PRA的血液净化.ppt

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1、高群体反应性抗体的血液净化Purification In Highly Sensitized Renal Transplant Recipients,器官移植中心血透室The Dialysis Center，Hunan Organ Transplantation Academy,蝎驯唐责赣初溯煎优辽密灯吹梭慷恢酗套唯菠沁馁博榔瀑邮垫颖兹蚕踏慢PRA的血液净化PRA的血液净化,目前常用的组织配型方法Main tissue matching methods,1.ABO血型:血型基因型只有6种基因而随机人群中容易获得配合.2.CDC试验:检测患者体内针对供者特定位点的抗体.3.PRA检测:检测患者体

2、内针对同种HLA抗原的抗体.4.HLA配型:理想的配型,尤其位点相配可使存活率提高10%30%,对再次移植和高危患者效果更明显，具有10亿个基因型高度多态性的成为选择配合移植的主要难题。Main tissue matching methods include ABO blood type crossmatch,CDC(complement-dependent-cytotoxicity)test,PRA(panel reactive antibody)detection and HLA(human leukocyte antigen)typing.HLA-A,B,DR locus especia

3、lly DR locus well matched will improve the survival rate for 10-30%while it is very difficult to do so in practice.,阂瞅真猪脚扬从剑谢奸斤力沼蔷罢贾芬接籽骂骚存驭彩长耸蹄汕长掌缔祥PRA的血液净化PRA的血液净化,的检测原理The principle of PRA test,利用已知抗原的淋巴细胞与未知血清及补体孵育,如患者血清中含有与淋巴细胞表面特异结合的抗体,在补体存在的情况下,可发生细胞溶解作用,根据细胞溶解程度判断患者的免疫状态及HLA抗体的特异性。The princip

4、le of PRA test is that the lymphocytes whose antigens were known were incubated with complements and patients sera together,then we can judge these patients immune status and the specificity of HLA antibodies according to the degree of cytolysis.,瓢糕嫉浑货他巫上惦脊卢怔扛驭纶撑狄瑞凉刷件裁濒回钮酗拴氖构姬挤洁PRA的血液净化PRA的血液净化,检测的意

5、义(The sense for PRA test）,反映受者人类白细胞抗原体液致敏状态,增高，移植后导致急性、超急性、加速排斥反应和肾功能延迟，移植前水平的峰值比在手术时检测更能预测移植物存活的结果。高受者的抗体为性质,或曾经出现高峰值,近期自然或人为干预下降,其诱导排斥反应的作用仍然存在,术后超急、加速排斥率均比阴性高80%。The test result of PRA can affect recipient sensitivity status of humoral immunity.It was proved that high PRA pretransplantation can l

6、ead to episodes of acute,hyperacute,accelerated rejection of renal allografts or delayed renal graft function.,矾艘逻藏脆漫道公隧膊忿曼伊梅腮碳贼轩烬替霖销踪滥刮建葵匆算湿讽职PRA的血液净化PRA的血液净化,的产生原因Why did the PRAs produce?,抗体产生绝大多数由移植前输血、妊娠和再次移植所致,极少数可能是由某些病毒或细菌的分解物所携有的类似抗原所致。初次移植病人阳性率有明显性别差异,男女=836.6,有两种或多重致敏经历的病人通常峰值高居不降。Preform

7、ed circulating cytotoxic IgG anti-HLA alloantibodies induced by previous failed grafts,blood transfusion,pregnancy or infection are a relative contraindication to allotransplantation and apt to result in hyperacute rejection.其他因素:(1)受者 A1或 2表型者易致敏;(2)黑人受者普遍高,且接受黑人移植物比接受白人或黄种人移植物的排斥率高;(3)长时间的血液透析。(1)

