狼疮性肾炎的生物标志物研究进展

doi:10.3877/cma.j.issn.2095-3216.2022.03.009

狼疮性肾炎(LN)是系统性红斑狼疮(SLE)最常见和最严重的表现之一，20%~60%的SLE患者会出现肾脏损伤。抗双链DNA抗体、补体成分C3和C4、尿蛋白肌酐比值等作为LN诊断传统生物标志物，在监测疾病活动和早期肾脏病理损害方面缺乏特异性和敏感性。LN诊断的金标准是肾组织病理活检，这是一种有创检查，不利于早期诊断和反复监测。寻找能替代肾组织病理活检的新型生物标志物，对早期诊断、疾病活动监测、改善预后具有重要意义。本文总结了血液和尿液中新型生物标志物的研究进展，并对其临床应用前景提出展望，为临床诊断工作提供理论支持。

关键词: 狼疮性肾炎, 新型生物标志物, 传统生物标志物, 血液, 尿液

Lupus nephritis (LN) is one of the most common and serious manifestations of systemic lupus erythematosus (SLE). Kidney damage occurs in 20% to 60% of patients with SLE. As traditional biomarkers for LN diagnosis, anti-double-stranded DNA antibodies, complement components C3 and C4, and urine protein-creatinine ratio, etc., lack specificity and sensitivity in monitoring disease activity and early renal pathological damage. The gold standard for LN diagnosis is pathological biopsy of renal tissue, which is an invasive examination that is not suitable for early diagnosis and repeated monitoring. Finding novel biomarkers that can replace renal biopsy is of great significance for early diagnosis, monitoring of disease activity, and improving prognosis. This paper summarized the research progress for novel biomarkers in blood and urine, and put forward the prospect of their clinical application, providing theoretical support for clinical diagnosis.

Key words: Lupus nephritis, Novel biomarkers, Traditional biomarkers, Blood, Urine

表1 狼疮性肾炎的生物标志物

组别		组份	表达		引用文献
传统生物标志物		补体蛋白	C3, C4	减少	[5，6，7]
		自身抗体	抗dsDNA抗体	增加	[8，9，10]
			抗核小体抗体	增加	[12，13]
			抗Sm抗体	增加	[14，15]
			抗核糖核蛋白抗体	增加	[14，16]
			抗磷脂抗体	增加	[17，18]
			尿蛋白/肌酐比值	增加	[19，20]
新型生物标志物	尿液中新型生物标志物	黏附分子	VCAM-1	增加	[22，23]
			ICAM-1	增加	[23，24，25]
		生长因子	PDGF-Rβ	增加	[26]
			TGF-β1	增加	[27，28]
		趋化因子	MCP-1	增加	[29，30]
		miRNAs	miR-3201, miR-1273e, miR-654	减少	[32，34]
			miR-21, miR-155	增加	[33]
		其他新型生物标志物	NGAL	增加	[30，35]
			ACT	增加	[36]
			纤溶酶	增加	[37]
			CD163	增加	[41，42，43]
	血液中新型生物标志物	细胞因子	IL-25	增加	[44，45]
			IFN-Ⅰ	增加	[47，48]
		趋化因子	CCL2, CCL4, CCL5, CXCL10, CXCL12	增加	[49，50]
		脂肪分子	ADPN	增加	[51，52]
		自身抗体	抗C1q抗体	增加	[10，53]

表1 狼疮性肾炎的生物标志物

组别		组份	表达		引用文献
传统生物标志物		补体蛋白	C3, C4	减少	[5，6，7]
		自身抗体	抗dsDNA抗体	增加	[8，9，10]
			抗核小体抗体	增加	[12，13]
			抗Sm抗体	增加	[14，15]
			抗核糖核蛋白抗体	增加	[14，16]
			抗磷脂抗体	增加	[17，18]
			尿蛋白/肌酐比值	增加	[19，20]
新型生物标志物	尿液中新型生物标志物	黏附分子	VCAM-1	增加	[22，23]
			ICAM-1	增加	[23，24，25]
		生长因子	PDGF-Rβ	增加	[26]
			TGF-β1	增加	[27，28]
		趋化因子	MCP-1	增加	[29，30]
		miRNAs	miR-3201, miR-1273e, miR-654	减少	[32，34]
			miR-21, miR-155	增加	[33]
		其他新型生物标志物	NGAL	增加	[30，35]
			ACT	增加	[36]
			纤溶酶	增加	[37]
			CD163	增加	[41，42，43]
	血液中新型生物标志物	细胞因子	IL-25	增加	[44，45]
			IFN-Ⅰ	增加	[47，48]
		趋化因子	CCL2, CCL4, CCL5, CXCL10, CXCL12	增加	[49，50]
		脂肪分子	ADPN	增加	[51，52]
		自身抗体	抗C1q抗体	增加	[10，53]

