周異群(綜述)　朱玉嫻　朱同玉(審校)

(1上海羅氏制藥有限公司　上海　201102; 2復旦大學附屬中山醫(yī)院泌尿外科　上?！?00032)

腎移植術(shù)后,移植物功能延遲恢復(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(donation after brain death,DBD)相比,心臟死亡器官捐獻 (donation after cardiac death,DCD)腎移植受者DGF和原發(fā)性無功能 (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間[2-3]。 DCD供腎熱缺血時間<45 min有利于維持移植腎的長期功能,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。一些學者主張在DCD供腎移植中使用強效免疫抑制劑治療,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DGF患者進行常規(guī)誘導治療可預(yù)防早期排斥反應(yīng),有效的誘導治療也可能減少初始缺血再灌注損傷。因此,白細胞IL-2受體拮抗劑(IL-2 receptor antagonists,IL-2RA)與抗胸腺細胞球蛋白(anti-thymocyte globulin,ATG)誘導治療在1997—2002年間飆升了3倍[5]。免疫抑制療法分為誘導治療和維持治療兩部分。移植時,對于免疫高風險受者,誘導治療可抑制移植排斥反應(yīng)中抗原的識別和T細胞的激活[6]。免疫抑制劑誘導治療通過抑制白細胞富集導致的血管充血以及內(nèi)皮細胞損傷來降低DGF的發(fā)生率[3]。有研究顯示未進行誘導治療組DGF的發(fā)生率顯著高于使用誘導治療組[3]。目前使用較多的誘導治療藥物包括:ATG;(巴利昔單抗和賽尼哌),非T細胞耗竭性單克隆抗體,阻斷IL-2受體(anti-CD52)。

誘導治療T-淋巴細胞清除可以逆轉(zhuǎn)缺血再灌注對慢性移植物失功的影響,尤其是在DGF高風險患者中,使用多克隆抗體使T淋巴細胞耗竭,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,它有劑量依賴性耗竭T細胞的作用,同時具有劑量依賴性不良反應(yīng)。

在一項前瞻性、隨機的臨床試驗研究中,Goggins等[10]比較了ATG在術(shù)中和術(shù)后的使用對尸體供腎移植受者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]在一項納入227例HLA 致敏高風險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利珠單抗 (31.5%vs.44.6%,P=0.044) 。但是,Brennan等[12]研究表明,在延長冷缺血時間致組織損傷的高風險人群中,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論,但使用ATG誘導治療DGF高危患者是合理的,因為急性排斥反應(yīng)在這個亞群中發(fā)生率更高[13]。但同時ATG與強效免疫抑制治療缺陷相關(guān)。使用ATG導致的感染并發(fā)癥較為常見,最常見的是巨細胞病毒(cytomegalovirus,CMV)感染。有研究表明,ATG使用導致的CMV感染率是對照組的3.4倍[8]。

因此,為開發(fā)既能阻斷T細胞增殖,又不消耗T淋巴細胞且不良反應(yīng)小的抗體,已經(jīng)進行了多方努力。單克隆抗體(如IL-2RA)由于其強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]。

淋巴細胞的增殖起始于IL-2/IL-2R途徑與CD25分子在淋巴細胞中選擇性表達,這就表明CD25抑制劑可以降低缺血再灌注的發(fā)生率[15]。在移植標準風險人群中,IL-2RA與多克隆抗淋巴細胞抗體具有同等療效[16]。Peng 等[17]進行了一項回顧性隊列研究,旨在評估IL-2RA與ATG誘導治療在DCD腎移植受者中的療效和安全性。結(jié)果表明,兩組DGF發(fā)生率無顯著性差異,但術(shù)后6個月時,IL-2RA組的感染發(fā)生率顯著低于ATG誘導治療組(P=0.025)。Lebranchu等[15]進行了一項隨機的單中心研究,旨在比較巴利昔單抗與抗胸腺細胞球蛋白誘導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,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ATG使用飆升,但其在降低低免疫風險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有優(yōu)勢。表1比較了IL-2RA誘導治療或透析與抗胸腺細胞球蛋白治療的DGF發(fā)生風險。

歐洲和美國的專家建議,在治療高免疫風險的患者時選用以淋巴細胞為靶向治療目標的多克隆抗體,在治療低免疫風險的患者時,選用以IL-2/IL-2R為靶向治療目標的單克隆抗體[12,19-21]。因此,一些移植中心開始著手在誘導治療前對腎移植患者的風險進行分層,鑒于DCD供腎移植受者DGF發(fā)生風險高的特點,風險分層模型對預(yù)測DGF發(fā)生是有益的。接受DCD供腎的受者發(fā)生DGF的風險高,但有些學者認為不能將DGF發(fā)生率高僅僅歸因于DCD。Schadde等[22]定義高風險的標準包括群體反應(yīng)性抗體(panel reactive antibodies,PRA)>20,非裔美國人腎移植。2012年Foster等[23]研究表明,成人尸體供腎移植受者被認為是高風險人群,被定義為進行DCD供腎移植,冷缺血時間>24 h,非裔美國人,PRA>20%,或者經(jīng)歷再次移植;低風險人群定義為本地供者,冷缺血時間<24 h,非-非裔美國人,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可能會延長DGF的修復時間,一般可采取延遲給藥方案或減量使用[25-26]。英國器官移植學會指南指出[27],誘導治療聯(lián)合CNIs延遲/減量可能減少DGF的發(fā)生或縮短DGF持續(xù)時間。但是,CNI延遲或減量會增加急性排斥反應(yīng)的發(fā)生風險,Gaynor等[28]分析術(shù)后1年的Tac水平與活檢證實的急性排斥反應(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),估算的風險比為6.33。 Sawinski等[29]的一項Meta分析顯示:與MMF+CNI維持治療相比,MMF+CNI撤除增加BPAR發(fā)生風險。因此延遲/減量使用CNIs可減少DGF的發(fā)生,但也會增加BPAR的發(fā)生風險。

SRL對DGF的治療作用尚存爭議,Tahir等[38]對SRL的治療作用進行了研究,8例ECD患者使用Tac+MMF±激素治療無效,DGF持續(xù)時間延長(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DGF的持續(xù)時間(P=0.01)[39-40]。因此,SRL對DGF的預(yù)防作用還有待進一步證實。

結(jié)語由于DCD供體腎移植引起DGF比較常見,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險的不同,免疫抑制劑方案也需相應(yīng)調(diào)整。目前臨床應(yīng)對DGF高發(fā)生率,通常是給予CNI減量延遲方案,同時加強其他免疫抑制劑,如生物制劑及MPA類藥物。需要注意的是,DGF的狀態(tài)下,MPA類藥物AUC比無DGF受者更低,此時MPA類藥物的劑量更難以把握,因此,在臨床實踐中,需加強MPA類藥物濃度監(jiān)測以達到降低移植物排斥的風險。

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