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A doença periodontal (DP) é uma doença inflamatória dos tecidos de suporte dos dentes, causada por microorganismos específicos. É relatado que a incidência possa ser de até 100% em cães a partir de um ano de idade. A DP está entre as doenças relacionadas com alteração glomerular, sendo a proteinúria sua característica. A glomerulonefrite é o tipo mais comum de glomerulonefropatia, sendo uma das maiores causas de doença renal crônica (DRC) em cães. É caracterizada por proteinúria, onde a relação proteína/creatinina urinária (RPCU), na maioria dos casos, encontra-se acima de 3,5, podendo estar associada com hipoalbuminemia e sinais de inflamação na urinálise. Azotemia também pode estar presente em diferentes níveis. Muitos estudos são realizados a fim de avaliar a relação da DP com lesões em órgãos distantes, porém ainda não há consenso entre os resultados. O objetivo do presente estudo foi avaliar a possível relação entre a DP, em diferentes graus, com alterações renais, por meio de aferição da RPCU e da creatinina sérica. Foram atendidos no Hospital de Clínicas Veterinárias da Universidade Federal do Rio Grande do Sul 25 pacientes entre agosto de 2016 e janeiro de 2017. Desses, 18 preencheram os critérios de inclusão. Todos os pacientes passaram por exame clínico geral, exame oral completo, exames de sangue (hemograma, creatinina, ureia, fosfatase alcalina - FA, alanina-amino-transferase – ALT e albumina), ultrassonografia abdominal, urinálise e RPCU. Foram encaminhados para profilaxia dentária onde foi estabelecido o grau de DP e realizado o tratamento adequado. O acompanhamento pós operatório deu-se aos 10 e aos 30 dias, com novas coletas de sangue e urina em cada uma dessas ocasiões. Os dados foram analisados no programa Excel e posteriormente exportados para o programa SPSS v. 20.0 para análise estatística. Para avaliar alterações entre as coletas e entre os graus de DP foi utilizado o modelo de Equações de Estimações Generalizadas, sendo considerado um nível de significância de 5%. Foi diagnosticado apenas um paciente com alteração em RPCU (0,18%) e um em creatinina (0,18%). Não foi encontrada relação estatisticamente significativa entre diferentes graus de DP, nem ao longo das coletas pré e pós profilaxia. Sendo assim, concluiu-se que os pacientes analisados não apresentaram alterações nos parâmetros laboratoriais estudados independente do nível de DP e da realização de profilaxia dentária. / Periodontal disease (PD) is an inflammatory disease of the tissues supporting the teeth, caused by specific microorganisms. It is reported that the incidence may be up to 100% in dogs from one year of age. PD is among the diseases related to glomerular alteration, proteinuria being its characteristic. Nephritic glomerulopathy is the most common type of glomerulonephropathy, being one of the major causes of cronic renal disease (CKD) in dogs. It is characterized by proteinuria, where the ratio of urinary protein / creatinine (UPC) in most cases is above 3.5, although it may be associated with hypoalbuminemia and signs of inflammation in the urinalysis. Azotemia is also present in different levels. Many studies are conducted to evaluate the relationship of PD with lesions in distant organs, but there is still no consensus among the results. The objective of the present study was to evaluate the possible relationship between PD, to different degrees, with values of UPC and serum creatinine. Twenty-five patients were attended at the Hospital de Clínicas Veterinárias do Rio Grande do Sul between August 2016 and January 2017. Of these, 18 met the inclusion criteria. All patients underwent general clinical examination, complete oral examination, blood tests (complete blood count, serum creatinine, urea, alkaline phosphatase - AL, alanine amino transferase – ALT and albumin), abdominal ultrasound, urinalysis and UPC. They were referred for dental prophylaxis where the degree of PD was established and the appropriate treatment was performed. The postoperative follow-up occurred at 10 and 30 days, with new collections of blood and urine at each of these occasions. The data were analyzed in the Excel program and later exported to the SPSS v. 20.0 for statistical analysis. In order to evaluate changes between the collections and between the DP degrees, the Generalized Estimates Equation model was used, and a significance level of 5% was considered. Only one patient with RPCU (0.18%) and serum creatinine (0.18%) were diagnosed. No statistically significant relationship was found between different degrees of PD nor during pre and post prophylaxis collections. Therefore, it is concluded that the patients analyzed did not present alterations in the renal parameters studied regardless of the level of PD and the performance of dental prophylaxis.

