Abstract
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.
摘要
目的
BK病毒相关肾病(BKPyVAN)是移植肾丢失的常见原因之一。然而, 由于BKPyVAN和I型T细胞介导的排斥反应(TCMR)具有相似的病理表现, 因此在猿猴空泡病毒40(SV40)染色阴性时, 病理鉴别两者具有难度.
创新点
本文首次研究了供体来源的细胞游离DNA(ddcfDNA)能否区分BKPyVAN和I型TCMR.
方法
采用目标区域杂交捕获测序检测法, 对12例肾功能稳定、22例I型TCMR、21例病理证实BKPyVAN和5例疑似PyVAN患者的ddcfDNA进行检测.
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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Acknowledgments
This study was supported by the Science and Technology Department of Zhejiang Province (No. 2019C03029), the Bethune Charitable Foundation (No. G-X-2019-0101-12), the National Natural Science Foundation of China (Nos. 81870510, 81770719, 81770752, and 81370851), and the Zhejiang Provincial Natural Science Foundation of China (No. LQ18H050002).
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Jia SHEN and Rending WANG contributed to study design and data interpretation. Luying GUO and Rending WANG contributed to data analysis, data interpretation, and writing. Wenhua LEI, Shuaihui LIU, Pengpeng YAN, Jingyi ZHOU, and Qin ZHOU contributed to data collection. Haitao LIU, Feng LIU, and Tingya JIANG performed data analysis. Huiping WANG, Jianyong WU, and Jianghua CHEN contributed to manuscript-writing advice. All authors have read and approved the final manuscript, and therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.
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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, and Rending WANG declare that they have no conflict of interest.
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Informed consent was obtained from all patients for being included in the study. Additional informed consent was obtained from all patients for which identifying information is included in this article.
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Shen, J., Guo, L., Lei, W. et al. Urinary donor-derived cell-free DNA as a non-invasive biomarker for BK polyomavirus-associated nephropathy. J. Zhejiang Univ. Sci. B 22, 917–928 (2021). https://doi.org/10.1631/jzus.B2100131
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DOI: https://doi.org/10.1631/jzus.B2100131
Key words
- Donor-derived cell-free DNA (ddcfDNA)
- BK polyomavirus-associated nephropathy (BKPyVAN)
- T cell-mediated rejection (TCMR)
- Urine
- Differential diagnosis