csa应用难治性肾病综合征课件

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,*,*,*,CsA,在难治性肾病综合征中的应用,难治性肾病综合征的认识,排除,:,“,假”难治,“真”难治,“,真,”,难治,-,（,1,）,病理类型难治,膜增生性肾小球肾炎（,MPGN),局灶性节段性肾小球硬化症,(FSGS),膜性肾病,(MN),中，重度系膜增生性肾小球肾炎（包括部分,IgA,肾病,),肾小球轻微病变性肾病（部分）,病理类型轻，但出现：,1.,激素依赖,2.,激素抵抗,3.,激素加用其他免疫抑制药物无效,“,真,”,难治,-,（,2,）,难治性肾病综合征的治疗困惑,大剂量、长疗程糖皮质激素的副作用,激素依赖、激素抵抗、频繁复发,细胞毒类的副作用及疗效不佳,嘌呤抑制剂起效的相对缓慢,难治性肾病综合征复杂的免疫病理机制,循环及局部产生的免疫复合物在肾小球基底膜上沉积,炎症细胞（单核、淋巴、中性粒细胞）浸润及损害,补体系统激活,各种细胞因子、趋化因子、粘附分子参与其中,CD4,B7,CD28,CD40,CD40L,MHC,II,TCR,Calcineurin,MAP kinases,IL-2,IL-2 R,Other,T cell,B cell,Target of rapmycin,(TOR),IL-15, IL-7, IL-9 et al.,Cyclin/CDK,M,G,2,G,1,S,de novo nucleotide synthesis,GC,anti-CD40L,FK506, CsA,GC,I,B,Sirolimus,T cell,GC-R,NF-,B,MMF,anti-IL-2R,舒莱、赛尼哌,Aza,CTX,anti-CD40,LEF,OKT3,免疫,细胞活化过程,FTY720,诱导归巢,免疫抑制剂,第一代,GC,，,CTX,，,AZA,第二代,CsA,第三代,MMF,，,FK506,，,Sirolimus,第四代,OKT3,，,Anti-IL2-R,，,FTY720,，,Anti-CD40,，,Anti-CD40L,，,Leflunomide,，,Anti-CD80/CD86,，,化学结构,新山地明活性成分环孢素分子结构,11,个氨基酸构成环状多肽,分子结构式,:C,62,H,111,N,11,O,12,分子量,:1202.64,CH,3,CH,CH,CH,2,CH,CH,3,C,H,HO,CH,C,N,MeVal,Abu,MeGly,MeLeu,MeLeu,MeLeu,CH,3,D-Ala,Ala,MeLeu,Val,O,环孢素分子结构,作用机制,新山地明选择性、可逆性抑制,IL-2,介导的,T,淋巴细胞增殖,1),新山地明抑制辅助,T,淋巴细胞产生和释放,IL-2,2),新山地明抑制细胞毒性,T,淋巴细胞增殖,3),新山地明抑制辅助,T,淋巴细胞,/,细胞毒性,T,淋巴,细胞表面,IL-2,受体的表达，从而抑制两种,T,淋巴,细胞活性,抗原提呈细胞,T,辅助细胞,CD4,CsA,供体,HLA,IL-1,IL-2,T,辅助细胞,CD4,T,辅助细胞,CD8,CsA,IL-2,受体,IL-2,受体,IL-4,5,6,受体,IL-4,5,6,CD4,CD8,B,细胞,B,细胞,CD4,CD8,B,细胞,补体激活,肾 脏,免疫反应的激活和扩增,细胞免疫,体液免疫,IL-2,Buurman WA et al. J Immuol. 1986;136:4035-4039,Morris PJ. Cyclosporine. In: Morris PJ, ed. Kidney transplantation: Principles and Practice. 3rd ed,1988:285-317,4),新山地明作用于细胞周期的,G,0,和,G,1,期,作用机制,:,新山地明不同于其他免疫抑制剂,与传统免疫抑制剂相比,新山地明的选择性作用机制,未导致骨髓抑制,(,动物模型和人体研究证实,),1,显著降低严重感染,2-5,显著降低排斥反应发生率,3-6,Wish JB.Transplant Proc 1986;18(suppl 2):15-18,Canadian Multicentre Transplant Study Group. N Engl J Med 1986;314:1219-25,Canafax DM et al. Transplant Proc 1986;18(suppl 1):192-6,Shaffer D et al. Am J Surg 1987;153:381-6,Sutherland DER et al. Am J Kidney Dis 1985;5:318-27,Feduska NJ et al. Transplant Proc 1986;18(suppl 1):136-40,药代动力学,新山地明,vs.,传统环孢素,吸收,分布,代谢,/,排泄,个体间吸收差异很大,个体间,AUC,曲线变化非常大,部分存在,2,个峰值,群体间血药浓度,/,用药不稳定,环孢素血浓度,(,g/L,),在稳定的移植患者中传统环孢素,的典型药代动力学图象,吸收,:,传统环孢素局限性,0 2 4 6 8 10 