Pretransplant comprehensive scores to predict long term graft outcomes

尽管肾移植（KT）的短期结局有所改善，但长期结局的进展相当。 同种异体移植物的存活率还没有达到。以间质纤维化为特征的慢性移植物功能障碍（CAD） 肾小管萎缩（IFTA）占移植肾5年内丢失的四分之一。预防肾 移植物功能障碍和损失是移植中一个关键的未满足的需求。从报告的证据来看，移植后 移植物存活是由供体因素、急性移植周围损伤和 肾移植受者因素我们最近报道了死者肾脏的转录组 包括在KT时预测长期移植功能的基因签名。这些签名 对引发和可能维持移植后损伤的固有供体机制的了解。 此外，尽管最近有报道称受体外周血转录特征是一个预测因子， 早期急性排斥反应，移植前KT受体外周血转录谱的影响， 长期结果以前没有测试过。此外，没有全面的生物标志物， 可以在移植前用于预测移植结果。考虑到多因素 CAD的本质，我们的初步数据，以及我们知识的空白，我们有独特的能力来填补这些未满足的需求。 需要通过研究导致肾移植纤维化的早期应激因素， approach.为了实现这一目标，我们已经建立了一个队列， 同种异体肾移植在我们的研究中，供体肾脏在植入前和受体移植前进行了评估。 收集外周血单核细胞（PBMC）。接受者队列还包括纵向 PBMC、方案活检和详细的临床元数据，允许基因表达谱的相关性 组织学特征和临床参数。在这个探索性的建议中，我们假设早期细胞 供体肾脏中的分子事件触发局部炎症反应，当与 受体免疫状态，传播和维持移植后肾损伤，导致移植物损失。具体目标 (SA)包括：SA 1（1）鉴定肾移植受体植入前外周血分子谱， 与免疫激活与静止相关联，并确定移植后移植物功能。(2)辨别 与长期移植物功能相关的患者PBMC中的纵向移植后分子变化。 SA 2整合肾脏供体和受体外周血基因表达谱， 供体/受体临床特征，用于构建复合评分以预测长期结果。 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， 决定移植结果并最终导致CAD。新的预后生物标志物将使早期 识别进展为CAD的高风险患者，从而开发新的治疗药物 有可能避免不可逆移植物损伤并改善长期结局的模式。

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.