Molecular Classification Predicts Clinical Outcomes of Kidney Transplant Recipients With Microvascular Inflammation, Donor-specific Antibodies-negative and C4d-negative

BACKGROUND: Microvascular inflammation (MVI), donor-specific antibodies (DSAs)-negative and C4d-negative, was recently defined as a distinct phenotype by Banff 2022 and has been associated with adverse clinical outcomes. We have developed a model for rejection-related molecular classification of renal allograft biopsies using gene expression profiling of formalin-fixed paraffin-embedded renal biopsy tissue and evaluated its performance in patients with MVI. METHODS: Using this updated gene expression profiling-based multiclass model, we evaluated 138 biopsy specimens obtained from a large US transplant center, which included 42 biopsies diagnosed as MVI, DSA-negative, and C4d-negative. Clinical outcomes of patients in this MVI biopsy group were analyzed in relation to their molecular classifications. RESULTS: The molecular rejection classifications exhibited robust concordance with histology diagnoses of no rejection, antibody-mediated rejection, and T-cell-mediated rejection in this independent cohort, with concordance rates varying in each group from 85% to 93%. The molecular classification also showed a significant association with differential renal function and graft survival in the MVI, DSA-negative, and C4d-negative group. CONCLUSIONS: Our model demonstrates significant molecular differentiation among antibody-mediated rejection, T-cell-mediated rejection, and no rejection. In addition, our model classified MVI, DSA-negative, and C4d-negative samples into molecular subgroups associated with divergent clinical outcomes.