title: Association of C4d deposition with clinical outcomes in IgA nephropathy.
abstract: OBJECTIVE
  Several studies have suggested that activation of the complement system is a contributing pathogenic mechanism in IgA nephropathy (IgAN). C4d staining is an inexpensive and easy-to-perform method for the analysis of renal biopsies. This study aimed to assess the clinical and prognostic implications of C4d staining in IgAN.
  
  
  METHODS
  This retrospective cohort study included 283 patients with IgAN in 11 hospitals in Spain who underwent a renal biopsy between 1979 and 2010. The primary predictor was mesangial C4d staining. Secondary predictors included demographic, clinical, and laboratory characteristics, and Oxford pathologic classification criteria. The primary end point was the cumulative percentage of patients who developed ESRD, defined as onset of chronic dialysis or renal transplantation. C4d was analyzed by immunohistochemical staining using a polyclonal antibody. Kaplan-Meier and Cox proportional hazards analyses were performed to evaluate the effect of C4d staining on renal survival.
  
  
  RESULTS
  There were 109 patients (38.5%) and 174 patients (61.5%) who were classified as C4d positive and C4d negative, respectively. Renal survival at 20 years was 28% in C4d-positive patients versus 85% in C4d-negative patients (P<0.001). Independent risk factors associated with ESRD were as follows: proteinuria (hazard ratio [HR] per every 1 g/d increase. 1.16; 95% confidence interval [95% CI], 1.03 to 1.31; P=0.01), eGFR (HR per every 1 ml/min per 1.73 m(2) increase, 0.96; 95% CI, 0.94 to 0.97; P<0.001), T2 Oxford classification (tubular atrophy/interstitial fibrosis, >50%; HR, 4.42; 95% CI, 1.40 to 13.88; P=0.01), and C4d-positive staining (HR, 2.45; 95% CI, 1.30 to 4.64; P=0.01).
  
  
  CONCLUSIONS
  C4d-positive staining is an independent risk factor for the development of ESRD in IgAN. This finding is consistent with the possibility that complement activation is involved in the pathogenesis of this disease.
authors.affiliation: Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.
authors.forename: Mario
authors.initials: M
authors.lastname: Espinosa
authors.forename: Rosa
authors.initials: R
authors.lastname: Ortega
authors.forename: Marina
authors.initials: M
authors.lastname: Sánchez
authors.forename: Alfons
authors.initials: A
authors.lastname: Segarra
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Salcedo
authors.forename: Fayna
authors.initials: F
authors.lastname: González
authors.forename: Rafael
authors.initials: R
authors.lastname: Camacho
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Valdivia
authors.forename: Rocio
authors.initials: R
authors.lastname: Cabrera
authors.forename: Katia
authors.initials: K
authors.lastname: López
authors.forename: Fernando
authors.initials: F
authors.lastname: Pinedo
authors.forename: Eduardo
authors.initials: E
authors.lastname: Gutierrez
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valera
authors.forename: Miryam
authors.initials: M
authors.lastname: Leon
authors.forename: Maria Angeles
authors.initials: MA
authors.lastname: Cobo
authors.forename: Rosa
authors.initials: R
authors.lastname: Rodriguez
authors.forename: Jose
authors.initials: J
authors.lastname: Ballarín
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Arce
authors.forename: Beatriz
authors.initials: B
authors.lastname: García
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Muñoz
authors.forename: Manuel
authors.initials: M
authors.lastname: Praga
mesh_terms: D000328:Adult; D001706:Biopsy; D015935:Complement C4b / Q000032:analysis*; D018450:Disease Progression; D058625:End Stage Liver Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D005919:Glomerular Filtration Rate; D005922:Glomerulonephritis, IGA / Q000150:complications / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D006972:Hypertelorism / Q000150:complications; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000737:chemistry / Q000473:pathology*; D008297:Male; D050527:Mesangial Cells / Q000737:chemistry*; D008875:Middle Aged; D010446:Peptide Fragments / Q000032:analysis*; D011379:Prognosis; D011507:Proteinuria / Q000209:etiology; D012189:Retrospective Studies; D012307:Risk Factors; D055815:Young Adult
chemical_list: D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d
keywords: IgA nephropathy; complement; survival