and bone fragments were obtained for cell culture (n = 13), in which we evaluated osteoblastic proliferation. Comparing patients to controls of literature indicate reduced bone remodeling and altered bone microarchitecture. In corroboration, mean osteoblast proliferation was lower in patient samples when compared with those for normal osteoblasts obtained from age-matched, gender-matched donor organs (n = 5). Concentrations of 25-hydroxyvitamin-D3 correlated negatively with proteinuria and positively with osteoblast proliferation in culture