Glomerulonefritis C3 en un paciente con síndrome de Alport: un caso raro

El síndrome de Alport es una entidad hereditaria que se produce principalmente por una mutación en los genes que codifican el colágeno tipo IV. Por otro lado, la glomerulonefritis C3 es una entidad rara que presenta un patrón de glomerulonefritis membranoproliferativa y su etiología se basa en un control anormal de la activación de la vía alternativa del complemento. A continuación se describe un caso de un paciente, de sexo masculino, que cursa con un síndrome nefrótico corticorresistente en el que se documenta un patrón de glomerulonefritis membranoproliferativa en la biopsia renal con depósitos de C3 en la inmunofluorescencia, asociada a una deleción heterocigota en el gen CFHR1 en el estudio genético de las proteínas reguladoras del complemento. Además, en el panel genético realizado por corticorresistencia se encuentra una variante COL4A5 asociada al síndrome de Alport ligado al X. Estas entidades pueden presentarse con un curso clínico diverso, pero al estar asociadas pueden acelerar la progresión a enfermedad renal crónica, por lo que se hace necesario hacer un seguimiento clínico más estricto.

Alport Syndrome is a hereditary entity that occurs mainly due to a mutation in the genes that encode type IV collagen. C3 glomerulonephritis is a rare entity with a pattern of membranoproliferative glomerulonephritis and its etiology is based on abnormal control of the activation of the alternative complement pathway. We describe a case of a male patient who presents with a corticosteroid nephrotic syndrome in which a pattern of membranoproliferative glomerulonephritis is documented in the renal biopsy with C3 deposits in the immunofluorescence, associated with a heterozygous deletion in the gene CFHR1 in the genetic study of complement regulatory proteins. Furthermore, a variant COL4A5 associated with X-linked Alport syndrome is found in the genetic panel for corticosteroid resistance. These entities can present with a diverse clinical course, but when associated they can accelerate progression to chronic kidney disease, which is why makes it necessary to do a more strict clinical follow-up.

Progress of C3 glomerulopathy / 国际儿科学杂志

C3 glomerulopathy is a rare disease of glomeruli mediated by abnormal activation of alternative complement pathway secondary to congenital genetic defects and acquired autoantibodies.Renal biopsy is the gold standard for diagnosing C3 glomerulopathy.C3 glomerulopathy encompasses both dense deposit disease and C3 glomerulonephritis.The main glomerular immunofluorescence staining is C3, with few or without immunoglobulins deposition, which is the obvious pathological feature.The clinical manifestations of C3 glomerulopathy are usually various, with limited detection methods and therapies and poor prognosis.This article mainly reviews the progress of C3 glomerulopathy in recent years, in order to improve clinical understanding of C3 glomerulopathy, and choose individualized therapy.

Pathology of C3 Glomerulopathy

C3 glomerulopathy is a renal disorder involving dysregulation of alternative pathway complement activation. In most instances, a membranoproliferative pattern of glomerular injury with a prevalence of C3 deposition is observed by immunofluorescence microscopy. Dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) are subclasses of C3 glomerulopathy that are distinguishable by electron microscopy. Highly electron-dense transformation of glomerular basement membrane is characteristic of DDD. C3GN should be differentiated from post-infectious glomerulonephritis and other immune complex-mediated glomerulonephritides showing C3 deposits.

Clinical and pathological characteristics of children with C3 glomerulopathy / 中华实用儿科临床杂志

Objective To investigate the clinicopathological features and treatment of children with C3 glomerulopathy (C3 G).Methods Seven children diagnosed as C3 G by clinical and pathological characteristics were enrolled in this study.The clinicopathological data and the prognosis were analyzed.Results Of the 7 cases,4 cases were female and 3 cases were male,with the mean age of (7.7-± 3.1) years old (1.5-10.4 years old) at onset,the duration from onset to renal biopsy was (3.4 ± 2.4) months (1-6 months) and 1 of them had a second renal biopsy 4.2 years later,and mean age was (8.4 ± 3.6) years old (1.8-13.3 years old) on diagnosis.Clinical features:among the 7 patients,6 cases had hematuria,among them 1 case had gross hematuria and 5 cases had microscopic hematuria;6 cases had low level of serum complement C3,5 cases had heavy proteinuria and low serum albumin,and anemia was observed in 2 cases respectively.Five cases had complement factor H and H factor antibody by examination,and 1 of them had low serum factor H,but none of them had serum antibody to factor H.Four cases had genetic evaluation,and only 1 case revealed risk variants in the C3 gene(R304R,T612T,V807V,A915A,P1632P)and CFH gene(p.H402Y,p.E936D).Clinically,4 cases were diagnosed as nephrotic syndrome of nephritis type,2 cases were diagnosed as nephritic syndrome,and 1 case was diagnosed as nephrotic syndrome of simple type.Immunofluorescence study showed that all the cases had intense deposition of C3,and 6 cases were accompanied by the deposition of immunoglobulin.Under light microscopy,3 cases showed the feature of membrane proliferative glomemlonephritis,2 cases with endocapillary prolifera-tive glomerulonephritis,1 case with mesangial proliferative glomerulonephritis,and 1 case with endoeapillary proliferative IgA nephropathy.Under electron microscopy,3 cases who had typical ribbon-like dense deposits in glomerular basement membrane were of dense deposit disease,and the rest were C3 glomerulonephritis.All patients had steroid and immune inhibitor treatment,and during the follow-up stage of (2.6 ± 1.8) years(1.1-5.6 years),4 cases showed normal urinalysis,2 cases had microproteinurine and microscopic hematuria,and 1 case had urinary protein ± to + + and microscopic hematuria.Conclusions C3G has variety of pathological-clinical manifestation.Interpretation of individual cases depends on integration of information from the biopsy together with clinical,serological,and genetic features.Patients with steroid and immune inhibitor treatment had some clinical improvement of their urinalysis.

