腹膜透析滤出液中游离mtDNA 与腹膜透析患者腹腔微炎症的相关性分析.pdf

中国血液净化2023年10月 第22卷 第10期 Chin J Blood Purif,October,2023,Vol.22,No.10 临床研究 腹膜透析滤出液中游离mtDNA与腹膜透析患者腹腔微炎症的相关性分析邱杰山1暨利军1王燕翔1王丹萍1陈静静1方燊燊1【摘要】目的探讨腹膜透析滤出液中游离线粒体 DNA(mitochondrial DNA，mtDNA)与腹膜透析(peritoneal dialysis，PD)患者腹膜及腹腔微炎症的相关性。方法收集行PD治疗的患者85例，分为A组(1.5%葡萄糖腹膜透析液治疗组)和B组高浓度(2袋以上2.5%或4.25%)葡萄糖腹膜透析液治疗组。检测血生化指标，腹膜透析滤出液中白细胞介素6(interleukin 6，IL-6)、肿瘤坏死因子(tu-mor necrosis factor-，TNF-)、白细胞介素1(interleukin 1，IL-1)及白细胞介素(inter-leukin 18，IL-18)及mtDNA。比较2组患者上述指标的差异；将mtDNA分别与临床参数做相关性分析；通过多元回归分析明确影响腹膜透析滤出液中mtDNA浓度的危险因素。结果 B组患者透析龄长于A组(t=-2.206,P=0.030)，血白蛋白(Alb)低于 A 组(t=2.635,P=0.010)，腹膜透析滤出液中 IL-6(t=-4.835,P0.001)、TNF-(t=-6.557,P0.001)、IL-1(t=-2.395,P=0.019)、IL-18(t=-2.318,P=0.023)及游离mtDNA(t=-3.920,P0.001)均高于A组。腹膜透析滤出液中mtDNA与IL-6(r=0.721,P0.001)、TNF-(r=0.418,P0.001)、IL-1(r=0.771,P0.001)、IL-18(r=0.634,P0.001)及透析龄(r=0.240,P=0.030)均呈正相关,与Alb呈负相关(r=-0.319,P=0.003)。多元回归分析显示腹膜透析液中葡萄糖浓度升高(=0.358,P=0.005)、长透析龄(=0.292,P0.001)及Alb降低(=-0.272,P=0.027)是腹膜透析滤出液中mtDNA水平升高的危险因素。结论腹膜透析滤出液中mtDNA与PD患者腹膜及腹腔慢性微炎症状态相关。高浓度葡萄糖腹膜透析液、长透析龄及低蛋白血症是导致其水平升高的危险因素。【关键词】腹膜透析；腹膜透析滤出液；线粒体DNA；微炎症中图分类号：R459.5文献标识码：Adoi:10.3969/j.issn.1671-4091.2023.10.005The correlation between free mtDNA in outflow dialysate and peritoneal micro-inflammation in pa-tients undergoing peritoneal dialysisQIU Jie-shan1,JI Li-jun1,WANG Yan-xiang1,WANG Dan-ping1,CHEN Jing-jing1,FANG Shen-shen11Department of Nephrology,Xianju People s Hospital(Southeast Dis-trict of Zhejiang Provincial Peoples Hospital),Xianju 317300,ChinaCorresponding author:QIU Jie-shan,Email:【Abstract】Objective To investigate the relationship between free mitochondrial DNA(mtDNA)levelin outflow dialysate and chronic peritoneum inflammation in patients undergoing peritoneal dialysis(PD).Methods A total of 85 patients with PD for more than 6 months were enrolled and divided into group A(us-ing dialysate with 1.5%glucose)and group B(using dialysate with 2.5%or 4.25%glucose more than twice aday).Blood samples were collected and serum biochemical parameters were tested.The outflow dialysate wascollected to measure interleukin-6(IL-6),tumor necrosis factor-(TNF-),interleukin-1(IL-1),interleukin-18(IL-18)and