[1]	董雅倩，卢宪媛，唐斓，等. 狼疮性肾炎发病机制、生物标志物及治疗现状研究进展[J]. 实用医学杂志，2018, 34(10): 1605-1609.
[2]	张凯聪，张丽，梁馨苓. 狼疮性肾炎生物标志物[J]. 肾脏病与透析肾移植杂志，2018, 27(5): 463-467.
[3]	Chen YE, Korbet SM, Katz RS, et al. Value of a complete or partial remission in severe lupus nephritis [J]. Clin J Am Soc Nephrol, 2008, 3(1): 46-53.
[4]	中国狼疮肾炎诊断和治疗指南编写组. 中国狼疮肾炎诊断和治疗指南[J]. 中华医学杂志，2019(44): 3441-3455.
[5]	Su B, Chen B, Lu G. Relationship of complement activation pathway to clinical and pathological characteristics and renal outcome in patients with lupus nephritis [J]. Z Rheumatol, 2021, Epub ahead of print.
[6]	Durcan L, Petri M. The clinical and serological associations of hypocomplementemia in a longitudinal sle cohort [J]. Semin Arthritis Rheum, 2020, 50(5): 1081-1086.
[7]	Shen F, Liu M, Pei F, et al. Role of uromodulin and complement activation in the progression of kidney disease [J]. Oncol Lett, 2021, 22(6): 829.
[8]	Wang X, Xia Y. Anti-double stranded DNA antibodies: origin, pathogenicity, and targeted therapies [J]. Front Immunol, 2019, 10: 1667.
[9]	Andrianova IA, Ponomareva AA, Mordakhanova ER, et al. In systemic lupus erythematosus anti-dsDNA antibodies can promote thrombosis through direct platelet activation [J]. J Autoimmun, 2020, 107: 102355.
[10]	Jia Y, Zhao L, Wang C, et al. Anti-double-stranded DNA isotypes and anti-C1q antibody improve the diagnostic specificity of systemic lupus erythematosus [J]. Dis Markers, 2018, 2018: 4528547.
[11]	Soliman S, Mohan C. Lupus nephritis biomarkers [J]. Clin Immunol, 2017, 185: 10-20.
[12]	Rodriguez-Jimenez NA, Perez-Guerrero EE, Gamez-Nava JI, et al. Anti-nucleosome antibodies increase the risk of renal relapse in a prospective cohort of patients with clinically inactive systemic lupus erythematosus [J]. Sci Rep, 2020, 10(1): 12698.
[13]	Shang X, Ren L, Sun G, et al. Anti-dsDNA, anti-nucleosome, anti-C1q, and anti-histone antibodies as markers of active lupus nephritis and systemic lupus erythematosus disease activity [J]. Immun Inflamm Dis, 2021, 9(2): 407-418.
[14]	Migliorini P, Baldini C, Rocchi V, et al. Anti-Sm and anti-RNP antibodies [J]. Autoimmunity, 2005, 38(1): 47-54.
[15]	Dumestre-Pérard C, Clavarino G, Colliard S, et al. Antibodies targeting circulating protective molecules in lupus nephritis: interest as serological biomarkers [J]. Autoimmun Rev, 2018, 17(9): 890-899.
[16]	Bastian HM, Roseman JM, Mcgwin G, et al. Systemic lupus erythematosus in three ethnic groups. XII. Risk factors for lupus nephritis after diagnosis [J]. Lupus, 2002, 11(3): 152-60.
[17]	Moroni G, Ventura D, Riva P, et al. Antiphospholipid antibodies are associated with an increased risk for chronic renal insufficiency in patients with lupus nephritis [J]. Am J Kidney Dis, 2004, 43(1): 28-36.
[18]	Ding X, Chen C, Zhang J, et al. Antiphospholipid antibodies in patients with proliferative and membranous lupus nephritis [J]. Clin Rheumatol, 2020, 39(5): 1531-1535.
[19]	Salesi M, Karimifar M, Farajzadegan Z, et al. The protein-creatinine ratio in spot morning urine samples and 24-h urinary protein excretion in patients with systemic lupus erythematosus [J]. Rheumatol Int, 2009, 29(5): 503-507.
[20]	Medina-Rosas J, Yap KS, Anderson M, et al. Utility of urinary protein-creatinine ratio and protein content in a 24-hour urine collection in systemic lupus erythematosus: a systematic review and meta-analysis [J]. Arthritis Care Res (Hoboken), 2016, 68(9): 1310-1319.
