Capillary C4d and Kidney Allograft Outcome in Relation to Morphologic Lesions Suggestive of Antibody-Mediated Rejection

Clin J Am Soc Nephrol. 2015 Aug 7;10(8):1435-43. doi: 10.2215/CJN.09901014. Epub 2015 Jun 12.


Background and objectives: Recent studies highlighting a role of C4d- antibody-mediated rejection (ABMR) have debated whether C4d staining has independent value as a rejection marker. Considering the presumed role of complement as an important effector of graft injury, this study hypothesized that capillary C4d, a footprint of antibody-triggered complement activation, indicates a particularly severe manifestation of ABMR.

Design, setting, participants, & measurements: This large retrospective clinicopathologic study sought to assess the clinical predictive value of C4d staining in relation to ABMR morphology. Overall, 885 renal allograft recipients who underwent transplantation between 1999 and 2006 (median duration of follow-up, 63.3 [interquartile range, 40.6-93.5] months; 206 graft losses) were included if they had had one or more indication biopsies. A total of 1976 biopsy specimens were reevaluated for capillary C4d staining (C4d data were available for 825 patients) and distinct morphologic lesions suggestive of ABMR, including glomerulitis, peritubular capillaritis, capillary microthrombi, transplant glomerulopathy, and severe intimal arteritis.

Results: C4d+ patients, with or without ABMR features, had worse death-censored 8-year graft survival (53% or 67%) than C4d- patients (66% or 81%; P<0.001). In Cox regression analysis, C4d was associated with a risk of graft loss independently of baseline confounders and ABMR morphology (hazard ratio, 1.85 [95% confidence interval, 1.34 to 2.57]; P<0.001). The risk was higher than that observed for C4d- patients, a finding that reached statistical significance in patients showing fewer than two different ABMR lesions. Moreover, in a mixed model, C4d was independently associated with a steeper decline of eGFR (slope per year, -8.23±3.97 ml/min per 1.73 m(2); P<0.001).

Conclusions: These results suggest that detection of intragraft complement activation has strong independent value as an additional indicator of ABMR associated with adverse kidney transplant outcomes.

Keywords: C4d; antibody-mediated rejection; complement; kidney transplantation; transplant outcomes.

Publication types

  • Evaluation Study

MeSH terms

  • Adult
  • Allografts
  • Biomarkers / analysis
  • Biopsy
  • Capillaries / immunology*
  • Capillaries / pathology
  • Chi-Square Distribution
  • Complement Activation*
  • Complement C4b / analysis*
  • Female
  • Glomerular Filtration Rate
  • Graft Rejection / immunology*
  • Graft Rejection / mortality
  • Graft Rejection / pathology
  • Graft Rejection / physiopathology
  • Graft Survival
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Kidney / immunology*
  • Kidney / pathology
  • Kidney / physiopathology
  • Kidney Transplantation / adverse effects*
  • Kidney Transplantation / mortality
  • Male
  • Middle Aged
  • Peptide Fragments / analysis*
  • Predictive Value of Tests
  • Proportional Hazards Models
  • Retrospective Studies
  • Risk Factors
  • Time Factors
  • Treatment Outcome


  • Biomarkers
  • Peptide Fragments
  • Complement C4b
  • complement C4d