free mtDNA in the fluid.The differences of these parameters were compared between the twogroups.The correlation between mtDNA in outflow dialysate and clinical parameters was analyzed.Multivari-ate regression was used to define the risk factors for mtDNA in dialysate.Results PD duration was longer(t=-2.206,P=0.030)and serum albumin was lower(t=2.635,P=0.010)in group B than in group A.IL-6,TNF-,IL-1,IL-18 and free mtDNA in the dialysate were significantly higher in group B than in group A(t=-4.835,-6.557,-2.395,-2.318 and-3.920 respectively;P0.001,0.001,=0.019,=0.023 and 0.001 respec-tively).Free mtDNA level in the dialysate was positively correlated with the levels of IL-6,TNF-,IL-1 andIL-18 in dialysate and PD duration(r=0.721,0.418,0.771,0.634 and 0.240 respectively;P0.001,0.001,0.001 and=0.03 respectively),and was negatively correlated with serumAlb(r=-0.319,P0.01).Multivari-基金项目：浙江省中医药科技计划项目(2023ZL793)；仙居县人民医院青年创新人才支持计划(21yja02)作者单位：317300 仙居，1仙居县人民医院(浙江省人民医院浙东南院区)肾脏内科通讯作者：邱杰山 317300 仙居，1仙居县人民医院(浙江省人民医院浙东南院区)肾脏内科Email: 739中国血液净化2023年10月 第22卷 第10期 Chin J Blood Purif,October,2023,Vol.22,No.10ate linear regression showed that higher glucose concentration in dialysate(=0.358,P=0.005),longer PD du-ration(=0.292,P=0.000)and lower serum Alb concentration(=-0.272,P=0.027)were the risk factors forhigher free mtDNA in outflow dialysate.Conclusion Elevated mtDNA in outflow dialysate is associatedwith chronic micro-inflammatory status of the peritoneum in PD patients.Higher glucose concentration in di-alysate,longer PD duration and lower serum Alb concentration are the risk factors for higher free mtDNA inoutflow dialysate.【Key words】Peritoneal dialysis;Outflow dialysate;Mitochondrial DNA;Micro-inflammation腹膜透析(peritoneal dialysis，PD)患者的腹膜组织由于长期暴露在高浓度葡萄糖腹膜透析液(peritoneal dialysis fluid，PDF)中使氧化应激产 物、糖 基 化 终 产 物(advanced glycosylationend products,AGEs)及炎性介质等持续刺激腹膜组织而导致腹膜慢性炎性损伤1,2。其中AGEs诱导的炎症介质及氧化应激产物在此过程中起到了重要的作用3。AGEs可通过诱导线粒体氧化应激损伤而释放线粒体DNA(mitochondrial DNA,mtDNA)，而mtD-NA的特定基序可作为病原体相关分子模式(patho-gen associated molecular patterns，PAMPs)与TOLL 样受体 9(toll like receptor 9，TLR9)识别并激活固有免疫应答，导致肿瘤坏死因子-(tu-mor necrosis factor-，TNF-)及白细胞介素6(interleukin 6，IL-6)的表达上调，从而放大炎症并加重细胞损伤4。