Risk stratification for sensitized patients in Kidney Paired Donation program

肾脏配对捐赠计划中敏感患者的风险分层

• 批准号: 8876574
• 负责人: Stanislaw M Stepkowski
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8876574
• 关键词: Affect; Algorithms; Alleles; Allergic; Antibodies; Antigens; Authorization documentation; Binding; Biological Assay; Blood; Blood Group Incompatibility; Blood Transfusion; Cells; Characteristics; Classification; Complement; Complement 1q; Data; Decision Making; Dialysis procedure; Dideoxy Chain Termination DNA Sequencing; Digit structure; Donor Selection; Donor person; End stage renal failure; Epitopes; Evaluation; Exclusion; Goals; Grant; HLA Antigens; Health; Histocompatibility; IgG1; IgG2; IgG3; IgG4; Immunoglobulin G; Ions; Kidney; Kidney Transplantation; Laboratories; Life; Living Donors; Measures; Methods; Molecular; Neoadjuvant Therapy; Organ; Organ Donations; Organ Donor; Paper; Patients; Pregnancy; Process; Research; Research Design; Resolution; Risk; Risk Factors; Serotyping; Serum; Specificity; Stratification; Techniques; Technology; Testing; Therapeutic; Transplant Recipients; Transplantation; United Network for Organ Sharing; United States; Waiting Lists; aggressive therapy; antigen binding; base; clinically relevant; cost effective; cytotoxic; desensitization; high risk; immunogenic; improved; leukocyte antigen typing; meetings; next generation sequencing; novel; programs; virtual

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.

描述（由申请人提供）：美国有60万例终末期肾病（ESRD）患者接受治疗，其中40万例接受透析治疗。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长的等待名单上。虽然在过去十年中，每年从已故捐赠者那里进行的肾脏移植数量保持不变（11，000例），但器官捐赠的新研究表明，每年活体肾脏移植的数量（5，600例）可能会增加50%。特别是，每年有3，000名愿意接受活体供体的患者由于血液不相容（50%）或先前对其供体过敏（50%）而没有接受移植。为了适应这些患者，肾脏配对捐赠（KPD）计划在这些不相容的配对中找到匹配，并安排捐赠者的交换。然而，由于在KPD计划中50%的患者中难以为致敏患者找到匹配的供体，因此需要显着改进搜索方法。对致敏患者的评价是过时的和不完整的，因为建议在低（2位）分辨率下（在10 - 20秒内）鉴定组织相容性白细胞抗原（HLA）-A、-B、-DR、-DQ抗原。 KPD UNOS试点：HLA-A、-B、-Bw 4、6、-Cw、-DR、-DQ和-DP，具有-DR 51/52/53抗原。该要求与通过单抗原珠（SAB）测定在等位基因（4位数）水平上测量的患者抗体（Ab）反应性不一致。此外，执行移植的许可是基于与供体细胞的负流交叉配型（FXM），其通常与虚拟交叉配型（VXM）不相关。事实上，我们最近的数据表明，阴性FXM可能无法发现高致敏患者中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 Next Generation Sequencing（NGS）方法来鉴定所有KPD供体和受体的4位HLA-A、-B、-C、-DR、-DQ和-DP等位基因; 2）使用受体抗体的基于表位的分析来改进供体-受体匹配算法，以描述不可接受的等位基因和可接受的错配等位基因;和3）通过稀释研究、与补体（C '）结合活性相关的IgG亚类分型（IgG 3> IgG 1> IgG 2> IgG 4）和细胞毒性潜能的C1 q结合测定来表征表位定义的DSA的强度，从而对致敏患者的风险进行分层。被认为是高风险的患者可以考虑进行积极的治疗和脱敏。患者和供体4位HLA分型和表位分析预计将允许在KPD计划和非配对捐赠中为致敏患者最有效地选择供体。