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Journal of Zhejiang University SCIENCE B 2021 Vol.22 No.11 P.917-928


Urinary donor-derived cell-free DNA as a non-invasive biomarker for BK polyomavirus-associated nephropathy

Author(s):  Jia SHEN, Luying GUO, Wenhua LEI, Shuaihui LIU, Pengpeng YAN, Haitao LIU, Jingyi ZHOU, Qin ZHOU, Feng LIU, Tingya JIANG, Huiping WANG, Jianyong WU, Jianghua CHEN, Rending WANG

Affiliation(s):  Kidney Disease Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China; more

Corresponding email(s):   rd_wangjia@zju.edu.cn

Key Words:  Donor-derived cell-free DNA (ddcfDNA), BK polyomavirus-associated nephropathy (BKPyVAN), T cell-mediated rejection (TCMR), Urine, Differential diagnosis

Jia SHEN, Luying GUO, Wenhua LEI, Shuaihui LIU, Pengpeng YAN, Haitao LIU, Jingyi ZHOU, Qin ZHOU, Feng LIU, Tingya JIANG, Huiping WANG, Jianyong WU, Jianghua CHEN, Rending WANG. Urinary donor-derived cell-free DNA as a non-invasive biomarker for BK polyomavirus-associated nephropathy[J]. Journal of Zhejiang University Science B, 2021, 22(11): 917-928.

@article{title="Urinary donor-derived cell-free DNA as a non-invasive biomarker for BK polyomavirus-associated nephropathy",
author="Jia SHEN, Luying GUO, Wenhua LEI, Shuaihui LIU, Pengpeng YAN, Haitao LIU, Jingyi ZHOU, Qin ZHOU, Feng LIU, Tingya JIANG, Huiping WANG, Jianyong WU, Jianghua CHEN, Rending WANG",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Urinary donor-derived cell-free DNA as a non-invasive biomarker for BK polyomavirus-associated nephropathy
%A Luying GUO
%A Wenhua LEI
%A Shuaihui LIU
%A Pengpeng YAN
%A Haitao LIU
%A Jingyi ZHOU
%A Feng LIU
%A Tingya JIANG
%A Huiping WANG
%A Jianyong WU
%A Jianghua CHEN
%A Rending WANG
%J Journal of Zhejiang University SCIENCE B
%V 22
%N 11
%P 917-928
%@ 1673-1581
%D 2021
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2100131

T1 - Urinary donor-derived cell-free DNA as a non-invasive biomarker for BK polyomavirus-associated nephropathy
A1 - Jia SHEN
A1 - Luying GUO
A1 - Wenhua LEI
A1 - Shuaihui LIU
A1 - Pengpeng YAN
A1 - Haitao LIU
A1 - Jingyi ZHOU
A1 - Qin ZHOU
A1 - Feng LIU
A1 - Tingya JIANG
A1 - Huiping WANG
A1 - Jianyong WU
A1 - Jianghua CHEN
A1 - Rending WANG
J0 - Journal of Zhejiang University Science B
VL - 22
IS - 11
SP - 917
EP - 928
%@ 1673-1581
Y1 - 2021
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2100131

BK polyomavirus-associated nephropathy (BKPyVAN) is a common cause of allograft failure. However, differentiation between BKPyVAN and type I t cell-mediated rejection (TCMR) is challenging when simian virus 40 (SV40) staining is negative, because of the similarities in histopathology. This study investigated whether donor-derived cell-free DNA (ddcfDNA) can be used to differentiate BKPyVAN. Target region capture sequencing was applied to detect the ddcfDNAs of 12 recipients with stable graft function, 22 with type I TCMR, 21 with proven BKPyVAN, and 5 with possible PyVAN. We found that urinary ddcfDNA levels were upregulated in recipients with graft injury, whereas plasma ddcfDNA levels were comparable for all groups. The median urinary concentrations and fractions of ddcfDNA in proven BKPyVAN recipients were significantly higher than those in type I TCMR recipients (10.4 vs. 6.1 ng/mL, P<0.001 and 68.4% vs. 55.3%, P=0.013, respectively). Urinary ddcfDNA fractions (not concentrations) were higher in the BKPyVAN-pure subgroup than in the BKPyVAN-rejection-like subgroup (81.30% vs. 56.64%, P=0.025). With a cut-off value of 7.81 ng/mL, urinary ddcfDNA concentrations distinguished proven BKPyVAN from type I TCMR (area under the curve (AUC)=0.848, 95% confidence interval (95% CI): 0.734 to 0.963). These findings suggest that urinary ddcfDNA is a non-invasive biomarker which can reliably differentiate BKPyVAN from type I TCMR.