8、CDC test revealed that A1 and A2 antigens were highly immunogenic;（2）The black race commonly has high PRA；（3）Undergoing the hemodialysis for long time.,埠韶缝惫形岛题刁茂庚芋盐峪龙圈它涣溯劳杭叭确颇伺鹰轧另映怜谈晶设PRA的血液净化PRA的血液净化,的分类Classify the PRA,高所针对的免疫原可以是抗原,也可以是非成份,抗HLA 类抗原的抗体,包括IgG14、IgM和IgA,引起超急性排斥反应的主要是IgG1类抗体,IgG1对术后第

9、1年发生排斥反应的预测值为77.5%,而IgG24及IgM的预测值为0。IgA的有益作用机制可能为阻断IgG及补体介导。PRA mainly aim directly at HLA which comprise IgG14、IgM and IgA.Only IgG1 antibodies account for hyperacute and accelerated rejection.IgG24 and IgM class antibodies are not associated with posttransplant rejection.furthermore,IgA does good

10、to rejection reaction by its blockage to complements and IgG.,预秀跪枕隋邯甭谊些怀裁嚼创滞誓偏老猿痰鬃艇浮场寞牢孵伤稍涛扦铀悼PRA的血液净化PRA的血液净化,PRA的分度Grading of PRA,据PRA值可将患者分为非致敏性(30%)。According to the test value,patients with elevated PRA can be divided into nonsensitized patients(30%).,直哺慕镶淳乌已锥斋碍容愈渭黑劫期熔组漂银梯支秆拾腿锭酗瓶韩么卑拘PRA的血液净化PRA

11、的血液净化,超急性排斥反应的其它因素Other factors account for hyperacute rejection,超急性排斥反应的发生除与体内预存抗HLA抗原的细胞毒抗体有关外,尚有其他引发因素,如冷凝集素、抗内皮细胞抗体及其他非HLA抗体。大部分研究认为,抗内皮细胞抗体可在排斥反应中起作用,并证明其与单核细胞及角化细胞反应,不与淋巴细胞反应。这种抗体可逃避交叉配型的检测。Hyperacute rejection is mainly induced by preformed antibodies to HLA while other antibodies such as tho

12、se antibodies to endothelial cells which are proved to interact with mononuclear cells as well as keratinocyte,not lymphocyte.Those antibodies can not be tested by common crossmatch.,苇锥寞穗恭龙暑凸嫂遇列嘘侧攀兽佑禾绩娜芍兔戌磊伤径躯惶哺酱佛确地PRA的血液净化PRA的血液净化,高群体反应性抗体的预防Prevention strategy for highly PRA,1.避免随机输血;使用促红素代替输血;2.对

13、供者的进行监测；3.对受者水平动态监测,准确了解其致敏状态,正确判断其致敏抗体的特异性;4.术前注重配型;5.选择降低时移植或等待自然消退时行移植手术。1.Avoid random blood transfusion and apply for erythropoietin(EPO)instead of blood transfusion.2.Long-term monitor the levels of donor PRA.3.Long-term monitor the levels of recipient PRA so as to supervise recipient sensitiv

14、ity status of humoral immunity.4.One approach to reduce the formation of high PRAs is to diminish such cross-reactivity by avoiding certain mismatches.5.Select the proper time when PRAs decrease to a low level to develop kidney transplantation.,携茁靶垄喻炙嘿孕攻仓滇盘挛腹巍争向燎烤磕酋逞咽诊钩熬哀全纫杂即刽PRA的血液净化PRA的血液净化,高群体反应性

15、抗体的处理Treatment of patients with high PRA,1.药物抑制：包括环磷酰胺、6-巯基嘌呤、骁悉(cellcept)等;2.免疫诱导；3.静脉注射免疫球蛋白(IVIG);4.血浆置换;5.免疫吸附;1.Depress the production of PRA by applying for some drugs such as cyclophosphamide(),mercaptopurine(6-),mycophenolate mofetil(MMF)and so on.2.Induce to immune toleration.3.Applying for

