ANCA相关性小血管炎肾损害患者尿液肾损伤生物标志物的检测及意义
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摘要
目的:探讨ANCA相关性小血管炎(AASV)肾损害患者尿液中肾损伤生物标志物的表达及变化特点,以探寻在AASV早期诊断及治疗的应用价值。方法:用酶联免疫吸附法(ELISA)检测AASV组及对照组尿液β连环蛋白(β-catenin)、尿海藻糖酶(trehalase)、中性粒细胞明胶酶相关脂质运载蛋白分子(Neutrophil Gelatinase-Associated Lipocalin,NGAL),与血清ANCA及血肌酐(Scr)、胱抑素C(Cys C)、C-反应蛋白(CRP)、尿微量白蛋白/肌酐比值(ACR)、β2-微球蛋白(β2-M)等临床指标比较,建立患者的ROC曲线来评价尿液β-catenin、trehalase、NGAL对AASV的诊断及疾病活动的预测价值。结果:(1)AASV组患者尿液β-catenin(P<0.01)、trehalase(P<0.01)、NGAL(P<0.05)水平显著高于对照组,且尿液β-catenin、trehalase在AASV活动期与缓解期之间差异有统计学意义(P<0.01)。(2)与治疗前相比,活动期治疗后尿液β-catenin、trehalase水平明显下降(P<0.05)。(3)AASV患者尿β-catenin水平与Scr、β2-MG、ACR呈正相关,与GFR呈负相关(P<0.05);尿trehalase水平与β2-MG呈正相关(P<0.05);尿NGAL水平与BUN、Cys C、ACR呈正相关(P<0.05)。(4)尿液β-catenin、trehalase、NGAL诊断AASV肾损害的ROC曲线下面积(AUC)分别为0.966(P<0.001)、0.903(P<0.001)、0.752(P<0.05);尿β-catenin、trehalase判断AASV病情活动性的AUC均大于血清ANCA滴度(P<0.05)。结论:尿液β-catenin、trehalase、NGAL可能是诊断AASV敏感性和特异性较高的生物学标志物。
Objective: To investigate the expression and changes of urine biomarkers of renal injury in patients with ANCA associated small vessel vasculitis( AASV) for the potential value of early diagnosis and treatment of AASV. Methods: Urine biomarkers including beta catenin( β-catenin),urinary trehalase and neutrophil gelatinase associated lipocalin( NGALwere detected in AASV patients with enzyme-linked immunosorbent assay. The urine biomarkers were compared to serum ANCN and other clinical indicators.. The ROC curve of the urine biomarkers was established to evaluate the predictive value of diagnosis and disease activity of AASV patients. Results:( 1) The levels of urinary β-catenin,trehalase and NGAL in the AASV group were significantly higher than those in the normal control group. There was significant difference in urine β-catenin and trehalase between the active AASV group and the inactive AASV group.( 2) Compared to non-treatment group,urine β-catenin and trehalase levels were significantly decreased in the treatment group( P < 0. 05).( 3) Urinary β-catenin in AASV patients was positively correlated with Scr,β2-MG and ACR,negatively correlated with GFR( P < 0. 05). Urinary trehalase was positively associated with β2-MG( P < 0. 05). Urinary NGAL was positively correlated with BUN,Cys C and ACR( P < 0. 05).( 4) ROC curve area of urine β-catenin,trehalase and NGAL in diagnosis of renal damage in AASV was 0. 966,0. 903 and 0. 752,respectively. Area under the curve( AUC) of urine β-catenin,trehalase in judgment of AASV disease activity was higher than serum ANCA( P < 0. 05). Conclusion: Urinary β-catenin,trehalase and NGAL may be biomarkers with high sensitivity and specificity for the diagnosis of AASV.
