狼疮肾炎的研究和治疗进展.ppt

*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,赵明辉狼疮肾炎的研究和治疗进展,狼疮肾炎的发病机制,肾小球免疫复合物沉积的机理,ANA及其免疫复合物,其它致病性的自身抗体？靶抗原？,补体及补体相关蛋白,新病理类型的意义,Innate immunity,Acquired immunity,108 patients in leflunomide group,狼疮肾炎的发病机理的探索,Advanced sclerosing glomerulonephritis,中国实用内科 2004;24:175-176,中国实用内科 2004;24:175-176,Pred：1mg/kg/d:4-6周,Complete remission,J Am Soc Nephrol 2004;15:241-250,lung infection,76 patients in cyclophosphamide group,Innate immunity,问题：是否存在针对肾小球固有细胞的自身抗体？,Wang HY,et al.,J Am Soc Nephrol ;20-1103-12,第二军医大学附属长征医院,狼疮肾炎的自身抗体,多种自身抗体,抗DNA抗体起主导作用,循环免疫复合物,原位免疫复合物,临床现象,部分狼疮肾炎抗DNA抗体阴性,抗DNA抗体阳性不一定有肾损害,问题：是否存在针对肾小球固有细胞的自身抗体？,98%狼疮肾炎患者血清存在抗HMC抗体,靶抗原存在于 HMC细胞膜上,结合为抗原抗体反应,与抗DNA抗体的关系？,Du et al.,J Clin Immunol,2005,;25(3):279-285,Chen et al.,Renal Failure,2005;27:507-513,抗DNA抗体及去除抗DNA抗体的血清,偶联DNA的,亲和层析柱,LN患者血清,去除抗DNA,抗体的血清,Du et al.,J Clin Immunol,2006;26(2):138-44,亲和层析的,抗DNA抗体,识别多种靶抗原,靶抗原存在于细胞膜上,结合不需要DNA介导（DNA酶处理）,Du et al.,J Clin Immunol,2006;26(2):138-44,狼疮肾炎患者血清中存在针对,HMC,的自身抗体,抗DNA抗体及去除抗DNA抗体的血清,偶联DNA的,亲和层析柱,LN患者血清,去除抗DNA,抗体的血清,Du et al.,J Clin Immunol,2006;26(2):138-44,亲和层析的,抗DNA抗体,抗DNA抗体可识别HMC,靶抗原仍位于细胞膜,抗原抗体反应与DNA无关,抗DNA抗体与HMC的蛋白存在交叉反应？,Du H,et al.,Clin Exp Immunol,2006;145:2127,狼疮肾炎的发病机制,肾小球免疫复合物沉积的机理,ANA及其免疫复合物,其它致病性的自身抗体？靶抗原？,补体及补体相关蛋白,新病理类型的意义,Innate immunity,Acquired immunity,SLE：补体及补体相关蛋白,Factor H,（-）,（-）,C1q&CRP：acute phase proteins,Zhang J,et al.Plos Pathog ;5(1):e1000282.,Apoptotic cells?,IgG型抗C1q抗体与狼疮肾炎相关,SLE：6/30（20%）,LN-IV：71.95%,IgG型抗C1q抗体与病情活动相关,IgG2最为突出,抗原结合位点？,Fang QY,et al.Nephrol Dial Transplant ;24:1728,狼疮肾炎抗C1q抗体的抗原决定簇？,C1q整个分子：(+),C1q头状区,头状区整体,头状区A、B、C,C1q胶原区：(+),Tan Y 46:217882,抗C1q抗体可能并不影响C1q与CRP的结合,Anti-C1q,抗mCRP抗体阳性与狼疮肾炎相关,LN：57/96(59.4%),抗mCRP抗体与狼疮活动相关,SLEDAI,ARF,抗mCRP抗体与肾间质小管疾病相关,Tan Y,et al Human Immunol ;69:840-4,抗体是否与TINU相关？,抗体是否影响mCRP与其他蛋白的结合？,抗体的抗原决定簇？,狼疮肾炎的发病机制,肾小球免疫复合物沉积的机理,ANA及其免疫复合物,其它致病性的自身抗体？靶抗原？,补体及补体相关蛋白,新病理类型的意义,IV-G vs IV-S,血栓性微血管病(TMA),新月体形成,Innate immunity,Acquired immunity,ISN/RPS（2003年）,I,Minimal mesangial lupus nephritis,II,Mesangial proliferative lupus nephritis,III,Focal lupus nephritis(active or sclerotic lesions),IV,Diffuse segmental(IV-S)or global(IV-G)lupus nephritis,V,Membranous lupus nephritis,VI,Advanced sclerosing glomerulonephritis,Weening et al.,J Am Soc Nephrol,2004;15:241-250,IV-G vs IV-S,IV-S,IV-G,P,value,Number of