切换至 "中华医学电子期刊资源库"
高级检索
中华肾病研究电子杂志

中华肾病研究电子杂志 ›› 2022, Vol. 11 ›› Issue (05) : 241 -248. doi: 10.3877/cma.j.issn.2095-3216.2022.05.001

论著

低剂量免疫抑制剂治疗轻中症ANCA相关性肾血管炎的效果和肾脏预后分析
李子扬1, 包继文1, 尧欢珍1, 张敏芳1, 顾乐怡1, 倪兆慧1, 王玲1,†()   
  1. 1. 200120　上海交通大学医学院附属仁济医院肾脏科
  • 收稿日期:2021-09-29 出版日期:2022-10-28
  • 通信作者: 王玲

Analysis of the efficacy and renal prognosis of reduced-dose immunosuppressive regimen in patients with mild to moderate ANCA-associated renal vasculitis

Ziyang Li1, Jiwen Bao1, Huanzhen Yao1, Minfang Zhang1, Leyi Gu1, Zhaohui Ni1, Ling Wang1,†()   

  1. 1. Department of Nephrology, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200120, China
  • Received:2021-09-29 Published:2022-10-28
  • Corresponding author: Ling Wang
全文 ( ) 下载PDF ( ) 导出引用
引用本文：

李子扬, 包继文, 尧欢珍, 张敏芳, 顾乐怡, 倪兆慧, 王玲. 低剂量免疫抑制剂治疗轻中症ANCA相关性肾血管炎的效果和肾脏预后分析[J]. 中华肾病研究电子杂志, 2022, 11(05): 241-248.

Ziyang Li, Jiwen Bao, Huanzhen Yao, Minfang Zhang, Leyi Gu, Zhaohui Ni, Ling Wang. Analysis of the efficacy and renal prognosis of reduced-dose immunosuppressive regimen in patients with mild to moderate ANCA-associated renal vasculitis[J]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2022, 11(05): 241-248.

目的

高剂量免疫抑制剂治疗导致的继发感染是ANCA相关性血管炎患者最常见的死亡原因，本研究旨在探索低剂量的免疫抑制剂治疗是否可以在减少轻中症ANCA相关性肾血管炎患者继发感染的同时达到有效缓解，并分析治疗早期继发感染是否会加速肾功能的恶化。

方法

使用Fisher精确概率法比较初始糖皮质激素减量联合低频次静脉冲击环磷酰胺与标准方案的疗效及安全性差异；使用Kaplan-Meier生存曲线和Log-rank检验比较各因素影响下的肾脏存活率，将其中P<0.05的因素纳入多因素Cox风险回归模型以确定导致终末期肾病(ESRD)的危险因素，再使用受试者工作特征(ROC)曲线评价该危险因素的敏感性和特异性。

结果

最终纳入58例患者，其中标准方案组35例、初始糖皮质激素减量组23例。纳入患者的平均年龄是(62.45±12.70)岁，平均基线血肌酐水平是251.35 μmol/L。24个月内有9例(15.52%)进展为ESRD(标准方案组7例，初始糖皮质激素减量组2例，P＝0.21)，治疗3个月后有10例发生继发感染(标准方案组9例，初始糖皮质激素减量组1例，P＝0.035)。多因素Cox风险回归模型显示：基线血肌酐(HR 1.01, 95%CI: 1.001~1.014, P＝0.014)、初治3个月内继发感染(HR 9.83, 95%CI: 2.14~45.27, P＝0.003)、接受治疗后持续性血尿超过6个月(HR 5.60, 95%CI: 1.36~23.18, P＝0.017)是ANCA相关性肾血管炎患者进展为ESRD的危险因素。

结论

对轻中症ANCA相关性肾血管炎患者，初始糖皮质激素减量联合低频次静脉冲击环磷酰胺方案可明显降低继发感染率，且疗效不弱于标准方案。初治3个月内继发感染的患者早期进展为ESRD的风险更高。

关键词: ANCA相关性肾血管炎, 终末期肾病, 继发感染, 减量糖皮质激素, 环磷酰胺低频次静脉冲击
Objective

Secondary infection caused by high-dose immunosuppressive therapy is the most common cause of death in patients with ANCA-associated vasculitis. This study aimed to explore whether reduced-dose of immunosuppressive therapy could achieve effective remission together with less secondary infection in patients with mild to moderate ANCA-associated renal vasculitis, and to determine whether early secondary infections could accelerate the deterioration of renal function.