Objective: To investigate the expression and changes of urine biomarkers of renal injury in patients with ANCA associated small vessel vasculitis( AASV) for the potential value of early diagnosis and treatment of AASV. Methods: Urine biomarkers including beta catenin( β-catenin),urinary trehalase and neutrophil gelatinase associated lipocalin( NGALwere detected in AASV patients with enzyme-linked immunosorbent assay. The urine biomarkers were compared to serum ANCN and other clinical indicators.. The ROC curve of the urine biomarkers was established to evaluate the predictive value of diagnosis and disease activity of AASV patients. Results:( 1) The levels of urinary β-catenin,trehalase and NGAL in the AASV group were significantly higher than those in the normal control group. There was significant difference in urine β-catenin and trehalase between the active AASV group and the inactive AASV group.( 2) Compared to non-treatment group,urine β-catenin and trehalase levels were significantly decreased in the treatment group( P < 0. 05).( 3) Urinary β-catenin in AASV patients was positively correlated with Scr,β2-MG and ACR,negatively correlated with GFR( P < 0. 05). Urinary trehalase was positively associated with β2-MG( P < 0. 05). Urinary NGAL was positively correlated with BUN,Cys C and ACR( P < 0. 05).( 4) ROC curve area of urine β-catenin,trehalase and NGAL in diagnosis of renal damage in AASV was 0. 966,0. 903 and 0. 752,respectively. Area under the curve( AUC) of urine β-catenin,trehalase in judgment of AASV disease activity was higher than serum ANCA( P < 0. 05). Conclusion: Urinary β-catenin,trehalase and NGAL may be biomarkers with high sensitivity and specificity for the diagnosis of AASV.
引文
1.陈旻,于峰,张颖,等.426例抗中性粒细胞胞浆抗体相关性小血管炎患者多系统临床表现和肾脏病理分析.中华内科杂志,2005,44(11):828-831.
2 .Achenbach J,Mengel M,Tossidou I,et al.Parietal epithelia cells in the urine as a marker of disease activity in glomerular diseases.Nephrol Dial Transplant,2008,23(10):3138-3145.
3 .Ishihara R,Taketani S,Sasai-Takedatsu M,et al.ELISA for urinary trehalase with monoclonal antibodies:a technique for assessment of renal tubular damage.Clin Chem,2000,46(5):636-643.
4 .崔路可,龚蓉.NGAL在肾脏病领域的研究新进展.中国中西医结合肾病杂志,2014,15(12):1123-1125.
5 .Jennette JC,Falk RJ,Bacon PA,et al.2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides.Arthritis Rheum,2013,65(1):1-11.
6 .胡伟新,黎磊石.系统性血管炎肾脏损害.见:黎磊石,刘志红主编.中国肾脏病学.北京:人民军医出版社,2008.523-554.
7 .Mukhtyar C,Lee R,Brown D,et al.Modification and validation of the Birmingham Vasculitis Activity Score(Version 3).Ann Rheum Dis,2009,68(12):1827-1832.
8 .Hellmich B,Flossmann O,Gross WL,et al.EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis:focus on anti-neutrophil cytoplasm antibody-associated vasculitis.Ann Rheum Dis,2007,66(5):605-617.
9 .Peschel A,Basu N,Benharkou A,et al.Autoantibodies to h LAMP-2 in ANCA-negative pauci-immune focal necrotizing GN.J Am Soc Nephrol,2014,25(3):455-463.
10 .Sangaletti S,Tripodo C,Chiodoni C,et al.Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity.Blood,2012,120(15):3007-3018.
11 .Chen M,Xing GQ,Yu F,et al.Complement deposition in renal histopathology of patients with ANCA-associated pauci-immune glomerulonephritis.Nephrol Dial Transplant,2009,24(4):1247-1252.
12 .曾玲玲,胡章学.ANCA相关性小血管炎诱导缓解治疗进展.中国中西医结合肾病杂志,2015,16(1):85-87.
13 .Syed R,Rehman A,Valecha G,et al.Pauci-Immune Crescentic Glomerulonephritis:An ANCA-Associated Vasculitis.Bio Med Res Int,2015,2015(3):1-8.
14 .胡伟新,刘春蓓,谢红浪,等.霉酚酸酯与环磷酰胺治疗ANCA相关血管炎的临床对照研究.肾脏病与透析肾移植杂志,2005,24(6):501-507.
15 .Roth AJ,Ooi JD,Hess JJ,et al.Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis.J Clin Invest,2013,123(4):1773-1783.
16 .Kawai H,Banno S,Kikuchi S,et al.Retrospective analysis of factors predicting end-stage renal failure or death in patients with microscopic polyangiitis with mainly renal involvement.Clin Exp Nephrol,2014,18(5):795-802.
17 .李毅,张燕,赵明,等.抗中性粒细胞胞浆抗体相关性血管炎患者血清C反应蛋白水平及临床意义.临床肾脏病杂志,2014,14(4):226-229.
18 .刘霞,陈樱花,刘正钊,等.抗中性粒细胞胞质抗体相关性新月体肾炎治疗反应及远期预后的影响因素.肾脏病与透析肾移植杂志,2016,25(2):113-118.