结论:在有移植物损伤时,患者尿液中ddcfDNA水平增加,而血浆中ddcfDNA无明显改变。病理证实BKPyVAN组尿液ddcfDNA的浓度和百分比的中位数均明显高于I型TCMR组(10.4 vs. 6.1 ng/mL,P<0.001;68.4% vs. 55.3%,P=0.013)。在单纯BKPyVAN亚组中,尿液ddcfDNA的百分比较BKPyVAN排斥样改变组升高明显(81.30% vs. 56.64%,P=0.025),而ddcfDNA的浓度则无明显升高。尿液ddcfDNA浓度7.81 ng/mL可作为区分病理证实BKPyVAN和I型TCMR的阈值(AUC=0.848,95%置信区间:0.734-0.963)。


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[1]Agbor-EnohS, TuncI, de VlaminckI, et al., 2017. Applying rigor and reproducibility standards to assay donor-derived cell-free DNA as a non-invasive method for detection of acute rejection and graft injury after heart transplantation. J Heart Lung Transplantat, 36(9):1004-1012.

[2]AgrawalN, EcheniqueIA, MeehanSM, et al., 2017. Variability in assessing for BK viremia: whole blood is not reliable and plasma is not above reproach—a retrospective analysis. Transpl Int, 30(7):670-678.

[3]AhujaM, CohenEP, DayerAM, et al., 2001. Polyoma virus infection after renal transplantation: use of immunostaining as a guide to diagnosis. Transplantation, 71(7):896-899.

[4]BloomRD, 2019. Using (cell-free) DNA to incriminate rejection as the cause of kidney allograft dysfunction: do we have a verdict? Am J Transplant, 19(6):1609-1610.

[5]BloomRD, BrombergJS, PoggioED, et al., 2017. Cell-free DNA and active rejection in kidney allografts. J Am Soc Nephrol, 28(7):2221-2232.

[6]Blydt-HansenTD, GibsonIW, GaoA, et al., 2015. Elevated urinary CXCL10-to-creatinine ratio is associated with subclinical and clinical rejection in pediatric renal transplantation. Transplantation, 99(4):797-804.

[7]BuettnerM, XuH, BöhmeR, et al., 2012. Predominance of TH2 cells and plasma cells in polyoma virus nephropathy: a role for humoral immunity. Hum Pathol, 43(9):1453-1462.

[8]ChenXT, WangZY, HuangY, et al., 2019. Combined detection of urine specific gravity and BK viruria on prediction of BK polyomavirus nephropathy in kidney transplant recipients. Chin Med J, 133(1):33-40.

[9]ChenXT, ChenWF, LiJ, et al., 2020. Urine donor-derived cell-free DNA helps discriminate BK polyomavirus-associated nephropathy in kidney transplant recipients with BK polyomavirus infection. Front Immunol, 11:1763.

[10]ChristakoudiS, RunglallM, MobilloP, et al., 2019. Development of a multivariable gene-expression signature targeting T-cell-mediated rejection in peripheral blood of kidney transplant recipients validated in cross-sectional and longitudinal samples. EBioMedicine, 41:571-583.

[11]de VlaminckI, MartinL, KerteszM, et al., 2015. Noninvasive monitoring of infection and rejection after lung transplantation. Proc Natl Acad Sci USA, 112(43):13336-13341.

[12]DharnidharkaVR, CherikhWS, AbbottKC, 2009. An OPTN analysis of national registry data on treatment of BK virus allograft nephropathy in the United States. Transplantation, 87(7):1019-1026.

[13]DrachenbergCB, PapadimitriouJC, HirschHH, et al., 2004. Histological patterns of polyomavirus nephropathy: correlation with graft outcome and viral load. Am J Transplant, 4(12):2082-2092.

[14]DrachenbergCB, PapadimitriouJC, ChaudhryMR, et al., 2017. Histological evolution of BK virus-associated nephropathy: importance of integrating clinical and pathological findings. Am J Transplant, 17(8):2078-2091.