Made available in DSpace on 2016-08-19T18:16:07Z (GMT). No. of bitstreams: 1 Dissertacao Janeide.pdf: 1805392 bytes, checksum: 2720a3f24598c01180f7c7259186c12d (MD5) Previous issue date: 2012-07-31 / Introduction: Prevalence of glomerulopathies in a Teaching Hospital. Epidemiologic data on renal diseases based on populations are limited. A better view around the clinically significant glomerulonephritis can be acquired from diagnosis by renal biopsy. Objectives: To determine the prevalence of glomerulopathies, classify them according to the classification of the World Health Organization. Methods: Transversal descriptive study, based on medical records of biopsied patients as well as on their histopathological technical opinions of 409 renal biopsies, executed between january of 1999 and december of 2010 in Presidente Dutra School Medicine Hospital s Nephrology Service of the Universidade Federal do Maranhão (UFMA) Results: The most common glomerulopathy, both in adults and in patients under 20 years old, was segmental glomerulosclerosis and focal glomerulosclerosis (22%) and nephrotic syndrome was found as the most common glomerular syndrome at the moment of diagnosis, in patients of all ages. Most of the diagnoses occurred in patients between ages of 20 to 39 years old, corresponding to 42,05% of all biopsies, a number that decreases as patients are nearer to the extremities of life. There was a balance between sex distributions, but with a remarkable predominance of the female sex in lupus nephritis (88,60 %). Conclusion: The epidemiologic profile of glomerulopathies in a School Hospital in Maranhão resembled the ones found in national level. These data supply important bases to future studies on glomerulopathies in Maranhão. / Introdução: Prevalência das glomerulopatias em um Hospital Universitário. Dados epidemiológicos sobre as doenças renais com bases populacionais são limitados. Uma melhor percepção acerca do espectro das glomerulonefrites clinicamente significantes pode ser obtido através do diagnóstico por biópsia renal. Objetivos: Determinar a prevalência das glomerulopatias e classificá-las de acordo com Organização Mundial de saúde. Métodos: Estudo descritivo e transversal, com base nas informações dos prontuários dos pacientes biopsiados e dos respectivos laudos histopatológicos de 409 biópsias renais, realizadas entre janeiro de 1999 e dezembro de 2010 no Serviço de Nefrologia do Hospital Universitário da Universidade Federal do Maranhão (UFMA). Resultados: A glomerulopatia mais comum tanto em adultos quanto em menores de 20 anos foi a glomeruloesclerose segmentar e focal (22%) e a síndrome nefrótica apresentou-se como a síndrome glomerular mais comum no momento do diagnóstico, em todas as faixas etárias. A maior prevalência de diagnósticos ocorreu na faixa etária de 20 a 39 anos, correspondendo a 42,05% da biópsias, valor que decresce à medida que se aproxima dos extremos de vida. Houve um equilíbrio entre a distribuição por sexo, com predomínio do sexo feminino na nefrite lúpica (88,60%). Conclusão: O perfil epidemiológico das glomerulopatias em um Hospital Universitário no estado do Maranhão assemelhou-se aos demais achados nacionais. Esses dados fornecem bases importantes para futuros estudos sobre glomerulopatias no Maranhão.

