Change in levels of molecules related to inflammation and immune regulation in peripheral blood of patients with lupus nephritis and their values in predicting prognosis
-
摘要:目的
分析狼疮性肾炎(LN)患者外周血高迁移率族蛋白B1(HMGB1)、白细胞介素-32(IL-32)、基质金属蛋白酶-9(MMP-9)/基质金属蛋白酶抑制剂-1(TIMP-1)水平变化及其预测预后的价值。
方法选取2021年10月—2023年6月收治的86例LN患者为研究对象, 均给予诱导治疗6个月，再根据病情缓解情况分为缓解组(66例)和无反应组(20例)。比较2组基线资料、HMGB1、IL-32、MMP-9/TIMP-1水平变化及降低率; 分析外周血HMGB1、IL-32、MMP-9/TIMP-1水平降低率与治疗应答的偏相关性以及预测治疗应答的价值; 比较不同HMGB1、IL-32、MMP-9/TIMP-1降低率患者病情进展情况。
结果缓解组治疗1、3个月后HMGB1、IL-32、MMP-9/TIMP-1水平较治疗前降低，差异有统计学意义(P < 0.05); 缓解组治疗1、3个月后HMGB1、IL-32、MMP-9/TIMP-1水平低于无反应组，差异有统计学意义(P < 0.05); 缓解组治疗1、3个月后HMGB1、IL-32、MMP-9/TIMP-1水平降低率高于无反应组，差异有统计学意义(P < 0.05)。偏相关性分析显示, HMGB1、IL-32、MMP-9/TIMP-1水平降低率与治疗应答独立相关(P < 0.05); 治疗1、3个月后, HMGB1、IL-32、MMP-9/TIMP-1水平降低率联合预测缓解的曲线下面积(AUC)分别为0.910、0.932, 其中治疗3个月后联合预测的AUC最大，差异有统计学意义(P < 0.05)。根据治疗3个月后ROC曲线分析的最佳截断值将患者分为高降低率亚组和低降低率亚组, HMGB1、IL-32、MMP-9/TIMP-1高降低率亚组患者病情进展率低于低降低率亚组，差异有统计学意义(P < 0.05)。
结论LN患者外周血HMGB1、IL-32、MMP-9/TIMP-1高水平变化与治疗应答、病情进展显著相关，治疗1、3个月后HMGB1、IL-32、MMP-9/TIMP-1联合预测LN患者治疗应答的价值较高。
Abstract:ObjectiveTo analyze the change in levels of high mobility group box 1 protein (HMGB1), interleukin-32 (IL-32), matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinase-1 (TIMP-1) in peripheral blood of patients with lupus nephritis (LN) and their values in predicting prognosis.
MethodsA total of 86 patients with LN from October 2021 to June 2023 were selected and treated with induction therapy for 6 months. Based on remission status of the disease, patients were divided into remission group (n=66) and non-responder group (n=20). Baseline data, change in levels and reduction rates of HMGB1, IL-32 and MMP-9/TIMP-1, and the partial correlation of reduction rates of HMGB1, IL-32 and MMP-9/TIMP-1 levels in peripheral blood with treatment response as well as their predictive values for treatment response were compared between the two groups. Disease progression was compared between patients with different reduction rates of HMGB1, IL-32 and MMP-9/TIMP-1.
ResultsHMGB1, IL-32 and MMP-9/TIMP-1 levels in the remission group decreased significantly at 1 and 3 months after treatment compared to before treatment (P < 0.05); the levels of HMGB1, IL-32 and MMP-9/TIMP-1 in the remission group were significantly lower than those in the non-responder group at 1 and 3 months after treatment (P < 0.05); the reduction rates of HMGB1, IL-32 and MMP-9/TIMP-1 levels in the remission group were significantly higher than those in the non-responder group at 1 and 3 months after treatment (P < 0.05). Partial correlation analysis showed that the reduction rates of HMGB1, IL-32 and MMP-9/TIMP-1 levels were independently significantly correlated with treatment response (P < 0.05). One and three months after treatment, the values of the area under the curve (AUC) for the combined prediction of remission by the reduction rates of HMGB1, IL-32 and MMP-9/TIMP-1 levels were 0.910 and 0.932 respectively, with the AUC being the largest at 3 months after treatment (P < 0.05). Patients were divided into high and low reduction rate subgroups based on theoptimal cut-off value from the ROC curve analysis at 3 months after treatment, and the disease progression rate was significantly lower in the high reduction rate subgroup than in the low reduction rate subgroup for HMGB1, IL-32 and MMP-9/TIMP-1 (P < 0.05).
ConclusionThe great change in levels of HMGB1, IL-32 and MMP-9/TIMP-1 in peripheral blood of LN patients is significantly correlated with treatment response and disease progression, and the combined detections of HMGB1, IL-32 and MMP-9/TIMP-1 levels at 1 and 3 months after treatment have high value in predicting the treatment response of LN patients.