Glomerulonefritis C3: una nueva categoría de glomerulonefritis con implicaciones etiopatogénicas / C3 glomerulonephritis: a new category of glomerulonephritis with etiopathogenic implications / Glomerulonefrite C3: uma nova categoria de glomerulonefrite com envolvimentos etiopatogênicas

Introducción: las glomerulonefritis con depósitos exclusivos de la fracción C3 del complemento (GN-C3) pueden implicar alteración en la vía alterna de este. Objetivos: describir retrospectivamente una serie de casos de GN-C3 y determinar la frecuencia con que los pacientes continúan con alteraciones renales y/o hipocomplementemia. Métodos: se evaluaron las características histológicas y clínicas y la evolución de los 22 casos de GN-C3 diagnosticados entre 2004 y 2012 en el Departamento de Patología (Facultad de Medicina, Universidad de Antioquia). Resultados: 14 de los pacientes fueron niños y 12 fueron hombres; la mediana de edad fue de 13 años (rango: 3-65). Diez se presentaron como síndrome nefrítico, siete como GN rápidamente progresiva, tres como insuficiencia renal aguda, uno como insuficiencia renal crónica y uno como síndrome nefrótico-nefrítico; 21 tenían hipocomplementemia C3. Todas las biopsias mostraron GN proliferativa. Ocho pacientes tuvieron remisión completa; cuatro, alteraciones persistentes del uroanálisis; seis desarrollaron enfermedad renal crónica, en cinco de ellos terminal; en cuatro no hubo seguimiento. En nueve pacientes hubo seguimiento de los niveles séricos de C3 y en todos ellos se normalizaron entre 1 y 3 meses después de la biopsia. Conclusiones: las GN-C3 pueden producir alteraciones renales persistentes o recurrentes y evolucionar a la insuficiencia renal terminal. Es recomendable el seguimiento clínico a largo plazo, con mediciones repetidas de los niveles de C3.

Introduction: Glomerulonephritis with only deposits of C3 (GN-C3) could involve alteration on the complement alternative pathway. Objective: To describe retrospectively a series of GNC3 cases and to determine the frequency with which patients continue with renal alterations and/or hypocomplementemia. Methods: The 22 cases of GN-C3 diagnosed between 2004 and 2012 at the Department of Pathology, Faculty of Medicine, University of Antioquia (Medellin, Colombia) were included. Their histological and clinical characteristics and their outcome were evaluated. Results: 14 patients were children and 12 were males. Mean age was 13 years (range: 3-65). Ten presented as a nephritic syndrome, seven as a rapidly progressive GN, three as acute renal failure, one as chronic renal failure, and one as a nephrotic-nephritic syndrome. The C3 fraction of complement was low in 21 cases. All biopsies showed proliferative GN. There was complete remission in eight patients, persistent urinalysis alterations in four, chronic renal failure in six, five of them end-stage. No follow-up was done in four. In nine patients follow-up determination of C3 serum levels was done; in all of them they normalized between 1 to 3 months after biopsy. Conclusions: GN-C3 can produce persistent or recurrent kidney alterations and end-stage renal disease. Long-term follow-up with repeated determinations of C3 is advisable.

