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Advances in Clinical Medicine
Vol. 12  No. 10 ( 2022 ), Article ID: 57230 , 9 pages
10.12677/ACM.2022.12101399

肝移植供体保存技术及进展

涂欣鑫*，李钺#

重庆医科大学附属第二医院，重庆

收稿日期：2022年9月24日；录用日期：2022年10月17日；发布日期：2022年10月27日

摘要

目的：肝移植是终末期肝病和肝恶性肿瘤的最终选择。肝移植技术得到了显著改善，但移植后并发症仍不可避免。移植供体的保存是肝移植的基础，随着器官供需矛盾的日益加剧，边缘化、脂肪变性和心脏循环死亡的供体增加，我们迫切需要更有效、更低成本的保存技术来延长供体缺血时间。本研究介绍了几种经典保存技术的发展过程、几种新的保存方案的进展以及几种保存方案之间的差异，旨在探索更合适的保存技术来指导临床实践，减少资源浪费。方法：通过PubMed、维普、中国知网、万方、重庆医科大学图书馆数据库进行了系统文献检索(1960~2022)，纳入UW液、HTK液、Celsior液、HTK-N、IGL-1液、Polysol液、SCOT液、CZ-1液等或比较两种或多种保存液的文章。结果：共有387篇论文关于UW液、HTK液95篇，Celsior液46篇，HTK-N液12篇，IGL-1液45篇，Polysol液8篇，SCOT液20篇，CZ-1液2篇和102篇HMP和74篇多种保存技术的比较研究。目前临床应用较多的的有HTK液、UW液和Celsior液，两者之间的差异较小，但对肝脏的缺血–再灌注损伤仍然存在。新型溶液有HTK-N、IGI-L液、Polysol液、SCOT液、CZ-1液等。HMP作为最新动态保存方式，也逐渐应用于临床。几种保存技术各有优缺点。结论：已用于临床的HTK液、UW液和Celsior液之间差异性较小，IGL-I液除UW液和Celsior的优点外，还减少高钾血症和钙离子超载的发生，具有更好的器官冲洗效果，更好地减少缺血再灌注损伤。其他技术在动物实验和临床试验中逐渐显示出其优势。HMP作为最新的动态保存模式，可降低肝细胞和内皮细胞损伤。然而，目前理论上有效的保存方案仍处于实验阶段，存在许多不确定性，因此需要更深入的探索。