-
-
表 1 2组基线资料比较(x±s)[n(%)]
基线资料 分类 无反应组(n=20) 缓解组(n=66) t/χ2 P 年龄/岁 35.68±11.01 33.99±10.84 0.609 0.544 性别 男 6(30.00) 16(24.24) 0.267 0.605 女 14(70.00) 50(75.76) 体质量指数/(kg/m2) 23.70±0.63 23.81±0.59 0.719 0.474 糖尿病 3(15.00) 6(9.09) 0.115 0.734 高血压 2(10.00) 4(6.06) 0.011 0.916 冠心病 1(5.00) 2(3.03) 0.076 0.783 临床分型 肾病综合征 9(45.00) 31(46.97) 0.755 0.450 孤立性血尿/蛋白尿 6(30.00) 18(27.27) 急性肾炎 5(25.00) 17(25.76) 病理分型 Ⅰ型 1(5.00) 2(3.03) 0.069 0.962 Ⅱ型 2(10.00) 8(12.12) Ⅲ型 7(35.00) 25(37.88) Ⅳ型 8(40.00) 27(40.91) Ⅴ型 2(10.00) 4(6.06) 有肾外表现 11(55.00) 32(48.48) 0.261 0.610 疾病活动度 轻度 2(10.00) 4(6.06) 0.777 0.678 中度 6(30.00) 26(39.39) 重度 12(60.00) 36(54.55) 
下载: 导出CSV
表 2 2组外周血HMGB1、IL-32、MMP-9/TIMP-1水平变化比较(x±s)
指标 组别 n 治疗前 治疗1个月后 治疗3个月后 HMGB1/(μg/L) 无反应组 20 80.91±16.04 78.56±13.48# 76.85±15.29# 缓解组 66 82.83±14.60 69.04±10.71* 61.37±17.60* IL-32/(pg/mL) 无反应组 20 16.00±5.36 15.48±5.08# 15.26±4.99# 缓解组 66 15.79±5.21 8.63±2.71* 4.02±1.27* MMP-9/TIMP-1 无反应组 20 1.39±0.41 1.29±0.43# 1.23±0.40# 缓解组 66 1.42±0.45 1.01±0.33* 0.84±0.27* HMGB1: 高迁移率族蛋白B1; IL-32: 白细胞介素-32; MMP-9: 基质金属蛋白酶-9; TIMP-1: 基质金属蛋白酶抑制剂-1。
与治疗前比较, *P < 0.05; 与缓解组比较, #P < 0.05。
下载: 导出CSV
表 3 2组外周血HMGB1、IL-32、MMP-9/TIMP-1水平降低率比较(x±s)
% 组别 n HMGB1水平降低率 IL-32水平降低率 MMP-9/TIMP-1水平降低率 治疗1个月后 治疗3个月后 治疗1个月后 治疗3个月后 治疗1个月后 治疗3个月后 无反应组 20 2.90±0.94* 5.02±1.64* 3.25±1.04* 4.63±1.50* 7.19±2.35* 11.51±3.80* 缓解组 66 16.65±5.48 25.91±0.61 45.35±14.88 74.54±9.86 28.87±9.56 40.85±12.94 与缓解组比较, * P < 0.05。
下载: 导出CSV
表 4 外周血HMGB1、IL-32、MMP-9/TIMP-1水平降低率与治疗应答的偏相关性分析
变量 偏相关性系数 95%CI P HMGB1水平降低率 0.811 0.759~0.836 < 0.001 IL-32水平降低率 0.845 0.800~0.869 < 0.001 MMP-9/TIMP-1水平降低率 0.803 0.744~0.845 < 0.001
下载: 导出CSV
表 5 外周血HMGB1、IL-32、MMP-9/TIMP-1水平降低率预测治疗应答的价值
时点 指标 AUC 95%CI 最佳截断值/% 敏感度/% 特异度/% P 治疗1个月后 HMGB1水平降低率 0.753 0.648~0.839 6.34 74.24 75.00 < 0.001 IL-32水平降低率 0.755 0.650~0.841 14.69 83.33 70.00 < 0.001 MMP-9/TIMP-1水平降低率 0.798 0.697~0.877 10.95 77.27 80.00 < 0.001 联合 0.910 0.828~0.961 — 87.88 80.00 < 0.001 治疗3个月后 HMGB1水平降低率 0.772 0.669~0.856 12.41 77.27 70.00 < 0.001 IL-32水平降低率 0.778 0.675~0.860 34.94 77.27 70.00 < 0.001 MMP-9/TIMP-1水平降低率 0.814 0.715~0.889 17.78 87.88 70.00 < 0.001 联合 0.932 0.856~0.975 — 90.91 85.00 < 0.001
下载: 导出CSV
-
[1] 鲍星兰, 王丹丹, 靳子义, 等. 脐带间充质干细胞移植治疗难治性狼疮性肾炎的远期预后分析[J]. 实用临床医药杂志, 2023, 27(10): 1-5, 20. doi: 10.7619/jcmp.20230609 [2] 陈刚, 王小芳. 脂代谢紊乱与系统性红斑狼疮相关性研究[J]. 中华实用诊断与治疗杂志, 2017, 31(6): 554-555. [3] MOK C C, ONNO TENG Y K O, SAXENA R, et al. Treatment of lupus nephritis: consensus, evidence and perspectives[J]. Nat Rev Rheumatol, 2023, 19(4): 227-238. doi: 10.1038/s41584-023-00925-5