Introdução: as glomerulonefrite com depósitos exclusivos da fração C3 do complemento (GN-C3) podem implicar alteração na via alterna deste. Objetivos: descrever retrospectivamente uma série de casos de GN-C3 e determinar a frequência com que os pacientes continuam com alterações renais e/ ou hipocomplementemia. Métodos: avaliaram-se as características histológicas e clínicas e a evolução dos 22 casos de GN-C3 diagnosticados entre 2004 e 2012 no Departamento de Patologia (Faculdade de Medicina, Universidade de Antioquia). Resultados: 14 dos pacientes foram meninos e 12 foram homens; a média de idade foi de 13 anos (casta: 3-65). Dez se apresentaram como síndrome nefrítico, sete como GN rapidamente progressiva, três como insuficiência renal aguda, um como insuficiência renal crônica e um como síndrome nefrótico-nefrítico; 21 tinham hipocomplementemia C3. Todas as biopsias mostraram GN proliferativa. Oito pacientes tiveram remissão completa; quatro, alterações persistentes do uroanálise; seis desenvolveram doença renal crônica, em cinco deles terminal; em quatro não teve seguimento. Em nove pacientes teve seguimento dos níveis séricos de C3 e em todos eles se normalizaram entre 1 e 3 meses depois da biopsia. Conclusões: as GN-C3 podem produzir alterações renais persistentes.

Progress of C3 glomerulopathy / 中国小儿急救医学

C3 glomerulopathy is a group of diseases with immunofluorescence staining C3 along the glomerular capillary loops deposition,may be accompanied by other immunoglobulin deposition,but C3 sedi-mentary classic way was more than other immunoglobulin and complement activation ingredients ( such as C1q,C4). C3 glomerulopathy is a group of primary glomerular disease and relatively rare. This article mainly reviewed the pathological characteristic of C3 glomerulopathy,clinical manifestation,diagnosis and treatment, in order to improve clinical understanding of C3 glomerulopathy.

C3 glomerulopathy: Advances in diagnosis and treatment / 第二军医大学学报

C3 glomerulopathy is a recently defined disease category comprising several rare types of glomerulonephritis (GN), including dense deposit disease (DDD), C3 glomerulonephritis (C3GN), and CFHRS nephropathy. These disorders share a common etiology involving dysregulation of the complement alternative pathway (AP), with genetic defects and/ or autoantibodies seen in a proportion of patients. Currently no consistently effective therapy has been found for C3 glomerulopathy; clinical evaluation of agents targeting specific components of the complement system is undergoing. The appropriate timing and duration of proposed therapies need to be further explored. This review focuses on the clinical and histological features, complement tests and treatments of C3 glomerulopathy.

C3 glomerulonephritis in 7 children / 中华实用儿科临床杂志

Objective To analyze the clinical characteristics of 7 pediatric patients with C3 glomerulonephritis (C3-GN).Methods The clinical manifestations,pathological features,therapies,prognosis of patients from Jun.2006 to Nov.2011 were analyzed retrospectively.Results All of the patients were presented as acute nephritic syndrome,and 4 patients with macroscopic hematuria,other 3 cases with severe proteinuria.Five patients with eyelid edema.All the patients showed decreased level of serum complement C3,while serum complement C4 was normal.Investigations showed elevation of 24 h urine protein,5 patients with elevated antistreptolysin O titers.Three patients with renal dysfunction.Isolated C3 deposition in mesangial and endothelial areas(+ +-+ + +) was confirmed by immunofluorescence.Light microscope revealed membrane proliferative glomerulonephritis and mesangial proliferative glomerulonephritis.Electron microscope showed swelling and hyperplasia of endothelial cells without electron-dense deposition or podocyte foot fusion.Based on conventional treatment,administration of immunosuppressant was performed in 3 patients with severe pathological changes.After a follow-up of 2 months to 5 years,the prognosis seems to be benign.Conclusions Children with C3-GN are usually presented as acute nephritic syndrome,characterized by isolate C3 deposition in immunofluorescence.Electron microscope showed lesion of endothelial cells,while no electron-dense deposits in mesangial and endothelial areas.The mechanism may be associated with dysregulation of alternative complement pathway,and seems had a good short-term prognosis.

Pathology of C3 Glomerulonephritis

C3 glomerulonephritis (C3GN) is a recently described entity that shows a glomerulonephritis on light microscopy, bright C3 staining and the absence of C1q, C4, and immunoglobulins on immunofluorescence microscopy and mesangial and/or subendothelial electron-dense deposits on electron microscopy. The term 'C3 glomerulopathy' is often used to include C3GN and dense deposit disease (DDD), CFHR5 nephropathy, those of which result from dysregulation of the alternative pathway of complement. C3GN shares some aspects of atypical hemolytic uremic syndrome, MPGN, late stage of post infectious glomerulonephritis and other glomerulonephrtis. When C3GN is considered, measurement of serum complement proteins including C3, CFH, CFI, CFB and testing for the presence of C3 nephritic factor, anti-factor H autoantibodies are necessary. To screening for mutations, genes that encode complement regulators should be evaluated. This disorder equally affected all ages, both genders, and typically presented with hematuria and proteinuria. In both the short and long term, renal function remained stable in the majority of patients.