Improvement in Paired Donation Program

描述(由申请人提供)：配对捐献联盟(APD)使活体捐赠者的肾脏移植成为可能，这些活体捐赠者因ABO血型不合和/或致敏患者存在捐赠者特异性抗体(Abs；DSA)而无法移植。APD计划可以为2000名患者选择捐赠者和接受者提供便利。在美国进行的所有肾移植手术中，活体捐赠占45%-50%(约6000/年)。仅就俄亥俄州而言，在每年被诊断为终末期肾病的3300名患者中，有825名患者会有自愿的活体捐赠者。由于这些自愿捐赠者中有三分之一通常是血型不合的，275名患者有自愿但血型不相容的捐赠者。类似的全国性分析将解释每年2000对自愿但不相容的配对。Apd计划由27个州的75个移植项目组成，已经进行了约50例移植，其中包括10例第一批“延长的利他捐赠者链”中的移植手术，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，以执行不同地点的受者和捐赠者的交叉匹配；2)改进用于分析交叉匹配结果和其他参数的计算机程序；以及3)有效地验证生存结果。目前，两种常用的交叉配型分析(流式交叉配型和补体依赖细胞毒)需要活体供体细胞。相反，我们需要调整一种分析方法，允许使用供者淋巴细胞提取液，其中供者人类白细胞抗原被捕获到珠子上(珠子-人类白细胞抗原分析)。第二种方法使用预包被供体类型蛋白的珠子来检测单一的人类白细胞抗原反应性抗体(单人类白细胞抗原试验)。这两种分析方法都将对照流动交叉匹配法进行验证。该项目有三个目标：目标1：建立灵敏和可重复性的筛查方法。在第一阶段，所有4项检测(两项旧的和两项新的)将使用致敏患者的血清进行，以对抗20-30个不同的捐赠者(1800个组合)。目的2：用APD机程序改进配型。AIM 1的结果将通过使用辛普森规则数值积分方法计算特异值和选择性值的曲线下面积(AUC)被合并到软件中。目的3：验证apd程序的生存结果。移植后将跟踪观察存活结果，以验证选择的质量，并进一步完善apd计划。在拨款结束时，我们将建立一个中央筛查中心，每年可以招募多达2000对新的配对。与透析相比，每一次移植在5年内节省了20万美元--更不用说改善了患者的生命--这项提议具有成本效益。 公共卫生相关性：该应用程序满足了非常重要的公众需求，即开发国家肾脏配对捐赠计划，这是一项帮助拥有自愿但不相容的活体捐赠者的终末期肾病患者的新战略。我们已经开发了一种复杂的计算机化算法和先进的实验室方法，将不相容的供受者对与该国的其他对配对，使它们变得相容。该计划可以匹配多达2000对新的配对，与透析成本相比，在5年内为每个移植患者节省了200,000多美元的医疗保险。

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.