供者来源性细胞游离DNA在肾移植诊疗中的研究进展与应用

杨洋; 张健; 林俊

doi:10.3969/j.issn.1674-7445.2022.04.007

供者来源性细胞游离DNA在肾移植诊疗中的研究进展与应用

doi: 10.3969/j.issn.1674-7445.2022.04.007

100050 北京，首都医科大学附属北京友谊医院泌尿外科

基金项目:

国家自然科学基金 82000717

北京市自然科学基金 7192043

北京市自然科学基金 7194250

北京市医院管理中心“青苗计划” QML20190106

详细信息

作者简介:

通讯作者:
林俊，Email：bfhlinjun@hotmail.com

中图分类号: R617, R692
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出版历程
- 收稿日期: 2022-02-24
- 网络出版日期: 2022-07-14
- 刊出日期: 2022-07-15

Research progress and application of donor-derived cell-free DNA in diagnosis and treatment of kidney transplantation

Department of Urology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China

More Information

Corresponding author: Lin Jun, Email: bfhlinjun@hotmail.com

摘要

摘要: 肾移植术后排斥反应的早期诊断及治疗对于减少移植物损伤至关重要。供者来源性细胞游离DNA（dd-cfDNA）检测是基于二代测序等技术，通过浓度法及绝对定量法检测循环体液中源于坏死、凋亡的供肾组织DNA片段含量，具有监测同种异体移植物损伤的临床应用潜力。相比传统血清肌酐等检测指标，dd-cfDNA检测可提前数周至数月监测到移植物损伤，为临床治疗和延缓移植物失功提供了“时间窗”。随着近年来对dd-cfDNA研究的不断深入，dd-cfDNA因其兼具无创性、灵敏度高和能够对治疗效果进行实时评估等特点受到广泛关注。本文综述了目前有关dd-cfDNA检测在肾移植诊疗中多维度应用的研究证据与结论，并讨论了dd-cfDNA未来的研究和临床应用方向，旨在为dd-cfDNA检测广泛应用于我国的临床实践提供参考依据。
- 肾移植 /
- 供者来源性细胞游离DNA (dd-cfDNA) /
- 排斥反应 /
- 生物标志物 /
- 移植物损伤 /
- 抗体介导的排斥反应(AMR) /
- T细胞介导的排斥反应(TCMR) /
- BK病毒相关性肾病(BKVAN)
Abstract: Early diagnosis and treatment of rejection after kidney transplantation play a critical role in alleviating allograft injury. Detection of donor-derived cell-free DNA (dd-cfDNA) could be performed based on the next-generation sequencing and other techniques. The content of DNA fragments derived from necrotic and apoptotic donor kidney tissues in circulating body fluids could be determined by concentration and absolute quantitative methods, which has application potential in monitoring allograft injury in clinical practice. Compared with traditional serum creatinine and other indicators, dd-cfDNA detection may monitor allograft injury from several weeks to months in advance, providing a "time window" for clinical treatment and delaying graft failure. Along with deepening research of dd-cfDNA in recent years, dd-cfDNA has captivated widespread attention due to its non-invasiveness, high sensitivity and real-time evaluation of therapeutic effect. In this article, current study evidence and conclusions related to multidimensional application of dd-cfDNA detection in diagnosis and treatment of kidney transplantation were reviewed, and the future research and clinical application direction of dd-cfDNA were discussed, aiming to provide reference for widespread application of dd-cfDNA detection in clinical practice in China.
- Kidney transplantation /
- Donor-derived cell-free DNA (dd-cfDNA) /
- Rejection /
- Biomarker /
- Allograft injury /
- Antibody-mediated rejection (AMR) /
- T-cell mediated rejection (TCMR) /
- BK virus-associated nephropathy (BKVAN)

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参考文献(50)