[21]	Kong DH, Kim YK, Kim MR, et al. Emerging roles of vascular cell adhesion molecule-1 (VCAM-1) in immunological disorders and cancer [J]. Int J Mol Sci, 2018, 19(4): 1057.
[22]	王鹏，张吉才. 尿液蛋白标志物联合检测在狼疮性肾炎中的诊断价值[J]. 川北医学院学报，2018, 33(5): 688-692.
[23]	吴春益，杨满球，周展眉，等. 尿液粘附分子：活动性狼疮肾炎的标志物[J]. 南方医科大学学报，2015, 35(9): 1272-1276, 1282.
[24]	Bui TM, Wiesolek HL, Sumagin R. ICAM-1: a master regulator of cellular responses in inflammation, injury resolution, and tumorigenesis [J]. J Leukoc Biol, 2020, 108(3): 787-799.
[25]	Guo Liu RN, Cheng QY, Zhou HY, et al. Elevated blood and urinary ICAM-1 is a biomarker for systemic lupus erythematosus: a systematic review and meta-analysis [J]. Immunol Invest, 2020, 49(1-2): 15-31.
[26]	Vanarsa K, Soomro S, Zhang T, et al. Quantitative planar array screen of 1000 proteins uncovers novel urinary protein biomarkers of lupus nephritis [J]. Ann Rheum Dis, 2020, 79(10): 1349-1361.
[27]	Xing Q, Su H, Cui J, et al. Role of Treg cells and TGF-β1 in patients with systemic lupus erythematosus: a possible relation with lupus nephritis [J]. Immunol Invest, 2012, 41(1): 15-27.
[28]	Paradowska-Gorycka A, Roszak M, Stypinska B, et al. IL-6 and TGF-β gene polymorphisms, their serum levels, as well as HLA profile, in patients with systemic lupus erythematosus [J]. Clin Exp Rheumatol, 2019, 37(6): 963-975.
[29]	Bona N, Pezzarini E, Balbi B, et al. Oxidative stress, inflammation and disease activity biomarkers in lupus nephropathy [J]. Lupus, 2020, 29(3): 311-323.
[30]	Gómez-Puerta JA, Ortiz-Reyes B, Urrego T, et al. Urinary neutrophil gelatinase-associated lipocalin and monocyte chemoattractant protein 1 as biomarkers for lupus nephritis in colombian SLE patients [J]. Lupus, 2018, 27(4): 637-646.
[31]	Correia de Sousa M, Gjorgjieva M, Dolicka D, et al. Deciphering miRNAs′ action through miRNA editing [J]. Int J Mol Sci, 2019, 20(24): 6249.
[32]	Cardenas-Gonzalez M, Srivastava A, Pavkovic M, et al. Identification, confirmation, and replication of novel urinary microRNA biomarkers inlupus nephritis and diabetic nephropathy [J]. Clin Chem, 2017, 63(9): 1515-1526.
[33]	Khoshmirsafa M, Kianmehr N, Falak R, et al. Elevated expression of miR-21 and miR-155 in peripheral blood mononuclear cells as potential biomarkers for lupus nephritis [J]. Int J Rheum Dis, 2019, 22(3): 458-467.
[34]	Tu Y, Guo R, Li J, et al. MiRNA regulation of MIF in SLE and attenuation of murine lupus nephritis with miR-654 [J]. Front Immunol, 2019, 10: 2229.
[35]	Cost NG, Noh PH, Devarajan P, et al. Urinary NGAL levels correlate with differential renal function in patients with ureteropelvic junction obstruction undergoing pyeloplasty [J]. J Urol, 2013, 190(4 Suppl): 1462-1467.
[36]	Aggarwal A, Gupta R, Negi VS, et al. Urinary haptoglobin, alpha-1 anti-chymotrypsin and retinol binding protein identified by proteomics as potential biomarkers for lupus nephritis [J]. Clin Exp Immunol, 2017, 188(2): 254-262.
[37]	Qin L, Stanley S, Ding H, et al. Urinary pro-thrombotic, anti-thrombotic, and fibrinolytic molecules as biomarkers of lupus nephritis [J]. Arthritis Res Ther, 2019, 21(1): 176.