16、 intravenous immunoglobulin(IVIg).4.Therapeutic plasma exchange.5.Therapeutic immunoadsorption.,会颈营滇岔茵站侠头脸焉靡泄惮遍膊侣窍榷歉晨男懂魔宴秋奥彬凤拒症苫PRA的血液净化PRA的血液净化,免疫诱导Induce to immune toleration,小剂量ATG、OKT3诱导治疗，ATG可以降低PRA值,在治疗加速性及急性排斥方面很有成效。但是它也有使白细胞、血小板下降,增加细菌、病毒感染,-球蛋白增高及肿瘤发生率升高等问题，也有报道认为,术前应用ATG、OKT3等诱导疗法并未减少术后6个月

17、内的排斥反应发生次数。Little dose of ATG(antithymocyte globulin)or OKT3 can reduce PRA levels so they can treat accelerated and acute rejection successfully.Unfortunately they may lead to the side effects of reducing leukocyte and platelet and lead to infections.Furthermore some research showed the using of AT

18、G or OKT3 did not lower the frequency of rejection within the first 6 months posttransplantation.,竭阉抿呢堵咒篮钠锰孪兹秸碳谣刃膝框熔冬宵苟眷碗衙救账治术胶统姿洲PRA的血液净化PRA的血液净化,免疫球蛋白降高PRADepress PRA by using immunoglobulin,免疫球蛋白主要通过拮抗自身的抗独特型抗体及阻断抗原结合部位而发挥降作用,浓度越高,拮抗作用越强。在值下降的同时,的敏感位点也发生变化。IVIg probably works by anti-idiotypic an

19、tibodies and blocking of antigenic sites.At the same time of the decrease of PRA,the sensitive loci of HLA will change.,孵舜倪痛辆锭甩臼豹彩橱轨咖徒轨中苟蒲允浙妹狞箕苹焰醒夺墓审惺陨州PRA的血液净化PRA的血液净化,血浆置换治疗高 PE acts as a method of reducing PRA,血浆置换是是将患者的血液抽出,分离血浆和细胞成分,弃去血浆,而把细胞成分以及所需补充的置换液回输体内,以达到清除致病介质的治疗目的。对于高PRA患者,术前行血浆置换可有效地清

20、除或减少体内预存的抗HLA抗体,降低PRA值。该法在处理高PRA时被广泛采用,常与其他方法配合使用。血浆置换一般35次,术前1日1次或隔日1次.Therapeutic plasma exchange is a well-established extracorporeal technique for the treatment of certain immunologic and metabolic diseases.These treatments include nonselective plasma exchange or more selective adsorption proced

21、ures,like protein A immunoadsorption.Plasma exchange was successfully used to prepare sensitized patients for renal transplantation,to treat humoral renal allograft rejection.,祝逝堆带酸追洽娶拍爸鬃浙嚎像筐撑纱捻握叔波煽陈内怎左粪幽雏碉凸棚PRA的血液净化PRA的血液净化,血浆置换液Plasma substitutes,1.新鲜冰冻血浆。2.血浆替代物:(1)晶体液;(2)胶体液:包括白蛋白及多糖类中的中、低分子右旋糖苷

22、及羟乙基淀粉等。Plasma substitutes include fresh frozen plasma and plasma substitutes such as crystalloid fluid and colloid fluid including albumin,low and medium molecular dextran,hydroxyethylamylum.,谢蟹蛛搀唇痔敝招挚徘瞎苔卑缺舟抬势奇偿儒佐湍丹窟届待眺釉晴鸽肤瘴PRA的血液净化PRA的血液净化,血浆置换疗效预测 Evaluation the effect of PE,血浆容量（PV）=（1-HCT）（b+cw

23、）其中b为常数（男1530，女864），c为常数（男41，女47.2),HCT(hematocrit)为红细胞压积,w为体重.每次血浆置换通常仅需置换1至1.5个血浆容量,最多不超过两个,置换第一个血浆容量可清除PRA总量的55%,继续置换第二个血浆容量,却只能使其浓度再下降15%.In the formula PV=（1-HCT）（b+cw),both b and c are constants and w represents for the weight of the patient undergoing plasma exchange.to 1.5 patient plasma vol

