Glomerulopatia membranosa: novos conhecimentos na fisiopatologia e possibilidades terapeuticas / Membranous glomerulonephritis: new insights in pathophysiology and therapeutic approach

Avanços dos conhecimentos moleculares na última década têm permitido a identificação de proteínas podocitárias que atuariam como alvos antigênicos na glomerulonefrite membranosa (GNM). Estudos envolvendo anticorpos contra estruturas podocitárias tem promovido o conceito autoimune da forma idiopática desta glomerulopatia. Neste contexto, o receptor de fosfolipase A2 do tipo M (PLA2R) tem merecido destaque como o primeiro e mais importante autoantígeno descrito na GNM idiopática humana. A presença do anticorpo anti-PLA2R tem sido destacada entre 70% e 89% de portadores da GNM idiopática, diferenciando das formas secundárias. Diversos estudos têm sugerido a detecção do anti-PLA2R como diagnóstico e apontado a correlação de seus níveis circulantes com a atividade clínica e resposta terapêutica. Entretanto, a coexistência de outros autoanticorpos sugere uma complexa via patogênica envolvendo diferentes antígenos podocitários. Estudos adicionais são necessários para esclarecer o tempo de aparecimento e o papel de cada anticorpo antipodócito no diagnóstico e progressão da GNM.

During the last decade, several major breakthroughs have led to the identification of human podocyte membrane antigens. Experimental involving antipodocyte antibodies in human membranous nephropathy (MN) have opened a new line of thinking about this disease, relating as an autoimmune kidney disease. In this setting, the M-type phospholipase A2 receptor (PLA2R) was identified as the first major antigen target in human primary MN. Studies have demonstrated anti-PLA2R antibodies against PLA2R ranging from 70 to 89% in patients with MN, but not in those with secondary MN. It has been suggested that the serum level of anti-PLA2R could be used for the diagnosis of idiopathic MN and for the monitoring of response to treatment. However, the coexistence of autoantibodies suggests a complex pathogenic pathway that involves different podocyte targets. New experimental models are needed to elucidate the appearance time and the role of each anti-podocyte antibody in MN development and progression.

Estructura de la barrera de filtración y sus alteraciones: Segunda parte / Glomerular filtration barrier structure and its alterations: Second part

La segunda parte de este trabajo tiene como objetivo principal, reafirmar conceptos vertidos en la primera parte yanalizar la fisiopatologia de algunas nefropatias que se originan en las alteraciones de la barrera de filtración glomerular (BFG). Si bien el podocito (P) ha ocupado el centro de la BFG,recientes estudios ontogenicos han demostrado que el endotelioglomerular tiene una función y estructura únicas en relación al resto del sistema endotelial del organismo,posee poros, en vez de fenestras y diafragmas; por lo tanto, es necesario, tener una visión mas integrada de la BFG. En el endotelio se han hallado dos factores de crecimiento: la angiopoietina 1 y 2 que son antagónicas e intervienenactivamente en algunas afecciones glomerulares. Someramente hemos analizado aspectos del ciclo celularmencionando algunas proteínas reguladoras en sentido positivo o negativo: las ciclinas y las kinasas respectivamente. Ante una agresión pueden responder positivamentey mantener la integridad de la BFG o desembocar en diversos tipos de nefropatias. El sistema renina angiotensina se expresa en los podocitosy, en el endotelio, sus efectos son bastante conocidos pero aun no se sabe como actúan a nivel de la BFG. La nefropatia diabética (ND) fue considerada hace años como patología mesangial primaria y los borramientos de los foot procesess (FP) como secundarios a la proteinuria; sin embargo, en la actualidad, ha sido ampliamente reconocido el hecho de que la principal causa radica en los podocitos y su proteína la nefrina. En cuanto a la nefropatia membranosa MN se ha sugerido que la patogenia radica en una activación de los podocitospor la fracción del complemeto C5b-9.Los sindromes nefróticos cortico resistentes (SNCR) son causados por mutaciones recesivas del gen NPHS2 (podocina). En niños las mutaciones del gen MPHS1 expresan la nefrina, además de la podocina, laminina B2...

