肾移植新兴生物标志物之研究进展

郑瑾; 薛武军

doi:10.3969/j.issn.1674-7445.2023.02.003

肾移植新兴生物标志物之研究进展

doi: 10.3969/j.issn.1674-7445.2023.02.003

郑瑾,
薛武军^,

710061 西安，西安交通大学第一附属医院肾脏病医院肾移植科

基金项目:

国家自然科学基金 82170768

详细信息

作者简介:

通讯作者:
薛武军，博士，主任医师，教授，研究方向为肾移植，Email：xwujun126@xjtu.edu.cn

中图分类号: R617, R692
计量
- 文章访问数: 499
- HTML全文浏览量: 162
- PDF下载量: 128
- 被引次数: 0
出版历程
- 收稿日期: 2022-10-16
- 网络出版日期: 2023-03-15
- 刊出日期: 2023-03-15

Research progress on emerging biomarkers in kidney transplantation

Zheng Jin,
Xue Wujun^,

Department of Kidney Transplantation, Kidney Disease Hospital, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China

More Information

Corresponding author: Xue Wujun, Email: xwujun126@xjtu.edu.cn

摘要

摘要: 宿主对移植器官的免疫反应复杂多样，能否利用生物标志物解释移植物免疫反应的复杂性和疾病损伤的程度至关重要。传统的生物标志物如估算肾小球滤过率、免疫抑制药血药浓度等在精准识别移植肾免疫性和非免疫性损伤方面缺乏灵敏度和特异度。移植肾活组织检查虽然是目前诊断术后并发症的“金标准”，但是存在有创和费用昂贵等缺点。新兴生物标志物在移植肾亚临床损伤的无创诊断、治疗反应的预测和免疫抑制方案的个体化调整方面具有潜在优势。本文综述了肾移植领域近年来已经进入和有希望进入临床应用的新兴生物标志物，包括血液、尿液和组织生物标志物，并分析了其应用范围和效果，以期能促进有前景的新兴生物标志物更好地、合理地应用于临床。
- 肾移植 /
- 生物标志物 /
- 无创监测 /
- 排斥反应 /
- 估算肾小球滤过率 /
- 供者特异性抗体 /
- 供者来源性细胞游离DNA /
- 细胞外囊泡 /
- 单核苷酸多态性（SNP）
Abstract: The hosts could show complex and diverse immune responses to the allografts. Whether biomarkers can be employed to explain the complexity of graft immune responses and the degree of disease damage are of significance. Conventional biomarkers, such as estimated glomerular filtration rate and blood concenrtation of immunosuppressant, lack of sensitivity and specificity in accurately identifying between immune and non-immune renal allograft injuries. Although renal biopsy is the "gold standard" for the diagnosis of postoperative complications, it still has disadvantages, such as invasiveness and high price, etc. Emerging biomarkers have potential advantages in the non-invasive diagnosis of subclinical injury of renal allograft, prediction of treatment response and individualized adjustment of immunosuppressive regimen. In this article, emerging biomarkers including blood, urine and tissue biomarkers that have been applied and are expected to be applied in clinical practice in the field of kidney transplantation were reviewed, and the range of application and effect of these biomarkers were evaluated, aiming to promote appropriate and rational application of these promising emerging biomarkers in clinical practice.
- Kidney transplantation /
- Biomarker /
- Non-invasive monitoring /
- Rejection /
- Estimated glomerular filtration rate /
- Donor specific antibody /
- Donor-derived cell-free DNA /
- Extracellular vesicle /
- Single nucleotide polymorphism(SNP)

HTML全文

下载: 全尺寸图片幻灯片

参考文献(44)