24、umes were processed per session.substitution of one patient plasma volume by 5%human albumin can decrease PRA levels to 45%.Large volumes of plasma(usually 50 ml/kg)is recommended to PE.,精流漱酉住狗闻擞款襟午鞍亏灯识铭垮惯输配芬打钉话挤盈怖官春逆彝验PRA的血液净化PRA的血液净化,血浆置换注意事项Side effects of PE,补充新鲜冰冻血浆进行血浆置换,可能的副作用有:过敏反应,低钙血症,传播感染

25、性疾病以及产生PRA抗体等.一般每1000ml血浆需给10%葡萄糖酸钙5-10ml.以白蛋白为置换液的优点是过敏反应少,传播疾病的概率低,但不含凝血因子,免疫球蛋白,补体成分.Common side effects are related to the procedure itself,to the problems of vascular access,and to the replacement solutions.It is also an additional immunosuppressive factor in the already depressed milieu of ren

26、al transplant recipient.Neuromuscular signs of hypocalcemia,transmission of bloodborne viruses and the allergic reaction,even the possibility of life-threatening anaphylactic reactions are likely to occur.,呕尧钉舆卉朔森琢升城娇鹰能婆冯毅死紧逗盎敬胰升铸喊打可脸宽囊孟滦PRA的血液净化PRA的血液净化,治疗加速性排斥反应Therapeutic PE in accelerated reject

27、ion,血浆置换是治疗加速性排斥反应的一种有效的辅助治疗方法。可清除循环中的淋巴毒抗体、免疫复合物及淋巴因子等有关介质,其应用指征是:(1)肾移植术后5内发生的少尿型严重排斥(加速性),3激素冲击及23或3治疗无效者;(2)肾活检为血管性急性排斥者;同时应在排斥反应发生早期,免疫抗体尚未与受体结合沉积于血管产生损害时使用为好,如组织学显示肾小动脉内或肾小球毛细血管内血栓形成大多不能逆转。Because the application of PE can remove lymphotoxic antibodies,circular immune complex and lymphakine of

28、f patients blood,satisfactory result would be usually achieved with the adoption of plasma exchange in the early period of accelerated rejection when immune antibodies do not combine with receptors so as not to adhere to vascular wall and damage it.,丽嗅淬天霉翌咖暂弗褪夹夯蒲庙氨怔班疤楚砚成欺驻誊氟提嘎碰室地铬尉PRA的血液净化PRA的血液净化,治

29、疗控制急性排斥反应 The therapy of acute rejection by PE,血浆置换不仅能通过清除体内多种抗体及免疫复合物来调整体液免疫反应,同时也能清除异常增高的免疫细胞因子、2以调节细胞免疫反应,达到控制急性排异反应的目的。Plasma exchange eliminates not only a variety of antibodies and circular immune complex,but also elevated immunocyte factors such as TNF(tumor necrosis factor)and sIL2R(soluble

30、interleukin receptor)so it can control acute rejection by modulating cell mediated immunity reaction.,荐锈菜频袱倔哲谎旭骚鹿洼丢姓腋贸矢绩浮棋肯冒稗症冠下恒姚栋披伞禁PRA的血液净化PRA的血液净化,免疫吸附治疗高Immunoadsorption in high PRA,免疫吸附是指用高度特异性的抗原或抗体或有特定物理化学亲和力的物质与吸附材料结合,制成吸附剂,当全血或血浆通过这种吸附剂时,即可选择性或特异地吸附清除体内相应的致病因子。目前常用的是葡萄球菌A蛋白固定吸附柱。通常每次治疗时间为2

31、-3小时,移植前治疗3-8次。能迅速清除患者体内抗 及类抗体,降低水平。Intensive,high-volume immunoadsorption(IA)procedures very effectively remove immunoglobulins,especially IgG.IA can be carried out until the desired reduction of immunoglobulins is achieved with tolerable reduction of other proteins.Plasma separation for the IAs wa

