Risk stratification for sensitized patients in Kidney Paired Donation program

描述（由申请人提供）：美国有60万终末期肾病（ESRD）患者接受治疗，其中40万接受透析治疗。虽然ESRD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长的等待名单上。尽管在过去十年中，每年来自已故捐赠者的肾脏移植数量保持不变（11,000例），但新的器官捐赠研究表明，每年活体肾脏移植数量（5600例）可能会增加50%。特别是，每年有3000名愿意接受活体供体的患者由于血液不相容（50%）或先前获得的对供体的过敏（50%）而没有进行移植。为了适应这些患者，配对肾脏捐赠（KPD）计划在这些不相容的配对中寻找匹配并安排交换捐赠者。然而，由于在KPD项目中50%的致敏患者很难找到匹配的供体，因此需要在搜索方法上进行重大改进。对致敏患者的评估是过时和不完整的，因为建议以低（2位数）分辨率识别组织相容性白细胞抗原(HLA)-A, -B, -DR， -DQ抗原

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 The evaluation for sensitized patients is outdated and incomplete, as it is recommended to identify histocompatibility leukocyte antigen (HLA)-A, -B, -DR, -DQ antigens at low (2-digit) resolution (in KPD UNOS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.