*Purpose: BK Polyomavirus nephropathy (BKVN) is an important cause of dysfunction and failure of renal transplants. Elevated levels of donor-derived cell-free DNA (dd-cfDNA) in the urine of renal allograft recipients indicates organ injury. Tubular epithelium infected by BK virus leads to BKVN. The earliest clinical manifestation of BKVN was characterized by BK viruria, especially >10⁷ copies /ml. This study assessed the combined use of dd-cfDNA and BKV DNA loads in the urine to diagnose BKVN.

*Methods: Donor-derived cell-free DNA was assayed in 40 urine samples with paired BKV DNA loads in the urine (>10⁷copies/ml). Eighteen (45%) cases met criteria for definitive BKVN. Ten (25%) cases met criteria for resolving BKVN. Twelve (30%) cases are BKV-infection only (non-BKVN). Performance characteristics of dd-cfDNA for diagnosis of definitive BKVN were determined for samples at graft biopsy, and ddcfDNA quantification through Target Region Capture Sequencing and reads calculated by Maximum Likehood Estimation (MLE).

*Results: The absolute quantification of ddcfDNA in 40 urine samples is 7.9±5.5 ng/ml. The mean level of absolute quantification of ddcfDNA (14.35ng/ml) in definitive BKVN group is significant higher than in resolving BKVN group (4.90ng/ml, P=0.0056) and non-BKVN group (6.44ng/ml, P=0.025). But there is no significant difference between resolving BKVN group and non-BKVN group (P=0.202). There was not significant difference observed in application of relative ddcfDNA quantitative method. There is no difference in urinary BKV loads among 3 groups (median 2.9×10⁸ vs 3.5×10⁷ vs 1.4×10⁸ copies/ml, P=0.284). Plasma BKV loads in definitive BKVN group (median, 3000 copies/ml) is significantly higher than resolving BKVN group (median, 0 copies/ml, P=0.015) and non-BKVN group (median, 0 copies/ml, P=0.003). Mean serum creatinine level in definitive BKVN group (223.5±114.9 μmol/L) is slightly higher than resolving BKVN group (182.9±70.9 μmol/L, P=0.186), but is significantly higher than non-BKVN group (130.7±39.4 μmol/L, P=0.014). The receiver operating characteristic analysis by combining urinary dd-cfDNA and BK viruria (>10⁷copies/ml) reveals that the optimal cut-off is 10.2 ng/ml to detect BKVN, with high sensitivity (55.6%), specificity (92.3%), and area under the ROC curve (0.759).

*Conclusions: The combined use of absolute quantification of dd-cfDNA and BK viruria (>10⁷copies/ml) testing may improve the noninvasive diagnosis of definitive BKVN in kidney transplant recipients. Patients with dd-cfDNA+/ BK viruria (>10⁷copies /ml) have a high probability of definitive BKVN.

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