title: Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure.
abstract: BACKGROUND
  Late graft failure (LGF) is believed to be the consequence of immunologic and nonimmunologic insults leading to progressive deterioration in kidney function. We studied recipients with new onset late kidney graft dysfunction (n=173) to determine the importance of C4d staining and circulating donor-specific antibody (DSA) in subsequent LGF.
  
  
  METHODS
  One hundred seventy-three subjects transplanted before October 1, 2005 (mean time after transplant 7.3+/-6.0 years) had a baseline serum creatinine level of 1.4+/-0.3 mg/dL before January 1, 2006 and underwent biopsy for new onset graft dysfunction after that date (mean creatinine at biopsy 2.7+/-1.6 mg/dL). Statistical analysis was based on central DSA and blinded pathology determinations.
  
  
  RESULTS
  Subjects were divided into four groups based on C4d and DSA: no C4d, no DSA (group A; n=74); only DSA (group B; n=31); only C4d (group C; n=28); and both C4d and DSA (group D; n=40). Among DSA+ recipients (groups B and D), group D had broader reactivity and a stronger DSA response. After 2 years, groups C and D (C4d+) were at significantly greater risk for LGF than groups A and B. Adjusting for inflammation (Banff i, t, g, and ptc scores) did not change the outcome. Local diagnosis of calcineurin inhibitor nephrotoxicity was spread across all four subgroups and did not impact risk of LGF.
  
  
  CONCLUSIONS
  Evidence of antibody-mediated injury (DSA or C4d) is common (57%) in patients with new onset late kidney allograft dysfunction. The risk of subsequent graft failure is significantly worse in the presence of C4d+ staining.
authors.affiliation: Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. rgaston@uab.edu
authors.forename: Robert S
authors.initials: RS
authors.lastname: Gaston
authors.forename: J Michael
authors.initials: JM
authors.lastname: Cecka
authors.forename: Bert L
authors.initials: BL
authors.lastname: Kasiske
authors.forename: Ann M
authors.initials: AM
authors.lastname: Fieberg
authors.forename: Robert
authors.initials: R
authors.lastname: Leduc
authors.forename: Fernando C
authors.initials: FC
authors.lastname: Cosio
authors.forename: Sita
authors.initials: S
authors.lastname: Gourishankar
authors.forename: Joseph
authors.initials: J
authors.lastname: Grande
authors.forename: Philip
authors.initials: P
authors.lastname: Halloran
authors.forename: Lawrence
authors.initials: L
authors.lastname: Hunsicker
authors.forename: Roslyn
authors.initials: R
authors.lastname: Mannon
authors.forename: David
authors.initials: D
authors.lastname: Rush
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Matas
mesh_terms: D000328:Adult; D001706:Biopsy; D015935:Complement C4b; D003404:Creatinine / Q000097:blood; D005006:Ethnicity; D005260:Female; D006085:Graft Survival / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology; D006650:Histocompatibility Testing; D006801:Humans; D007111:Immunity, Cellular; D007518:Isoantibodies / Q000097:blood; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010446:Peptide Fragments / Q000097:blood; D016016:Proportional Hazards Models; D012307:Risk Factors; D014184:Transplantation, Homologous / Q000276:immunology / Q000473:pathology; D017211:Treatment Failure
chemical_list: D006680:HLA Antigens; D007518:Isoantibodies; D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d; D003404:Creatinine