心臟死亡器官捐獻(xiàn)腎移植術(shù)后腎功能延遲恢復(fù)的免疫抑制劑選擇

周異群(綜述)　朱玉嫻　朱同玉(審校)

(1上海羅氏制藥有限公司　上?！?01102; 2復(fù)旦大學(xué)附屬中山醫(yī)院泌尿外科　上?！?00032)

腎移植術(shù)后,移植物功能延遲恢復(fù)(delayed graft function,DGF)可伴隨急性排斥反應(yīng)和慢性移植腎腎病發(fā)生,是移植物存活的主要障礙[1]。尸體供腎移植(deceased donor kidney transplant,DDKT)受者DGF發(fā)生率約50%。與腦死亡器官捐獻(xiàn)(donation after brain death,DBD)相比,心臟死亡器官捐獻(xiàn) (donation after cardiac death,DCD)腎移植受者DGF和原發(fā)性無(wú)功能 (primary nonfunction,PNF)的發(fā)生率增加5.73倍,其主要原因是DCD供腎增加熱缺血和冷缺血時(shí)間[2-3]。 DCD供腎熱缺血時(shí)間<45 min有利于維持移植腎的長(zhǎng)期功能,相比DBD供腎,再灌注損傷也是引發(fā)DCD供腎移植受者DGF和PNF的重要原因。而宿主炎癥反應(yīng)是持續(xù)性再灌注損傷的基礎(chǔ)[3]。

為了預(yù)防缺血再灌注損傷(ischemia-reperfusion injury,IRI)和降低DGF的發(fā)生率,通常采用免疫抑制療法來(lái)抑制免疫反應(yīng)。免疫應(yīng)答引起的缺血再灌注是造成DGF的主要原因。鑒于DCD供腎的DGF發(fā)生率高,尤其應(yīng)重視降低早期排斥反應(yīng)發(fā)生率。一些學(xué)者主張?jiān)贒CD供腎移植中使用強(qiáng)效免疫抑制劑治療,使移植物在DGF期間免于免疫損傷,且避免使用鈣調(diào)神經(jīng)磷酸酶抑制劑(calcineurin inhibitor,CNI)[4]。對(duì)DGF患者進(jìn)行常規(guī)誘導(dǎo)治療可預(yù)防早期排斥反應(yīng),有效的誘導(dǎo)治療也可能減少初始缺血再灌注損傷。因此,白細(xì)胞IL-2受體拮抗劑(IL-2 receptor antagonists,IL-2RA)與抗胸腺細(xì)胞球蛋白(anti-thymocyte globulin,ATG)誘導(dǎo)治療在1997—2002年間飆升了3倍[5]。免疫抑制療法分為誘導(dǎo)治療和維持治療兩部分。移植時(shí),對(duì)于免疫高風(fēng)險(xiǎn)受者,誘導(dǎo)治療可抑制移植排斥反應(yīng)中抗原的識(shí)別和T細(xì)胞的激活[6]。免疫抑制劑誘導(dǎo)治療通過(guò)抑制白細(xì)胞富集導(dǎo)致的血管充血以及內(nèi)皮細(xì)胞損傷來(lái)降低DGF的發(fā)生率[3]。有研究顯示未進(jìn)行誘導(dǎo)治療組DGF的發(fā)生率顯著高于使用誘導(dǎo)治療組[3]。目前使用較多的誘導(dǎo)治療藥物包括:ATG;(巴利昔單抗和賽尼哌),非T細(xì)胞耗竭性單克隆抗體,阻斷IL-2受體(anti-CD52)。

誘導(dǎo)治療T-淋巴細(xì)胞清除可以逆轉(zhuǎn)缺血再灌注對(duì)慢性移植物失功的影響,尤其是在DGF高風(fēng)險(xiǎn)患者中,使用多克隆抗體使T淋巴細(xì)胞耗竭,可預(yù)防或降低缺血再灌注的作用和改善DGF[7-9]。常用的多克隆抗體有ATG,它有劑量依賴(lài)性耗竭T細(xì)胞的作用,同時(shí)具有劑量依賴(lài)性不良反應(yīng)。