[1]	HART A, LENTINE KL, SMITH JM, et al. OPTN/SRTR 2019 annual data report: kidney[J]. Am J Transplant, 2021, 21 (Suppl 2): 21-137. DOI: 10.1111/ajt.16502.
[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]	OBRIȘCĂ B, BUTIU M, SIBULESKY L, et al. Combining donor-derived cell-free DNA and donor specific antibody testing as non-invasive biomarkers for rejection in kidney transplantation[J]. Sci Rep, 2022, 12(1): 15061. DOI: 10.1038/s41598-022-19017-7.
[4]	SNOPKOWSKI C, SALINAS T, LI C, et al. Urinary cell mRNA profiling of kidney allograft recipients: a systematic investigation of a filtration based protocol for the simplification of urine processing[J]. J Immunol Methods, 2021, 498: 113132. DOI: 10.1016/j.jim.2021.113132.
[5]	VAN BAARDWIJK M, CRISTOFERI I, JU J, et al. A decentralized kidney transplant biopsy classifier for transplant rejection developed using genes of the Banff-human organ transplant panel[J]. Front Immunol, 2022, 13: 841519. DOI: 10.3389/fimmu.2022.841519.
[6]	CLAYTON PA, LIM WH, WONG G, et al. Relationship between eGFR decline and hard outcomes after kidney transplants[J]. J Am Soc Nephrol, 2016, 27(11): 3440-3446. DOI: 10.1681/ASN.2015050524.
[7]	NAESENS M, LERUT E, EMONDS MP, et al. Proteinuria as a noninvasive marker for renal allograft histology and failure: an observational cohort study[J]. J Am Soc Nephrol, 2016, 27(1): 281-292. DOI: 10.1681/ASN.2015010062.
[8]	HART A, SINGH D, BROWN SJ, et al. Incidence, risk factors, treatment, and consequences of antibody-mediated kidney transplant rejection: a systematic review[J]. Clin Transplant, 2021, 35(7): e14320. DOI: 10.1111/ctr.14320.
[9]	LOUPY A, HAAS M, ROUFOSSE C, et al. The Banff 2019 kidney meeting report (Ⅰ): updates on and clarification of criteria for T cell- and antibody-mediated rejection[J]. Am J Transplant, 2020, 20(9): 2318-2331. DOI: 10.1111/ajt.15898.
[10]	郭晖. 亚临床排斥反应与计划性活检[M]//陈实, 郭晖. 移植病理学. 北京: 人民卫生出版社, 2009: 458-466.
[11]	ANG A, SCHIEVE C, ROSE S, et al. Avoiding surveillance biopsy: use of a noninvasive biomarker assay in a real-life scenario[J]. Clin Transplant, 2021, 35(1): e14145. DOI: 10.1111/ctr.14145.
[12]	LIM M, PARK BK, LEE KW, et al. Two-week protocol biopsy in renal allograft: feasibility, safety, and outcomes[J]. J Clin Med, 2022, 11(3): 785. DOI: 10.3390/jcm11030785.
[13]	GWINNER W, KARCH A, BRAESEN JH, et al. Noninvasive diagnosis of acute rejection in renal transplant patients using mass spectrometric analysis of urine samples: a multicenter diagnostic phase Ⅲ trial[J]. Transplant Direct, 2022, 8(5): e1316. DOI: 10.1097/TXD.0000000000001316.
[14]	WESTPHAL SG, MANNON RB. Emerging biomarkers in kidney transplantation and challenge of clinical implementation[J]. Curr Opin Organ Transplant, 2022, 27(1): 15-21. DOI: 10.1097/MOT.0000000000000941.
[15]	CALIFF RM. Biomarker definitions and their applications[J]. Exp Biol Med (Maywood), 2018, 243(3): 213-221. DOI: 10.1177/1535370217750088.
[16]	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.
[17]	BU L, GUPTA G, PAI A, et al. Clinical outcomes from the assessing donor-derived cell-free DNA monitoring insights of kidney allografts with longitudinal surveillance (ADMIRAL) study[J]. Kidney Int, 2022, 101(4): 793-803. DOI: 10.1016/j.kint.2021.11.034.
[18]	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.
[19]	CHEN XT, QIU J, WU ZX, et al. Using both plasma and urine donor-derived cell-free DNA to identify various renal allograft injuries[J]. Clin Chem, 2022, 68(6): 814-825. DOI: 10.1093/clinchem/hvac053.
[20]	BUNNAPRADIST S, HOMKRAILAS P, AHMED E, et al. Using both the fraction and quantity of donor-derived cell-free DNA to detect kidney allograft rejection[J]. J Am Soc Nephrol, 2021, 32(10): 2439-2441. DOI: 10.1681/ASN.2021050645.
[21]	FRIEDEWALD JJ, KURIAN SM, HEILMAN RL, et al. Development and clinical validity of a novel blood-based molecular biomarker for subclinical acute rejection following kidney transplant[J]. Am J Transplant, 2019, 19(1): 98-109. DOI: 10.1111/ajt.15011.
[22]	ZHANG W, YI Z, KEUNG KL, et al. A peripheral blood gene expression signature to diagnose subclinical acute rejection[J]. J Am Soc Nephrol, 2019, 30(8): 1481-1494. DOI: 10.1681/ASN.2018111098.
[23]	VAN LOON E, GAZUT S, YAZDANI S, et al. Development and validation of a peripheral blood mRNA assay for the assessment of antibody-mediated kidney allograft rejection: a multicentre, prospective study[J]. EBioMedicine, 2019, 46: 463-472. DOI: 10.1016/j.ebiom.2019.07.028.
[24]	ROEDDER S, SIGDEL T, SALOMONIS N, et al. The kSORT assay to detect renal transplant patients at high risk for acute rejection: results of the multicenter AART study[J]. PLoS Med, 2014, 11(11): e1001759. DOI: 10.1371/journal.pmed.1001759.