12,时间（小时）,0,300,600,900,1200,个体内吸收差异很大,导致群体内血药浓度,/,用药不稳定,许多患者药物吸收后的血中药物浓度差异显著,可达,3,倍,29,名稳定肾移植患者,二次测定相隔,1,周,剂量不变,12,小时,AUC,（药物暴露）,(h.,g/L,),5000,4000,3000,2000,1000,0,吸收,:,传统环孢素局限性,传统环孢素的吸收局限性,吸收受多种因素影响,生物利用度变异大,吸收,:,传统环孢素局限性,增加患者管理难度,影响临床疗效,传统环孢素生物利用度,%,比例,%,吸收,:,传统环孢素局限性源自剂型化学特性,亲脂性,不溶于水,与水和,GI,分泌液接触时,形成大颗粒,巨乳液,高分子量,GI,粘膜通透性,易被蛋白酶降解和灭活,口服的吸收度低、变异大、不可预测,降解和吸收需要,胆盐和胰酶参与,吸收,/,血药浓度受,胆汁分泌和胃肠道动力的影响,传统环孢素的化学性质导致其药代动力学局限性,新山地明,:,全新剂型优化化学特性,新山地明剂型的进步,表面活性剂,亲水性溶剂,亲脂性溶剂,环孢素原药,微乳化技术带来新山地明,的问世,新山地明,是环孢素微乳浓缩剂型,新山地明,是四种成分的精确平衡,亲脂性溶剂,亲水性溶剂,表面活性剂,环孢素,新山地明,:,全新剂型优化化学特性,新山地明与液体接触后自然形成透明的微乳液,环孢素原药,传统环孢素剂型,新山地明,药物与水相溶,新山地明,:,全新剂型优化化学特性,满足环孢素最佳剂型的两个标准,最佳环孢素剂型标准,新山地明,快速释放环孢素,全部肠道都可吸收药物,在被液体稀释过程中，始终使环孢素在吸收窗内保持微乳状态,0,250,500,750,1000,1,2,3,4,5,6,7,8,9,10,11,12,13,-1,0,峰浓度,(C,max,),用药,T,max,用药,谷浓度,(C,min,),AUC,(Total Exposure),时间,(h),环孢素血药浓度,(ng/ml),新山地明,:,全新剂型改善吸收,新山地明,平均峰浓度,生物利用度,(AUC),达峰时间,传统环孢素基础药代动力学,59%,29%,1,小时,新山地明,:,全新剂型改善吸收,新山地明吸收不受胆汁影响，优于传统环孢素,0,200,400,600,800,新山地明,传统环孢素,新山地明,传统环孢素,T,管开放,T,管关闭,N=11,N=7,N=11,N=5,Cmax,Coh(ng/ml),新山地明,:,全新剂型改善吸收,新山地明的剂量与生物利用度呈线性关系，优于传统环孢素,剂量,(mg),0,5,000,10,000,15,000,0,200,400,600,800,新山地明,山地明,AUC(ng/ml),48,例健康志愿者服用单剂传统环孢素和新山地明后的剂量,AUC,关系,药代动力学,:,分布,环孢素广泛分布于机体各组织中,浓度最高部位：肝脏、脂肪,其次：脾脏、肾脏、胰腺,在血液中,41-58%,：红细胞,4-9%,：淋巴细胞,5-12%,：粒细胞,33-47%,：血浆,药代动力学,:,代谢与排泄,新山地明代谢,99%的在人体肝脏内通过细胞色素,P-450酶,被代谢为约15种产物,新山地明,排泄,代谢产物主要通过胆汁分泌,经肠道排出体外,少部分（6%）通过尿液排出体外,少于,1%,经尿以原形排出,新山地明药代动力学小结,新山地明更易于患者管理,吸收更快速、更完全,生物利用度高，用药量减少,剂量与生物利用度呈线性,易与调整剂量,血药浓度变异性小,/,药代动力学稳定,更便于,监测，更可预测,药物相互作用,增加环孢素血药浓度的药物,钙通道阻滞剂,Diltizaem,尼卡地平,维拉帕米,糖皮质激素,甲基强的松龙,抗真菌药物,氟康唑,伊曲康唑,酮康唑,抗生素,克拉霉素,红霉素,其他药物,别嘌醇钠,溴隐亭,氯奎,丹那唑,甲氨蝶呤,甲氧氯普胺,对,T,淋巴细胞亚群有特异性抑制作用,1,2,3,辅助性,T,细胞（,Th,）和细胞毒性,T,细胞（,Tc,）为其主要靶细胞，作用于淋,巴细胞激活的早期阶段,抑制,T,淋巴细胞合成和释放白介素,-2,（,IL-2,）,抑制,IL-2,受体（,IL-2R,）的合成,非免疫抑制作用,4,5,6,恢复基底膜的电荷屏障,恢复基底膜的机械屏障,新山地明,治疗肾病综合征的最新作用机制,1.Meyrier A. J Nephrol 1997:10(1):14-24,2.Sherach EM. Annu Rev Immunol. 1985;3:397-423.,3.Tejani A, Ingulli E. Contrib Nephrol. 1995;114:1-5.,4.Ambatavanan S, Fauvel JP ,Sibley RK,Myers BD,J Am Soc Nephrol 1996;7:290-8,5.Zietse R, Wenting GJ, Kramer P, Schalekamp MA, Weimar W. Clin Sci (Lond). 1992 Jun;82(6):641-50,6.Zietse R, Derkx FH, Schalekamp MA, Weimar W. Contrib Nephrol.1995;114:6-18.,钙调免疫抑制剂,可能成为难治性肾病综合征的理想药物,他克莫司：仅有小样本及该例报道,环孢素,A,：,已有大量循证医学证据,CsA,在难治性肾病综合征中的应用,已有大量循证医学证据,Cyclosporin versus cyclophosphamide for patients with steroid-dependent and frequently relapsing idiopathic nephrotic syndrome: a multicentre randomized controlled trial,Ponticell C,et al,Nephrol Dial Transplant. 