Improvement in Paired Donation Program

描述（由申请人提供）：配对捐赠联盟（APD）使得由于ABO血型不相容和/或致敏患者存在供者特异性抗体（Abs； DSA）而无法移植的活体供者肾脏成为可能。APD项目可以帮助2000名患者选择供体和受体。在美国，活体捐献占所有肾移植的45-50%（~6000例/年）。仅在俄亥俄州，每年诊断为终末期肾病的3300名患者中，有825名患者将有一个自愿的活体捐赠者。由于这些自愿献血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献血者。类似的全国范围的分析将包括每年2000对自愿但不相容的伴侣。APD项目由27个州的75个移植项目组成，已经进行了约50例移植，其中10例移植是在第一个“扩展利他捐赠者链”中进行的，其中包括一名利他捐赠者。拟议的项目需要解决以下重要问题：1)开发和验证诊断工具，以便在不同地点的受援者和捐助者之间进行交叉匹配；2)改进交叉匹配结果及其他参数分析的计算机程序；3)有效验证生存结果。目前，两种常用的交叉配型试验（流动交叉配型和补体依赖性细胞毒性）需要活体供体细胞。相反，我们需要采用一种允许使用供体淋巴细胞提取物的检测方法，其中供体HLA抗原被捕获到珠上（珠-HLA检测）。第二种检测方法使用预先包被供体型蛋白的珠粒检测单个HLA反应性抗体（single -HLA assay）。这两种分析都将根据流动交叉匹配方法进行验证。该项目有三个目标：目标1：建立敏感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）将与致敏患者的血清进行对比，对照20-30种不同的供体（1800种组合）。目的2：改进APD计算机程序的匹配。Aim 1的研究结果将通过使用辛普森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）纳入软件。目的3：验证APD程序的生存结果。移植后的生存结果将被跟踪，以验证选择的质量，并进一步改善APD计划。在拨款结束时，我们将建立一个中央筛选中心，每年可招募多达2000对新配对。与透析相比，每次移植在5年内可以节省20万美元，更不用说病人生活的改善了，这个建议是划算的。

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. PUBLIC HEALTH RELEVANCE: The application addresses very important public need to develop national Kidney Paired Donation program, a new strategy to help end-stage renal disease patients who have willing but incompatible living donors. We have already developed a sophisticated computerized algorithm and advanced laboratory methods to match the incompatible donor/recipient pair to other pair in the country, in such fashion that they become compatible. Up to 2000 new pairs can be matched in this program, saving Medicare more than $200,000 over 5 years for each transplanted patients compared to the dialysis cost.