The main objective of this second part of the “Glomerular Filtration Barrier (GFB)” review is to highlight some concepts previously defined in the first part of this issue and to analyze current concepts regarding the pathophysiologyof some glomerular diseases derived from alterations in this barrier. Although the podocyte always dominated the focus of our attention, recent evidences derived from ontogenic analysis of the endothelial barrier encouraged us to build up an integrated vision of the GFB. It is widely recognized that the endothelial layer has unique features like those related to structural and functional characteristics –like thepresence of fenestrae and diaphragm- that are distinctive. Two endothelial-derived growth factors (angiotoietin1 and 2) have antagonistic functions and are believed to have a role in some glomerular diseases. We have already mentioned that some regulatory proteins,such as cyclines and proteases, are able to react to different stimuli by retaining the integrity of the GFB or otherwise inducing glomerular injury. Podocytes and endotelial cells also express components of the renin-angiotensin-system; whose effects on the GFBare incompletely recognized. The renal involvement in diabetes mellitus was considered until recently as a primary mesangial condition with the effacement of the foot processes as a consequence of the increased urine protein excretion. Nonetheless it has been amply recognized the involvement of the podocyteborne protein, nephrine. C5b-9-complement associated podocyte activation has been considered as responsible for the development ofmembranous nephropathy. Similarly, steroid-resistant nephrotic syndrome, in children was associated with autosomic recessive genes mutations encoding different proteins with deficit of nephrin,podocyn, laminin B-2, phospholipase C-e.; and in adult patients alteration of ACTN4 as well as in the TRPC6 calcium...

Mecanismos de lesao glomerular cronica / Mechanisms of glomerular chronic injury

Nos anos 80, Brenner e colaboradores demonstraram uma associacao estreita entre anomalias da hemodinamica glomerular, especialmente a hipertensao intracapilar, e o desenvolvimento de esclerose glomerular em varios modelos de lesao cronica. Essa relacao e analoga a conhecida associacao entre hipertensao sistemica e macrovasculopatias. Varios mecanismos, tais como a proliferacao celular, a lesao endotelial e a microtrombose intracapilar, podem ligar a hipertensao intracapilar ao processo de esclerose glomerular, estimulando por exemplo a proliferacao de celulas mesangiais e a producao de matriz mesangial. Futuros estudos sobre a interacao entre eventos mecanicos e celulares devem contribuir para a elucidacao desse complexo processo

Morphological pattern of glomerular diseases in patients with nephrotic syndrome in northern Pakistan

Nephrotic syndrome can result from a large number of glomerular lesions. The primary or idiopathic nephrotic syndrome is a condition which develops as a result of primary glomerular disorders of kidney. A study was carried out from May 1994 to June 1995 including all the renal biopsies of the cases presenting as nephrotic syndrome. Cases of nephrotic syndrome secondary to systemic disorders were excluded from the study. Out of 185 renal biopsies received during this period, cases of primary nephrotic syndrome were 58 [31.3%]. Sixty five% were male and thirty five% were female patients. Average age was twenty-seven years. Cases of membranoproliferative glomerulonephritis comprised 32.7%, lesions consistent with minimal change disease were 24.2%, mesangial proliferative glomerulonephritis 20.7%, focal segmental glomerulosclerosis 13.8% and membranous glomerulonephritis was seen in 8.6% of the cases. Lesions consistent with minimal change disease was the predominant finding in patients below 15 years of age [47.4%] Membra-noproliferative glomerulonephritis was seen predominantly in patients above 15 years of age [33.3%] rate

Glomerulonefrite em pediatria / Gomerulonephritis in children

Os autores apresentam uma apreciaçäo clínico-patológica das glomerulonefrites na infância, relatando sua experiência no HUPE-UERJ). 1) GN com lesäo mínima: 128 casos (54,7% pré-escolares e 67,9% do sexo masculino): com prognóstico muito bom. 2) Esclerose focal e segmentar: 37 casos, quatro em remissäo, 11 com SN em atividade, 16 evoluíram para IRC (sete óbitos) e seis näo foram acompanhados. 3) GN membranosa: 10 casos, quatro em remissäo, quatro com SN em atividade e dois foram perdidos do acompanhamento. 4) GN endoteliomesangial: 257 casos, todos evoluíram para cura embora 15,3% apresentassem complicaçöes graves. 5) GN mesangial: oito casos, dois em remissäo, três com SBN em atividade, um em IRC e dois óbitos. 6) GN crescêntica: 11 pacientes, sete estäo bem, um em IRC e três morreram. 7) GN membranoproliferativa: seis pacientes: um em remissäo, dois em IRC, dois com SN em atividade e um faleceu

Membranous glomerulonephritis and the nephrotic syndrome in a patient with Landry-Guillain-Barré-Strohl syndrome

Membranous glomerulonephritis and the nephrotic syndrome concurrent with the Miller-Fisher variant of the Landry-Guillain-Barré-Strohl syndrome (LGBS), acute post-infective polyneuritis, is reported in a 49-year-old man. The onset of heavy proteinuria coincided with the development of the neurological disturbance. While immunosuppressive therapy appeared to hasten improvemente in the neurological disease, no such improvemente occurred in the glomerulopathy