Improvement in Paired Donation Program

描述（由申请人提供）：配对捐赠联盟（APD）使活体捐赠者的肾脏移植成为可能，这些捐赠者由于ABO血型不相容和/或致敏患者中存在供体特异性抗体（Ab; DSA）而无法移植。APD计划可以为2000例患者选择供体和受体。活体捐赠占美国所有肾移植手术的45-50%（约6000/年）。仅在俄亥俄州，每年有3,300名患者被诊断患有终末期肾病，其中825名患者将有一个自愿的活体捐赠者。由于这些自愿捐赠者中有三分之一通常是不相容的，275名患者有自愿但不相容的捐赠者。类似的全国性分析将每年对2000对自愿但不相容的夫妇进行统计。APD计划由27个州的75个移植计划组成，已经进行了约50例移植，其中包括第一个“扩展利他捐赠链”中的10例移植，其中包括一名利他捐赠者。 拟议的项目需要解决的重要问题：1）开发和验证诊断工具，以执行交叉配血的受体和捐赠者谁是在不同的位置; 2）改善计算机程序的交叉配血结果和其他参数的分析;和3）有效地验证生存结果。目前，两种常用的交叉配型试验（流式交叉配型和补体依赖性细胞毒性）需要活供体细胞。相反，我们需要调整允许使用供体淋巴细胞提取物的测定，其中供体HLA抗原被捕获到珠上（珠-HLA测定）。第二种检测使用预先包被有供体型蛋白质的珠粒来检测单个HLA反应性抗体（Single-HLA检测）。将根据流式交叉配血法对这两种检测方法进行验证。该项目有三个目标：目标1：建立灵敏和可重复的筛选方法。在第一阶段，所有4项检测（两项旧检测和两项新检测）将使用来自致敏患者的血清针对20-30个不同供体（1800种组合）进行。目的2：通过APD计算机程序提高匹配。通过使用Simpson规则数值积分方法计算特异性和选择性值的曲线下面积（AUC），将目标1的结果纳入软件中。目的3：验证APD程序所得出的生存结果。移植后将随访生存结果，以验证选择的质量，并进一步改进APD计划。 在赠款结束时，我们将建立一个集中的筛选中心，每年能够招募多达2000对新的。与透析相比，每次移植在5年内节省20万美元-更不用说改善患者的生活-这一建议具有成本效益。

DESCRIPTION (provided by applicant): The Alliance for Paired Donation (APD) makes possible the transplantation of kidneys from living donors who otherwise are not transplanted because of ABO blood group incompatibility and/or the presence of donor-specific antibodies (Abs; DSA) in sensitized patients. The APD program may facilitate selection of donors and recipients for 2000 patients. Living donation accounts for 45-50% (~6000/year) of all kidney transplants performed in the United States. For Ohio alone, out of 3,300 patients each year diagnosed with end-stage renal disease, 825 patients would have a willing living donor. Since one third of these willing donors are typically incompatible, 275 patients have willing but incompatible donors. Similar nationwide analysis would account each year for 2000 willing but incompatible pairs. The APD program, composed of 75 transplant programs in 27 states, has already performed ~50 transplants, including 10 transplants in the first "extended altruistic donor chain" that included one altruistic donor. The proposed project needs to address important issues: 1) to develop and validate diagnostic tools to perform crossmatches of recipients and donors who are in different locations; 2) to improve the computer program for the analysis of crossmatch results and other parameters; and 3) to efficiently validate the survival results. At the present time, two used crossmatch assays (flow crossmatch and complement-dependent cytotoxicity) require live donor cells. Instead, we need to adapt an assay allowing using donor lymphocyte extracts wherein donor HLA antigens are captured onto beads (Bead-HLA assay). The second assay uses beads pre-coated with donor-type proteins to detect single HLA reactive anybodies (Single-HLA assay). Both these assays will be validated against the flow crossmatch method. The project has three aims: Aim 1: To establish sensitive and reproducible screening methods. In the first phase, all 4 assays (two old and two new) will be run with sera from sensitized patients against 20-30 different donors (1800 combinations). Aim 2: To improve matching by APD computer program. The findings from Aim 1 will be incorporated into the software by calculating the area under the curve (AUC) for the specificity and selectivity values using the Simpson's rule numerical integration methods. Aim 3: To validate the survival results made by APD program. The survival results will be followed after transplantation to validate the quality of choices and to further improve the APD program. At the grant conclusion, we will establish a centralized screening center able to enlist up to 2000 new pairs per year. As each transplant saves $200,000 during 5 years as compared with dialysis - to say nothing of the improved life of the patient - this proposal is cost-effective.