[38]	Kanno Y, Miyashita M, Seishima M, et al. α2AP is associated with the development of lupus nephritis through the regulation of plasmin inhibition and inflammatory responses [J]. Immun Inflamm Dis, 2020, 8(3): 267-278.
[39]	Tokunaga Y, Imaoka H, Kaku Y, et al. The significance of CD163-expressing macrophages in asthma [J]. Ann Allergy Asthma Immunol, 2019, 123(3): 263-270.
[40]	Li J, Yu YF, Liu CH, et al. Significance of M2 macrophages in glomerulonephritis with crescents [J]. Pathol Res Pract, 2017, 213(9): 1215-1220.
[41]	Allam M, Fathy H, Allah DA, et al. Lupus nephritis: correlation of immunohistochemical expression of C4d, CD163-positive M2c-like macrophages and Foxp3-expressing regulatory T cells with disease activity and chronicity [J]. Lupus, 2020, 29(8): 943-953.
[42]	Gupta R, Yadav A, Aggarwal A. Urinary soluble CD163 is a good biomarker for renal disease activity in lupus nephritis [J]. Clin Rheumatol, 2021, 40(3): 941-948.
[43]	Mejia-Vilet JM, Zhang XL, Cruz C, et al. Urinary soluble CD163: a novel noninvasive biomarker of activity for lupus nephritis [J]. J Am Soc Nephrol, 2020, 31(6): 1335-1347.
[44]	Selvaraja M, Abdullah M, Arip M, et al. Elevated interleukin-25 and its association to Th2 cytokines in systemic lupus erythematosus with lupus nephritis [J]. PLoS One, 2019, 14(11): e0224707.
[45]	Li Y, Wang R, Liu S, et al. Interleukin-25 is upregulated in patients with systemic lupus erythematosus and ameliorates murine lupus by inhibiting inflammatory cytokine production [J]. Int Immunopharmacol, 2019, 74: 105680.
[46]	Chyuan IT, Tzeng HT, Chen JY. Signaling pathways of type I and type III Interferons and targeted therapies in systemic lupus erythematosus [J]. Cells, 2019, 8(9): 963.
[47]	Elkon KB, Wiedeman A. Type I IFN system in the development and manifestations of SLE [J]. Curr Opin Rheumatol, 2012, 24(5): 499-505.
[48]	Ding X, Ren Y, He X. IFN-I mediates lupus nephritis from the beginning to renal fibrosis [J]. Front Immunol, 2021, 12: 676082.
[49]	Devarapu SK, Kumar VS, Rupanagudi KV, et al. Reprint of " dual blockade of the pro-inflammatory chemokine CCL2 and the homeostatic chemokine CXCL12 is as effective as high dose cyclophosphamide in murine proliferative lupus nephritis" [J]. Clin Immunol, 2017, 185: 119-127.
[50]	Jakiela B, Kosaka J, Plutecka H, et al. Urinary cytokines and mRNA expression as biomarkers of disease activity in lupus nephritis [J]. Lupus, 2018, 27(8): 1259-1270.
[51]	Diaz-Rizo V, Bonilla-Lara D, Gonzalez-Lopez L, et al. Serum levels of adiponectin and leptin as biomarkers of proteinuria in lupus nephritis [J]. PLoS One, 2017, 12(9): e0184056.
[52]	Gamez-Nava JI, Diaz-Rizo V, Perez-Guerrero EE, et al. Assessment of serum macrophage migration inhibitory factor (MIF), adiponectin, and other adipokines as potential markers of proteinuria and renal dysfunction in lupus nephritis: a cross-sectional study [J]. Biomark Res, 2020, 8: 55.
[53]	Emad G, Al-Barshomy SM. Anti-C1q antibodies in lupus nephritis and their correlation with the disease activity [J]. Saudi J Kidney Dis Transpl, 2020, 31(2): 342-352.
[54]	程根阳，张娜，胡晓舟，等．多种抗体联合检测在狼疮性肾炎诊断中意义[J]．中华实用诊断与治疗杂志，2010，24(3)：295-296.

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Research progress in biomarkers of lupus nephritis

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