Assessment of Biomarker Guided CNI Substitution in Kidney Transplantation

肾移植中生物标志物引导的 CNI 替代评估

• 批准号: 10654057
• 负责人: Peter Scott Heeger
• 金额: $ 420.94万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2029-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654057
• 关键词: 3-Dimensional; Acute; Address; Affect; Allografting; Biological Markers; Biopsy; Calcineurin inhibitor; Canada; Cessation of life; Characteristics; Clinical; Clinical Trials; Enrollment; Ensure; Event; FDA approved; Failure; Future; Glomerular Filtration Rate; Goals; HLA-DR Antigens; Health; Human; Imaging Techniques; Immune; Immunologic Markers; Immunologics; Immunosuppression; Infrastructure; Infusion procedures; Injury; Kidney Transplantation; Life; Mediating; Medical; Molecular; Molecular Profiling; Morbidity - disease rate; Multicenter Studies; Multicenter Trials; Mycophenolic Acid; Neurocognitive; Observational Study; Outcome; Outcome Measure; Pathway interactions; Patient Outcomes Assessments; Patient Participation; Patients; Phenotype; Population; Prednisone; Productivity; Prognostic Marker; Prospective Studies; Protocols documentation; Randomized; Randomized, Controlled Trials; Research Design; Retrospective Studies; Risk; Safety; Self Administration; Stratification; T cell receptor repertoire sequencing; T-Lymphocyte; Tacrolimus; Testing; Therapeutic; Time; Toxic effect; Transplant Recipients; Transplantation; United States National Institutes of Health; Work; antibody-mediated rejection; arm; clinical care; cohort; design; donor-specific antibody; evidence base; fibrogenesis; follow-up; graft function; human leukocyte antigen testing; immunosuppressed; improved; improved outcome; insight; instrument; isoimmunity; kidney allograft; novel; outcome prediction; peripheral blood; post-transplant; predictive marker; primary endpoint; prospective; prospective test; racial diversity; risk stratification; secondary endpoint; specific biomarkers; standard of care; subcutaneous; success; vasoconstriction

Current standard of care for kidney transplant (KTx) recipients has only modestly improved long-term aggregate graft and/or patient survival, identifying a crucial unmet medical need. As the at-risk KTx population is heterogeneous, the currently employed and relatively homogeneous therapeutic approach to immunosuppression in KTx in the US and Canada is suboptimal, and results in a significant proportion of over- immunosuppressed recipients, many with tacrolimus-related toxicities. In this U01 application, Co-PIs Heeger and Nickerson will build upon their past, productive collaborative efforts, their established multicenter trial consortium and infrastructure, as well as their expertise in biomarkers and mechanistic studies to address this unmet need. The overarching goal of the proposed work is to determine the utility of the HLA-DR/DQ molecular mismatch (mMM) score, as a risk stratifying biomarker in KTx. While retrospective studies showed strong correlations between the HLA-DR/DQ mMM score and the risk of developing biopsy proven acute rejection (BPAR) and/or donor specific antibodies (DSA), no prospective studies have tested the HLA mMM score as a risk stratifying biomarker for immunological KTx injury. Nor have any studies attempted to test whether and how the HLA-DR/DQ mMM score performs as a predictor of outcome following a change in transplant immunosuppression. Herein, we propose a multicenter observational study with a nested randomized controlled (RCT) trial to address these deficiencies. We will prospectively test the utility of the HLA-DR/DQ mMM score as a prognostic biomarker of primary alloimmunity [T cell mediated rejection (TCMR), DSA, and antibody mediated rejection (ABMR)] in KTx (Aim 1, observational study of 800 KTx). We will also test the hypothesis that the HLA-DR/DQ mMM score is a predictive biomarker that identifies KTx recipients who will tolerate substituting the calcineurin inhibitor with self-administered, subcutaneous abatacept (costimulatory blockade), without an unacceptable increased risk of BPAR, while reducing the morbidity of CNI off-target effects (300 KTx, Nested RCT with a non-inferiority endpoint, Aim 2). Accompanying mechanistic studies (Aim 3) will provide novel immunological and molecular insights that will also aid in interpreting graft and recipient outcomes of the trial. If successful, the work will provide crucial information capable of positively, and directly affecting clinical care. The results from the proposed work also have the potential to influence positively the design of future RCTs by providing an HLA-DR/DQ mMM score-based stratification or enrichment strategy for enrolling subjects into trials most likely to be informative for the proposed study agent-- thereby increasing likelihood of trial success in the shortest possible time.

当前的肾脏移植标准（KTX）受体仅适度改善了长期 总体移植物和/或患者生存，确定至关重要的未满足医疗需求。作为高危KTX人群 是异质的，目前使用的，相对均匀的治疗方法 在美国和加拿大，KTX的免疫抑制是次优的，导致相当一部分过度 免疫抑制的接受者，许多与克莫司有关的毒性。在此U01应用程序中，Co-Pis Heeger 尼克森将基于他们过去的富有成效的合作努力，他们既定的多中心审判 财团和基础设施，及其在生物标志物和机械研究方面的专业知识来解决这一问题 未满足的需求。拟议工作的总体目标是确定HLA-DR/DQ的实用性 分子不匹配（MMM）得分，作为KTX中的风险分层生物标志物。回顾性研究表明 HLA-DR/DQ MMM分数与发展活检证明急性的风险之间的密切相关性 排斥（BPAR）和/或供体特异性抗体（DSA），没有前瞻性研究测试了HLA MMM 评分是免疫KTX损伤的风险分层生物标志物。没有任何研究试图测试 HLA-DR/DQ MMM分数是否以及如何作为结果的预测指标 移植免疫抑制。在此，我们提出了一项具有嵌套的多中心观察性研究 随机对照（RCT）试验解决这些缺陷。我们将前景测试 HLA-DR/DQ MMM评分是原发性同种免疫的预后生物标志物[T细胞介导的排斥反应（TCMR）， KTX中的DSA和抗体介导的排斥（ABMR）]（AIM 1，800 KTX的观察性研究）。我们也会 测试HLA-DR/DQ MMM分数是识别KTX接收者的预测生物标志物的假设 谁将用自我管理的，皮下的Abatacept忍受钙调神经蛋白抑制剂的代替 （COSCOMIMULATION BLOCKADE），没有无法接受的BPAR风险增加，同时降低了CNI的发病率 脱离目标效果（300 ktx，嵌套的RCT具有非效率终点，AIM 2）。伴随的机械 研究（AIM 3）将提供新颖的免疫学和分子见解，这也将有助于解释移植物 和接受试验的接受者结果。如果成功，这项工作将提供能够积极的重要信息， 并直接影响临床护理。拟议工作的结果也有可能影响 通过提供基于HLA-DR/DQ MMM得分的分层或 将受试者纳入试验的丰富策略，最有可能对拟议的研究代理人提供信息 - 因此，在最短的时间内会增加试验成功的可能性。