此外，mtDNA还可通过直接及间接方式触发Nod样受体蛋白3(nod like receptorprotein 3，NLRP3)炎性小体活化，使白细胞介素-1(interleukin 1，IL-1)及白细胞介素 18(interleukin 18，IL-18)的表达上调5。研究显示6PD患者腹膜及腹腔慢性炎症与患者腹膜纤维化相关，但其相关机制尚不完全清楚。游离mtDNA具有更强的致炎性5，且其可能是PD患者腹膜慢性炎症损伤的重要始动因素，但二者的关系尚不明确，本研究旨在探讨腹膜透析滤出液中游离mtDNA浓度与PD患者腹膜及腹腔微炎症状态的相关性及可能的分子机制。1研究对象与方法1.1 研究对象收集2022年1月2023年1月在仙居县人民医院肾内科行腹膜平衡试验的持续非卧床腹膜透析(continuous ambulatory peritoneal dialysis,CAPD)患 者 85 例。纳 入 标 准：年 龄 18 岁；CAPD治疗12月并定期随访；每日PDF交换35次，每日透析剂量为610 L；现有的透析治疗方案已持续1月。排除标准：1月内有急性局部或全身严重感染；服用激素、免疫抑制剂或血管活性药物；合并血液系统肿瘤及其他实体器官肿瘤；合并自身免疫性疾病如系统性红斑狼疮、克罗恩病、系统性血管炎、类风湿性关节炎等；肝功能不全(丙氨酸氨基转移酶大于正常上限2倍)及肝硬化；合并严重心脑血管疾病。本研究经浙江省仙居县人民医院伦理委员会审核批准(仙医伦审2022研第071号)。1.2方法1.2.1一般资料患者来院行腹膜平衡试验(peritonealequilibration test,PET)时收集患者信息并留取空腹血标本，检测血肌酐(Scr)、尿素氮(BUN)、血尿酸(UA)、血白蛋白(Alb)、血红蛋白(Hb)及C反应蛋白(CRP)。在PET 4小时时留取患者腹膜透析滤出液标本，检测IL-6、TNF-、IL-1、IL-18及游离mtDNA。根据文献7计算残余肾功能(resid-ual renal function,RRF)。RRF(ml/min)=(尿液尿素氮浓度/血清尿素氮浓度)24h 尿量/1440+(尿 液 肌 酐 浓 度/血 清 肌 酐 浓 度)24h 尿 量/1440)/2。1.2.2分组根据患者既有的PD治疗方案，分为：A组：每日常规34袋1.5%葡萄糖乳酸钠PDF治疗方案；B组：每日至少需使用2袋以上2.5%的PDF或需使用4.25%的PDF。1.2.3一般指标检测采用日立7600全自动生化仪(日立株式会社，日本)检测Scr、BUN、Alb及CRP。Sysmex XS-800i全自动血液分析仪(日本希森美康公司，日本)检测Hb。酶联免疫吸附(ELISA)法检测腹膜透析滤出液中 IL-6、TNF-、IL-1 及 IL-18(Solarbio，美国)，具体操作方法严格按照试剂盒说明书进行，ELISA检测采用复孔，重复2次后取平均值，以减少误差。1.2.4实时定量PCR法检测腹膜透析滤出液中游离mtDNA参照文献8腹膜透析滤出液20 ml，以1500 g离心10分钟，取上清液200 ul，使用QIAamp DNA试剂盒提取无细胞DNA。通过扩增线粒体细胞色素B(cy-tochrome B，Cyto B)基因的高度保守区来量化mtD-NA 拷贝数。Cyto B 的正向引物序列为 5-AT-740中国血液净化2023年10月 第22卷 第10期 Chin J Blood Purif,October,2023,Vol.22,No.10GACCCCAATACGCAAAAT-3，反 向 引 物 序 列 为 5-CGAAGTTTCATCATGCGGAG-3。PCR 引物和 TaqMan 酶由擎科生物科技(北京擎科生物科技有限公司，中国)设计和合成。含mtDNA基因片段的已知质粒用灭菌去离子水10倍稀释为标准品，标准品经10倍浓度梯度稀释至8个浓度，用实时荧光定量 PCR法测定，制备标准曲线，根据建立的标准曲线计算mtDNA拷贝数，以拷贝数/ul表示，检测数据重复2次，取平均值。1.3统计学分析采用SPSS 16.0软件进行统计学分析。符合正态分布的计量数据用(xs)表示，组间比较采用独立样本t检验；计数资料以n(%)表示，组间比较采用c2检验；两因素相关性分析采用Pearson相关分析法；多元回归分析采用Stepwise回归模型，选入标准为P0.05，剔除标准为P0.10。以P0.05为差异有统计学意义。2结果2.12组患者一般情况、腹膜透析滤出液中炎性介质及游离mtDNA的比较2组患者在性别、年龄、Scr、BUN、UA、Hb、CRP及糖尿病病史等方面均无统计学差异。B组患者透析龄长于A组，血Alb及RRF低于A组，腹膜透析滤出液中IL-6、TNF-、IL-1、IL-18及游离mtDNA均高于A组患者，详见表1。