patients,20,152,Hemoglobin(meanSD)(g/L),104.621.76,92.7621.81,0.024,Urine protein(g/24 hours),3.215,2-12,5.35,3-21,0.003,Serum creatinine(meanSD)(mg/dL),1.00.27,2.072.05,0.021,Creatinine clearance rate(meanSD)(ml/min),81.2919.74,56.1234.15,0.002,Number of positive ANA(%),20(100%),100(100%),1.0,Number of anti-cardiolipin antibody(%),5/15(33.3%),8/98(8.2%),0.014,C3(meanSD)(g/L),0.460.19,0.380.16,0.045,ANCA,4/20(20%),7/152(4.6%),0.008,Fibrinoid necrosis,5/20(25%),7/152(4.6%),0.006,AI score(meanSD),8.752.73,10.933.36,0.006,Endocapillary hypercellualrity(meanSD),2.350.59,2.920.34,0.001,Interstitial inflammation(meanSD),1.050.22,1.510.78,0.01,Scr doubling at 5-year follow up,1/19,29/152,0.149,Yu F,et al.,Lupus,In press,TMA in LN,Yu F,et al.Nephrol Dial Transplant Aug 23,Epub,LN+TTP-HUS,LN-IV-G,P,value,No of patients,7,55,HGB(g/L),75.622.4,95.621.6,0.022,Thrombocytopenia,7(100%),8(14.5%),0.001,PLT(x10,9,/L),64.723.0,161.972.2,0.001,AKI(%),6(85.8),6(10.9),0.001,AP(%),1(14.3),9(16.4),1.0,SLEDAI,21.47.1,17.55.2,0.087,ADAMTS-13 activity,40.77.34%,81%13%（n）,0.001,IgG ADAMTS-13 Ab,6/7,0/50(n),AECA,6/7,0/50(n),AI score,11.73.1,10.92.8,0.494,CI score,4.862.54,2.711.76,0.005,Yu et al.Kidney Int ;76:307-317,CrGN,Non-CrGN(IV),P value,No.of patients,33,119,AKI(%),33(100),32(26.9),0.001,Hemoglobin(g/L),84.6119.46,95.0321.97,0.015,ANCA,11(30.3%),3(2.5%),0.001,AI score,13.483.09,10.223.09,0.001,CI score,4.852.17,2.861.77,0.001,IF-IgA,1.521.06,1.950.87,0.017,IF-IgM,1.270.98,1.660.95,0.039,IF-C1q,1.760.97,2.20.83,0.01,Treatment failure,9(27.3%),7(5.9%),0.001,Relapse during FU,9(37.5%),17(15.2%),0.012,Ccr at remission(ml/min),45.7712.34,73.2511.64,0.001,CrGN-LN:ANCA?,内容,狼疮肾炎的发病机理的探索,狼疮肾炎治疗的进展,狼疮肾炎治疗的策略,诱导缓解治疗,长期保护肾功能,减少复发,维持缓解治疗,尽快控制炎症,争取完全缓解,治疗,目标,减少副作用,为患者提供自行缓解的机会,No%,Szeto CC,et al.,4 adverse events,Membranous lupus nephritis,Wang HY,et al.,Nephrol Dial Transplant ;24:1728,狼疮肾炎患者血清中存在针对HMC的自身抗体,血栓性微血管病(TMA),Mesangial proliferative lupus nephritis,7 patients withdrawn,Serum creatinine(meanSD)(mg/dL),Szeto CC,et al.,靶抗原存在于 HMC细胞膜上,Anti-TNF-:infliximab,Wang HY,et al.,抗DNA抗体与HMC的蛋白存在交叉反应？