在一項(xiàng)前瞻性、隨機(jī)的臨床試驗(yàn)研究中,Goggins等[10]比較了ATG在術(shù)中和術(shù)后的使用對(duì)尸體供腎移植受者DGF的影響,結(jié)果表明,在血管重建之前使用ATG顯著降低DGF的發(fā)生率。Noel等[11]在一項(xiàng)納入227例HLA 致敏高風(fēng)險(xiǎn)腎移植受者的研究中發(fā)現(xiàn),使用ATG組的DGF發(fā)生率顯著低于使用達(dá)利珠單抗 (31.5%vs.44.6%,P=0.044) 。但是,Brennan等[12]研究表明,在延長(zhǎng)冷缺血時(shí)間致組織損傷的高風(fēng)險(xiǎn)人群中,應(yīng)用ATG并未降低DGF發(fā)生率。Requiao-Moura等[8]也發(fā)現(xiàn)在移植術(shù)中使用ATG未能預(yù)防DGF的發(fā)生。

盡管以上研究存在爭(zhēng)論,但使用ATG誘導(dǎo)治療DGF高?；颊呤呛侠淼?因?yàn)榧毙耘懦夥磻?yīng)在這個(gè)亞群中發(fā)生率更高[13]。但同時(shí)ATG與強(qiáng)效免疫抑制治療缺陷相關(guān)。使用ATG導(dǎo)致的感染并發(fā)癥較為常見(jiàn),最常見(jiàn)的是巨細(xì)胞病毒(cytomegalovirus,CMV)感染。有研究表明,ATG使用導(dǎo)致的CMV感染率是對(duì)照組的3.4倍[8]。

因此,為開(kāi)發(fā)既能阻斷T細(xì)胞增殖,又不消耗T淋巴細(xì)胞且不良反應(yīng)小的抗體,已經(jīng)進(jìn)行了多方努力。單克隆抗體(如IL-2RA)由于其強(qiáng)效的高靶向性免疫抑制和最小的不良反應(yīng),已被證明具有較優(yōu)的早期治療效果[14-15]。

淋巴細(xì)胞的增殖起始于IL-2/IL-2R途徑與CD25分子在淋巴細(xì)胞中選擇性表達(dá),這就表明CD25抑制劑可以降低缺血再灌注的發(fā)生率[15]。在移植標(biāo)準(zhǔn)風(fēng)險(xiǎn)人群中,IL-2RA與多克隆抗淋巴細(xì)胞抗體具有同等療效[16]。Peng 等[17]進(jìn)行了一項(xiàng)回顧性隊(duì)列研究,旨在評(píng)估IL-2RA與ATG誘導(dǎo)治療在DCD腎移植受者中的療效和安全性。結(jié)果表明,兩組DGF發(fā)生率無(wú)顯著性差異,但術(shù)后6個(gè)月時(shí),IL-2RA組的感染發(fā)生率顯著低于ATG誘導(dǎo)治療組(P=0.025)。Lebranchu等[15]進(jìn)行了一項(xiàng)隨機(jī)的單中心研究,旨在比較巴利昔單抗與抗胸腺細(xì)胞球蛋白誘導(dǎo)治療在療效和安全性方面的優(yōu)劣,結(jié)果表明,兩組DGF和急性排斥反應(yīng)發(fā)生率相當(dāng),但巴利昔單抗組CMV感染發(fā)生率顯著降低(P=0.005)。盡管近些年來(lái)ATG使用飆升,但其在降低低免疫風(fēng)險(xiǎn)腎移植受者的移植物失功率、DGF發(fā)生率以及提高受者存活率上并沒(méi)有優(yōu)勢(shì)。表1比較了IL-2RA誘導(dǎo)治療或透析與抗胸腺細(xì)胞球蛋白治療的DGF發(fā)生風(fēng)險(xiǎn)。