1993;8(12):1326-32,A randomized trial of cyclosporine in steroid-resistant idiopathic nephrotic syndrome,Ponticell C,et al,Kidney Int. 1993 Jun;43(6):1377-84,Treatment of idiopathic nephrotic syndrome with cyclosporin A in children,Hamed RM,et al J Nephrol. 1997 Sep-Oct;10(5):266-70,Cyclosporin A plus prednisone treatment of steroid-sensitive frequently relapsing nephrotic syndrome in children,Aksu N,etal,Turk J Pediatr. 1999 Apr-Jun;41(2):225-30,Long-term results of cyclosporine-induced remission of relapsing nephrotic syndrome in children,Kim PK,et al,Yonsei Med J. 1997 Oct;38(5):307-18,Cyclosporine in patients with steroid-resistant nephrotic syndrome: an open-label, nonrandomized, retrospective study,.,Ghiggeri GM, et al, Clin Ther. 2004 Sep;26(9):1411-8,Recurrence of severe steroid dependency in cyclosporin A-treated childhood idiopathic nephrotic syndrome,Kemper MJ, et al, NDT. 2004 May;19(5):1136-41,C1-C2 point monitoring of low-dose cyclosporin a given as a single daily dose in children with steroid-dependent relapsing nephrotic syndrome,Single-centre experience with cyclosporin in 106 children with idiopathic focal segmental glomerulosclerosis,Nakahata T, et al, Clin Nephrol. 2005 Oct;64(4):258-63,Mahmoud I, et al,Nephrol Dial Transplant. 2005 Apr;20(4):735-42,Initial treatment of idiopathic nephrotic syndrome in children: prednisone versus prednisone plus cyclosporine A:,a prospective, randomized trial,Hoyer PF,et al, J Am Soc Nephrol. 2006 Apr;17(4):1151-7,CsA,在难治性肾病综合征中需要,关注的问题,疗效：不同病理类型,副作用：尤其是肾毒性,复发问题：,肾病综合征对,CsA,的反应,（回顾性分析）,根据病理类型分析,根据以前对激素敏感性分析,INS,(n=150),MCD,(n=42),FSGS,(n=68),敏感,(n=66),抵抗,(n=81),CR,60(74%),14(21%),48(72%),24(30%),PR,11(13%),19(28%),9(14%),21(26%),Failure,11(13%),35(51%,）,9(14%),36(44%),Meyrier. Karger, basel:1995:28,治疗成人,FSGS,新山地明,组激素抵抗型,FSGS,的患者缓解率69，安慰剂组为,4,安慰剂 激素,（,n,23,）,p,0.001,0,20,40,60,80,100,新山地明,组,安慰剂组,Cattran DC et al. Kid Int 1999,；,56,：,2220,2226.,新山地明,激素（,n,26,）,缓解率：,新山地明,VS,安慰剂）,治疗成人,FSGS,长期随访结果,新山地明,组部分缓解,安慰剂组部分缓解,新山地明,组完全缓解,蛋白尿的缓解率,（）,12,24,52,78,104,P,0.001,P,0.05,0,20,40,60,80,100,新山地明,+,低剂量激素治疗,26,周之后，超过,40%,的激素抵抗型,FSGS,患者获得持续缓解,随访时间,(,周,),Cattran