,Mycophenolate mofetil(MMF),Anti-CD20(rituximab):RCT,维持药物全血浓度（2-15ng/ml）,经典治疗方案及其限制,激素联合环磷酰胺仍为基本治疗方案,Pred：1mg/kg/d:4-6周,超过15的病人对环磷酰胺治疗不敏感,环磷酰胺的毒副作用,复发率,第5年为25%,新的治疗手段,非生物制剂,Mycophenolate mofetil(MMF),Mizoribine:new IMPDH inhibitor,Tacrolimus,Leflunomide(LEF),生物制剂,IVIG,Immuno-absorborption,Anti-TNF-,:infliximab,Induced human lupus syndrome,Anti-CD20(rituximab):RCT,Loss of an autoreactive memory B cell subset,MMF治疗的价值,免疫抑制疗效肯定,疗效与CTX相仿,不良反应发生率与IVC相仿,肾功能影响药物代谢：肾功能不全易造成蓄积,药物代谢监测：酶酚酸,CD4阳性T细胞计数,国际多中心RCT,370例活动性LN:24w,MMF=185：3g/d,缓解率,MMF vs IVC：56.2%vs 53.0%,不良反应：相仿,Appel et al.J Am Soc Nephrol ;20-1103-12,FK506治疗狼疮肾炎,多为临床观察性研究,免疫抑制治疗疗效肯定（n=5,9,18),缓解率：77.8%-100%,北大医院5例LN-IV(G/A)的诱导治疗,FK506,开始剂量3mg/d，治疗量2-6mg/d,维持药物全血浓度（2-15ng/ml）,强的松,初始剂量1mg/kg.d，4-6周减量,2周时白蛋白升高,刘玉春等。中国实用内科 2004;24:175-176,Mok CC,et al.Kidney Int 2005;68:813-7,Szeto CC,et al.Rheumatol ;47:1678-81,刘玉春等。,中国实用内科,2004;24:175-176,来氟米特（LEF）作用机理,抑制嘧啶的从头合成途径,抑制酪酸激酶的活性,抑制NF-kB的激活,LEF,A77 1726,二氢乳清酸脱氢酶,DHODH,De novo pyrimidine synthesis,-,狼疮性肾炎的、期或难治性狼疮,“关节病性银屑病”以及,“红皮病性银屑病”,肾移植的排异反应,SFDA批准新适应证的临床试验,试验参加单位,北京大学第一医院（牵头单位）,解放军总医院,哈尔滨医科大学附属第二医院,复旦大学附属华山医院,上海第二医科大学附属仁济医院,第二军医大学附属长征医院,第一军医大学附属南方医院,中山大学附属第一医院,经北京大学第一医院医学伦理委员会批准,Wang HY,et al.Lupus ;17(7):638-644,来氟米特治疗狼疮肾炎临床试验 ,诱导缓解治疗,多中心、前瞻、随机、开放、阳性药物对照临床观察,目的：LEF治疗活动性狼疮性肾炎的疗效和安全性,LEF和CTX组,两组病人入选比例1.4:1,观察时间为6个月,肾活检病理类型为III、IV或V型（活动型）,AI,4,SLEDAI狼疮活动积分,8分,Wang HY,et al.Lupus ;17(7):638-644,用药方法,LEF组：,LEF:,前三天50,mg/d,以后30mg/d,强的松（龙）：,维持量510mg/d,CTX组：,CTX:,m,2,/m，iv,激素同LEF组,Wang HY,et al.Lupus ;17(7):638-644,184 eligible pts enrolled,108 patients in leflunomide group,76 patients in cyclophosphamide group,99 patients completed trial,9 patients withdrawn,2 lost to follow-up,3 age17,4 adverse events,herpes zoster,lung infection,rash,thrombocytopenia,69 patients completed trial,7 patients withdrawn,2 lost to follow-up,1 age17,4 adverse events,lung infection,leucopenia,Wang HY,et al.Lupus ;17(7):638-644,二组患者的基础情况,LEF(No=108),CYC(No=76),Sex(male/female),14/94,6/70,Age(years),30.31,9.41,30.45,10.86,Disease duration*(months),35.21(0.3-336),20.43(0.0-240),Proteinuria(g/d),4.56,3.64,3.89,2.92,Serum albumin(g/L),26.45,6.58,26.81,7.72,Serum creatinine(,mol/L),85.00,63.47,93.50,55.54,C3(g/L),0.53,0.30,0.48,0.25,SLEDAI,19.20,6.05,20.89,8.68,Wang HY,et al.Lupus ;17(7):638-644,疗 效,FAS人群,LEF group,(N=108),No%,CYC group,(N=76),No%,Complete remission,22,20.37,13,17.11,Partial remission,63,58.33,46,60.53,Treatment failure,23,21.30,17,22.37,PP人群,LEF group,(N=99),No%,CYC group,(N=69),No%,Complete remission,22,22.22,13,18.84,Partial remission,59,59.60,43,63.32,Treatment failure,18,18.18,13,18.84,Wang HY,et al.Lupus ;17(7):638-644,