Benchmarking urinary cell transcriptomes for noninvasive differentiation of BK polyomavirus-associated nephropathy from T cell-mediated rejection

To address this conundrum, we performed unbiased RNA sequencing of urinary cells matched to biopsies classified as BKVN with intragraft inflammation (BKVN-P), BKVN without inflammation (BKVN-N), TCMR, or no rejection (NR). BKVN-N displayed dominant host DNA replication, cell cycle, and repair programs, while BKVN-P samples exhibited expansive innate immune activation, antigen presentation, chemokine upregulation, and epithelial injury.

Both BKVN subtypes shared signatures of T cell exhaustion and mature and tolerogenic dendritic cell activation but differed in immune orientation—Th1 predominance in BKVN-N versus Treg and CD8 enrichment in BKVN-P. Compared to TCMR samples, BKVN-P lacked robust TCR/CD28 signaling and was enriched for viral and innate modules; BKVN-N lacked alloimmune activation. B cell exhaustion characterized BKVN-N, while BKVN-P displayed robust B cell activation with metabolic downregulation.