Orientador: Priscylla Tatiana Chalfun Guimarães-Okamoto / Resumo: A doença renal crônica (DRC) em cães apresenta grande morbidade e alta taxa de mortalidade, sendo considerada a alteração renal mais comum, tendo a nefropatia glomerular como a alteração de maior prevalência. Este estudo tem por objetivo avaliar a prevalência das alterações glomerulares em conjunto com avaliação da razão proteína creatinina urinárias (RPC), dos níveis séricos de albumina e creatinina e pressão arterial sistólica comparando os parâmetros clínicos e laboratoriais entre o grupo de animais com a lesão predominante e o grupo abrangendo os demais tipos de lesões glomerulares que foram encontrados. Foram utilizados 24 cães com doença renal crônica que morreram. As lesões glomerulares foram classificadas segundo Cianciolo et al. (2013) por meio da análise histopatológica de tecidos renais corados pelas técnicas histoquímicas de hematoxilina e eosina, tricrômico de Masson, ácido periódico de Schiff e vermelho Congo. Foram inclusos animais com exames de urina com sedimento inativo, RPC, creatinina e albumina sérica. Para análise estatística foram utilizados os últimos valores obtidos antes do óbito, não excedendo o limite de quatro semanas. Não foi observado diferenças entre RPC, albumina e creatinina séricas e pressão arterial sistólica entre os animais com alteração membranosa e o grupo contendo os demais tipos de lesão glomerular encontrados em cães com DRC. Na DRC, independentemente do tipo de lesão glomerular, os parâmetros clínicos e laboratoriais avaliados neste... (Resumo completo, clicar acesso eletrônico abaixo) / Mestre

C3 glomerulopathy (C3G) encompasses a group of severe renal diseases characterized by “dominant C3” deposition in the renal glomerulus. Patients typically present as nephritic nephrotics, with hematuria, hypertension, heavy proteinuria and edema. Within ten years of diagnosis, 50% of affected patients progress to end-stage renal disease and require dialysis or renal transplantation. No treatment is available to halt disease progression and thus both disease recurrence and allograft loss are common after transplantation. Genetic studies of C3G have firmly implicated dysregulation of the alternative pathway (AP) of complement in disease pathogenesis. In addition to genetic factors, acquired factors like autoantibodies can also exaggerate AP activity in the circulation to cause C3G. Although AP dysregulation in the circulation (i.e. fluid-phase dysregulation) has been well studied in these patients, AP activity in the glomerular microenvironment is not well understood. In this body of work, we used MaxGel, an ex-vivo surrogate for the glomerular extracellular matrix, to study AP activity and regulation. We showed that C3 convertase can be assembled on MaxGel and elucidated the dynamics of its formation and decay in the presence of complement regulators. We confirm that on MaxGel factor H (fH) inhibits C3 convertase formation and accelerates its decay, while properdin has a stabilizing effect. We also show that the complement factor H-related proteins (FHRs) are vital to the regulation of AP activity. Consistent with our MaxGel data, CFHR gene-fusion events have been reported as genetic drivers of disease in a few familial cases of C3G. One such familial case in which we identified and characterized the rearrangement event results from a novel CFHR5-CFHR2 fusion gene. The fusion gene is translated into a circulating FHR-5/-2 protein that consists of the first two SCRs of FHR-5 followed by all four SCRs of FHR-2. The structural repetition of SCR1-2 followed by another SCR1-2 motif facilitates the formation of complex FHR-1, FHR-2 and FHR-5 multimers, which have enhanced affinity for C3b and by out-competing fH, lead to impaired C3 convertase regulation in the glomerular microenvironment. Finally, we tested gene therapy as a tool to rescue the disease phenotype and restore fluid-phase AP complement control in a mouse model of C3G (Cfh-/-/huCR1-Tg mice). Using the piggyBac transposon system, we introduced a construct derived from complement regulator 1 (CR1) into Cfh-/-/huCR1-Tg mice. Delivery of sCR1-AC via hydrodynamic tail vein injection provided constitutive circulatory expression of sCR1-AC, and in animals followed for 6 months, we found that long-term expression of this complement regulator rescued the renal phenotype. These results suggest that sCR1 may be a potential therapy for patients with this disease.