2.2腹膜透析滤出液中游离mtDNA与Alb、透析龄、IL-6、TNF-、IL-1、及IL-18的相关性分析相关性分析显示腹膜透析滤出液中mtDNA与血浆白蛋白呈负相关，与透析龄、IL-6、TNF-、IL-1及IL-18均呈正相关，详见表2。2.3影响腹膜透析滤出液中mtDNA水平的多元回归分析多元回归分析结果显示PDF中葡萄糖浓度升高、长透析龄及低蛋白血症是PD患者腹膜透析滤出液中mtDNA水平升高的危险因素，详见表3。3讨论mtDNA来源于祖先细菌基因组，不同细胞类型的mtDNA拷贝数不同9。学者已在不同的生物流体中观察到mtDNA的存在，包括血浆、血清、脑脊液及分泌物等，且其可作为炎症的潜在生物标记和死亡率的预测因子10,11。研究发现只有游离的mtDNA能够引起机体炎性反应12。而炎症及氧化应激反应可使细胞线粒体受损或细胞死亡，从而使mtDNA释放入细胞外液13。与核DNA相比，mtDNA特别容易受表1A组与B组患者一般情况、腹膜透析滤出液中炎性介质及游离mtDNA的比较组别性别年龄透析龄RRF伴糖尿病Scr男，n(%)岁,(xs)月,(xs)ml/min,(xs)n(%)mol/l,(xs)A组(n=54)30(55.556)58.90711.65018.25911.5962.4441.58616(29.630)761.704252.131B组(n=31)18(58.065)62.6457.49524.45213.8492.0210.6207(22.581)690.973228.515t/c2值0.049-1.797-2.2061.4200.5031.287P值0.8170.0760.0300.0210.3320.202组别BUNUAAlbHbCRPmmol/l,(xs)mol/l,(xs)g/L,(xs)g/L,(xs)mg/L,(xs)A组(n=54)22.5278.988408.75672.47136.1045.557101.41113.9674.9834.113B组(n=31)26.0736.872387.711130.35433.3194.108100.26612.0444.1502.462t/c2值-1.8990.8272.6350.3831.168P值0.0610.4130.0100.7020.246组别MtDNA104拷贝/l,IL-6IL-1IL-18TNF-(xs)pg/ml,(xs)pg/ml,(xs)pg/ml,(xs)pg/ml,(xs)A组(n=54)0.4450.15023.9633.26326.6506.014134.35718.13321.6392.408B组(n=31)0.5920.19127.5553.35530.0756.895144.48221.45825.2652.534t/c2值-3.920-4.835-2.395-2.318-6.557P值0.0010.0010.0190.0230.001注：A组：每日常规34袋1.5%葡萄糖腹膜透析液治疗组；B组：每日需使用2袋以上2.5%或需使用4.25%的葡萄糖腹膜透析液治疗组；RRF：残余肾功能；Scr：血肌酐；BUN：尿素氮；UA：血尿酸；Alb：血白蛋白；Hb：血红蛋白；CRP：C反应蛋白；mtDNA：线粒体DNA；IL-6：白细胞介素6；IL-1：白细胞介素-1；IL-18：白细胞介素18；TNF-：肿瘤坏死因子-。表2 腹膜透析滤出液中游离mtDNA与Alb、透析龄、IL-6、TNF-、IL-1及IL-18的相关性分析因素r值P值Alb(g/L)-0.3190.003透析龄(月)0.2400.028IL-6(pg/ml)0.7210.001TNF-(pg/ml)0.4180.001IL-1(pg/ml)0.7710.001IL-18(pg/ml)0.6340.001注：Alb：血白蛋白；mtDNA：线粒体DNA；IL-6：白细胞介素6；TNF-：肿瘤坏死因子-；IL-1：白细胞介素-1；IL-18：白细胞介素18。741中国血液净化2023年10月 第22卷 第10期 Chin J Blood Purif,October,2023,Vol.22,No.10表3影响腹膜透析滤出液中mtDNA浓度因素的多元回归分析因素BSEtP常量0.5350.9177.2160.001PDF葡萄糖浓度2.6730.9410.3582.8900.005透析龄3.4110.8720.2923.6280.000Alb-1.4060.614-0.272-2.3050.027注：PDF：葡萄糖腹膜透析液；Alb：血白蛋白。到氧化损伤，因为其亚细胞定位靠近产生活性氧簇(reactive oxygen species，ROS)的电子传输链14。腹膜间皮细胞(mesothelial cells，MCs)可通过分泌细胞因子及募集白细胞发挥独特的生物学作用15。常规的含糖PDF是pH约5.2的偏酸性非生理性高渗液体MCs对pH值的变化很敏感，可使炎性细胞因子的产生增加16。此外，AGEs可刺激血管内皮生长因子的产生，使腹膜通透性增加、小动脉炎性改变及新生血管生成，且这种损伤随PDF浓度的升高而加重17。