[15]GielisEM, LedeganckKJ, DendoovenA, et al., 2019. The use of plasma donor-derived, cell-free DNA to monitor acute rejection after kidney transplantation. Nephrol Dial Transplant, 35(4):714-721.

[16]GniewkiewiczMS, CzerwińskaM, GozdowskaJ, et al., 2019. Urinary levels of CCL2 and CXCL10 chemokines as potential biomarkers of ongoing pathological processes in kidney allograft: an association with BK virus nephropathy. Pol Arch Intern Med, 129(9):592-597.

[17]HaasM, LoupyA, LefaucheurC, et al., 2018. The Banff 2017 Kidney Meeting Report: revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant, 18(2):293-307.

[18]HirschHH, RandhawaPS, 2019. BK polyomavirus in solid organ transplantation—Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant, 33(9):e13528.

[19]HirschHH, KnowlesW, DickenmannM, et al., 2002. Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med, 347(7):488-496.

[20]HirschHH, BrennanDC, DrachenbergCB, et al., 2005. Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation, 79(10):1277-1286.

[21]HuangE, SethiS, PengA, et al., 2019. Early clinical experience using donor-derived cell-free DNA to detect rejection in kidney transplant recipients. Am J Transplant, 19(6):1663-1670.

[22]KantS, BrombergJ, HaasM, et al., 2020. Donor-derived cell-free DNA and the prediction of BK virus-associated nephropathy. Transplant Direct, 6(11):e622.

[23]KnowlesWA, PipkinP, AndrewsN, et al., 2003. Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. J Med Virol, 71(1):115-123.

[24]MannonRB, HoffmannSC, KampenRL, et al., 2005. Molecular evaluation of BK polyomavirus nephropathy. Am J Transplant, 5(12):2883-2893.

[25]PangXL, DoucetteK, LeBlancB, et al., 2007. Monitoring of polyomavirus BK virus viruria and viremia in renal allograft recipients by use of a quantitative real-time PCR assay: one-year prospective study. J Clin Microbiol, 45(11):3568-3573.

[26]RomagnaniP, CrescioliC, 2012. CXCL10: a candidate biomarker in transplantation. Clin Chim Acta, 413(17-18):1364-1373.

[27]SchützE, FischerA, BeckJ, et al., 2017. Graft-derived cell-free DNA, a noninvasive early rejection and graft damage marker in liver transplantation: a prospective, observational, multicenter cohort study. PLoS Med, 14(4):e1002286.

[28]ShenJ, GuoLY, YanPP, et al., 2020. Prognostic value of the donor-derived cell-free DNA assay in acute renal rejection therapy: a prospective cohort study. Clin Transplant, 34(10):e14053.

[29]SigdelTK, VitaloneMJ, TranTQ, et al., 2013. A rapid noninvasive assay for the detection of renal transplant injury. Transplantation, 96(1):97-101.

[30]SigdelTK, GaoYQ, HeJT, et al., 2016. Mining the human urine proteome for monitoring renal transplant injury. Kidney Int, 89(6):1244-1252.

[31]WeseslindtnerL, HedmanL, WangYL, et al., 2020. Longitudinal assessment of the CXCL10 blood and urine concentration in kidney transplant recipients with BK polyomavirus replication—a retrospective study. Transpl Int, 33(5):555-566.

[32]YapiciÜ, KersJ, Slavujevic-LeticI, et al., 2016. Intragraft blood dendritic cell antigen-1-positive myeloid dendritic cells increase during BK polyomavirus-associated nephropathy. J Am Soc Nephrol, 27(8):2502-2510.

[33]ZengG, HuangY, HuangY, et al., 2016. Antigen-specificity of T cell infiltrates in biopsies with T cell-mediated rejection and BK polyomavirus viremia: analysis by next generation sequencing. Am J Transplant, 16(11):3131-3138.

[34]ZhouQ, LiuF, GuoLY, et al., 2021. A novel urine cell-free DNA preservation solution and its application in kidney transplantation. Nephrology, 26(8):684-691.

[35]ZhouY, YangGD, LiuHT, et al., 2019. A noninvasive and donor-independent method simultaneously monitors rejection and infection in patients with organ transplant. Transplant Proc, 51(6):1699-1705.

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