Urine Donor–Derived Cell-Free DNA Helps Discriminate BK Polyomavirus-Associated Nephropathy in Kidney Transplant Recipients With BK Polyomavirus Infection

Abstract

Background: Studies have shown that plasma donor-derived cell-free DNA (dd-cfDNA) can predict renal allograft antibody-mediated rejection. This study was performed to evaluate the value of urine dd-cfDNA concentration and dd-cfDNA fraction (%) for discriminating BK polyomavirus-associated nephropathy (BKPyVAN) in kidney transplant recipients with urinary BK polyomavirus (BKPyV) infection. Methods: In this retrospective single-center observational study, we enrolled kidney transplant recipients who were diagnosed with urine BKPyV infection between August 2018 and May 2019 at the First Affiliated Hospital of Sun Yat-sen University. Urine dd-cfDNA was measured by using a novel target region capture sequencing methodology. The pathological diagnosis of BKPyVAN was confirmed by anti-SV40-T immunohistochemical staining and classified using the American Society for Transplantation schema. Receiver operating characteristic curve analysis was used to investigate the relations of urine dd-cfDNA and dd-cfDNA% to intrarenal allograft BKPyV infection states. Results: In total, 93 patients were enrolled, including 40 cases of proven BKPyVAN, seven cases of probable BKPyVAN, 23 cases of possible BKPyVAN, and 23 cases of resolving BKPyVAN. Urine dd-cfDNA level in proven BKPyVAN (22.09 ± 21.27 ng/ml) was comparable to that in probable BKPyVAN (15.64 ± 6.73 ng/ml, P = 0.434) but was significantly higher than that in possible BKPyVAN (5.60 ± 3.53 ng/ml) and resolving BKPyVAN (5.30 ± 3.34 ng/ml) (both Ps < 0.05). Urine dd-cfDNA% of proven BKPyVAN (0.71 ± 0.21) was lower than that of probable BKPyVAN (0.91 ± 0.04, P < 0.001), but was significantly higher than that of possible BKPyVAN (0.56 ± 0.30) and resolving Chen et al. Donor-Derived cfDNA in Kidney BKPyVAN BKPyVAN (0.46 ± 0.28) (both Ps < 0.05). For distinguishing biopsy-proven BKPyVAN from biopsy-excluded BKPyVAN, the discrimination capacity of urine dd-cfDNA (AUC: 0.842, 95% CI: 0.735, 0.918) was superior to that of plasma BKPyV DNA load (AUC: 0.660, 95% CI: 0.537, 0.769) with 0.181 (95% CI: 0.043, 0.319) difference between areas under ROC curves (P = 0.010). Conclusion: The elevated urine dd-cfDNA level may help discriminate BKPyVAN in kidney transplant recipients with BKPyV viruria.

Detection of BK polyomavirus-associated nephropathy using plasma graft-derived cell-free DNA: Development of a novel algorithm from programmed monitoring

“…Our results were consistent with those reported by Chen ( 13 ), that plasma GcfDNA (cp/mL) was more diagnostic efficient than GcfDNA percentage ( 9 , 26 ). With an AUC of 0.68 for pathologically proven BKPyVAN and an AUC of 0.62 for clinically diagnosed BKPyVAN, the ability of GcfDNA (cp/mL) at biopsy time to diagnose BKPyVAN was still relatively poor.…”

“…Chen et al reported that urine GcfDNA concentration in BKPyVAN was higher than that in T cellmediated rejection (TCMR), borderline change, and negative biopsies (12). Chen et al reported that elevated urine GcfDNA levels may help to distinguish BKPyVAN in kidney transplant recipients with BKPyV viruria (13). Kant et al suggested that GcfDNA may be a useful noninvasive test to assess progression of BKPyV to BKPyVAN (14).…”

“…Chen et al. reported that elevated urine GcfDNA levels may help to distinguish BKPyVAN in kidney transplant recipients with BKPyV viruria ( 13 ). Kant et al.…”

Levels of donor‐derived cell‐free DNA and chemokines in BK polyomavirus‐associated nephropathy

“…23 In addition, two recent studies have discussed a diagnostic value of dd-cfDNA and/or viral cfDNA in urine. 24,25 Beside quantification of dd-cfDNA, assessment of serum and urinary chemokines, in particular, C-X-C motif chemokine ligand (CXCL) 9…”

Current Status of Biomarkers and Molecular Diagnostic Tools for Rejection in Liver Transplantation: Light at the End of the Tunnel?

“…52 Another report of 93 renal transplant recipients showed that urinary dd cfDNA has the ability to distinguish acute rejection from viral infection with a sensitivity of 96%, specificity of 91%, and AUROC of 0.745 at a threshold of 0.84%. 53 This disparity may be explained by the ability of hepatocytes to have unlimited proliferation compared to stable cells as in renal parenchyma and cardiac muscle. Consequently, we see higher baseline levels of cfDNA in liver transplant recipients in the absence of hepatocyte damage.…”