有学者18发现：在AGEs暴露的动脉中，包括细胞骨架、连接基因及蛋白质在内的多条信号途径失调。相反，AGEs 受体基因缺陷的小鼠用含有高AGEs的腹膜透析液治疗时可免于炎症和上述腹膜病理损伤19。AGEs还可诱导MCs氧化应激损伤，1项连续的腹膜活检研究显示：在使用含糖PDF维持PD治疗后6个月，就已出现了MCs的单层剥落而使腹膜间充质细胞暴露于 PDF，从而诱导腹膜纤维化的发生20，在此过程中，MCs发生损伤及凋亡，而使mtDNA游离到细胞外，激活免疫应答，损伤腹膜组织8。本研究也发现使用高浓度葡萄糖PDF患者的腹膜透析滤出液中IL-6、TNF-、IL-1、IL-18及mtDNA均高于使用低浓度PDF的患者，提示使用高浓度葡萄糖PDF患者腹腔mtDNA及炎性介质的水平升高。已知mtDNA可作为PAMPs结合于TLR9，通过活化 丝 裂 原 蛋 白 激 酶(mitogen protein kinase，MAPK)和核因子-B(nuclear factor-B，NF-B)促进该通路下游的炎性介质 IL-6 及 TNF-的表达21。炎症状态又可刺激MCs分泌IL-6及TNF-，过表达的IL-6可通过转录因子STAT3趋化中性粒细胞及单核巨噬细胞等炎性细胞向腹腔浸润，造成组织损伤22。研究发现23小鼠腹膜过表达的IL-6可通过调控Th1细胞而诱发腹膜局部的慢性炎性损伤及纤维化，IL-6是腹膜炎性损伤不可或缺的因素，因为IL-6缺乏的小鼠的腹膜炎性损伤明显减弱。此外，IL-6还可促进MCs和血管内皮细胞分泌血管生长因子，在腹膜炎性细胞浸润、血管新生及纤维化中发挥重要的作用24。TNF-可使培养的人MCs中纤维连接蛋白(fibronectin，FN)mRNA表达增强，并介导腹膜局部免疫炎症及纤维化25。另有研究发现PD患者腹膜透析滤出液中mtDNA表达水平与IL-6、TNF-及 IFN-均呈正相关8，与本研究结果相似，提示mtDNA可能通过活化MAPK通路诱导腹膜及腹腔炎症。NLRP3炎性小体可被PAMPs激活，通过ROS信号通路，活化半胱氨酸蛋白酶-1(caspase-1)及下游的炎性介质IL-1及IL-18的表达26。经高糖腹膜透析液(2.5%和4.25%)刺激的MCs的NLRP3mRNA表达明显增强，且细胞培养上清液中IL-1的表达显著升高，而通过 RNA 干扰技术下调 NLRP3 的表达后，IL-1的表达也显著下降，提示高糖腹膜透析液可激 活 腹 膜 间 皮 细 胞 ROS-NLRP3-IL-1 炎 性 通路27。细胞内 ROS 升高可诱导线粒体应激，导致mtDNA片段泄漏，触发STING信号，进而活化NLRP3炎性小体及级联炎性反应，使IL-1及IL-18的表达显著增强28。mtDNA转染也可通过活化STING而促进 NLRP3 介导的细胞凋亡、损伤及炎症29。且mtDNA是NLRP3炎性小体活化过程中重要的因素，因为已有研究表明0细胞(缺乏mtDNA)无法分泌IL-1以响应NLRP3诱导的刺激30。本研究也发现腹膜透析滤出液中mtDNA与IL-1及IL-18表达呈正相关，提示mtDNA可能通过激活NLRP3炎性小体而参与腹腔炎性反应。4结论综上所述，本研究发现腹膜透析滤出液中游离mtDNA水平升高与IL-6、TNF-、IL-1及IL-18均呈正相关，提示游离mtDNA是反映PD患者腹膜及腹腔微炎症状态的有效标记物。IL-6 及 TNF-是MAPK通路下游的重要炎性介质，而IL-6及TNF-是NLRP3炎性小体下游的炎性介质，提示mtDNA可能作为PAMPs通过激活MAPK信号通路及NLRP3炎性小体参与PD患者腹膜及腹腔炎症损伤。作者贡献：邱杰山：研究设计、数据统计分析及论文撰写；暨利军：论文审阅及修改；王燕翔、陈静静：指标检测；王丹萍：标本收集及临床数据收集；方燊燊：试验数据核对。利益冲突声明：本文作者无相关利益冲突。742中国血液净化2023年10月 第22卷 第10期 Chin J Blood Purif,October,2023,Vol.22,No.10参 考 文 献1HamadaC,TominoY.Recentunderstandingofperitonealpathology in peritoneal dialysis patients in JapanJ.Blood Purif,2021,50(6):719-728.2Helmke A,Hsing AM,Gaedcke S,et al.Peritoneal dialy-sate-range hypertonic glucose promotes T-cell IL-17productionthatinducesmesothelialinflammationJ.Eur J Immunol,2021,51(2):354-367.3Vareesangthip K,Vongsanim S,Fan S,et 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