[1]	WEKERLE T, SEGEV D, LECHLER R, et al. Strategies for long-term preservation of kidney graft function[J]. Lancet, 2017, 389(10084): 2152-2162. DOI: 10.1016/S0140-6736(17)31283-7.
[2]	HARIHARAN S, ISRANI AK, DANOVITCH G. Long-term survival after kidney transplantation[J]. N Engl J Med, 2021, 385(8): 729-743. DOI: 10.1056/NEJMra2014530.
[3]	FILIPPONE EJ, FARBER JL. The monitoring of donor-derived cell-free DNA in kidney transplantation[J]. Transplantation, 2021, 105(3): 509-516. DOI: 10.1097/TP.0000000000003393.
[4]	OELLERICH M, SHERWOOD K, KEOWN P, et al. Liquid biopsies: donor-derived cell-free DNA for the detection of kidney allograft injury[J]. Nat Rev Nephrol, 2021, 17(9): 591-603. DOI: 10.1038/s41581-021-00428-0.
[5]	GARG N, MANDELBROT DA, PARAJULI S, et al. The clinical value of donor-derived cell-free DNA measurements in kidney transplantation[J]. Transplant Rev (Orlando), 2021, 35(4): 100649. DOI: 10.1016/j.trre.2021.100649.
[6]	GIELIS EM, BEIRNAERT C, DENDOOVEN A, et al. Plasma donor-derived cell-free DNA kinetics after kidney transplantation using a single tube multiplex PCR assay[J]. PLoS One, 2018, 13(12): e0208207. DOI: 10.1371/journal.pone.0208207.
[7]	SHEN J, ZHOU Y, CHEN Y, et al. Dynamics of early post-operative plasma ddcfDNA levels in kidney transplantation: a single-center pilot study[J]. Transpl Int, 2019, 32(2): 184-192. DOI: 10.1111/tri.13341.
[8]	HAN F, WAN S, SUN Q, et al. Donor plasma mitochondrial DNA is correlated with posttransplant renal allograft function[J]. Transplantation, 2019, 103(11): 2347-2358. DOI: 10.1097/TP.0000000000002598.
[9]	KIM K, MOON H, LEE YH, et al. Clinical relevance of cell-free mitochondrial DNA during the early postoperative period in kidney transplant recipients[J]. Sci Rep, 2019, 9(1): 18607. DOI: 10.1038/s41598-019-54694-x.
[10]	CHEN XT, CHEN WF, LI J, et al. Urine donor-derived cell-free DNA helps discriminate BK polyomavirus-associated nephropathy in kidney transplant recipients with BK polyomavirus infection[J]. Front Immunol, 2020, 11: 1763. DOI: 10.3389/fimmu.2020.01763.
[11]	BLOOM RD, BROMBERG JS, POGGIO ED, et al. Cell-free DNA and active rejection in kidney allografts[J]. J Am Soc Nephrol, 2017, 28(7): 2221-2232. DOI: 10.1681/ASN.2016091034.
[12]	WHITLAM JB, LING L, SKENE A, et al. Diagnostic application of kidney allograft-derived absolute cell-free DNA levels during transplant dysfunction[J]. Am J Transplant, 2019, 19(4): 1037-1049. DOI: 10.1111/ajt.15142.
[13]	OELLERICH M, SHIPKOVA M, ASENDORF T, et al. Absolute quantification of donor-derived cell-free DNA as a marker of rejection and graft injury in kidney transplantation: results from a prospective observational study[J]. Am J Transplant, 2019, 19(11): 3087-3099. DOI: 10.1111/ajt.15416.
[14]	BROMBERG JS, BRENNAN DC, POGGIO E, et al. Biological variation of donor-derived cell-free DNA in renal transplant recipients: clinical implications[J]. J Appl Lab Med, 2017, 2(3): 309-321. DOI: 10.1373/jalm.2016.022731.
[15]	SCHÜTZ E, ASENDORF T, BECK J, et al. Time-dependent apparent increase in dd-cfDNA percentage in clinically stable patients between one and five years following kidney transplantation[J]. Clin Chem, 2020, 66(10): 1290-1299. DOI: 10.1093/clinchem/hvaa175.
[16]	SIGDEL TK, ARCHILA FA, CONSTANTIN T, et al. Optimizing detection of kidney transplant injury by assessment of donor-derived cell-free DNA via massively multiplex PCR[J]. J Clin Med, 2018, 8(1): 19. DOI: 10.3390/jcm8010019.
[17]	ZHANG H, ZHENG C, LI X, et al. Diagnostic performance of donor-derived plasma cell-free DNA fraction for antibody-mediated rejection in post renal transplant recipients: a prospective observational study[J]. Front Immunol, 2020, 11: 342. DOI: 10.3389/fimmu.2020.00342.
