A molecular biopsy test based on arteriolar under‐hyalinosis reflects increased probability of rejection related to under‐immunosuppression

Calcineurin inhibitor immunosuppressive drugs induce changes such as arteriolar hyalinosis (ah) in kidney transplants, raising the possibility that molecular changes in biopsies related to histologic ah can provide information about drug exposure. We hypothesized that molecular changes associated with less‐than‐expected hyalinosis might highlight a subpopulation of patients with under‐immunosuppression/nonadherence at intermediate times of biopsy posttransplant (TxBx). Using gene expression data from 562 indication biopsies, we developed a molecular classifier for predicting the expected ah lesions (M ah ) at a particular TxBx. M ah ‐scores increased linearly with log(TxBx), but some biopsies had lower scores than expected for TxBx. The deviation of individual M ah ‐scores below the predicted regression line of M ah ‐scores vs TxBx is defined as “low hyalinosis index.” Low hyalinosis indices were frequent in biopsies between 3 months and 3 years posttransplant, particularly among biopsies lacking histologic hyalinosis (ah0), and were associated with T cell–mediated rejection and a subset of recent‐onset antibody‐mediated rejection without glomerular double contours. In patients with medical records available for review, low hyalinosis indices were frequently associated with physician‐recorded concerns about nonadherence (suspected or proven). We conclude that the M ah classifier and hyalinosis index identify indication biopsies with rejection for which the possibility of patient nonadherence should be considered.