Identification of the complement C4d fragment in peritubular capillaries as a specific marker for antibody mediated rejection in renal transplantation revealed the critical role of antibodies in graft survival. In this thesis, I document the design and findings of studies performed to investigate the clinical impact of anti-HLA antibodies present before and/or after transplantation. Over time, the detection techniques for anti-HLA antibodies has evolved from the less sensitive complement-dependent lymphocytotoxicity (CDC) crossmatching (XM) to more sensitive solid phase assays such as Luminex®. Studies have been conducted to compare the predictive value of different antibody detection techniques. The first result chapter presents antibody specificity in positive CDC B-cell crossmatch (BXM), analysed with highly specific Luminex® assays. The study also investigates the predictive value of BXM in the general transplant population. I found that donor-specific anti-HLA antibodies (DSA) are only present in one third of positive BXM and are associated with poor outcomes. The novel finding is that >80% of the DSA detected by BXM are complement-fixing IgG₁ and IgG₃ subclasses. Transplant glomerulopathy (TG) is type of chronic renal graft rejection. The pathogenesis of TG is unclear. In the second result chapter, I report risk factors and involvement of anti-HLA antibodies in the development of TG. This study shows that glomerular rejection, delayed graft function, HLA presensitization and DSA have a univariate effect on TG development. Multivariate analysis revealed that DSA are an independent predictor of TG, after adjustment for other risk factors. I have further investigated the role of BXM in a unique, well-matched, highly sensitized patient group transplanted under the national renal exchange programme. I compared Luminex® antibody analysis with BXM in predicting transplant outcomes. In highly sensitized patients, DSA are found in two thirds of positive BXM. In univariate analyses, BXM is associated with humoral rejection whereas DSA defined by Luminex® are associated with total and all rejection types. The major finding is that, by multivariate analysis, DSA defined by Luminex® are an independent predictor of total and humoral rejection, but BXM are not. These interesting findings are reported in the third result chapter. Studies reported in this thesis define the clinical significance of anti-HLA antibodies in renal transplant outcomes. Method comparison studies provide useful information on antibody specificity and their impact on graft survival. Collectively, a better understanding of alloantibodies associated with graft rejection and limitation of antibody detection methods may facilitate donor selection and choice of immunosuppressants, and consequently improve transplant outcomes. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1379925 / Thesis (Ph.D.) - University of Adelaide, School of Medicine, 2010

A doença periodontal (DP) é uma doença inflamatória dos tecidos de suporte dos dentes, causada por microorganismos específicos. É relatado que a incidência possa ser de até 100% em cães a partir de um ano de idade. A DP está entre as doenças relacionadas com alteração glomerular, sendo a proteinúria sua característica. A glomerulonefrite é o tipo mais comum de glomerulonefropatia, sendo uma das maiores causas de doença renal crônica (DRC) em cães. É caracterizada por proteinúria, onde a relação proteína/creatinina urinária (RPCU), na maioria dos casos, encontra-se acima de 3,5, podendo estar associada com hipoalbuminemia e sinais de inflamação na urinálise. Azotemia também pode estar presente em diferentes níveis. Muitos estudos são realizados a fim de avaliar a relação da DP com lesões em órgãos distantes, porém ainda não há consenso entre os resultados. O objetivo do presente estudo foi avaliar a possível