[18]	HUANG E, SETHI S, PENG A, et al. Early clinical experience using donor-derived cell-free DNA to detect rejection in kidney transplant recipients[J]. Am J Transplant, 2019, 19(6): 1663-1670. DOI: 10.1111/ajt.15289.
[19]	WIJTVLIET VPWM, PLAEKE P, ABRAMS S, et al. Donor-derived cell-free DNA as a biomarker for rejection after kidney transplantation: a systematic review and Meta-analysis[J]. Transpl Int, 2020, 33(12): 1626-1642. DOI: 10.1111/tri.13753.
[20]	XIAO H, GAO F, PANG Q, et al. Diagnostic accuracy of donor-derived cell-free DNA in renal-allograft rejection: a Meta-analysis[J]. Transplantation, 2021, 105(6): 1303-1310. DOI: 10.1097/TP.0000000000003443.
[21]	STITES E, KUMAR D, OLAITAN O, et al. High levels of dd-cfDNA identify patients with TCMR 1A and borderline allograft rejection at elevated risk of graft injury[J]. Am J Transplant, 2020, 20(9): 2491-2498. DOI: 10.1111/ajt.15822.
[22]	JORDAN SC, BUNNAPRADIST S, BROMBERG JS, et al. Donor-derived cell-free DNA identifies antibody-mediated rejection in donor specific antibody positive kidney transplant recipients[J]. Transplant Direct, 2018, 4(9): e379. DOI: 10.1097/TXD.0000000000000821.
[23]	YANG JYC, SARWAL RD, SIGDEL TK, et al. A urine score for noninvasive accurate diagnosis and prediction of kidney transplant rejection[J]. Sci Transl Med, 2020, 12(535): eaba2501. DOI: 10.1126/scitranslmed.aba2501.
[24]	HUMMEL EM, HESSAS E, MÜLLER S, et al. Cell-free DNA release under psychosocial and physical stress conditions[J]. Transl Psychiatry, 2018, 8(1): 236. DOI: 10.1038/s41398-018-0264-x.
[25]	SHEN J, GUO L, YAN P, et al. Prognostic value of the donor-derived cell-free DNA assay in acute renal rejection therapy: a prospective cohort study[J]. Clin Transplant, 2020, 34(10): e14053. DOI: 10.1111/ctr.14053.
[26]	STEGGERDA J, PHAN PIZZO H, GARRISON J, et al. Use of donor derived cell-free DNA assay to monitor treatment response to allograft rejection in pediatric renal transplant recipients[J]. Am J Transplant, 2020, 20(suppl 3): 673.
[27]	KYESO Y, BHALLA A, SMITH AP, et al. Donor-derived cell-free DNA kinetics post-kidney transplant biopsy[J]. Transplant Direct, 2021, 7(6): e703. DOI: 10.1097/TXD.0000000000001149.
[28]	KANT S, BROMBERG J, HAAS M, et al. Donor-derived cell-free DNA and the prediction of BK virus-associated nephropathy[J]. Transplant Direct, 2020, 6(11): e622. DOI: 10.1097/TXD.0000000000001061.
[29]	HEN J, GUO L, LEI W, et al. Urinary donor-derived cell-free DNA as a non-invasive biomarker for BK polyomavirus-associated nephropathy[J]. J Zhejiang Univ Sci B, 2021, 22(11): 917-928. DOI: 10.1631/jzus.B2100131.
[30]	HART A, SMITH JM, SKEANS MA, et al. OPTN/SRTR 2018 annual data report: kidney[J]. Am J Transplant, 2020, 20 (Suppl s1): 20-130. DOI: 10.1111/ajt.15672.
[31]	OLAITAN OK, LOEB S, HETTERMAN E, et al. Donor-derived cell-free DNA for surveillance in simultaneous pancreas and kidney transplant recipients, can we extrapolate from kidney transplant alone[J]. Am J Transplant, 2019, 19(suppl 3): D264.
[32]	AL-SAFFAR F, HSU J, FUENTES J SJ, et al. Combined allosure and allomap testing in multi-organ heart transplantation rejection surveillance[J]. J Heart Lung Transplant, 2020, 39(4): S260-S261.
[33]	MCCLURE T, GOH SK, COX D, et al. Donor-specific cell-free DNA as a biomarker in liver transplantation: a review[J]. World J Transplant, 2020, 10(11): 307-319. DOI: 10.5500/wjt.v10.i11.307.