DC et al.Kid Int 1999;56:2220-26,治疗成人,FSGS,长期随访结果,随访时间（周）,新山地明,组,安慰剂组,两组同一随访时间相比均为,P,0.05,0,20,40,60,80,100,120,140,160,180,200,220,0,10,20,30,40,50,60,肌酐清除率,(Ccr),下降,50%,的患者比例,随访,4,年时，新山地明,组肾功能好于安慰剂组,(,P,0.05),Cattran DC et al.Kid Int 1999;56:2220-26,治疗成人,MCD,缓解情况,对环孢素无反应,对环孢素有反应,Matsumoto H et al. Clinical Nephrology 2001,；,55,：,143,148.,单独,使用低剂量环孢素可以使成人,MCD,患者缓解,3,1,2,8,6,2,0,2,4,6,8,10,12,全部病例,复发病例,首发病例,获得缓解的患者数量,n=11,n=7,n=4,Mild proteinuria,Moderate proteinuria,Heavy proteinuria,=4 to 8 g/d with or without,renal insufficiency,ACEI,ARB, dietary protein restriction,Maintain BP 125/75, Observe for 6 mo,ACEI,ARB, dietary protein restriction,Maintain BP 125/75, Observe for = 6 mo,Persistent nephrotic range proteinuria,Persistent heavy protein-uria and/or decreasing renal function,Cytotoxic/steroids,Cyclosporine,Cytotoxic/steroids,Cyclosporine,治疗成人,MN,J Am Soc Nephrol, 16: 1188-1194, 2005,治疗成人,MN,Cyclosporin A treatment for idiopathic membranous nephropathy,CSA therapy at a dosage of 5 mg.kg-1.d-1 is effective in inducing remission of nephrotic syndrome in adult IMN patients within three months,with a response rate of 80%,A relatively high rate of relapse (50%) was observed within 2 years after the withdrawal of CsA treatment,Yao X, et al,Chin Med J (Engl). 2001 Dec;114(12):1305-8,治疗成人,MN,The remission of nephrotic syndrome with cyclosporin treatment does not attenuate the progression of idiopathic membranous nephropathy,IMN nephrotic patients treated with prednisolone and low doses of cyclosporin A showed a high remission rate of nephrotic syndrome.,Goumenos DS, et al, Clin Nephrol. 2004 Jan;61(1):17-24,治疗,IgAN,Long term treatment of IgA nephropathy with cyclosporine A,CsA significantly lowered moderate to high proteinuria in patients with IgAN.,The therapy was well tolerated and side-effects were not so severe as to require CsA withdrawal,Ren Fail. 2000 Jan;22(1):55-62,儿童患者的疗效,Single-centre experience with cyclosporin in 106 children with idiopathic focal segmental glomerulosclerosis,CsA is effective in the treatment of children with idiopathic FSGS:,a high relapse rate on drug withdrawal,Mahmoud I,etal,Nephrol Dial Transplant. 