Background: Early detection of subclinical alloimmune activity in histologically normal kidney allografts is essential for improving long-term graft outcomes. Prior studies suggest that subtle molecular alterations precede functional decline; however, independent validation and systematic assessment across multiple timepoints remain limited. Methods: We analyzed transcriptomic profiles derived from histologically normal 1-year surveillance biopsies in GSE181757, a public kidney transplant cohort including 97 progressors and 343 nonprogressors, with progression defined by decline in estimated glomerular filtration rate (eGFR). To evaluate robustness and temporal stability, we performed external validation using GSE25902, which includes protocol biopsies obtained at 0, 6, and 24 months from 24 recipients classified according to the Chronic Allograft Damage Index. Results: (AUC, 0.788), chemokine signatures (AUC, 0.799), and natural killer cell cytotoxicity (AUC, 0.799). Conclusions: Across two independent cohorts and multiple timepoints, histologically normal kidney allografts exhibited early and reproducible alloimmune activation that predicted subsequent injury. Immune pathway-level signatures outperformed individual genes and may support improved early risk stratification in kidney transplantation.
Filho et al. (Fri,) studied this question.