Continuous Transcriptomic Indices for Assessing the Spectrum of Kidney Transplant Rejection: International Derivation and Validation Study

Abstract Kidney allograft rejection is currently defined by categorical Banff histologic thresholds, despite reflecting a continuous spectrum of immune injury. Here we developed four continuous molecular indices capturing rejection severity and injury stage: antibody-mediated microvascular injury (AMR/MVI), T cell–mediated tubulointerstitial inflammation (TCMR/TI), inflammatory activity and chronic injury. Using transcriptomic profiling of formalin-fixed biopsies with the Banff Human Organ Transplant (B-HOT) panel, indices were trained against continuous histologic scores in 415 biopsies and validated in independent European and US cohorts (total N=2,076). Molecular indices accurately discriminated Banff phenotypes while revealing substantial within-category heterogeneity and clinically meaningful reclassification of intermediate cases. Elevated molecular scores in histologically rejection-free biopsies anticipated subsequent rejection. In multivariable Cox models, all four indices independently predicted five-year graft failure and improved prognostic discrimination beyond histology alone. These continuous molecular indices provide a quantitative framework that complements biopsy interpretation and refines risk stratification across the rejection spectrum.