关键词

供体保存，保存液，肝移植，进展

Donor Preservation Technology and Progress of Liver Transplantation

Xinxin Tu*, Yue Li#

The Second Affiliated Hospital of Chongqing Medical University, Chongqing

Received: Sep. 24th, 2022; accepted: Oct. 17th, 2022; published: Oct. 27th, 2022

ABSTRACT

Background: Liver transplantation is the final choice for end-stage liver disease and liver malignancies. At present, liver transplantation technology has been significantly improved, but post-transplant complications are still inevitable. The preservation of transplanted donors is the basis of organ transplantation techniques and the quality of donor preservation is one of the most important factors affecting the outcome of liver transplantation. With the increasingly imbalance between organ supply and demand, the increasing supply liver of marginalization, fatty degeneration and more cardiac circulation death donor, we desperately need more effective, low-cost preservation techniques to prolonged donor ischemia time. The development process of several classical preservation techniques, the advance of several new preservation solutions and the differences between several solutions are introduced in this study and which aims to explore more appropriate preservation techniques to guide clinical practice and reduce resource waste. Methods: PubMed, VIP, CNKI, Wanfang, Embase and Chongqing Medical University library databases were utilized. Articles from 1960 to 2022 which contain the controduction of UWs, HTKs, Celsior solution, HTK-N solution, IGL-1 solution, Polysol solution, SCOT solution, and CZ-1 solution or comparing graft outcomes between two or more different perfusion/preservation solutions were included. Results: There are 387 papers about UW solution, 95 papers about HTK solution, 46 papers about Celsior solution, 12 papers about HTK-N solution, 45 papers about IGL-1 solution, 8 papers about Polysol solution, 20 papers about SCOT solution, 2 papers about CZ-1 solution and 102 papers about HMP and 74 of them are comparative studies about multiple preservation techniques. At present, HTK, UW and Celsior solutions are widely used in clinical, and the new solutions are HTK-N, IGI-L, Polysol, SCOT, CZ-1, etc. The difference between them is small, but the ischemia-reperfusion injury of the liver still remains. However, many of new solutions include HTK-N, IGI-L, Polysol, SCOT, CZ-1, etc. had been researched. As the latest dynamic preservation mode, HMP is also gradually applied in clinical practice. Conclusion: The HTKs, UWs and Celsior solution that have been used in clinical practice are less different. As for the new solutions, IGL-I, with the advantages of both UW fluid and Celsior, which can reduce the occurrence of hyperkalemia and calcium ion overload, have a better organ flushing effect, and better reduce ischemia and reperfusion injury. Other solutions have gradually shown their advantages in animal experiments and clinical trials. As the latest dynamic preservation mode, HMP can reduce the hepatocyte and endothelial cell damage. However, the current theoretical effective preservation solutions are still in the experimental stage with many uncertainties and thus require more intensive exploration.

Keywords:Donors Preservation, Preservation Solution, Liver Transplantation, Progress

Copyright © 2022 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

肝移植是终末期肝病及肝恶性肿瘤的最终选择。目前肝移植技术已得到重大提升，但移植后并发症仍不可避免。肝移植供体保存技术的改进，可尽量减少移植后IRI [1]。目前临床最常使用的保存方法为单纯冷藏保存 [2]，当供肝切除后，需要通过特殊的液体，将肝脏中的血液、胆汁完全清洗干净，然后浸泡0℃~4℃的特殊供体肝脏保存液当中保存、运输。

供肝的保存液需要有合适的物理环境(如渗透压、血管通透性、电解质平衡及充分的胶体成分)以抑制细胞肿胀；适宜的生化环境(如谷胱甘肽)可以防止移植后肝衰竭 [3]。器官移植保存液主要包括两种类型：细胞内液型：高钾、低钠和无钙等特点，如EC液、UW液、Ross液、Collins C2液、CZ-1液、武汉WMO-1液等；细胞外液型：低钾、高钠的特点，如Celsior液、Polysol液、SCOT液等 [4]。

2. 介绍

2.1. 供肝保存发展历程

早在1962年，Kukral [5] 最早在犬肝移植中使用低温灌注用于供肝保存，使供肝离体后保存2小时，移植后存活了20天。Wall [6] 等1977年提出低温保存技术用于人类肝移植。1987年，UW液的推出，使供体保存取得显著临床进展 [7]。因其具有葡萄糖含量减少、乳糖盐含量增加、充当胶体成分的羟乙基淀粉丰富等特点成为供肝保存液的金标准，而且UW液中丰富的磷酸盐可有效防止酸中毒，谷胱甘肽、别嘌噙醇可有效抗击自由基的生成而大大减轻了IRI [8]。但是，其低钠含量促进缺血期间钙的积累，导致肾小球和再灌注期间胆管中的钙依赖性内皮功能障碍 [9]。此外，高钾会增加高钾血症诱发的心脏骤停的风险，需要在再灌注前进行肝脏冲洗 [10]。此外，在容器袋中低温储存可能导致腺苷晶体的形成 [11]。因此，UW的使用受到了严峻的挑战，并开发了具有潜在更多益处的替代解决方案。

20世纪70年代初HTK液由德国研制而成。最早作为心脏停搏液用于心脏移植，目前临床上可保存心脏4~8小时。是一种低钠离子浓度、稍高钾离子浓度计组氨酸为缓冲剂的等渗性液体 [10]。在较大的温度范围内(5℃~35℃)阻止细胞酸中毒，尤其是对热缺血时产生的酸中毒有较好的预防及中和效果 [12]。

