Continuous indices to assess the phenotypic spectrum of kidney transplant rejection

The Banff classification for kidney transplant pathology dichotomizes the rejection continuum into distinct diagnostic categories, introducing artificial cutoff points and threshold effects. To better reflect the underlying disease spectrum, in this cohort study of 19,500 biopsies from 8873 patients across 10 centers worldwide, we developed two indices for quantifying antibody-mediated rejection/microvascular inflammation and T-cell-mediated rejection/tubulointerstitial inflammation from histological lesion scores and calculated indices for overall activity and chronicity. These indices demonstrate excellent discrimination for the main diagnostic categories of rejection (AUCs from 0.95 to 0.99), with consistent performance across derivation and validation datasets. These indices strictly confine intermediate phenotypes to low index values and are associated to graft failure even within the diagnostic categories, thus reflecting the underlying rejection continuum. In this work, we demonstrate that four continuous indices provide implementable and interpretable global evaluation of kidney transplant histology that align with the continuous nature of the rejection process regardless of the underlying disease cause.