The Clinical and Pathologic Phenotype of Antibody-Mediated Vascular Rejection Diagnosed Using Arterial C4d Immunoperoxidase

INTRODUCTION: The diagnosis of antibody-mediated vascular rejection (AM-VR) should be reliable and accurate. We hypothesized that arterial C4d (C4d(art)) immunoperoxidase deposition represents endothelial interaction with antibody. METHODS: From 3309 consecutive, kidney transplant biopsies from a single center, 100 vascular rejection (VR) cases were compared against rejection without arteritis (n = 540) and normal controls (n = 1108). The clinical utility of C4d(art) for diagnosis and classification of AM-VR was evaluated against an independent reference test. RESULTS: C4d(art) occurred in 20.4% of acute, 11.0% of subclinical, and 46% of VR episodes. Semiquantitative C4d(art) score significantly correlated with immunodominant donor-specific antibodies (DSAs) (rho = 0.500, P < 0.001), peritubular capillary C4d (C4d(ptc)), microvascular inflammation, and Banff v scores. Banff v3 arteritis suggested AM-VR. Addition of C4d(art) to Banff antibody-mediated rejection (AMR) schema increased diagnostic sensitivity for AM-VR from 57.9% to 93.0%, accuracy 74.0% to 92.0%, and specificity 95.4% to 90.2% versus Banff 2019 (using C4d(ptc)). Death-censored graft failure was associated with C4d(art) AM-VR criteria using Cox regression (adjusted hazard ratio [HR] 4.310, 95% CI 1.322–14.052, P = 0.015). VR was then etiologically classified into AM-VR (n = 57, including 36 mixed VR) or “pure” (TCM-VR, n = 43). AM-VR occurred within all post-transplant periods, characterized by greater total, interstitial, and microvascular inflammation, arterial and peritubular C4d, DSA levels, and graft failure rates compared with TCM-VR. Mixed VR kidneys had the greatest inflammatory burden and graft loss (P < 0.001). CONCLUSION: C4d(art) is a suggestive biomarker of the humoral alloresponse toward muscular arteries. Inclusion of C4d(art) into the Banff schema improved its diagnostic performance for detection of AM-VR and etiologic classification of arteritis.