[4] HISHAM F A, THARWAT S, SAMRA N E, et al. High mobility group box protein 1 (HMGB1) serum and urinary levels and gene polymorphism in Egyptian patients with systemic lupus erythematosus: a possible relation to lupus nephritis[J]. Lupus, 2022, 31(14): 1777-1785. doi: 10.1177/09612033221132484
[5] 丁昕宇, 李平, 白羽, 等. 狼疮性肾炎患者血清白细胞介素-32及肾损伤分子-1水平变化[J]. 中华实用诊断与治疗杂志, 2020, 34(1): 48-51. [6] 唐莉, 王鹏军, 曹李娜, 等. 狼疮性肾炎患者血清中基质金属蛋白酶-9、基质金属蛋白酶抑制因子-1的表达水平及其意义[J]. 广西医学, 2018, 40(22): 2688-2691. [7] 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, 99(44): 3441-3455. doi: 10.3760/cma.j.issn.0376-2491.2019.44.001 [8] 高丹, 路漫漫. 狼疮性肾炎患者临床病理特征及远期预后影响因素分析[J]. 中华实用诊断与治疗杂志, 2022, 36(1): 59-63. [9] 张国珍, 徐志泉, 周朝艾, 等. 儿童狼疮性肾炎46例临床特点及治疗随访观察[J]. 中国医学前沿杂志: 电子版, 2018, 10(8): 26-29. [10] 边彩月, 秦艺璐, 梁舒, 等. 血清和尿液联合检测免疫球蛋白结合蛋白1在狼疮性肾炎中的预测价值[J]. 实用临床医药杂志, 2024, 28(10): 83-86, 95. doi: 10.7619/jcmp.20233945 [11] LAKSHMI V R, VANGALA N, UPPIN M S, et al. Revisiting vasculopathy in lupus nephritis: a renal biopsy evaluation study[J]. Indian J Nephrol, 2022, 32(1): 28-33. doi: 10.4103/ijn.IJN_131_20
[12] LI S J, RUAN D D, WU W Z, et al. Potential regulatory role of the Nrf2/HMGB1/TLR4/NF-κB signaling pathway in lupus nephritis[J]. Pediatr Rheumatol Online J, 2023, 21(1): 130.
[13] SHEN J, ZHANG M Y, PENG M Y. Progress of exosome research in systemic lupus erythematosus[J]. Cytokine X, 2022, 4(2/3): 100066.
[14] ZICKERT A, PALMBLAD K, SUNDELIN B, et al. Renal expression and serum levels of high mobility group box 1 protein in lupus nephritis[J]. Arthritis Res Ther, 2012, 14(1): R36. http://www.researchgate.net/profile/Kevin_Tracey/publication/221845972_Renal_expression_and_serum_levels_of_high_mobility_group_box_1_protein_in_lupus_nephritis/links/0fcfd50868f9410944000000
[15] 张玮, 杨冉, 郭惠芳, 等. HMGB1和TNFAIP3在狼疮性肾炎系膜细胞增殖中的作用[J]. 中国药理学通报, 2017, 33(8): 1109-1113. [16] FENG X J, YANG R, TIAN Y X, et al. HMGB1 protein promotes glomerular mesangial matrix deposition via TLR2 in lupus nephritis[J]. J Cell Physiol, 2020, 235(6): 5111-5119. http://pubmed.ncbi.nlm.nih.gov/31667864/
[17] ADAWY A, LI L B, HIRAO H, et al. Potential involvement of IL-32 in cell-to-cell communication between macrophages and hepatoblastoma[J]. Pediatr Surg Int, 2023, 39(1): 275.