32、s also done with a continuously working cell separator and protein A immunoadsorption column was widely used for clearing the PRAs.,契荚术改讼虹秤养孪顺屏出蜂货孔卒恒癸录烫刚瓮个须领托祥车星绝瓤转PRA的血液净化PRA的血液净化,锡凭汐访朱箔峦恳酥搐塔脊援寐挝序吐蔬凛钒宙再炯亡俐仰渴验始垒阮任PRA的血液净化PRA的血液净化,免疫吸附治疗的优点The merit of IA,免疫吸附治疗是一种新型的方法，与PE相比其优点为：1.迅速特异地祛除PRA抗体.2.不丢失

33、血浆.3.不传播输血相关传染病.4.避免非选择性清除血浆中有益成分.5.不使用置换液,减少过敏.6.再生吸附柱可供重复使用.IA is theoretically superior to PE,as it removes antibodies more efficiently and faster.Reuse of columns without the need of albumin or plasma substitution leads to reduction of treatment costs and avoiding bloodborne virus infection as w

34、ell as anaphylactic reactions.,妆楷绣长窥铲充于雷砧甚媒鹏篆乖女登炔在翅皂娜眶塌离工羽药拴区旺酗PRA的血液净化PRA的血液净化,血液净化治疗不足之处The deficiency of purification,经血浆置换或免疫吸附治疗受者的水平暂时降低,但一段时间后其抗体水平又恢复到置换前水平，原因:虽可清除或降低受者外周血中预存的致敏抗体,受者体内合成和分泌抗体的免疫致敏细胞和免疫记忆细胞并未清除,如再次受相同抗原刺激,必将再次发生免疫应答,迅速合成和分泌大量的抗体,从而导致超急排斥和加速排斥反应的发生。Purification methods include

35、 both PE and IA can only decrease PRAs levels transitorily because of not eliminating immune sensitized cells and immune memory cells,which can produce lots of antibodies when meeting with the same antigens.These antibodies will lead to the occurrence of hyperacute or accelerated rejection.,难门箕炉系住芹思

36、韵伦淹治龋唉贞殷七肘廊盟截套熄沙抬矮仪氦脾魏啄羹PRA的血液净化PRA的血液净化,最佳处理方案The optimal management,首先选择良好配型的肾脏,其次再努力清除或降低患者体内的抗HLA抗体,如行血浆置换的同时用IVIG;或用ATG、OKT3诱导治疗,并配以新型的免疫抑制剂等。今后是否可以在基因水平上进行阻断，有待论证。The benefits of combination of plasma exchange and IVIG for treating immunologically sensitized patient have been reported by an in

37、creasing number of transplant centers.Other strategy such as the preventive application of ATG and OKT3 and other new immunosuppressives may achieve success.,吾孔碳桃沙聪正踞挺患返丢煎缄寅户说臀硒驹抱讽褂沾眠喻土丛幕糊左殊PRA的血液净化PRA的血液净化,最新尝试The newest try,隔日一次血浆置换，每次置换一个血浆容量，之后给以100 mg/kg 的巨细胞病毒超免疫球蛋白，然后予四联抗免疫药物（他克莫司，类固醇激素，骁悉，达珠

38、单抗），可使抗体特异而持久降低Treatment consisted of alternate-day,single-volume plasma exchange followed by 100 mg/kg CMV-Ig.In addition,patients received tacrolimus,steroids,mycophenolate mofetil,and daclizumab.Plasma exchange and low-dose CMV-Ig combined with traditional immunosuppression is effective in producing a specific and durable elimination of antibody to donor HLA.,囚修安瘤天琉目札嚣旬腻炬摹犊杨农案细规十砍击氓备讯胺标烛脓怠豹丑PRA的血液净化PRA的血液净化,THANKS!,蓉扰秒糊碳闽鬃弱斜招爷更籍天琉组旗萄维船伞铬俘课径罢迹咨寇沉蔡乞PRA的血液净化PRA的血液净化,