19 .Grouls S,Iglesias DM,Wentzensen N,et al.Lineage specification of parietal epithelial cells requires beta-catenin/Wnt signaling.J Am Soc Nephrol,2012,23(1):63-72.
20 .Bennett M,Dent CL,Ma Q,et al.Urine NGAL predicts severity of acute kidney injury after cardiac surgery:a prospective study.Clin J Am Soc Nephrol,2008,3(3):665-673.
21 .Lieberthal JG,Cuthbertson D,Carette S,et al.urinary biomarkers in relapsing antineutrophil cytoplasmic antibody-associated vasculitis.J Rheumatol,2013,40(5):674-683.
2 .Achenbach J,Mengel M,Tossidou I,et al.Parietal epithelia cells in the urine as a marker of disease activity in glomerular diseases.Nephrol Dial Transplant,2008,23(10):3138-3145.
3 .Ishihara R,Taketani S,Sasai-Takedatsu M,et al.ELISA for urinary trehalase with monoclonal antibodies:a technique for assessment of renal tubular damage.Clin Chem,2000,46(5):636-643.
4 .崔路可,龚蓉.NGAL在肾脏病领域的研究新进展.中国中西医结合肾病杂志,2014,15(12):1123-1125.
5 .Jennette JC,Falk RJ,Bacon PA,et al.2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides.Arthritis Rheum,2013,65(1):1-11.
6 .胡伟新,黎磊石.系统性血管炎肾脏损害.见:黎磊石,刘志红主编.中国肾脏病学.北京:人民军医出版社,2008.523-554.
7 .Mukhtyar C,Lee R,Brown D,et al.Modification and validation of the Birmingham Vasculitis Activity Score(Version 3).Ann Rheum Dis,2009,68(12):1827-1832.
8 .Hellmich B,Flossmann O,Gross WL,et al.EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis:focus on anti-neutrophil cytoplasm antibody-associated vasculitis.Ann Rheum Dis,2007,66(5):605-617.
9 .Peschel A,Basu N,Benharkou A,et al.Autoantibodies to h LAMP-2 in ANCA-negative pauci-immune focal necrotizing GN.J Am Soc Nephrol,2014,25(3):455-463.
10 .Sangaletti S,Tripodo C,Chiodoni C,et al.Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity.Blood,2012,120(15):3007-3018.
11 .Chen M,Xing GQ,Yu F,et al.Complement deposition in renal histopathology of patients with ANCA-associated pauci-immune glomerulonephritis.Nephrol Dial Transplant,2009,24(4):1247-1252.
12 .曾玲玲,胡章学.ANCA相关性小血管炎诱导缓解治疗进展.中国中西医结合肾病杂志,2015,16(1):85-87.
13 .Syed R,Rehman A,Valecha G,et al.Pauci-Immune Crescentic Glomerulonephritis:An ANCA-Associated Vasculitis.Bio Med Res Int,2015,2015(3):1-8.
14 .胡伟新,刘春蓓,谢红浪,等.霉酚酸酯与环磷酰胺治疗ANCA相关血管炎的临床对照研究.肾脏病与透析肾移植杂志,2005,24(6):501-507.
15 .Roth AJ,Ooi JD,Hess JJ,et al.Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis.J Clin Invest,2013,123(4):1773-1783.
16 .Kawai H,Banno S,Kikuchi S,et al.Retrospective analysis of factors predicting end-stage renal failure or death in patients with microscopic polyangiitis with mainly renal involvement.Clin Exp Nephrol,2014,18(5):795-802.
17 .李毅,张燕,赵明,等.抗中性粒细胞胞浆抗体相关性血管炎患者血清C反应蛋白水平及临床意义.临床肾脏病杂志,2014,14(4):226-229.
18 .刘霞,陈樱花,刘正钊,等.抗中性粒细胞胞质抗体相关性新月体肾炎治疗反应及远期预后的影响因素.肾脏病与透析肾移植杂志,2016,25(2):113-118.
19 .Grouls S,Iglesias DM,Wentzensen N,et al.Lineage specification of parietal epithelial cells requires beta-catenin/Wnt signaling.J Am Soc Nephrol,2012,23(1):63-72.
20 .Bennett M,Dent CL,Ma Q,et al.Urine NGAL predicts severity of acute kidney injury after cardiac surgery:a prospective study.Clin J Am Soc Nephrol,2008,3(3):665-673.
21 .Lieberthal JG,Cuthbertson D,Carette S,et al.urinary biomarkers in relapsing antineutrophil cytoplasmic antibody-associated vasculitis.J Rheumatol,2013,40(5):674-683.