Methods

The efficacy and safety of reduced-dose regimen and standard regimen were compared with Fisher′s precision probability test. The renal survival rate was estimated with the Kaplan-Meier method and compared with the log-rank test. Potential variates were examined by means of the multivariate Cox hazard regression model to determine the risk factors of end-stage renal disease, while the receiver operating characteristic (ROC) curve was applied to evaluate the sensitivity and specificity of the risk factors.

Results

A total of 58 patients were included, with 35 patients in the standard-dose glucocorticoids group and 23 in the reduced-dose glucocorticoids group. The average age of the included patients was 62.45±12.70 years, and the baseline serum creatinine was 251.35 μmol/L. 9 patients (15.52%) developed end-stage renal disease (ESRD) within 24 months (7 from the standard regimen group and 2 from the reduced-dose regemen group, P=0.21). 10 patients developed secondary infection 3 months after treatment (9 from the standard regimen group and 1 from the reduced-dose regemen group, P=0.035). Multivariate Cox regression model analysis displayed that the baseline serum creatinine (HR 0.007, 95%CI: 2.48-39.48, P=0.014), secondary infection rate within first 3 months (HR 2.28, 95% CI: 2.14-45.27, P=0.003), and persistent hematuria for more than 6 months (HR 1.723, 95%CI: 0.043-0.738, P=0.017) were risk factors of ESRD in patients with ANCA-associated renal vasculitis.

Conclusion

The regimen of initial reduced-dose immunosuppressive therapy could significantly reduce the secondary infection rate in patients with mild to moderate ANCA-associated renal vasculitis, while the efficacy was not inferior to that of the standard regimen. Patients who had secondary infection within the first 3 months of treatment were at higher risk of early progression to ESRD.