relação entre a DP, em diferentes graus, com alterações renais, por meio de aferição da RPCU e da creatinina sérica. Foram atendidos no Hospital de Clínicas Veterinárias da Universidade Federal do Rio Grande do Sul 25 pacientes entre agosto de 2016 e janeiro de 2017. Desses, 18 preencheram os critérios de inclusão. Todos os pacientes passaram por exame clínico geral, exame oral completo, exames de sangue (hemograma, creatinina, ureia, fosfatase alcalina - FA, alanina-amino-transferase – ALT e albumina), ultrassonografia abdominal, urinálise e RPCU. Foram encaminhados para profilaxia dentária onde foi estabelecido o grau de DP e realizado o tratamento adequado. O acompanhamento pós operatório deu-se aos 10 e aos 30 dias, com novas coletas de sangue e urina em cada uma dessas ocasiões. Os dados foram analisados no programa Excel e posteriormente exportados para o programa SPSS v. 20.0 para análise estatística. Para avaliar alterações entre as coletas e entre os graus de DP foi utilizado o modelo de Equações de Estimações Generalizadas, sendo considerado um nível de significância de 5%. Foi diagnosticado apenas um paciente com alteração em RPCU (0,18%) e um em creatinina (0,18%). Não foi encontrada relação estatisticamente significativa entre diferentes graus de DP, nem ao longo das coletas pré e pós profilaxia. Sendo assim, concluiu-se que os pacientes analisados não apresentaram alterações nos parâmetros laboratoriais estudados independente do nível de DP e da realização de profilaxia dentária. / Periodontal disease (PD) is an inflammatory disease of the tissues supporting the teeth, caused by specific microorganisms. It is reported that the incidence may be up to 100% in dogs from one year of age. PD is among the diseases related to glomerular alteration, proteinuria being its characteristic. Nephritic glomerulopathy is the most common type of glomerulonephropathy, being one of the major causes of cronic renal disease (CKD) in dogs. It is characterized by proteinuria, where the ratio of urinary protein / creatinine (UPC) in most cases is above 3.5, although it may be associated with hypoalbuminemia and signs of inflammation in the urinalysis. Azotemia is also present in different levels. Many studies are conducted to evaluate the relationship of PD with lesions in distant organs, but there is still no consensus among the results. The objective of the present study was to evaluate the possible relationship between PD, to different degrees, with values of UPC and serum creatinine. Twenty-five patients were attended at the Hospital de Clínicas Veterinárias do Rio Grande do Sul between August 2016 and January 2017. Of these, 18 met the inclusion criteria. All patients underwent general clinical examination, complete oral examination, blood tests (complete blood count, serum creatinine, urea, alkaline phosphatase - AL, alanine amino transferase – ALT and albumin), abdominal ultrasound, urinalysis and UPC. They were referred for dental prophylaxis where the degree of PD was established and the appropriate treatment was performed. The postoperative follow-up occurred at 10 and 30 days, with new collections of blood and urine at each of these occasions. The data were analyzed in the Excel program and later exported to the SPSS v. 20.0 for statistical analysis. In order to evaluate changes between the collections and between the DP degrees, the Generalized Estimates Equation model was used, and a significance level of 5% was considered. Only one patient with RPCU (0.18%) and serum creatinine (0.18%) were diagnosed. No statistically significant relationship was found between different degrees of PD nor during pre and post prophylaxis collections. Therefore, it is concluded that the patients analyzed did not present alterations in the renal parameters studied regardless of the level of PD and the performance of dental prophylaxis.

