title: Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies.
abstract: Dense deposit disease and glomerulonephritis with isolated C3 deposits are glomerulopathies characterized by deposits of C3 within or along the glomerular basement membrane. Previous studies found a link between dysregulation of the complement alternative pathway and the pathogenesis of these diseases. We analyzed the role of acquired and genetic complement abnormalities in a cohort of 134 patients, of whom 29 have dense deposit disease, 56 have glomerulonephritis with isolated C3 deposits, and 49 have primary membranoproliferative glomerulonephritis type I, with adult and pediatric onset. A total of 53 patients presented with a low C3 level, and 65 were positive for C3 nephritic factor that was significantly more frequently detected in patients with dense deposit disease than in other histological types. Mutations in CFH and CFI genes were identified in 24 patients associated with a C3 nephritic factor in half the cases. We found evidence for complement alternative pathway dysregulation in 26 patients with membranoproliferative glomerulonephritis type I. The complement factor H Y402H variant was significantly increased in dense deposit disease. We identified one at-risk membrane cofactor protein (MCP) haplotype for glomerulonephritis with isolated C3 deposits and membranoproliferative glomerulonephritis type I. Thus, our results suggest a critical role of fluid-phase alternative pathway dysregulation in the pathogenesis of C3 glomerulopathies as well as in immune complex-mediated glomerular diseases. The localization of the C3 deposits may be under the influence of MCP expression.
authors.affiliation: Department of Nephrology, Hôpital Necker-Enfants Malades AP-HP, Paris, France. aude.servais@nck.ap-hop-paris.fr
authors.forename: Aude
authors.initials: A
authors.lastname: Servais
authors.forename: Laure-Hélène
authors.initials: LH
authors.lastname: Noël
authors.forename: Lubka T
authors.initials: LT
authors.lastname: Roumenina
authors.forename: Moglie
authors.initials: M
authors.lastname: Le Quintrec
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ngo
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Dragon-Durey
authors.forename: Marie-Alice
authors.initials: MA
authors.lastname: Macher
authors.forename: Julien
authors.initials: J
authors.lastname: Zuber
authors.forename: Alexandre
authors.initials: A
authors.lastname: Karras
authors.forename: François
authors.initials: F
authors.lastname: Provot
authors.forename: Bruno
authors.initials: B
authors.lastname: Moulin
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Grünfeld
authors.forename: Patrick
authors.initials: P
authors.lastname: Niaudet
authors.forename: Philippe
authors.initials: P
authors.lastname: Lesavre
authors.forename: Véronique
authors.initials: V
authors.lastname: Frémeaux-Bacchi
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D016022:Case-Control Studies; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D003176:Complement C3 / Q000378:metabolism*; D003178:Complement C3 Nephritic Factor / Q000235:genetics / Q000378:metabolism; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism; D017244:Complement Factor I / Q000235:genetics / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000235:genetics*; D003165:Complement System Proteins / Q000235:genetics* / Q000378:metabolism*; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005602:France; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005921:Glomerulonephritis / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy; D015432:Glomerulonephritis, Membranoproliferative / Q000235:genetics* / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy; D006239:Haplotypes; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D007678:Kidney Glomerulus / Q000276:immunology* / Q000473:pathology; D008297:Male; D051916:Membrane Cofactor Protein / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D051437:Renal Insufficiency / Q000235:genetics / Q000276:immunology; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; C497857:CD46 protein, human; C493495:CFH protein, human; D003176:Complement C3; D003178:Complement C3 Nephritic Factor; D051916:Membrane Cofactor Protein; D017242:Complement Factor H; D003165:Complement System Proteins; C493611:CFI protein, human; D017244:Complement Factor I