Introduction: Antibody-mediated rejection (ABMR) has well-defined histomorphological lesions, like  linear C4d staining or microvascular inflammation [(g + ptc) ≥ 2] in peritubular capillaries (PTCs). Although these histologic features of ABMR (ABMRh) are usually compatible with donor-specific antibodies (DSA), it is demonstrated that recipients can develop ABMRh in the absence of DSAs. Indeed, DSA can not be found in 40-60% of patients with marked microvascular inflammation (MVI). We aimed to investigate the relationship between PTC macrophage (M), neutrophil, and HLA-DR positive cell infiltration with variable clinical presentations of ABMR.

Methods: A total of 125 patients with acute ABMR were categorized into four groups; Group 1: DSA (+) ABMR, Group 2: DSA (-) ABMR, Group 3: DSA (+) mixed rejection (ABMR+vascular rejection), and Group 4: DSA (-) mixed rejection. The degree of the glomerular and PTC macrophage (CD68+), neutrophil, and HLA-DR positive cells was graded. The loss of HLA-DR expression in PTC endothelium was accepted as PTC destruction. The follow-up biopsies were evaluated for the development of diffuse interstitial fibrosis (IF) and transplant glomerulopathy (TG).

Results: The type of ABMR showed a significant correlation with PTC C4d expression, the presence of TMA, PTC destruction, microvascular (PTC and glomerular) macrophage, neutrophil, and DR+ cell infiltration (p<0.01 for all). Group 3 showed the highest microvascular inflammation, PTC destruction, C4d expression, and TMA. Groups 4, 1, and 2 followed Group 3, respectively, and Group 2 showed the best outcome. Also, patients in Group 3 developed the highest and earliest IF and TG development during follow-up (p<0.01). Similarly, Groups 4, 1, and 2 followed Group 3 regarding the development of IF and TG development. PTC C4d staining intensity significantly correlated with PTC destruction and DSA positivity (p<0.001). Overall 5-year graft survival was 86%, 51%, 45%, and 26% for Groups 2, 1, 4, and 3, respectively (p<0.001). Overall 5-year graft survival was 87%, 54%, and 20% for patients with grades 1, 2, and 3 PTC destruction, respectively (p<0.001). Additionally, overall 5-year survival was 100%, 81%, and 21% for grades 1, 2, and 3 C4d depositions in PTCs, respectively (P<0.001).

Conclusion: ABMRh comprising characteristic histologic findings without detectable DSA represent a distinct phenotype with superior renal allograft survival than ABMRh with positive DSA. Additionally, PTC C4d deposition and the resulting PTC destruction were shown to significantly indicate graft failure and poor prognosis independent of the DSA positivity. Therefore, we concluded that ABMR should be divided into different subgroups for treatment, considering the presence of DSA and vascular rejection.