A prospective clinical trial of immunosuppression reduction in recipients of low eplet mismatched renal allografts: the kidney for life initiative

低 eplet 错配肾同种异体移植受者减少免疫抑制的前瞻性临床试验：肾脏生命倡议

• 批准号: 10704807
• 负责人: Bonnie Elizabeth Lonze
• 金额: $ 25.43万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704807
• 关键词: Acute; Adherence; Algorithms; Allografting; Amino Acids; Antibody Formation; Biological Assay; Blood Cells; Calcineurin inhibitor; Case Report Form; Chronic; Clinical; Clinical Trials; Clinical Trials Data Monitoring Committees; Collaborations; Computational algorithm; Consent Forms; Contractor; Country; Data; Data Analytics; Data Collection; Data Correlations; Dialysis procedure; Drug Side Effects; Educational Materials; Elements; End stage renal failure; Ensure; Evaluation; Funding; Gene Expression Profiling; Genes; Genotype; Glomerular Filtration Rate; Good Clinical Practice; Graft Survival; Grant; HLA Antigens; Immune; Immune Targeting; Immune system; Immunologics; Immunosuppression; Immunosuppressive Agents; Incidence; Individual; Infection; Injury; Investigation; Kidney; Kidney Transplantation; Life; Living Donors; Longevity; Manuals; Molecular; Monitor; Multicenter Studies; Organ; Outcome Assessment; Outcome Measure; Pathway interactions; Patient Recruitments; Patients; Pharmaceutical Preparations; Pharmacy facility; Procedures; Prospective cohort; Protocols documentation; Quality of life; Randomized, Controlled Trials; Recurrence; Registries; Research; Resolution; Retrospective Studies; Risk; Safety; Sample Size; Sampling; Serology; Site; Structure; Surface; Testing; Training; Translating; Transplant Recipients; Transplantation; cell free DNA; comorbidity; cost effective; data registry; design; donor-specific antibody; electronic data capture system; experience; improved; individual patient; infection rate; kidney allograft; living kidney donor; material transfer agreement; multi-site trial; nephrotoxicity; operation; patient oriented; patient population; precision medicine; premature; primary endpoint; programs; prospective; prospective test; randomized trial; recruit; retransplantation; risk prediction; secondary endpoint; transplant centers; trial comparing; trial planning; two-dimensional; willingness

PROJECT SUMMARY Kidney transplantation is the best available treatment for end stage renal disease as it improves both survival and quality of life and is more cost effective than dialysis. However, the lifespan of transplanted kidneys is shortened due to chronic immune-driven injury and the direct nephrotoxicity of immunosuppressive drugs. Premature graft loss and the need for re-transplantation worsens an already dire organ shortage. Prolonging graft survival may hinge on optimizing immunologic matching of donors with recipients, to minimize targets of immunologic attack and decrease the need for aggressive immunosuppression. HLA matching has historically relied upon comparison of donor and recipient HLA genotypes determined either by serologic analysis or two- dimensional gene sequences. With newer high-resolution genotyping, the physical structures of HLA antigens can be predicted, enabling comparisons of donor/recipient HLA genotypes at the molecular level. In brief, with high-resolution genotype data, a computer algorithm called HLAMatchmaker can distill gene sequences into strings of polymorphic amino acids termed ‘eplets’ that are located on the HLA molecule surface and are thus accessible to the host immune system. When donor and recipient HLA genotypes are translated into their corresponding eplets, we can tally the immunologically recognizable differences between them as the number of eplet mismatches. Retrospective data indicate that patients who, by chance, received deceaseddonorkidneys with a low eplet mismatch (MM) load have lower rates of de novo donor specific antibody (dnDSA) formation, superior graft survival, and may require less immunosuppression. With living donation, there is opportunity to evaluate multiple potential donors for a given recipient and compare their degree of eplet MM before choosing which donor to proceed with to transplant. Thus, living donor kidney transplant (LKDT) recipients are the optimal patient population in which to test whether optimizing eplet matching indeed yields transplants that are at lower alloimmune risk. In collaboration with the largest paired kidney exchange, the National Kidney Registry (NKR), we have begun combining eplet MM analysis with its existing donor-recipient matching algorithms in order to generate high volumes of low eplet MM living donor kidney transplants. These transplants are now being performed at centers across the country as part of this pilot program. Preliminary data indicate that dnDSA formation is rare occurred in these recipients, however the degree to which low eplet MM LDKT permits immunosuppression reduction is not known. This R34 grant will enable us to design a multi-center randomized trial to prospectively test immunosuppression reduction in recipients of low eplet MM LDKT, as well as to compare the safety and efficacy of low eplet MM LKDT to high eplet MM LDKT. If our hypothesis is correct, we will establish a pathway by which donor/recipient matching can be optimized to maximize graft longevity and ultimately improve both patient survival and quality of life.

项目概要 肾移植是终末期肾病的最佳治疗方法，因为它可以提高生存率 和生活质量，并且比透析更具成本效益。然而，移植肾的寿命 由于慢性免疫驱动损伤和免疫抑制药物的直接肾毒性而缩短。 移植物过早丧失和重新移植的需要加剧了本已严重的器官短缺。延长 移植物的存活可能取决于优化供体与受体的免疫匹配，以尽量减少移植物的靶标 免疫攻击并减少积极免疫抑制的需要。 HLA 匹配历史上有 依赖于通过血清学分析或两种方法确定的供体和受体 HLA 基因型的比较 维度基因序列。通过更新的高分辨率基因分型，HLA 抗原的物理结构 可以预测，从而能够在分子水平上比较供体/受体 HLA 基因型。简而言之，与 高分辨率基因型数据，一种名为 HLAMatchmaker 的计算机算法可以将基因序列提取为 称为“eplet”的多态性氨基酸串位于 HLA 分子表面，因此 可以进入宿主免疫系统。当供体和受体的 HLA 基因型被转化为各自的 HLA 基因型时 相应的 eplet，我们可以将它们之间的免疫学可识别差异计算为数量 elet 不匹配的情况。回顾性数据表明，偶然接受死者捐肾的患者 具有低eplet错配（MM）负载的从头供体特异性抗体（dnDSA）形成率较低， 移植物存活率较高，并且可能需要较少的免疫抑制。通过活体捐赠，您有机会 评估给定受体的多个潜在捐赠者，并在选择之前比较他们的 eplet MM 程度 选择哪个捐赠者进行移植。因此，活体肾移植 (LKDT) 受者是最佳选择 测试优化 eplet 匹配是否确实能产生较低移植率的患者群体 同种免疫风险。与最大的配对肾脏交换国家肾脏登记处 (NKR) 合作， 我们已经开始将 eplet MM 分析与其现有的供体-受体匹配算法相结合，以便 产生大量低 eplet MM 活体肾移植。目前这些移植手术正在进行中 作为该试点计划的一部分，在全国各地的中心进行。初步数据表明，dnDSA 这些受体中很少发生形成，但是低 eplet MM LDKT 允许的程度 免疫抑制的减少尚不清楚。这笔 R34 拨款将使我们能够设计一个多中心随机 前瞻性测试低 eplet MM LDKT 接受者免疫抑制减少的试验，以及 比较低 eplet MM LKDT 与高 eplet MM LDKT 的安全性和有效性。如果我们的假设是正确的，我们 将建立一条途径，通过该途径可以优化供体/受体匹配，以最大限度地延长移植物的寿命和 最终提高患者的生存率和生活质量。