Key words: ANCA-associated renal vasculitis, End-stage renal disease, Secondary infection, Reduced-dose glucocorticoids, Reduced-frequency intravenous pulse therapy of cyclophosphamide
图1 研究对象筛选分组及预后流程注：AAV：ANCA相关性血管炎；ESRD，终末期肾病
表1 ANCA相关性肾血管炎患者的临床特点及结局
项目 全部患者(n＝58) 标准方案组(n＝35) 初始糖皮质激素减量组(n＝23) P值
基线数据        
  年龄 62.45±12.70 61.14±12.19 64.44±13.47 0.92
  性别(女/男) 42/16 25/10 17/6 0.54
  MPA/GPA 53/5 34/1 19/4 0.08
  BVAS 13.24±2.15 13.00±2.02 13.61±2.31 0.20
  血肌酐(μmol/L) 251(156, 445) 285(164, 463) 210(152, 346) 0.29
  UACR (mg/g) 875(514, 1404) 868(586, 1338) 878(376, 1723) 0.79
  白蛋白≤25 g/L 2 0 2 0.15
  淋巴细胞比例≤10% 10 6 4 0.62
  CRP (mg/L) 8.1(2.4, 35.6) 5.4(2.4, 27.1) 13(0.7, 46.0) 0.29
  ESR (mm/h) 78±34 84±33 68±34 0.74
肾外及全身表现(例)        
  发热 7 4 3 0.58
  关节痛 6 4 2 0.55
  体重下降至少2 kg 4 1 3 0.17
  肺部渗出 9 4 5 0.24
  胸腔积液 4 2 2 0.52
既往史(例)        
  高血压 39 24 15 0.51
  糖尿病 12 9 3 0.20
  慢性肺部疾病 10 4 6 0.04
随访时间(月) 17(8, 31) 25(9, 39) 12(6, 24) 0.10
环磷酰胺累积量(g)        
  3个月 1.24±0.63 1.28±0.65 1.18±0.59 0.60
  6个月 2.57±1.17 2.67±1.20 2.40±1.13 0.76
24个月结局[例(%)]        
  终末期肾病 9(15.52) 7(20) 2(8.7) 0.21
3个月结局[例(%)]        
  缓解率 49(84.48) 30 (85.71) 19(82.61) 0.51
  继发感染率 10(17.24) 9(25.72) 1(4.35) 0.04
  ANCA转阴率 28(48.28) 18(51.43) 10(43.48) 0.37
  肌酐下降率 28(9, 43) 27(15, 42) 28(2, 51) 0.70
6个月结局[例(%)]        
  缓解率 50(86.21) 29(82.86) 21(91.30) 0.31
  继发感染率 15(25.86) 10(28.57) 5(21.74) 0.40
  持续性血尿 13(22.31) 9(25.71) 4(17.39) 0.34
  不良反应 17(29.31) 10(28.57) 7(30.43) 0.55
图2 标准方案组和初始糖皮质激素减量组终末期肾病发生率和3个月继发感染率比较
图3 基线血肌酐≥200 μmol/L与基线血肌酐<200 μmol/L的肾脏存活率比较(Kaplan-Meier生存曲线)
图4 3个月内有无继发感染肾脏存活率比较(Kaplan-Meier生存曲线)
图5 6个月内血尿消失或持续肾脏存活率比较(Kaplan-Meier生存曲线)
图6 伯明翰评分≥15或<15的肾脏存活率比较(Kaplan-Meier生存曲线)注：BVAS：伯明翰评分
图7 尿白蛋白肌酐比≥3 500 mg/g或<3 500 mg/g的肾脏存活率比较(Kaplan-Meier生存曲线)注：UACR：尿白蛋白肌酐比
表2 终末期肾病患者多因素分析(Kaplan-Meier分析)
因素 Log-rank检验P值
基线血肌酐 0.013
3个月内继发感染 <0.001
6个月持续性血尿 0.003
BVAS≥15 0.016
UACR>3 500 mg/g 0.015
3个月内ANCA转阴 0.692
年龄≥65岁 0.891
白蛋白≤25 g/L 0.606
淋巴细胞比≤10% 0.799
高血压 0.459
糖尿病 0.383
慢性肺部疾病 0.536
表3 多因素COX回归分析
  HR 95%CI P值
基线血肌酐 1.008 1.001~1.014 0.014
3个月内继发感染 9.835 2.137~45.270 0.003
6个月持续性血尿 5.603 1.355~23.181 0.017
BVAS≥15 － － 0.759
UACR>3 500 mg/g － － 0.178
图8 基线血肌酐、3个月内继发感染和持续性血尿超过6个月对ESRD的预测价值评价
表4 基线血肌酐预测终末期肾病的各临界值对应的灵敏度和特异度
截断值 灵敏度 特异度 约登指数
61.00 1.00 0.00 0.00
63.50 1.00 0.02 0.02
72.00 1.00 0.04 0.04
81.50 1.00 0.06 0.06
88.50 1.00 0.08 0.08
93.50 1.00 0.10 0.10
96.00 1.00 0.12 0.12
107.50 1.00 0.14 0.14
119.00 1.00 0.18 0.18
125.50 1.00 0.20 0.20
133.95 1.00 0.22 0.22
140.95 1.00 0.24 0.24
148.00 1.00 0.27 0.27
154.35 1.00 0.29 0.29
158.85 1.00 0.31 0.31
162.50 1.00 0.33 0.33
167.50 1.00 0.35 0.35
171.50 1.00 0.37 0.37
172.50 1.00 0.39 0.39
175.50 1.00 0.41 0.41
183.50 1.00 0.43 0.43
195.50 1.00 0.45 0.45
203.50 1.00 0.47 0.47
207.50 1.00 0.49 0.49
214.50 1.00 0.51 0.51
223.50 1.00 0.53 0.53
235.00 1.00 0.55 0.55
244.85 1.00 0.57 0.57
251.35 1.00 0.59 0.59
258.50 1.00 0.63 0.63
273.50 1.00 0.65 0.65
288.50 1.00 0.67 0.67
310.00 0.89 0.67 0.56
336.50 0.89 0.69 0.58