近年来，HTK在临床上用于肾脏和肝脏等脏器的保存。1994年首次在肝移植中以随机方式将UW与HTK进行比较，发现这些溶液在移植物的初始无功能和患者生存率方面具有相似的结果 [13]。四川大学华西医院对比研究了UW液比HTK液具有更长的ICU住院时间 [10]，这可能与UW液组手术时间长于HTK组有关，但两者住院总时间无明显差异，两组术中及早期并发症的发生率差异不大，1年、3年、5年移植物的存活率也无明显差异。西班牙的一项研究指出单独HTK液保存供肝引起原发/继发同种异体移植功能障碍高于UW液与HTK液混合，单独使用HTK液移植后转氨酶、动脉血管并发症、90天胆道并发症、排斥反应及再移植率均高于UW液与HTK液混合 [14]。Coskun的研究也指出将HTK液中有效成分加入UW液中，能改善移植后IRI发生率 [15]。Robbin [16] 等人的一项回顾性研究指出：HTK与UW保存液在移植物存活率方面、术后血液化学结果、动脉并发症、早期同种异体移植功能障碍、原发性移植物无功能的发生率等方面均无差异。然而，UW液胆道狭窄的发生率高于HTK液。在儿童肝移植中，Richard [17] 等研究比较了儿科肝移植中使用HTK液与UW液后其早期移植物功能、移植物和患者生存率和胆管并发症后发现胆管狭窄在UW组中更常见。其移植后生存率无明显差异。在终末期肝泡棘球蚴病肝移植中，Shaddick [18] 等在一项队列研究指出UW液和HTK液具有相似的功效和安全性，但仍需要更大规模的随机临床试验去求证。

1994年研发出Celsior液，仿细胞外型溶液的一种。结合了UW和HTK液的优点，具有高钠低钾的特点，可有效地抑制细胞水肿，目前已成功用于心、肝、肾、胰腺等 [19]。同时，它具有组氨酸/乳糖醛酸缓冲系统，能有效防止细胞肿胀；含有丰富的还原型谷胱甘肽及羟自由基的清除剂，防止缺血再灌注损伤；丰富的谷氨酸盐为高能磷酸化合物提供底物；高镁离子含量能降低钙超载；低粘度能更好的进行组织扩散等，无需对肝脏进行再灌注 [20]。由于其低粘度，高钠，低钾和抗氧化特性，Celsior液被认为特别适用于保存肝脏移植物。

总之，HTK液、UW液和Celsior液之间差异性较小，并被广泛应用于临床中，但对肝脏的缺血再灌注损伤依然存在，因此需要不断研制出更有益的新型溶液，以延长移植缺血时间和质量，促进供肝的更好移植，减少资源浪费。

2.2. 新型溶液

2.2.1. HTK-N

Annika [21] 等提出一种改良的HTK溶液，称为HTK-N。其具有更大的抗氧化能力，并提供固有的毒性以及改善的耐寒性，旨在减轻器官移植中的冷藏损伤。补充氨基酸甘氨酸、丙氨酸和精氨酸，N-乙酰组氨酸部分取代组氨酸，天冬氨酸和乳生物酸酯取代氯化物。另有研究报道，HTK-N具有保护肠黏膜作用 [22]。但目前只运用于动物模型，也逐渐开始进行临床试验，一项前瞻性、多中心、单盲III期临床实验指出，旨在比较HTK-N与HTK保存供体后对移植后移植功能和肾脏、肝脏或肾胰联合移植后的损伤，对未来供体保存具有广泛前景 [23]。