歐洲和美國(guó)的專(zhuān)家建議,在治療高免疫風(fēng)險(xiǎn)的患者時(shí)選用以淋巴細(xì)胞為靶向治療目標(biāo)的多克隆抗體,在治療低免疫風(fēng)險(xiǎn)的患者時(shí),選用以IL-2/IL-2R為靶向治療目標(biāo)的單克隆抗體[12,19-21]。因此,一些移植中心開(kāi)始著手在誘導(dǎo)治療前對(duì)腎移植患者的風(fēng)險(xiǎn)進(jìn)行分層,鑒于DCD供腎移植受者DGF發(fā)生風(fēng)險(xiǎn)高的特點(diǎn),風(fēng)險(xiǎn)分層模型對(duì)預(yù)測(cè)DGF發(fā)生是有益的。接受DCD供腎的受者發(fā)生DGF的風(fēng)險(xiǎn)高,但有些學(xué)者認(rèn)為不能將DGF發(fā)生率高僅僅歸因于DCD。Schadde等[22]定義高風(fēng)險(xiǎn)的標(biāo)準(zhǔn)包括群體反應(yīng)性抗體(panel reactive antibodies,PRA)>20,非裔美國(guó)人腎移植。2012年Foster等[23]研究表明,成人尸體供腎移植受者被認(rèn)為是高風(fēng)險(xiǎn)人群,被定義為進(jìn)行DCD供腎移植,冷缺血時(shí)間>24 h,非裔美國(guó)人,PRA>20%,或者經(jīng)歷再次移植;低風(fēng)險(xiǎn)人群定義為本地供者,冷缺血時(shí)間<24 h,非-非裔美國(guó)人,以及PRA<20%。

表1　尸體腎移植受者接受ATG,IL-2RA或透析等不同治療方案的治療效果Tab 1　Treatment effect of ATG,IL-2RA or dialysis on cadaver kidney transplant recipients

DGF:Delayed graft fuction;CMV:Cytomegalovirus;NS:No significance.

維持免疫抑制方案維持治療方案旨在長(zhǎng)期抑制急性排斥反應(yīng),防止移植物功能的惡化。為了有效抑制急性排斥反應(yīng),目前常用激素+MMF+CNIs三聯(lián)方案[24]。但CNIs具有腎毒性,而DGF患者本身存在腎功能不全的情況,CNIs可能會(huì)延長(zhǎng)DGF的修復(fù)時(shí)間,一般可采取延遲給藥方案或減量使用[25-26]。英國(guó)器官移植學(xué)會(huì)指南指出[27],誘導(dǎo)治療聯(lián)合CNIs延遲/減量可能減少DGF的發(fā)生或縮短DGF持續(xù)時(shí)間。但是,CNI延遲或減量會(huì)增加急性排斥反應(yīng)的發(fā)生風(fēng)險(xiǎn),Gaynor等[28]分析術(shù)后1年的Tac水平與活檢證實(shí)的急性排斥反應(yīng)(biopsy-proven acute rejection,BPAR)的關(guān)系,研究顯示,低Tac水平與BPAR的發(fā)生率高顯著相關(guān),估算的風(fēng)險(xiǎn)比為6.33。 Sawinski等[29]的一項(xiàng)Meta分析顯示:與MMF+CNI維持治療相比,MMF+CNI撤除增加BPAR發(fā)生風(fēng)險(xiǎn)。因此延遲/減量使用CNIs可減少DGF的發(fā)生,但也會(huì)增加BPAR的發(fā)生風(fēng)險(xiǎn)。

SRL對(duì)DGF的治療作用尚存爭(zhēng)議,Tahir等[38]對(duì)SRL的治療作用進(jìn)行了研究,8例ECD患者使用Tac+MMF±激素治療無(wú)效,DGF持續(xù)時(shí)間延長(zhǎng)(42.3±38.3)天,移植后(46.5±20.6)天轉(zhuǎn)換為SRL+MMF±激素治療,結(jié)果顯示,SRL可改善患者腎功能。但也有研究顯示SRL治療與DGF顯著相關(guān),顯著延長(zhǎng)DGF的持續(xù)時(shí)間(P=0.01)[39-40]。因此,SRL對(duì)DGF的預(yù)防作用還有待進(jìn)一步證實(shí)。

結(jié)語(yǔ)由于DCD供體腎移植引起DGF比較常見(jiàn),免疫抑制劑降低早期排斥反應(yīng)受到重視。由于DGF的發(fā)生率和腎移植受者風(fēng)險(xiǎn)的不同,免疫抑制劑方案也需相應(yīng)調(diào)整。目前臨床應(yīng)對(duì)DGF高發(fā)生率,通常是給予CNI減量延遲方案,同時(shí)加強(qiáng)其他免疫抑制劑,如生物制劑及MPA類(lèi)藥物。需要注意的是,DGF的狀態(tài)下,MPA類(lèi)藥物AUC比無(wú)DGF受者更低,此時(shí)MPA類(lèi)藥物的劑量更難以把握,因此,在臨床實(shí)踐中,需加強(qiáng)MPA類(lèi)藥物濃度監(jiān)測(cè)以達(dá)到降低移植物排斥的風(fēng)險(xiǎn)。

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