345.50 0.89 0.71 0.60
356.00 0.89 0.73 0.62
368.40 0.89 0.76 0.64
371.90 0.89 0.78 0.66
380.00 0.78 0.78 0.55
388.30 0.67 0.78 0.44
398.80 0.67 0.80 0.46
424.50 0.56 0.80 0.35
449.00 0.56 0.82 0.37
460.00 0.44 0.84 0.28
465.00 0.33 0.84 0.17
473.20 0.22 0.84 0.06
488.20 0.22 0.86 0.08
500.50 0.11 0.86 －0.03
517.00 0.11 0.88 －0.01
532.00 0.11 0.90 0.01
538.50 0.11 0.92 0.03
546.00 0.11 0.94 0.05
581.00 0.11 0.96 0.07
627.00 0.11 0.98 0.09
719.50 0.11 1.00 0.11
799.00 0.00 1.00 0.00
表5 三类危险因素的敏感性分析结果和AUC结果
  灵敏度(%) 特异度(%) AUC P值
基线血肌酐 100 67 0.82 0.002
3个月内继发感染 66.67 91.84 0.79 0.006
血尿持续超过6个月 55.56 83.67 0.74 0.022
[1]
Li Z, Ma T, Chen M, et al. The prevalence and management of anti-neutrophil cytoplasmic antibody-associated vasculitis in China [J]. Kidney Dis (Basel), 2016, 1(4): 216-223.
[2]
Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides [J]. Arthritis Rheum, 2013, 65(1): 1-11.
[3]
Jones R, Tervaert J, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis [J]. N Engl J Med, 2010, 363(3): 211-220.
[4]
Millet A, Pederzoli-Ribeil M, Guillevin L, et al. Antineutrophil cytoplasmic antibody-associated vasculitides: is it time to split up the group? [J]. Ann Rheum Dis, 2013, 72(8): 1273-1279.
[5]
Geetha D, Jefferson J. ANCA-associated vasculitis: Core Curriculum 2020 [J]. Am J Kidney Dis, 2020, 75(1): 124-137.
[6]
de Groot K, Harper L, Jayne D, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial [J]. Ann Intern Med, 2009, 150(10): 670-680.
[7]
Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of primary small and medium vessel vasculitis [J]. Ann Rheum Dis, 2009, 68(3): 310-317.
[8]
Koukoulaki M, Iatrou C. The role of mycophenolate in the treatment of antineutrophil cytoplasmic antibody-associated vasculitis [J]. World J Nephrol, 2019, 8(4): 75-82.
[9]
Faurschou M, Westman K, Rasmussen N, et al. Brief report: long-term outcome of a randomized clinical trial comparing methotrexate to cyclophosphamide for remission induction in early systemic antineutrophil cytoplasmic antibody-associated vasculitis [J]. Arthritis Rheum, 2012, 64(10): 3472-3477.
[10]
Stone J, Merkel P, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis [J]. N Engl J Med, 2010, 363(3): 221-32.
[11]
Pepper R, McAdoo S, Moran S, et al. A novel glucocorticoid-free maintenance regimen for anti-neutrophil cytoplasm antibody-associated vasculitis [J]. Rheumatology (Oxford), 2019, 58(2): 260-268.
[12]
Walsh M, Merkel P, Peh C, et al. Plasma exchange and glucocorticoids in severe ANCA-associated vasculitis [J]. N Engl J Med, 2020, 382(7): 622-631.
[13]
Little M, Nightingale P, Verburgh CA, et al. Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis [J]. Ann Rheum Dis, 2010, 69(6): 1036-1043.
[14]
Lai Q, Ma T, Li Z, et al. Predictors for mortality in patients with antineutrophil cytoplasmic autoantibody-associated vasculitis: a study of 398 Chinese patients [J]. J Rheumatol, 2014, 41(9): 1849-1855.
[15]
Haris á，Polner K, Arányi J, et al. Simple, readily available clinical indices predict early and late mortality among patients with ANCA-associated vasculitis [J]. BMC Nephrol, 2017, 18(1): 76.
