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

Abstract

Background and objectives Recent studies highlighting a role of C4d2 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 C4d2 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 C4d2 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, 28.2363.97 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.

The role of C4d deposition in the diagnosis of antibody-mediated rejection after lung transplantation

“…Antibodies bound to HLA on endothelial cells can engage Fc receptors on NK cells or macrophages and elicit antibody-dependent cellular cytotoxicity (22). However, in contrast to our findings, C4d-positive AMR after kidney transplantation is associated with worse allograft survival than C4d-negative AMR (23, 24). This raises the suspicion that the lack of C4d deposition in some cases in our cohort is a false negative due to methodological problems with the assay rather than complement-independent pathways.…”

Anti-C1s monoclonal antibody BIVV009 in late antibody-mediated kidney allograft rejection—results from a first-in-patient phase 1 trial

“…1,2 The concept of alloantibody-triggered CP activation as a trigger of rejection is indirectly supported by 2 clinical observations: (1) capillary C4d in antibody-mediated rejection (ABMR), a marker of intragraft CP activation, is an independent predictor of adverse (ABO-compatible) allograft survival, 3,4 and (2) C1q-fixing donor-specific antibodies (DSA) confer a greater risk of rejection and graft failure than non-C1q-fixing antibodies. 1,2 The concept of alloantibody-triggered CP activation as a trigger of rejection is indirectly supported by 2 clinical observations: (1) capillary C4d in antibody-mediated rejection (ABMR), a marker of intragraft CP activation, is an independent predictor of adverse (ABO-compatible) allograft survival, 3,4 and (2) C1q-fixing donor-specific antibodies (DSA) confer a greater risk of rejection and graft failure than non-C1q-fixing antibodies.…”

Acute Rejection Phenotypes in the Current Era of Immunosuppression: A Single-Center Analysis

“…If present, C4d positivity is considered to be very specific for ABMR 48,49 and has been associated with an adverse outcome. 50 In our study, 71% and 48% of biopsies, classified as ‘suspicious for acute/active ABMR’ and acute/active ABMR, were C4d negative, but showed at least moderate microvascular inflammation. This is an interesting finding.…”