A doença periodontal (DP) é uma doença inflamatória dos tecidos de suporte dos dentes, causada por microorganismos específicos. É relatado que a incidência possa ser de até 100% em cães a partir de um ano de idade. A DP está entre as doenças relacionadas com alteração glomerular, sendo a proteinúria sua característica. A glomerulonefrite é o tipo mais comum de glomerulonefropatia, sendo uma das maiores causas de doença renal crônica (DRC) em cães. É caracterizada por proteinúria, onde a relação proteína/creatinina urinária (RPCU), na maioria dos casos, encontra-se acima de 3,5, podendo estar associada com hipoalbuminemia e sinais de inflamação na urinálise. Azotemia também pode estar presente em diferentes níveis. Muitos estudos são realizados a fim de avaliar a relação da DP com lesões em órgãos distantes, porém ainda não há consenso entre os resultados. O objetivo do presente estudo foi avaliar a possível relação entre a DP, em diferentes graus, com alterações renais, por meio de aferição da RPCU e da creatinina sérica. Foram atendidos no Hospital de Clínicas Veterinárias da Universidade Federal do Rio Grande do Sul 25 pacientes entre agosto de 2016 e janeiro de 2017. Desses, 18 preencheram os critérios de inclusão. Todos os pacientes passaram por exame clínico geral, exame oral completo, exames de sangue (hemograma, creatinina, ureia, fosfatase alcalina - FA, alanina-amino-transferase – ALT e albumina), ultrassonografia abdominal, urinálise e RPCU. Foram encaminhados para profilaxia dentária onde foi estabelecido o grau de DP e realizado o tratamento adequado. O acompanhamento pós operatório deu-se aos 10 e aos 30 dias, com novas coletas de sangue e urina em cada uma dessas ocasiões. Os dados foram analisados no programa Excel e posteriormente exportados para o programa SPSS v. 20.0 para análise estatística. Para avaliar alterações entre as coletas e entre os graus de DP foi utilizado o modelo de Equações de Estimações Generalizadas, sendo considerado um nível de significância de 5%. Foi diagnosticado apenas um paciente com alteração em RPCU (0,18%) e um em creatinina (0,18%). Não foi encontrada relação estatisticamente significativa entre diferentes graus de DP, nem ao longo das coletas pré e pós profilaxia. Sendo assim, concluiu-se que os pacientes analisados não apresentaram alterações nos parâmetros laboratoriais estudados independente do nível de DP e da realização de profilaxia dentária. / Periodontal disease (PD) is an inflammatory disease of the tissues supporting the teeth, caused by specific microorganisms. It is reported that the incidence may be up to 100% in dogs from one year of age. PD is among the diseases related to glomerular alteration, proteinuria being its characteristic. Nephritic glomerulopathy is the most common type of glomerulonephropathy, being one of the major causes of cronic renal disease (CKD) in dogs. It is characterized by proteinuria, where the ratio of urinary protein / creatinine (UPC) in most cases is above 3.5, although it may be associated with hypoalbuminemia and signs of inflammation in the urinalysis. Azotemia is also present in different levels. Many studies are conducted to evaluate the relationship of PD with lesions in distant organs, but there is still no consensus among the results. The objective of the present study was to evaluate the possible relationship between PD, to different degrees, with values of UPC and serum creatinine. Twenty-five patients were attended at the Hospital de Clínicas Veterinárias do Rio Grande do Sul between August 2016 and January 2017. Of these, 18 met the inclusion criteria. All patients underwent general clinical examination, complete oral examination, blood tests (complete blood count, serum creatinine, urea, alkaline phosphatase - AL, alanine amino transferase – ALT and albumin), abdominal ultrasound, urinalysis and UPC. They were referred for dental prophylaxis where the degree of PD was established and the appropriate treatment was performed. The postoperative follow-up occurred at 10 and 30 days, with new collections of blood and urine at each of these occasions. The data were analyzed in the Excel program and later exported to the SPSS v. 20.0 for statistical analysis. In order to evaluate changes between the collections and between the DP degrees, the Generalized Estimates Equation model was used, and a significance level of 5% was considered. Only one patient with RPCU (0.18%) and serum creatinine (0.18%) were diagnosed. No statistically significant relationship was found between different degrees of PD nor during pre and post prophylaxis collections. Therefore, it is concluded that the patients analyzed did not present alterations in the renal parameters studied regardless of the level of PD and the performance of dental prophylaxis.

