Transplantation in the Highly Sensitized Pediatric Patient
Transplantation in the Highly Sensitized Pediatric Patient
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DOI：
10.1161/circulationaha.113.001378
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发表时间：
2014-06-03
期刊：
影响因子：
37.8
通讯作者：
Chin, Clifford
中科院分区：
文献类型：
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作者：
Castleberry, Chesney;Ryan, Thomas D.;Chin, Clifford
20世纪60年代末，阿德里安·坎特罗维茨（Adrian Kantrowitz）医生在一名儿科患者身上进行了美国首例、世界首例心脏移植手术。1急性细胞排斥和其他因素导致预后不佳，限制了儿童和成人心脏移植项目的发展。基于环孢素的免疫抑制在20世纪80年代被引入，生存率显著提高。在20世纪80年代后期，每年的心脏移植量显著增加，但主要由于缺乏供体而停滞不前。在成人中使用长期机械循环支持装置（心室辅助装置）允许候选者进行移植的桥接，克服了由于供体池有限而导致的长时间等待。这些装置通常不适合小儿科患者。体外膜氧合提供儿科短期支持，但经常出现严重并发症，妨碍移植。3柏林心脏EXCOR儿童心室辅助装置是在20世纪90年代初为婴儿和幼儿开发的，4于1996年在欧洲获得批准使用，并于2011年获得美国食品和药物管理局批准在美国使用。5,6心室辅助装置的使用可导致致敏，这是移植的另一个障碍。致敏，即针对人类白细胞抗原（HLA）蛋白的循环抗体的发展，提出了一个重大挑战。致敏的危险因素包括接触血液制品、感染、妊娠和使用心室辅助装置。7-16先天性心脏病的手术，特别是使用人类同种移植物组织，是致敏的另一个危险因素，主要影响儿科患者。17-19虽然同种移植物经过处理和保存，但它们仍然具有免疫反应性，并可导致HLA抗体的形成。这些抗体可能对移植的移植物有害。HLA抗体介导的心脏排斥反应（AMR）最早由Hammond及其同事在20世纪80年代末描述，是儿童移植后不良预后的一个相当大的危险因素。31-33在移植前列出或避免供体抗原只是减轻HLA抗体引起的早期移植物损伤和损失的一种策略。具体地说，一个移植项目可能会基于能够识别供体抗原的抗体的存在而降低器官的功能。然而，这一策略进一步限制了捐助者的数量，并可能延长等待时间。因此，HLA抗体的存在是移植前后一个具有挑战性的问题。本文综述了以下内容：(1)HLA抗体的作用和分类，(2)评估抗体和临床意义的检测方法，(3)治疗选择，(4)对高度敏感的移植前候选药物的临床策略，(5)移植后患者抗AMR的临床策略。针对主要血型（ABO）抗原的抗体是另一种形式的致敏。这一选定的主题将在《儿童心力衰竭和移植的当前挑战》系列的另一篇综述中讨论。
The first cardiac transplant in the United States, and the second worldwide, was performed on a pediatric patient by Dr Adrian Kantrowitz in the late 1960s. 1 Acute cellular rejection and other factors led to poor outcomes, limiting the growth of pediatric and adult cardiac transplantation programs. Cyclosporine-based immunosuppression was introduced in the 1980s, and survival dramatically improved. A significant rise in annual cardiac transplantation volume ensued in the late 1980s2 but plateaued primarily because of a lack of donors. Use of long-term mechanical circulatory support devices (ventricular assist devices) in adults allowed the bridging of candidates to transplantation, combating long wait times resulting from a limited donor pool. These devices were often not suitable for smaller pediatric patients. Extracorporeal membrane oxygenation provides short-term pediatric support, but significant complications often develop, precluding transplantation. 3 The Berlin Heart EXCOR Pediatric Ventricular Assist Device was developed for infants and small children in the early 1990s, 4 gained approval for use in Europe in 1996, and was approved by the US Food and Drug Administration for use in the United States in 2011. 5, 6 Ventricular assist device use can lead to sensitization, another barrier to transplantation. Sensitization, the development of circulating antibodies directed against human leukocyte antigen (HLA) proteins, poses a significant challenge. Risk factors for sensitization include exposure to blood products, infections, pregnancy, and use of ventricular assist devices. 7–16 Surgery for congenital heart disease, especially with the use of human homograft tissue, is an additional risk factor for sensitization, affecting primarily pediatric patients. 17–19 Although homografts are processed and preserved, they remain immunologically reactive and can lead to HLA antibody formation. 19–29 These antibodies can be harmful to the transplanted graft. HLA antibody–mediated cardiac rejection (AMR), first described by Hammond and colleagues30 in the late 1980s, is a considerable risk factor for poor outcomes after pediatric transplantation. 31–33 Listing or avoiding donor antigens before transplantation is but one strategy to mitigate early graft injury and loss resulting from HLA antibodies. Specifically, a transplantation program may decline an organ on the basis of the presence of antibodies that could recognize the donor antigens. This strategy, however, further constricts the donor pool and potentially prolongs the wait time.The presence of HLA antibodies is thus a challenging problem before and after transplantation. This review addresses the following:(1) the role and classification of HLA antibodies,(2) detection methods to assess for antibodies and clinical implications,(3) therapeutic options,(4) clinical strategies toward the highly sensitized pretransplantation candidate, and (5) clinical strategies to combat AMR in the posttransplantation patient. Antibodies against major blood group (ABO) antigens represent another form of sensitization. This selected topic is addressed in a separate review as part of the series on Current Challenges in Pediatric Heart Failure and Transplantation.