[16]
Konstantinov K, Ulff-Møller C, Tzamaloukas A. Infections and antineutrophil cytoplasmic antibodies: triggering mechanisms [J]. Autoimmun Rev, 2015, 14(3): 201-203.
[17]
Nakazawa D, Shida H, Tomaru U, et al. Enhanced formation and disordered regulation of NETs in myeloperoxidase-ANCA-associated microscopic polyangiitis [J]. J Am Soc Nephrol, 2014, 25(5): 990-997.
[18]
Yates M, Watts R, Bajema I, et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis [J]. Ann Rheum Dis, 2016, 75(9)：1583-1594.
[19]
Goupil R, Brachemi S, Nadeau-Fredette A, et al. Lymphopenia and treatment-related infectious complications in ANCA-associated vasculitis [J]. Clin J Am Soc Nephrol, 2013, 8(3): 416-423.
[20]
Walsh M, Casian A, Flossmann O, et al. Long-term follow-up of patients with severe ANCA-associated vasculitis comparing plasma exchange to intravenous methylprednisolone treatment is unclear [J]. Kidney Int, 2013, 84(2): 397-402.
[21]
Charlier C, Henegar C, Launay O, et al. Risk factors for major infections in Wegener granulomatosis: analysis of 113 patients [J]. Ann Rheum Dis, 2009, 68(5): 658-663.
[22]
Tanaka H, Yamaguchi M, Katsuno T, et al. Association between sinusitis and relapse and changes in the myeloperoxidase-antineutrophil cytoplasmic antibody in microscopic polyangiitis [J]. PLoS One, 2020, 15(12): e0243572.
[23]
Zycinska K, Wardyn K, Zielonka T, et al. Chronic crusting, nasal carriage of Staphylococcus aureus and relapse rate in pulmonary Wegener′s granulomatosis [J]. J Physiol Pharmacol, 2008, 59(Suppl 6): 825-831.
[24]
Zandbergen G, Gieffers J, Kothe H, et al. Chlamydia pneumoniae multiply in neutrophil granulocytes and delay their spontaneous apoptosis [J]. J Immunol, 2004, 172(3): 1768-1776.
[1] 黄莺, 张炜, 杨清銮, 张冰琰, 邵凌云, 张文宏. 慢性脑膜炎脑脊液引流继发感染的相关危险因素[J]. 中华实验和临床感染病杂志(电子版), 2017, 11(06): 582-586.
[2] 吴红兵, 王志维, 李罗成, 任宗力, 胡俊霞, 宋鹏, 阮永乐. 心肾联合移植治疗终末期心肾疾病二例经验总结[J]. 中华移植杂志(电子版), 2022, 16(06): 369-372.
[3] 王婷燕, 申颖娇, 王爱平, 姚明凤. 递增式血液透析对终末期肾病患者肾功能、微炎症及死亡率的影响[J]. 中华肾病研究电子杂志, 2022, 11(04): 197-201.
[4] 张茵英, 吴茵, 赵鑫. 315例终末期肾病血液透析患者生活质量的调查分析[J]. 中华肾病研究电子杂志, 2019, 08(06): 253-257.
[5] 方蔷, 陈艳, 姜东升. 维持性血液透析患者抑郁发病率调查及其危险因素分析[J]. 中华肾病研究电子杂志, 2018, 07(05): 207-210.
[6] 曾庆亚, 佟颜杉, 孙亮, 牟洪宾, 陈蕊, 毕光宇, 刘昌华. Klotho G-395A基因多态性与ESRD患者钙磷代谢紊乱的相关性分析[J]. 中华肾病研究电子杂志, 2018, 07(05): 203-206.
[7] 关天俊. 终末期糖尿病肾病患者透析方式的选择[J]. 中华肾病研究电子杂志, 2016, 05(04): 159-162.
[8] 那宇, 柳慧敏. 高通量透析的研究进展[J]. 中华肾病研究电子杂志, 2015, 04(03): 123-126.
[9] 黄岩龙, 黄海长, 王文堂, 王威, 薛庄安, 章友康. 家族性青少年高尿酸血症肾病家系患者尿调节素编码基因突变位点研究[J]. 中华肾病研究电子杂志, 2015, 04(02): 87-91.
[10] 倪兆慧, 金海姣. 自动化腹膜透析的新应用[J]. 中华肾病研究电子杂志, 2015, 04(01): 10-13.
[11] 张赟辉, 罗军, 刘栗丽, 汪宏, 耿克明. 腹膜透析与血液透析对老年终末期肾病患者营养状况及炎症反应的影响[J]. 中华临床医师杂志(电子版), 2023, 17(04): 419-423.
[12] 李启春, 王峰. 拉萨维持性血液透析患者肾移植意愿调查研究[J]. 中华临床医师杂志(电子版), 2020, 14(07): 562-568.
[13] 白明悦, 杨淑娜, 胡红梅, 胡文立. 透析患者脑小血管病患病情况的研究现状及其机制探讨[J]. 中华脑血管病杂志(电子版), 2023, 17(05): 505-509.
阅读次数
全文


摘要

版权所有 中华医学会 中华医学电子音像出版社有限责任公司  京ICP备14006079号-1  网络出版服务许可证：(署)网出证(京)字第075号