2.2.2. IGL-1液

IGL-1液由法国里昂中心开发研制，它兼具UW液和Celsior的优点，有类似Celsior液的细胞外液型组成成分，IGL-1液钾离子含量低于UW液，可减少高钾血症及钙离子超载的发生，且IGL-1液黏度小，对供者器官的冲洗作用优于UW液。其通过AMPK和AKT两条途径激活内皮型一氧化氮合酶抑制内皮细胞功能紊乱和减轻移植物氧化应激反应 [24]。降低移植物中p-TOR/mTOR比值，降低炎症因子产生，能诱导自噬增加和细胞凋亡减少，更好地保护脂肪肝移植物免受冷缺血损伤。其中PEG35也能有效防止肝细胞肿胀 [25]。巴西布卢梅瑙圣伊莎贝尔医院回顾性分析比较在252例肝移植手中保存在IGL-1冷凝储存溶液中的脑死亡供体的肝脏移植物的结果。UW组患者(N = 155)的冷缺血时间(CIT)少于8小时，平均年龄为54 ± 11.35岁，而IGL-1组患者(N = 97)的CIT超过8小时，平均年龄为52 ± 12.5岁。移植后第1天AST水平有轻度差异，移植后第7天，两组ALT、AST和胆红素水平无统计学意义差异，两组患者的1年生存率相似 [26]。

有文献报道 [12]：分别灌注HTK液和IGL-1液，HTK液的移植物失功能(PGD)或原发性移植物无功能(PGNF)发生率比IGL-1液高。而感染发生率、术后第1天和第2天的平均AST和ALT也较高。灌注IGL-1的移植物的接受者比那些移植物灌注HTK的移植物具有更好的早期存活率。一项小鼠实验指出 [27]：补充亚硝酸盐到IGL-1可以保护肝脏免受IRI损伤。能显著降低细胞溶解，线粒体损伤和脂质过氧化，并增强抗氧化酶活性(超氧化物歧化酶，过氧化氢酶和谷胱甘肽过氧化物酶活性)和肝功能参数(门脉阻力，胆汁和溴磺基苯酞清除率)。

在IGL-1液与Celsior液的小鼠肝移植比较研究中，在用Celsior或IGL-1冷藏24小时后，乙酰胆碱诱导的内皮依赖性松弛(EDR)仅略有改变。在刚分离的动脉中，EDR仅由一氧化氮(NO)介导。然而，冷藏后动脉显示NO和环氧化酶(COX)依赖性松弛。冷藏后NO依赖性松弛的减少在Celsior中显着更明显。IGL-1溶液比Celsior获得了更好的肝脏保存和针对IRI的保护。肝损伤减轻，功能改善，氧化应激减少 [28]。

2.2.3. Polysol液

是一种细胞外液型多器官保存液，采用聚乙二醇作为高渗分子，含有多种氨基酸、维生素和抗氧化剂以供低温条件下的代谢需求。PEG抑制了肝细胞中的细胞肿胀，使它们保持相对良好的保存并恢复膜完整性。含有低K+/高Na+浓度，可减少肝脏再灌注后的同种异体抗原识别。可促进NO的产生，其血管舒张特性有助于抵消由于脂肪积累而导致的脂肪性肝微循环的恶化，促进移植后肝血运重建，以防止脂肪肝中脂质过氧化对再灌注的损害 [29]。PEG通过在糖萼上形成分子屏障来干扰凝血系统并减少血小板在体外和体内的粘附。这种PEG屏障可防止受损动脉上的急性血小板沉积。Polysol液目前仅用于动物实验机器灌注保存 [30]，在与HTK比较，Polysol液更好地促进门静脉血流、微循环改善。对肝脏的重量要求更小，门静脉的血管内皮生长因子(VEGF)上调更高，更有利于肝脏再生，从而提高了部分肝移植的保存质量 [31]。