2005 Apr;20(4):735-42,儿童患者的疗效,环孢素治疗儿童激素依赖型肾病综合征,环,孢素是儿童激素依赖型肾病综合征的有效治疗药物，86%的患儿对治疗有反应,43,43,14,43,完全反应,（,在治疗,3,个月后不再使用类固醇,）,43,部分反应,14,无反应,Garcia C et al. Transplant Proc 1998,；,30,：,4156,57,.,儿童患者的疗效,环孢素治疗儿童难治性肾病综合征,使用环孢素之前,使用环孢素之后,环孢素显著降低肾病患儿尿蛋白,P,=0.01,0,1,2,3,4,5,6,7,8,全部,FSGS,MCD,IgM,肾病,MPGN,狼疮肾炎,HIV,肾病,尿蛋白,g/24h,P,0.0001,P,0.001,P,=0.03,P,0.0001,P,=0.007,P,=0.06,病理分型,Singh A et al. Pediatr Nephrol 1999;13:26-32,减少肾毒性,Initial remission-inducing effect of,very low-dose,cyclosporin monotherapy for minimal-change nephrotic syndrome in Japanese adults,Matsumoto H, etal,Clin Nephrol. 2001 Feb;55(2):143-8,减少肾毒性,C1-C2 point monitoring of,low-dose cyclosporin a given as a single daily dose,in children with steroid-dependent relapsing nephrotic syndrome.,Nakahata T,et al,Clin Nephrol. 2005 Oct;64(4):258-63,减少肾毒性,Long-term treatment of focal segmental glomerulosclerosis in children with cyclosporine,given as a single daily dose,Chishti AS, etal, Am J Kidney Dis. 2001 Oct;38(4):754-60,减少肾毒性,Single-dose daily administration of cyclosporin A for relapsing nephrotic syndrome,2.4+/-1.1 mg/kg per day,No evidence of CsA nephrotoxicity was observed in a repeat renal biopsy,减少复发,Long-term low-dose,cyclosporin A in steroid dependent nephrotic syndrome of childhood,Neuhaus TJ, etal, Eur J Pediatr. 1992 Oct;151(10):775-8,减少复发,Follow-up study of children with nephrotic syndrome treated with,a long-term moderate dose of cyclosporine,Hino S, et al, Am J Kidney Dis. 1998 Jun;31(6):932-9,国内专家共识,CsA,应用于难治性肾病综合征,中华肾脏病杂志,2005,；,21,（,9,）：,556-557,CsA,应用于,难治性,MCD,激素依赖：大部分可取得完全或部分缓解,激素抵抗：部分可取得完全或部分缓解,与泼泥松,0.5mg/kg/d,合用显著提高缓解率,中华肾脏病杂志,2005,；,21,（,9,）：,556-557,CsA,应用于,难治性,FSGS,激素依赖：疗效较好,激素抵抗：单用疗效较差，若与泼泥松,0.5mg/kg/d,合用可显著提高疗效,中华肾脏病杂志,2005,；,21,（,9,）：,556-557,CsA,应用于,难治性,MN,可作为初始治疗,可在其他药物治疗无效时使用,中华肾脏病杂志,2005,；,21,（,9,）：,556-557,CsA,应用于,难治性,MsPGN(IgAN),激素或环磷酰胺治疗失败，可使用,中华肾脏病杂志,2005,；,21,（,9,）：,556-557,CsA,副作用,肾脏不良反应：急性，慢性,肝脏不良反应：,5-10%,，,3,月内,CsA,相关性高血压：,10-14%,其他不良反应：胃肠不适、腹泻、高尿酸血症,/,痛风、高血糖、多毛、齿龈增生、震颤、感染等。,新山地明,使用指导原则,起始剂量,成人起始剂量为5,mg/kg/d,，儿童起始剂量为,6mg/kg/d,激素抵抗型患者建议使用,新山地明,和低剂量口服皮质激素,MGN,患者至少需要3个月以上的疗程,对于肾功能异常的患者，起始治疗剂量为2.5,mg/kg/d,维持,出现缓解，可以缓慢地降低剂量（每月,0.5 mg,/,kg,/,d,），达到,2.5,3.0 mg,/,kg,/,d,的维持剂量。如果蛋白尿再次出现，恢复原有剂量,停止治疗,在,使用12年后，可以逐渐降低剂量至停药,，（每月,0.5 mg,/,kg,/,d,）,新山地明,使用指导原则,监测,如果使用正确的新山地明,剂量，并且在治疗期间对肾功能进行监测，可保护肾功能,如果在至少两次监测中，血肌酐超过30%基线，可以将剂量降低2550%,肾活检,对于激素依赖型,MCD,患者且,新山地明,使用超过,1,年考虑做活检,谢谢,！,