Hyperacute renal failure is rarely the initial presentation of systemic lupus erythematosus (SLE). Pregnancy can predispose untreated lupus nephritis to acute renal failure. Collapsing glomerulopathy (CG) type of renal failure is not a new clinicopathological entity. There have been documented cases prior to 1979. It is thought that detection bias coupled with the predilection for HIV has caused this form of glomerulopathy to be incorrectly named or diagnosed as 'malignant focal segmental glomerulosclerosis (FSGS)'. This is a case of CG described in lupus nephritis. We present a case of untreated lupus in a female in whom pregnancy triggered the exacerbation of lupus nephritis that presented as collapsing glomerulopathy.

De façon physiologique, la voie alterne (VA) du complément est activée en permanence. Elle doit donc être finement régulée à tous les niveaux de la cascade afin de ne pas être délétère pour l'hôte. Chez l'homme, deux pathologies rénales sont associées à une activation non contrôlée de la VA du complément: le syndrome hémolytique et urémique atypique et la glomérulopathie à dépôts de C3 (GP-C3). Pathologie du sujet jeune essentiellement, la GP-C3 regroupe deux entités, la maladie des dépôts denses (GN-DD) et la glomérulonéphrite à dépôts de C3 (GN-C3), d'expressions clinique et histologique hétérogènes et toutes les deux de pronostic rénal réservé en l’absence de traitement efficace disponible (médiane de survie rénale de l’ordre de 8 à 10 ans). Les anomalies de la VA du complément mises en évidence dans la GP-C3 sont essentiellement acquises en rapport avec la présence d'auto anticorps (Ac) dirigés contre la C3 convertase alterne, le C3NeF, ou contre le FH, une protéine régulatrice essentielle de la VA. Dans 15 à 20% des cas seulement, les anomalies sont génétiques en rapport avec des mutations du FH, du FI. Les approches in silico de modélisation moléculaire des protéines mutées apportent des éléments de réponse quant à la responsabilité potentielle d'une mutation dans l’activation non contrôlée de la VA, néanmoins, l'étude des conséquences fonctionnelles est indispensable pour relier l'anomalie à la survenue de la pathologie rénale mais aussi pour comprendre les mécanismes précis impliqués dans le déterminisme des lésions rénales, de GN-DD ou de GN-C3. J'ai dans un premier temps étudié les conséquences fonctionnelles de la première mutation de C3 identifiée dans une forme familiale de GN-C3. In silico, cette mutation I734T est située au niveau d'un site impliqué dans la liaison de C3 avec deux protéines régulatrices, le FH et CR1 et à proximité du site d’interaction avec le FB. In vitro, j'ai pu confirmer que la mutation était responsable d'une activation de la VA au niveau tissulaire en rapport avec un défaut induit de régulation par le FH mais surtout CR1, une protéine régulatrice membranaire, identifié pour la première fois comme acteur dans la physiopathologie de la GP-C3. Par ailleurs, en raison de l'expression exclusivement podocytaire de CR1 au niveau glomérulaire, nous avons émis l'hypothèse que les régulateurs pouvaient jouer un rôle déterminant dans la localisation préférentielle des dépôts de C3 au niveau glomérulaire dans cette pathologie. Dans une deuxième partie, à la fois clinique et expérimentale, j'ai travaillé sur les formes acquises de GP-C3 en étudiant un sous-groupe particulier de patients de la cohorte française de GP-C3, âgés de plus de 50 ans et présentant une gammapathie monoclonale. La partie clinique de ce travail a permis de démontrer que la fréquence des gammapathies monoclonales est très nettement augmentée dans la GP-C3 chez les patients âgés de plus de 50 ans comparée à la population générale, que le pronostic rénal est particulièrement sombre avec une médiane de survie rénale de l’ordre de 2 ans et demi mais que le traitement efficace du clone B sous-jacent permet d'améliorer significativement la survie rénale. Les données de l’étude clinique suggèrent indirectement qu’il existe un lien entre l'immunoglobuline (Ig) monoclonale et l'activation de la VA responsable de l'apparition des lésions rénales. Dans la partie expérimentale, j'ai étudié les mécanismes d'activation de la VA dans ce contexte de gammapathie afin de confronter les données de l’étude