title: Complement gene variants determine the risk of immunoglobulin-associated MPGN and C3 glomerulopathy and predict long-term renal outcome.
abstract: BACKGROUND
  Membranoproliferative glomerulonephritis (MPGN) is an uncommon cause of chronic nephropathy recently reclassified into immunoglobulin-associated MPGN (Ig-MPGN) and C3 glomerulopathy (C3G). In this study we aimed: (1) to evaluate the complement genetic and biochemical profile in patients with Ig-MPGN/C3G; (2) to investigate whether genetic variants and different patterns of complement activation (i.e., fluid versus solid phase) correlate with disease manifestations and outcomes.
  
  
  METHODS
  In 140 patients with idiopathic Ig-MPGN or C3G we performed complement biochemical and genetic screening and correlated genetic, biochemical and histology data with clinical features.
  
  
  RESULTS
  Mutations in genes encoding alternative pathway complement proteins were found in both Ig-MPGN and C3G, and mutations in the two components of the C3 convertase are the most prevalent. We also report a mutation in THBD encoding thrombomodulin in a C3G patient. The presence of mutations alone does not significantly increase the risk of Ig-MPGN or C3G, but it does so when combined with common susceptibility variants (CD46 c.-366A in Ig-MPGN; CFH V62 and THBD A473 in C3G). Finally, patients without complement gene mutations or C3NeFs--autoantibodies that stabilize the alternative pathway C3 convertase--have a higher risk of progressing to end-stage renal disease than patients with identified mutations and/or C3NeFs, suggesting the existence of different pathogenetic mechanisms that lead to renal disease.
  
  
  CONCLUSIONS
  We provide new insights into the pathogenesis of Ig-MPGN/C3G that underscore the complex nature of these diseases and suggest that the current C3G classification may miss many cases associated with abnormalities of the complement alternative pathway.
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, Italy.
authors.forename: Paraskevas
authors.initials: P
authors.lastname: Iatropoulos
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Mele
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Piras
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Valoti
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Bresin
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Curreri
authors.affiliation: Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Mondo
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Zito
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Gamba
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Bettoni
authors.affiliation: Unit of Pediatric Nephrology, Dialysis and Transplantation, Azienda Ospedaliera of Padova, Italy.
authors.forename: Luisa
authors.initials: L
authors.lastname: Murer
authors.affiliation: Department of Immunology, Assistance Publique-Hopitaux de Paris, Hopital Europeen George-Pompidou and INSERM UMRS 1138, Cordelier Research Center, Complement and Diseases Team, Paris, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Fremeaux-Bacchi
authors.affiliation: Division of Nephrology and Dialysis, Bambin Gesù Pediatric Hospital, Roma, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Vivarelli
authors.affiliation: Division of Nephrology and Dialysis, Bambin Gesù Pediatric Hospital, Roma, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Emma
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, Italy. Electronic address: erica.daina@marionegri.it.
authors.forename: Erica
authors.initials: E
authors.lastname: Daina
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, Italy; Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy; Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D000293:Adolescent; D003178:Complement C3 Nephritic Factor / Q000235:genetics; D003170:Complement Pathway, Alternative / Q000235:genetics*; D005260:Female; D005455:Fluorescent Antibody Technique; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015432:Glomerulonephritis, Membranoproliferative / Q000145:classification* / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007136:Immunoglobulins; D007676:Kidney Failure, Chronic / Q000209:etiology; D008297:Male; D060885:Multiplex Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D018180:Thrombomodulin / Q000235:genetics*; D055815:Young Adult
chemical_list: D003178:Complement C3 Nephritic Factor; D007136:Immunoglobulins; C546931:THBD protein, human; D018180:Thrombomodulin
keywords: C3 glomerulonephritis; C3 glomerulopathy; Dense-Deposit Disease; Membranoproliferative glomerulonephritis; Rare diseases