[25]	CRESPO E, ROEDDER S, SIGDEL T, et al. Molecular and functional noninvasive immune monitoring in the ESCAPE study for prediction of subclinical renal allograft rejection[J]. Transplantation, 2017, 101(6): 1400-1409. DOI: 10.1097/TP.0000000000001287.
[26]	VAN LOON E, GIRAL M, ANGLICHEAU D, et al. Diagnostic performance of kSORT, a blood-based mRNA assay for noninvasive detection of rejection after kidney transplantation: a retrospective multicenter cohort study[J]. Am J Transplant, 2021, 21(2): 740-750. DOI: 10.1111/ajt.16179.
[27]	BENICHOU G, WANG M, AHRENS K, et al. Extracellular vesicles in allograft rejection and tolerance[J]. Cell Immunol, 2020, 349: 104063. DOI: 10.1016/j.cellimm.2020.104063.
[28]	GOŁĘBIEWSKA JE, WARDOWSKA A, PIETROWSKA M, et al. Small extracellular vesicles in transplant rejection[J]. Cells, 2021, 10(11): 2989. DOI: 10.3390/cells10112989.
[29]	WANG J, LI X, WU X, et al. Expression profiling of exosomal miRNAs derived from the peripheral blood of kidney recipients with DGF using high-throughput sequencing[J]. Biomed Res Int, 2019: 1759697. DOI: 10.1155/2019/1759697.
[30]	QAMRI Z, PELLETIER R, FOSTER J, et al. Early posttransplant changes in circulating endothelial microparticles in patients with kidney transplantation[J]. Transpl Immunol, 2014, 31(2): 60-64. DOI: 10.1016/j.trim.2014.06.006.
[31]	TOWER CM, REYES M, NELSON K, et al. Plasma C4d⁺ endothelial microvesicles increase in acute antibody-mediated rejection[J]. Transplantation, 2017, 101(9): 2235-2243. DOI: 10.1097/TP.0000000000001572.
[32]	YANG J, BI L, HE X, et al. Follicular helper T cell derived exosomes promote B cell proliferation and differentiation in antibody-mediated rejection after renal transplantation[J]. Biomed Res Int, 2019: 6387924. DOI: 10.1155/2019/6387924.
[33]	ZHANG H, HUANG E, KAHWAJI J, et al. Plasma exosomes from HLA-sensitized kidney transplant recipients contain mRNA transcripts which predict development of antibody-mediated rejection[J]. Transplantation, 2017, 101(10): 2419-2428. DOI: 10.1097/TP.0000000000001834.
[34]	LUBETZKY ML, SALINAS T, SCHWARTZ JE, et al. Urinary cell mRNA profiles predictive of human kidney allograft status[J]. Clin J Am Soc Nephrol, 2021, 16(10): 1565-1577. DOI: 10.2215/CJN.14010820.
[35]	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.
[36]	SUTHANTHIRAN M, SCHWARTZ JE, DING R, et al. Urinary-cell mRNA profile and acute cellular rejection in kidney allografts[J]. N Engl J Med, 2013, 369(1): 20-31. DOI: 10.1056/NEJMoa1215555.
[37]	HRICIK DE, NICKERSON P, FORMICA RN, et al. Multicenter validation of urinary CXCL9 as a risk-stratifying biomarker for kidney transplant injury[J]. Am J Transplant, 2013, 13(10): 2634-2644. DOI: 10.1111/ajt.12426.
[38]	EL FEKIH R, HURLEY J, TADIGOTLA V, et al. Discovery and validation of a urinary exosome mRNA signature for the diagnosis of human kidney transplant rejection[J]. J Am Soc Nephrol, 2021, 32(4): 994-1004. DOI: 10.1681/ASN.2020060850.
[39]	HALLORAN PF, PEREIRA AB, CHANG J, et al. Microarray diagnosis of antibody-mediated rejection in kidney transplant biopsies: an international prospective study (INTERCOM)[J]. Am J Transplant, 2013, 13(11): 2865-2874. DOI: 10.1111/ajt.12465.
[40]	LOUPY A, LEFAUCHEUR C, VERNEREY D, et al. Molecular microscope strategy to improve risk stratification in early antibody-mediated kidney allograft rejection[J]. J Am Soc Nephrol, 2014, 25(10): 2267-2277. DOI: 10.1681/ASN.2013111149.
[41]	O'CONNELL PJ, ZHANG W, MENON MC, et al. Biopsy transcriptome expression profiling to identify kidney transplants at risk of chronic injury: a multicentre, prospective study[J]. Lancet, 2016, 388(10048): 983-993. DOI: 10.1016/S0140-6736(16)30826-1.
[42]	MENGEL M, LOUPY A, HAAS M, et al. Banff 2019 meeting report: molecular diagnostics in solid organ transplantation-consensus for the Banff human organ transplant (B-HOT) gene panel and open source multicenter validation[J]. Am J Transplant, 2020, 20(9): 2305-2317. DOI: 10.1111/ajt.16059.
[43]	SMITH RN. In-silico performance, validation, and modeling of the nanostring Banff human organ transplant gene panel using archival data from human kidney transplants[J]. BMC Med Genomics, 2021, 14(1): 86. DOI: 10.1186/s12920-021-00891-5.
[44]	PUTTARAJAPPA CM, MEHTA RB, ROBERTS MS, et al. Economic analysis of screening for subclinical rejection in kidney transplantation using protocol biopsies and noninvasive biomarkers[J]. Am J Transplant, 2021, 21(1): 186-197. DOI: 10.1111/ajt.16150.