title: Defining the complement biomarker profile of C3 glomerulopathy.
abstract: OBJECTIVE
  C3 glomerulopathy (C3G) applies to a group of renal diseases defined by a specific renal biopsy finding: a dominant pattern of C3 fragment deposition on immunofluorescence. The primary pathogenic mechanism involves abnormal control of the alternative complement pathway, although a full description of the disease spectrum remains to be determined. This study sought to validate and define the association of complement dysregulation with C3G and to determine whether specific complement pathway abnormalities could inform disease definition.
  
  
  METHODS
  This study included 34 patients with C3G (17 with C3 glomerulonephritis [C3GN] and 17 with dense deposit disease [DDD]) diagnosed between 2008 and 2013 selected from the C3G Registry. Control samples (n=100) were recruited from regional blood drives. Nineteen complement biomarkers were assayed on all samples. Results were compared between C3G disease categories and with normal controls.
  
  
  RESULTS
  Assessment of the alternative complement pathway showed that compared with controls, patients with C3G had lower levels of serum C3 (P<0.001 for both DDD and C3GN) and factor B (P<0.001 for both DDD and C3GN) as well as higher levels of complement breakdown products including C3d (P<0.001 for both DDD and C3GN) and Bb (P<0.001 for both DDD and C3GN). A comparison of terminal complement pathway proteins showed that although C5 levels were significantly suppressed (P<0.001 for both DDD and C3GN) its breakdown product C5a was significantly higher only in patients with C3GN (P<0.05). Of the other terminal pathway components (C6-C9), the only significant difference was in C7 levels between patients with C3GN and controls (P<0.01). Soluble C5b-9 was elevated in both diseases but only the difference between patients with C3GN and controls reached statistical significance (P<0.001). Levels of C3 nephritic factor activity were qualitatively higher in patients with DDD compared with patients with C3GN.
  
  
  CONCLUSIONS
  Complement biomarkers are significantly abnormal in patients with C3G compared with controls. These data substantiate the link between complement dysregulation and C3G and identify C3G interdisease differences.
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories.
authors.forename: Yuzhou
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Division of Nephrology, Department of Internal Medicine, Division of Nephrology, Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa;
authors.forename: Carla M
authors.initials: CM
authors.lastname: Nester
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Department of Anatomy and Cell Biology, Graduate Program, and.
authors.forename: Bertha
authors.initials: B
authors.lastname: Martin
authors.affiliation: Laboratory of Molecular Medicine, Department of Clinical Immunology, Rigshospitalet, Faculty of Health Sciences, University Hospital of Copenhagen, Copenhagen, Denmark; and.
authors.forename: Mikkel-Ole
authors.initials: MO
authors.lastname: Skjoedt
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Meyer
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories.
authors.forename: Dingwu
authors.initials: D
authors.lastname: Shao
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories.
authors.forename: Nicolò
authors.initials: N
authors.lastname: Borsa
authors.affiliation: Department of Cancer and Inflammation, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.
authors.forename: Yaseelan
authors.initials: Y
authors.lastname: Palarasah
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Division of Nephrology, Department of Internal Medicine, Division of Nephrology, Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa; richard-smith@uiowa.edu.
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002648:Child; D003176:Complement C3 / Q000378:metabolism*; D003178:Complement C3 Nephritic Factor / Q000378:metabolism*; D015933:Complement C3d / Q000378:metabolism; D003182:Complement C5 / Q000378:metabolism*; D015936:Complement C5a / Q000378:metabolism; D003184:Complement C7 / Q000378:metabolism*; D011415:Complement Factor B / Q000378:metabolism*; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative / Q000097:blood* / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D015415:Biomarkers; D003176:Complement C3; D003178:Complement C3 Nephritic Factor; D003182:Complement C5; D003184:Complement C7; D015933:Complement C3d; D015936:Complement C5a; D011415:Complement Factor B
keywords: C3 glomerulopathy; C3GN; alternative pathway; complement; dense deposit disease