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; 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.

项目摘要 肾脏移植是末期肾脏疾病的最佳治疗方法，因为它可以改善两种生存 和生活质量，比透析更具成本效益。但是，移植孩子的寿命是 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。 过早的移植物损失和重新移植的需求使已经很可怕的器官短缺加剧。延长 嫁接生存可能取决于优化捐助者与受体的免疫匹配，以最大程度地减少 免疫攻击并减少对侵略性免疫抑制的需求。 HLA匹配历史上有 依靠供体和受体HLA基因型的比较，通过血清学分析或两种 维基因序列。随着较新的高分辨率基因分型，HLA抗原的物理结构 可以预测，可以比较分子水平的供体/受体HLA基因型。简而言之 高分辨率基因型数据，一种称为HlamatchMatchMaker的计算机算法可以将基因序列提炼成 位于HLA分子表面上的“ eplets”的多态氨基酸串，因此 宿主免疫系统可访问。当捐助者和接受者HLA基因型被翻译成其 相应的Elets，我们可以将它们之间的免疫学识别差异作为数字 eplet不匹配。回顾性数据表明，偶然地接受了已故的Donorkidneys的患者 较低的EPLET不匹配（MM）负载的DE供体特异性抗体（DNDSA）形成率较低， 上移植的生存率，可能需要较少的免疫抑制。通过捐赠，有机会 评估给定接受者的多个潜在供体，并在选择之前比较其eplet MM的程度 哪个捐赠者继续移植。那是活着的供体肾脏移植（LKDT）的接受者是最佳的 测试优化EPET匹配的患者群体是否确实会产生较低的移植物 同种免疫风险。与最大的配对肾脏交易所，国家肾脏注册中心（NKR）合作， 我们已经开始将EPLET MM分析与现有的供体 - 复发匹配算法相结合，以便为了 产生大量的低EPLET MM活供体肾脏移植物。这些移植正在 作为该试点计划的一部分，在全国各地的中心演出。初步数据表明DNDSA 在这些接受者中很少发生形成，但是低EPLET MM LDKT允许的程度 免疫抑制还不清楚。 R34赠款将使我们能够设计一个多中心随机的 试验以预期测试低EPLET MM LDKT受体的免疫抑制作用，以及 比较低EPLET MM LKDT的安全性和易度性与高EPLET MM LDKT。如果我们的假设正确，我们 将建立一个可以优化捐助者/收件人匹配的途径，以最大化移植寿命和 最终改善了患者的生存和生活质量。