[34]	蒋廷亚, 周阳, 程东瑞. 供者来源游离DNA在移植肾损伤中的研究进展[J]. 中华器官移植杂志, 2019, 40(9): 566-569. DOI: 10.3760/cma.j.issn.0254-1785.2019.09.013. JIANG TY, ZHOU Y, CHENG DR. Research progress of donor-derived cell-free DNA in renal allograft injury[J]. Chin J Organ Transplant, 2019, 40(9): 566-569. DOI: 10.3760/cma.j.issn.0254-1785.2019.09.013.
[35]	HUNG EC, SHING TK, CHIM SS, et al. Presence of donor-derived DNA and cells in the urine of sex-mismatched hematopoietic stem cell transplant recipients: implication for the transrenal hypothesis[J]. Clin Chem, 2009, 55(4): 715-722. DOI: 10.1373/clinchem.2008.113530.
[36]	SIGDEL TK, VITALONE MJ, TRAN TQ, et al. A rapid noninvasive assay for the detection of renal transplant injury[J]. Transplantation, 2013, 96(1): 97-101. DOI: 10.1097/TP.0b013e318295ee5a.
[37]	GOH Y, HO S, RAMAN L, et al. Noninvasive renal transplant graft monitoring in single institution using cell-free DNA in recipient plasma via insertion-deletion allele polymorphism[J]. Am J Transplant, 2017, 17(suppl 3): 718.
[38]	ZHANG L, HU X, YIN L, et al. Early upsurge of cell free Alu DNA predicts declining long-term graft survival[J]. Am J Transplant, 2011, 11(suppl 2): 389.
[39]	YANG JYC, SARWAL RD, FERVENZA FC, et al. Noninvasive urinary monitoring of progression in IgA nephropathy[J]. Int J Mol Sci, 2019, 20(18): 4463. DOI: 10.3390/ijms20184463.
[40]	QUAGLIA M, MERLOTTI G, GUGLIELMETTI G, et al. Recent advances on biomarkers of early and late kidney graft dysfunction[J]. Int J Mol Sci, 2020, 21(15): 5404. DOI: 10.3390/ijms21155404.
[41]	CELEC P, VLKOVÁ B, LAUKOVÁ L, et al. Cell-free DNA: the role in pathophysiology and as a biomarker in kidney diseases[J]. Expert Rev Mol Med, 2018, 20: e1. DOI: 10.1017/erm.2017.12.
[42]	KNIGHT SR, THORNE A, LO FARO ML. Donor-specific cell-free DNA as a biomarker in solid organ transplantation. a systematic review[J]. Transplantation, 2019, 103(2): 273-283. DOI: 10.1097/TP.0000000000002482.
[43]	MARTUSZEWSKI A, PALUSZKIEWICZ P, KRÓL M, et al. Donor-derived cell-free DNA in kidney transplantation as a potential rejection biomarker: a systematic literature review[J]. J Clin Med, 2021, 10(2): 193. DOI: 10.3390/jcm10020193.
[44]	DENGU F. Next-generation sequencing methods to detect donor-derived cell-free DNA after transplantation[J]. Transplant Rev (Orlando), 2020, 34(3): 100542. DOI: 10.1016/j.trre.2020.100542.
[45]	VASCO M, BENINCASA G, FIORITO C, et al. Clinical epigenetics and acute/chronic rejection in solid organ transplantation: an update[J]. Transplant Rev (Orlando), 2021, 35(2): 100609. DOI: 10.1016/j.trre.2021.100609.
[46]	KANT S, BRENNAN DC. Donor-derived cell-free DNA in kidney transplantation: origins, present and a look to the future[J]. Medicina (Kaunas), 2021, 57(5): 482. DOI: 10.3390/medicina57050482.
[47]	JAIKARANSINGH V, KADAMBI PV. Donor-derived cell-free DNA (ddcf-DNA) and acute antibody-mediated rejection in kidney transplantation[J]. Medicina (Kaunas), 2021, 57(5): 436. DOI: 10.3390/medicina57050436.
[48]	KAMATH M, SHEKHTMAN G, GROGAN T, et al. Variability in donor-derived cell-free DNA scores to predict mortality in heart transplant recipients - a proof-of-concept study[J]. Front Immunol, 2022, 13: 825108. DOI: 10.3389/fimmu.2022.825108.
[49]	SORBINI M, TOGLIATTO GM, SIMONATO E, et al. HLA-DRB1 mismatch-based identification of donor-derived cell free DNA (dd-cfDNA) as a marker of rejection in heart transplant recipients: a single-institution pilot study[J]. J Heart Lung Transplant, 2021, 40(8): 794-804. DOI: 10.1016/j.healun.2021.05.001.
[50]	NISSAISORAKARN P, PATEL H, AMTUL A, et al. Protocol-based donor-derived cell-free DNA surveillance in kidney transplant recipients: a single-center experience[J]. Clin Nephrol, 2022, DOI: 10.5414/CN110760[Epub ahead of print].