Risk stratification for sensitized patients in Kidney Paired Donation program

描述(申请人提供)：美国有60万名终末期肾病(ESRD)患者接受治疗，其中40万人正在接受透析治疗。虽然终末期肾病的最佳治疗方法是肾移植，但由于器官短缺，超过10万名患者在不断增加的等待名单上。尽管在过去十年中，每年来自已故捐赠者的肾脏移植数量(11,000例)基本保持不变，但器官捐赠方面的新研究表明，每年活体肾移植的数量(5,600例)可能会增加高达50%。特别是，每年有3000名自愿活体捐赠者的患者因血型不合(50%)或先前对供者产生过敏(50%)而不进行移植。为了容纳这些患者，肾脏配对捐赠(KPD)计划在这些不相容的配对中寻找匹配的人，并安排捐赠者的交换。然而，由于很难为致敏患者找到匹配的捐赠者，这些患者占KPD计划患者的50%，因此搜索方法需要显著改进。对致敏患者的评估是过时的和不完整的，因为建议以低(两位数)分辨率(In)鉴定组织相容白细胞抗原(HLA)-A、-B、-DR、-DQ抗原 KPD UNOS Pilot：在分裂分辨水平上用-DR51/52/53抗原检测人类白细胞抗原-A、-B、-Bw4、6、-Cw、-DR、-DQ和-DP。这一要求与通过单一抗原珠(SAB)分析在等位基因(4位数)水平上测量的患者抗体(Ab)反应性不一致。此外，允许进行移植是基于与供体细胞的负流交叉匹配(FXM)，这通常与虚拟交叉匹配(VXM)无关。事实上，我们最近的数据表明，FXM阴性患者可能无法在高度致敏的患者中发现危险的供体特异性抗体(DSA)。为了克服这些问题，提出了3个目标：1)使用最先进的Illumina Ion Torrent下一代测序(NGS)方法，为所有KPD捐赠者和接受者识别4位数的HLA-A、-B、-C、-DR、-DQ和-DP等位基因；2)使用基于受体抗体表位的分析来改进供者-接受者匹配算法，以描述不可接受的等位基因和可接受的错配等位基因；以及3)通过稀释研究表征表位定义的DSA的强度，对与补体(C‘)结合活性相关的Ig G亚类进行分类，从而对致敏患者的风险进行分层。IgG1和GT；IgG2和GT；IgG4)，以及C1q结合检测细胞毒作用。然后，被认为是高风险的患者可能会被考虑进行积极的治疗和脱敏。患者和捐献者4位数的人类白细胞抗原分型和表位分析有望为KPD计划中的致敏患者和通过非配对捐献的致敏患者最有效地选择捐赠者。

DESCRIPTION (provided by applicant): There are 600,000 patients in United States treated for end-stage renal diseases (ESRD) with 400,000 on dialysis. While the best treatment for ESRD is kidney transplantation over 100,000 patients are on the constantly growing waiting list because of the organ shortage. Although the annual number of kidney transplants from deceased donors remains rather unchanged (11,000) over the last decade, new research in organ donation suggests that the number of annual live kidney transplants (5,600) could increase by up to 50%. In particular, each year 3,000 patients with a willing live donor are not transplanted because of blood incompatibility (50%) or previously acquired sensitization against their donor (50%). To accommodate these patients, kidney paired donation (KPD) programs find matches among these incompatible pairs and arrange exchanges of donors. However, due to the difficulty in finding matching donors for sensitized patients who are 50% of patients in KPD programs, there is a need for a significant improvement in searching methods. The evaluation for sensitized patients is outdated and incomplete, as it is recommended to identify histocompatibility leukocyte antigen (HLA)-A, -B, -DR, -DQ antigens at low (2-digit) resolution (in KPD UNOS pilot: HLA-A,-B,-Bw4,6, -Cw,-DR,-DQ and -DP with -DR51/52/53 antigens at the level of split resolution.). This requirement does not correspond to the patient's antibody (Ab) reactivity measured at allele (4-digit) level by a single antigen bead (SAB) assay. In addition, th permission to perform transplant is based on the negative flow crossmatch (FXM) with donor cells which often does not correlate with the virtual crossmatch (VXM). In fact, our recent data suggest that negative FXM may fail to discover dangerous donor-specific Abs (DSA) in highly sensitized patients. To overcome these problems 3 goals are proposed: 1) to use the most advanced Illumina Ion Torrent Next Generation Sequencing (NGS) method to identify 4-digit HLA-A, -B, -C, -DR, -DQ and -DP alleles for all KPD donors and recipients; 2) to improve donor-recipient matching algorithm using epitope based analysis of recipient antibodies to describe unacceptable alleles and acceptable mismatched alleles; and 3) to stratify the risk for sensitized patients by characterizing the strength of the epitope-defined DSA through dilution studies, typing of IgG subclasses relevant for complement (C')-binding activity (IgG3>IgG1>IgG2>IgG4), and C1q-binding assays for cytotoxic potentials. Patients deemed to be at high risk may then be considered for aggressive therapy and desensitization. Patient and donor 4-digit HLA typing and epitope analysis is expected to allow for the most effective selection of donors for sensitized patients both in KPD programs and through non-paired donation.