2.2.4. SCOT液

SCOT液为仿细胞外液型保存液，选用与IGL-1液相同的PEG作为胶体成分。动物试验证实，SCOT液在肝、肾、胰岛移植中的保存效果优于UW液，显示出一定的免疫特性，对减轻肝移植术后胆汁淤积的效果较好，目前已用于临床肝脏的保存 [32]。一项试点研究比较了37例(UW组21例，SCOT 15组16例)肝移植，松开门静脉后30分钟和术后第1天在全身血液中测定IL-10，IL-6，ALT和AST，指出：与UW相比，SCOT液可减少移植物IRI引起的全身细胞因子释放，并降低灌注后综合征和术后肾功能衰竭的发生率 [33] 。在HTK、UW、IGL-1、SCOT四种溶液的比较中，有文献报道，四种溶液在肝动脉血栓形成(HAT)、原发性移植物无功能(PGNF)、胆道非吻合口狭窄(NAS)的发生率和ICU住院时间上无明显差异，但IGL-1成本较低，经济效益更高 [32] 。另有文献报道，与UW溶液相比，使用SCOT 15冷藏保存可减少移植后的胆汁淤积 [34]。

2.2.5. CZ-1液

长征1号保存液(CZ-1液)是在UW液配方的基础上改良而成。目前大量动物试验证实，CZ-1液能保存肾脏72 h、肝脏24 h、心脏18 h，并已成功应用在动物器官移植模型上。一项CZ-1与UW液的比较研究中，通过微观移植器官的形态学，研究了长期冷藏过程中器官的生化生理功能及存活率。CZ-1和UW溶液在保存兔的肾脏，肝脏，心脏或肺部方面没有显著差异，在大鼠和兔子的几大器官中发现，在兔子的心脏，大鼠的肠粘膜和胰腺中，CZ-1溶液的效果优于UW溶液 [35]。

3. 最新进展

低温含氧机器灌注(HMP)是用于边缘肾脏和肝脏移植物的器官最新策略，是一种经典的动态器官保存方法，它能够向组织提供氧气和营养物质，并在移植前提供移植物的代谢循环 [36]。主要包括原位低温机器灌注(HMP)、常温机器灌注(NMP)和常温区域灌注(NRP)。NMP是动物实验中运用最广泛的方式，最重要的是控制含氧复温(COR)，将冷藏移植物缓慢地逐渐重新加热到亚正常或正常温度，提供能量代谢的温和适应和抵消复温损伤的发生 [37]。Philip [38] 等的研究首次证明了HMP空气驱动系统在临床相关DCD模型中保护肝脏移植物在移植前免受致命缺血损伤的功效。在雌性大白猪模型中，HMP通过减少炎症反应、氧化负荷、内质网应激、线粒体损伤和细胞凋亡使保存的肝脏功能更好，肝细胞和内皮细胞损伤更少。文献报道 [39]，在HMP保存和灌注中，二甲双胍能通过激活AMPK-eNOS介导途径促进细胞外NO释放；调节葡萄糖代谢，防止细胞死亡；降低肝糖异生和减少外周组织糖摄取等机制改善移植缺血再灌注损伤。褪黑素能增加器官保存液的协同作用，减少缺血再灌注损伤，预防氧化应激及炎症细胞因子释放 [40]。

4. 结论

随着肝移植的发展历史，对供体保存的研究逐渐深入，已用于临床的HTK液、UW液和Celsior液之间差异性较小，新型IGL-1液有效性较好。其他溶液经过动物实验和临床试验也逐渐体现优势。HMP作为最新动态保存方式，能获得更小的器官损伤，但目前理论上的有效保存方式仍处于试验阶段，存在许多不确定性，暂未进入临床。因此对于供体保存技术还需更深入的探索，以提高供体存活率、减少IRI及相关并发症发生率，提高资源利用率。

致谢

作者感谢重庆医科大学附属第二医院肝胆外科的支持。感谢提供文献、研究思想和设想的所有者。

文章引用

涂欣鑫,李 钺. 肝移植供体保存技术及进展
Donor Preservation Technology and Progress of Liver Transplantation[J]. 临床医学进展, 2022, 12(10): 9682-9690. https://doi.org/10.12677/ACM.2022.12101399

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