[18] 李莉, 张老追, 李玲玲, 等. 狼疮性肾炎患者血清和尿液中IL-32和KIM-1的表达水平及临床意义[J]. 河北医药, 2019, 41(3): 361-364, 369. [19] BONADIO A, OGUCHE S, LAVY T, et al. Computational design of matrix metalloprotenaise-9 (MMP-9) resistant to auto-cleavage[J]. Biochem J, 2023, 480(14): 1097-1107. http://www.semanticscholar.org/paper/5a3cadaecc2338b5a1ac95f201cb406b26b8a599
[20] ENE C D, NICOLAE I. The inflammatory profile orchestrated by inducible nitric oxide synthase in systemic lupus erythematosus[J]. J Pers Med, 2023, 13(6): 934.
[21] HASSAN N H, YOUSEF D M, ALSEMEH A E. Hesperidin protects against aluminum-induced renal injury in rats via modulating MMP-9 and apoptosis: biochemical, histological, and ultrastructural study[J]. Environ Sci Pollut Res Int, 2023, 30(13): 36208-36227. doi: 10.1007/s11356-022-24800-0
[22] NTRINIAS T, PAPASOTIRIOU M, BALTA L, et al. Biomarkers in progressive chronic kidney disease. still a long way to go[J]. Pril, 2019, 40(3): 27-39. http://pubmed.ncbi.nlm.nih.gov/32109222/
[23] YAMAKOSHI S, NAKAMURA T, MORI N, et al. Effects of exercise training on renal interstitial fibrosis and renin-angiotensin system in rats with chronic renal failure[J]. J Hypertens, 2021, 39(1): 143-152. http://pubmed.ncbi.nlm.nih.gov/32833922/
[24] BAUVOIS B, MOTHU N, NGUYEN J, et al. Specific changes in plasma concentrations of matrix metalloproteinase-2 and-9, TIMP-1 and TGF-beta1 in patients with distinct types of primary glomerulonephritis[J]. Nephrol Dial Transplant, 2007, 22(4): 1115-1122. http://europepmc.org/abstract/MED/17205957
[25] DO VALLE G T, RICCI S T, SILVA A O, et al. Ethanol consumption increases renal dysfunction and mortality in a mice model of sub-lethal sepsis[J]. Can J Physiol Pharmacol, 2021, 99(7): 699-707. http://www.xueshufan.com/publication/3113136266
-
期刊类型引用(13)
1. 刘倩. 难治性胃食管反流病的中医疗法研究近况. 湖北中医杂志. 2023(11): 63-66 . 
百度学术
2. 杨超，陈莉丽，杨振斌. 方晓华抑木扶土法临床运用验案举隅. 中国民间疗法. 2022(14): 105-108 . 百度学术
3. 郭丽，夏军权，刘晓桐. 难治性胃食管反流病中医药诊治研究进展. 光明中医. 2021(22): 3790-3793 . 百度学术
4. 贾军峰，李文萍. 和胃降逆饮联合西药及针刺治疗残胃引起的反流性食管炎的疗效及对血清胃动素的影响. 中国中西医结合消化杂志. 2020(12): 944-948 . 百度学术
5. 刘妍. 疏肝降逆汤联合中医特色护理治疗胃食管反流病效果研究. 药品评价. 2019(01): 44-46 . 百度学术
6. 马雪梅. 和胃降逆汤加减联合奥美拉唑、枸橼酸莫沙必利治疗肝胃郁热型胃食管反流病的临床观察. 中国民间疗法. 2019(05): 55-56 . 百度学术
7. 房晓娜. 和胃降逆汤加减治疗胃食管反流病肝胃郁热型临床观察. 实用中医药杂志. 2019(04): 413-414 . 百度学术
8. 邓粉会. 自拟和胃降逆汤辅助西药治疗胃食管反流病相关性支气管哮喘疗效观察. 人人健康. 2019(24): 114-115 . 百度学术
9. 黄太伟. 半夏厚朴汤加减治疗难治性胃食管反流病的疗效研究. 实用医技杂志. 2018(06): 625-626 . 百度学术
10. 高钟. 泮托拉唑、香砂养胃丸、左金丸联用治疗胃食管反流病的效果观察. 中国社区医师. 2018(19): 102-103 . 百度学术
11. 姚向东. 雷贝拉唑、莫沙必利与玄麦甘桔三联用药治疗咽喉反流疾病的临床疗效. 中国合理用药探索. 2018(02): 8-11 . 百度学术
12. 王巧凤，王胜业. 和胃降逆汤加减治疗肝胃郁热型胃食管反流病疗效观察. 北方药学. 2018(11): 131 . 百度学术
13. 王茜茜，李华岳. 加减乌梅丸方联合穴位针刺对胃食管反流病患者食管动力的影响. 中国中医药现代远程教育. 2018(23): 42-44 . 百度学术
其他类型引用(7)
计量
- 文章访问数: 38
- HTML全文浏览量: 7
- PDF下载量: 3
- 被引次数: 20
苏公网安备 32100302010246号