clinique. L'étude des biomarqueurs d'activation de la C3/C5 convertase et le démembrement des mécanismes d'activation ont permis de conclure que la GP-C3 associée aux gammapathies monoclonales est caractérisée par une activation tissulaire de la VA impliquant la C3 convertase mais aussi et surtout la C5 convertase. (...) / Complement alternative pathway is physiologically activated. It need to be tightly regulated to avaoid uncontrolled deleterious overactivation on host cell surface. In human, two renal diseaes are associated with uncontrolled AP activation, hemolytic uremic syndrom atypical (aHUS) and C3 glomerulopathy (C3G). C3G occures mainly in children and young adults and regoups two distinct histopathological entities, dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). Renal outcomes in C3G is poor since up to 50% of patients reach end stage renal disease 8 to 10 years after diagnosis. Complement abnormalities in C3G are mainly acquired induced by the presence of C3 Nephritic Factor (C3NeF): an autoantibdy targeting the AP C3 convertase. Less frequently C3G patients have anti-FH autoantibodies (Ref) or genetic abnormalities (variants in the FH, FI or CFHR5 genes. In silico analysis of mutated proteins give information about the role of mutation on AP overactivation. However, characterization of functional consequences of these mutations is required to proved the direct link between the abnormality and the occurrence of C3G. I first studied the functional consequences of the first C3 mutation, C3I734T, identified in a familial C3GN. In silico analysis revealed that the mutated residue, T734, is located on the C3 and C3b protein surface and that the substitution I734T may not be associated with major structural changes. The mutated amino acid is located on interaction site between C3b and complement regulatory proteins, FH and CR1. In vitro, the major defect of C3I734T was a decrease in binding to CR1, resulting in lower CR1 dependent cleavage of C3b by FI. These results provide evidence for a CR1 functional deficiency being responsible for deficient complement regulation. Binding of C3I734T to Factor H (FH) was normal, but C3I734T was less efficiently cleaved by Factor I, leading to enhanced C3 fragments binding on glomerular cells. In the second part of my work, I studied acquired C3G in patients with concomitant monoclonal gammopathy. In the clinical part of this study, we demonstrated The high prevalence of monoclonal gammopathy in C3G patients aged over 50, reaching 65% in the French C3G national cohort, strongly suggests a pathogenic link between the two conditions. Next, we demonstrated that renal outcomes is significantly worser in patients with monoclonal gammopathy compared to patients without monoclonal gammopathy but that efficient chemotherapy resulted in higher renal response rate and longer renal survival than conservative or immunosuppressive therapy. Results of the clinical part of the study strongly suggest a link betwwen the monoclonal gammopathy and the occurrence of C3G. In the experimental part of this work, I studied the mechanisms of complement AP activation in these population. Biomarkers of C3 and C5 convertase activation were present 40% and 81% of patients respectively. Anti-complement protein antibodies were found in 23/41 (56%) patients, including in most of patients, anti-FH and anti-CR1 antibodies. I found new antigenic target, C5 and properdin in few cases. The anti-FH and anti-CR1 antibodies were associated with clear functional consequences. Nevertheless, the anti-complement proteins reactivity was not carried out by the MIg in 75% of the cases. I discovered that the MIg induced a direct AP C3 convertase overactivation in 23/34 (67%) patients responsaible for a C5 convertase overactivation in presence of patients’ Ig, in a properdin dependant manner. Our results suggest that MIg and polyclonal autoantibodies could act in synergy: AP overactivation induced by the MIg could be amplified by the inefficient complement regulation, caused by the polyclonal anti-complement autoantibodies. All my results allow to better understand the pathophysiological mechanisms involved in C3G and open up reflection on therapeutic approaches for C3G associated with monoclonal gammopathy.