Pretransplant comprehensive scores to predict long term graft outcomes

移植前综合评分可预测长期移植结果

• 批准号: 10679624
• 负责人: Kellie J. Archer
• 金额: $ 20.75万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-16 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679624
• 关键词: Accounting; Acute; Allografting; Atrophic; Automobile Driving; Biological Markers; Biological Process; Biopsy; CD28 gene; CXCR4 gene; Cells; Characteristics; Chronic; Clinical; Complex; Data; Development; Early identification; Event; Fibrosis; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Goals; Graft Survival; Histologic; Immune; Immunologics; Impairment; Inflammatory Response; Injury; Injury to Kidney; Innate Immune Response; Kidney; Kidney Transplantation; Knowledge; Machine Learning; Mediating; Metadata; Modality; Modification; Molecular; Molecular Profiling; Nature; Organ; Organ Donor; Outcome; Patient Monitoring; Patients; Peripheral Blood Mononuclear Cell; Prognostic Marker; Protocols documentation; RANTES; Reporting; Research Design; Risk; Sampling; Testing; Time; Transplant Recipients; Transplantation; Tubular formation; Untranslated RNA; Variant; biomarker identification; cohort; deep neural network; genetic signature; graft dysfunction; graft function; high risk; immune activation; improved; injury burden; interstitial; kidney allograft; novel; novel therapeutics; organ injury; outcome prediction; peripheral blood; post-transplant; preimplantation; prevent; progression risk; prospective; repaired; response; risk prediction; stressor; transcriptome; transcriptome sequencing; transcriptomics; wound

Despite the improved short-term outcomes in kidney transplantation (KT), comparable progress in long-term allograft survival has not been achieved. Chronic allograft dysfunction (CAD) characterized by interstitial fibrosis and tubular atrophy (IFTA), accounts for one quarter of transplant kidneys lost within 5 years. Preventing kidney graft dysfunction and loss is a critical unmet need in transplantation. From reported evidence, posttransplant graft survival is determined by the complex interplay of donor factors, acute peri-transplantation injury, and kidney transplant recipient factors. We recently reported that the transcriptome of deceased donor kidneys encompasses a gene signature at the time of KT that predicts long-term graft function. These signatures shed light on the inherent donor mechanisms responsible for triggering and likely sustaining posttransplant injury. Furthermore, although a recipient peripheral blood transcriptional signature was recently reported as a predictor of early acute rejection, the effect of pretransplant KT recipient peripheral blood transcriptional profiles on long- term outcomes has not been previously tested. Moreover, there are no comprehensive biological markers from donors and recipients that can be used pretransplant to predict graft outcomes. Given the multifactorial nature of CAD, our preliminary data, and the gaps in our knowledge, we have the unique ability to fill these unmet needs by studying the early stressors that lead to kidney graft fibrosis deploying an unbiased comprehensive approach. Towards this goal, we have already established a cohort with prospective sequential sampling of kidney allografts. In our studies, donor kidneys were evaluated at pre-implantation and recipient pretransplant peripheral blood mononuclear cells (PBMCs) were collected. The recipient cohort also includes longitudinal PBMCs, protocol biopsies, and detailed clinical metadata, allowing for the correlation of gene expression profiles with histological features and clinical parameters. In this exploratory proposal, we hypothesize that early cellular and molecular events in the donor kidney trigger local inflammatory responses that, when combined with recipient immune state, propagate and sustain posttransplant kidney injury leading to graft loss. Specific aims (SA) include: SA1 (1) Identify kidney transplant recipient preimplantation peripheral blood molecular profiles that associate with immune activation vs quiescence and determine posttransplant graft function. (2) Discern longitudinal posttransplant molecular variations in patient's PBMCs that associate with long-term graft function. SA2 Integrate kidney donor and recipient peripheral blood gene expression profiles in association with donor/recipient clinical characteristics for constructing a composite score to predict long-term outcomes. IMPACT: Results of these studies will provide a unique understanding of the early molecular triggers that determine graft outcomes and ultimately lead to CAD. Novel prognostic biomarkers will enable the early identification of patients at higher risk for progression to CAD, allowing for the development of new therapeutic modalities that have the potential to avoid irreversible graft injury and improve long-term outcomes.

尽管肾移植(KT)的短期结果有所改善，但长期进展与之相当 同种异体移植物的存活率尚未达到。以间质纤维化为特征的慢性移植物功能障碍(CAD) 和肾小管萎缩(IFTA)，占移植肾在5年内丢失的四分之一。预防肾脏 移植物功能障碍和丢失是移植中一个严重的未得到满足的需求。从报告的证据来看，移植后 移植物存活率由供体因素、急性移植周损伤和 肾移植受者因素。我们最近报道了已故供体肾脏的转录组 包括KT时的一个基因签名，它预测了移植物的长期功能。这些签名丢掉了 阐明导致并可能维持移植后损伤的内在供体机制。 此外，尽管最近报道受者外周血转录特征是一种预测因素 移植前KT受者外周血转录水平对早期急性排斥反应的影响 任期结果之前从未接受过测试。此外，还没有全面的生物标记 来自供者和受者的数据，可以在移植前用来预测移植结果。给出了多因素 CAD的性质，我们的初步数据，以及我们知识中的空白，我们有独特的能力来填补这些未满足的 通过研究导致移植肾纤维化的早期应激源来满足需求 接近。为了实现这一目标，我们已经建立了一个队列，采用前瞻性序贯抽样 异体肾移植。在我们的研究中，供体肾脏在植入前和受者移植前进行了评估。 采集外周血单个核细胞(PBMC)。接受者队列还包括纵向 PBMC、常规活组织检查和详细的临床元数据，允许基因表达谱的相关性 有组织学特征和临床参数。在这个探索性的方案中，我们假设早期的细胞 供体肾脏中的分子事件会引发局部炎症反应，当与 受体处于免疫状态，传播并维持移植后肾损伤，导致移植物丢失。具体目标 (Sa)包括：SA1(1)确定肾移植受者植入前的外周血液分子图谱 与免疫激活和静止相关联，并决定移植后的移植物功能。(2)洞察力 移植后患者PBMCs中与长期移植功能相关的纵向分子变化。 SA2整合肾供受者外周血基因表达谱与 供者/受者的临床特征，用于构建预测长期结果的综合评分。 影响：这些研究的结果将提供对早期分子触发因素的独特理解 决定移植物的结果并最终导致冠心病。新的预后生物标志物将使早期 识别进展为冠心病风险较高的患者，从而开发新的治疗方法 有可能避免不可逆转的移植物损伤并改善长期结果的方法。