Current problems of chronic active antibody-mediated rejection

The Banff 2007 classification allows chronic rejection to be differentiated based on clinicopathological characteristics evidenced by two independent immunologic mechanisms; chronic active antibody-mediated rejection and chronic active T-lymphocyte mediated rejection. However, several incompletely understood issues concerning chronic active antibody-mediated rejection remain. Chronic active antibody-mediated rejection is characterized by C4d deposition in the capillary basement membrane(PTC), the presence of circulating anti-donor antibodies(DSA), and morphologic evidence of chronic tissue injury such as glomerular double contours compatible with transplant glomerulopathy (TPG), PTC basement membrane multilayering, interstitial fibrosis/tubular atrophy, and fibrous arterial intimal thickening. PTC basement membrane multilayering correlates highly with TPG, and most of TPG have evidence of either C4d-positive staining or DSA. However, the proposed criteria do not apply to all situations of chronic active antibody-mediated rejection. C4d is not a magic marker for antibody-mediated rejection. C4d staining is not always highly sensitive for detecting antibody-mediated rejection. Multi-institutional studies should be conducted to better understand the clinicopathological context of chronic antibody-mediated rejection. These studies should include well-designed serial protocol biopsies with evaluation by electron microscopy, C4d staining performed on frozen sections, and assessment using sensitive DSA detection methods.