title: Proliferative glomerulonephritis secondary to dysfunction of the alternative pathway of complement.
abstract: OBJECTIVE
  dense deposit disease (DDD) is the prototypical membranoproliferative glomerulonephritis (MPGN), in which fluid-phase dysregulation of the alternative pathway (AP) of complement results in the accumulation of complement debris in the glomeruli, often producing an MPGN pattern of injury in the absence of immune complexes. A recently described entity referred to as GN with C3 deposition (GN-C3) bears many similarities to DDD. The purpose of this study was to evaluate AP function in cases of GN-C3.
  
  
  METHODS
  Five recent cases of MPGN with extensive C3 deposition were studied. Renal biopsy in one case exhibited the classic findings of DDD. Three cases showed GN-C3 in the absence of significant Ig deposition; however, the classic hallmark of DDD-dense deposits along the glomerular basement membranes and mesangium-was absent. The remaining case exhibited features of both DDD and GN-C3.
  
  
  RESULTS
  Evidence of AP activation was demonstrable in all cases and included increased levels of soluble membrane attack complex (all cases), positive AP functional assays (four cases), and a positive hemolytic assay (one case). Autoantibodies were found to C3 convertase (two cases) and to factor H (one case). Factor H mutation screening identified the H402 allele (all cases) and a c.C2867T p.T956M missence mutation (one case). Laser microdissection and mass spectrometry of glomeruli of GN-C3 (two cases) showed a proteomic profile very similar to DDD.
  
  
  CONCLUSIONS
  These studies implicate AP dysregulation in a spectrum of rare renal diseases that includes GN-C3 and DDD.
authors.affiliation: Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA. sethi.sanjeev@mayo.edu
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Sethi
authors.forename: Fernando C
authors.initials: FC
authors.lastname: Fervenza
authors.forename: Yuzhou
authors.initials: Y
authors.lastname: Zhang
authors.forename: Samih H
authors.initials: SH
authors.lastname: Nasr
authors.forename: Nelson
authors.initials: N
authors.lastname: Leung
authors.forename: Julie
authors.initials: J
authors.lastname: Vrana
authors.forename: Carl
authors.initials: C
authors.lastname: Cramer
authors.forename: Carla M
authors.initials: CM
authors.lastname: Nester
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
mesh_terms: D000328:Adult; D000368:Aged; D001485:Basement Membrane / Q000276:immunology / Q000473:pathology; D001706:Biopsy; D002648:Child; D003176:Complement C3 / Q000235:genetics / Q000276:immunology*; D003178:Complement C3 Nephritic Factor / Q000276:immunology*; D011415:Complement Factor B / Q000235:genetics / Q000276:immunology; D017242:Complement Factor H / Q000235:genetics / Q000276:immunology; D015938:Complement Membrane Attack Complex / Q000235:genetics / Q000276:immunology; D003170:Complement Pathway, Alternative / Q000235:genetics / Q000276:immunology*; D005500:Follow-Up Studies; D005920:Glomerular Mesangium / Q000276:immunology / Q000473:pathology; D015432:Glomerulonephritis, Membranoproliferative / Q000145:classification / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000276:immunology / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D003176:Complement C3; D003178:Complement C3 Nephritic Factor; D015938:Complement Membrane Attack Complex; D017242:Complement Factor H; D011415:Complement Factor B