title: Association of Serum C3 Concentration and Histologic Signs of Thrombotic Microangiopathy with Outcomes among Patients with ANCA-Associated Renal Vasculitis.
abstract: OBJECTIVE
  Complement alternative pathway (cAP) activation has recently been recognized as a key pathogenic event in ANCA-associated vasculitis (AAV). cAP dysregulation is also a major determinant of thrombotic microangiopathies (TMA), which can in turn complicate AAV. We explored the prognostic significance of cAP activation and of histologic evidence of TMA in a cohort of patients with renal AAV.
  
  
  METHODS
  We studied 46 patients with AAV diagnosed between January 1990 and December 2011 at the Nephrology Unit of Parma University Hospital; 30 of them had undergone renal biopsy. We analyzed serum levels of C3 (sC3) and C4 (sC4) and, for 19 patients who had frozen plasma, plasma Bb and C5b-9 levels. We also reviewed all kidney biopsy specimens, specifically searching for histologic signs of TMA, and performed immunofluorescence or immunohistochemistry for C3d, C4d, Bb and C5b-9.
  
  
  RESULTS
  sC3 was below the lower limit of normal in 35% of the patients, whereas C4 was low in only 2%. Patients with low sC3 tended to be older (P=0.04) and to have lower eGFR at diagnosis (P=0.06). The median follow-up was 78 months (interquartile range, 18-135 months); 18 patients reached ESRD (10 of 14 and 8 of 26 in the low and normal sC3 groups, respectively). Death-censored renal survival was lower in the low sC3 group than in the normal sC3 group (log-rank test, P=0.01). Eight of the 30 patients who had undergone biopsy (27%) had histologic signs of TMA; these signs were more frequent in patients with low sC3 (5 of 10 versus 3 of 20; P=0.04). Notably, patients with histologic signs of TMA had a dramatically worse death-censored renal survival than patients without TMA (log-rank test, P=0.01), with ESRD occurring in 8 of 8 patients with TMA versus 8 of 22 patients without TMA.
  
  
  CONCLUSIONS
  Low sC3 levels and histologic signs of TMA are associated with a poor renal prognosis in patients with AAV.
authors.affiliation: Nephrology Unit and lmanenti@hotmail.com.
authors.forename: Lucio
authors.initials: L
authors.lastname: Manenti
authors.affiliation: Nephrology Unit and.
authors.forename: Augusto
authors.initials: A
authors.lastname: Vaglio
authors.affiliation: Nephrology Unit and.
authors.forename: Elisa
authors.initials: E
authors.lastname: Gnappi
authors.affiliation: Nephrology Unit and.
authors.forename: Umberto
authors.initials: U
authors.lastname: Maggiore
authors.affiliation: Nephrology Unit and.
authors.forename: Landino
authors.initials: L
authors.lastname: Allegri
authors.affiliation: Nephrology Unit and.
authors.forename: Marco
authors.initials: M
authors.lastname: Allinovi
authors.affiliation: Nephrology Unit and.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Urban
authors.affiliation: Nephrology Unit and.
authors.forename: Marco
authors.initials: M
authors.lastname: Delsante
authors.affiliation: Nephrology Unit and.
authors.forename: Maricla
authors.initials: M
authors.lastname: Galetti
authors.affiliation: Nephrology Unit and.
authors.forename: Maria
authors.initials: M
authors.lastname: Nicastro
authors.affiliation: Pathology Department, University Hospital of Parma, Parma, Italy.
authors.forename: Francesco P
authors.initials: FP
authors.lastname: Pilato
authors.affiliation: Nephrology Unit and.
authors.forename: Carlo
authors.initials: C
authors.lastname: Buzio
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis / Q000097:blood / Q000150:complications* / Q000175:diagnosis / Q000276:immunology / Q000401:mortality; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D003167:Complement Activation; D003176:Complement C3 / Q000032:analysis*; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D005455:Fluorescent Antibody Technique; D006785:Hospitals, University; D006801:Humans; D007558:Italy; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000276:immunology* / Q000473:pathology; D007674:Kidney Diseases / Q000097:blood / Q000150:complications* / Q000175:diagnosis / Q000276:immunology / Q000401:mortality; D007676:Kidney Failure, Chronic / Q000175:diagnosis / Q000209:etiology / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D057049:Thrombotic Microangiopathies / Q000097:blood / Q000175:diagnosis / Q000209:etiology* / Q000276:immunology / Q000401:mortality; D013997:Time Factors
chemical_list: D015415:Biomarkers; C038245:C3 protein, human; D003176:Complement C3
keywords: CKD progression; anti-neutrophil cytoplasmic antibody-associated vasculitis antibodies, antineutrophil cytoplasmic biopsy kidney failure, chronic thrombotic microangiopathies; complement; vasculitis