*Purpose: We aimed to identify urine-derived exosomal miRNAs as diagnostic biomarkers for antibody-mediated rejection (ABMR) after kidney transplantation.

*Methods: Exosomal miRNAs using differential ultracentrifugation were isolated in urine from 24 living kidney donors and 12 kidney transplant recipients with ABMR, 8 with T cell-mediated rejection (TCMR), 5 with BK virus nephropathy (BKVN), and 11 with no major abnormality (NOMOA) on for-cause biopsy. We characterized exosomes using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. In addition, miRNAs were analyzed using RNA sequencing to identify exosomal miRNA candidates in the discovery cohort. We also quantified the expression of miRNA candidates using RT-qPCR in a validation cohort which consists of 20 recipients with ABMR, 5 with TCMR, 8 with NOMOA, and 8 donors. The diagnostic potential of the exosomal miRNAs was evaluated by receiver operating characteristic (ROC) curves.

*Results: miR-221-3p, miR-455-3p, miR-126-3p, and miR-215-5p were significantly higher in the ABMR group compared with the NOMOA group. Furthermore, miR-221-3 and miR-215-5p were highly expressed in the allograft tissue with ABMR. Compared to each miRNA biomarker, the four combined exosomal miRNAs (miR-221-3p, miR-455-3p, miR-126-3p, miR-215-5p) improved the prediction performance determined by ROC curves in the validation set.

*Conclusions: Urinary exosomal miRNAs can be potent biomarkers for ABMR after kidney transplantation.

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