Characterization of Renal Allograft Fibrosis and Prediction of Outcome Using a Quantitative MRI Approach

项目摘要 肾移植是终末期肾病患者的首选治疗方法。然而， 同种异体移植物长期存活率的改善并不能与观察到的管理改善相匹配。 被拒绝的感觉。进行性同种异体移植物功能障碍是临床上常见的疾病。最终的共同之路 由组织病理学确定的几种原因造成的累积性和增量性肾损害是间质性的。 纤维化/肾小管萎缩(IFTA)，与肾功能障碍进展和移植物减少有关 生死存亡。IFTA的组织病理学评估和分期需要组织采样，但由于其局限性 侵袭性、并发症风险、个体间变异性和抽样误差。 在本提案中，我们将测试一种非对比高级多参数磁共振成像(MpMRI)协议，该协议包括 高级弛豫成像(T1标测和T1)和高级弥散加权成像(IVIMDWI) 移植肾纤维化的非侵入性标志物。这是因为我们的初步数据表明， MpMRI产生了高度可重复的参数测量，捕捉到了同种异体移植的纤维化。我们的预赛 Mpmri与IFTA相关的经验是有价值的，因为它混淆了生理学和病理生理学。 诸如血管血流、水肿和其他Banff表型等变量通常共存。多参数 该方法使我们能够同时捕获和表征这些并发的生理和 病理生理过程。作为次要目标，我们将评估尿RNA水平的价值基于 生物标志物，此前已被证实可用于IFTA的诊断。 在这项建议中，我们的目标是：1)获取接受适应症和监视活检的患者的数据，使用 非对比mpMRI方案包括先进的弥散加权和松弛测量方法，以 准确检测和分期同种异体移植物IFTA，以及2)炎症的其他组织病理学Banff指标。我们 将使用高级统计方法构建和验证诊断模型，包括 肾移植患者的独立模型构建和验证集，用于检测和分期 Banff测量和评估尿液纤维化生物标志物的附加值。3)我们将评估 在一项纵向研究中，mpMRI和尿液生物标记物的表现对预测肾脏结果的作用 患者队列长达24个月。 我们的长期目标是验证一种可靠的、先进的mpMRI定量方法，并开发模型 准确和非侵入性地测量移植肾纤维化和临床结果，这可能潜在地 通过启用早期检测、非侵入性纵向 监测疾病、新药的治疗效果和预测。

Project Summary Renal transplantation is the treatment of choice for patients with end stage renal disease. However, improvements in long-term allograft survival have not matched the observed improvements in the management of rejection. Progressive allograft dysfunction is frequently encountered clinically. The final common pathway of cumulative and incremental renal damage from several etiologies identified by histopathology is interstitial fibrosis/tubular atrophy (IFTA), which is associated with progression of renal dysfunction and reduced allograft survival. Histopathologic assessment and staging of IFTA requires tissue sampling, which is limited due to its invasive nature, risk of complications, inter-individual variability and sampling error. In this proposal, we will test a non-contrast advanced multiparametric MRI (mpMRI) protocol comprised of advanced relaxometry (T1 mapping and T1) and advanced diffusion weighted imaging (IVIM-DWI) as noninvasive markers of renal allograft fibrosis. This is motivated by our preliminary data demonstrating that mpMRI yields highly repeatable parameter measurements that capture allograft fibrosis. Our preliminary experience correlating mpMRI with IFTA is valuable, as confounding physiologic and pathophysiologic variables such as vascular flow, edema and other Banff phenotypes commonly co-exist. The multiparametric approach allows us to simultaneously capture and characterize these concurrent physiologic and pathophysiologic processes. As a secondary objective, we will assess the value of urinary RNA level based biomarkers, which have been previously validated for the diagnosis of IFTA. In this proposal, we aim to: 1) acquire data in patients undergoing indication and surveillance biopsy, using a non-contrast mpMRI protocol comprised of advanced diffusion weighted and relaxometry methods in order to accurately detect and stage allograft IFTA, and 2) other histopathological Banff measures of inflammation. We will build and validate diagnostic models using advanced statistical methods including machine learning in independent model-building and validation sets of renal transplant patients for detection and staging of each Banff measure, and assess the added value of urinary biomarkers of fibrosis. 3) We will evaluate the performance of mpMRI and urinary biomarkers to predict renal outcomes in a longitudinal study for the entire patient cohort up to 24 months. Our long-term objective is to validate a robust quantitative advanced mpMRI approach and develop models that accurately and non-invasively measure renal allograft fibrosis and clinical outcome, which may potentially impact the care of renal transplant patients by enabling early detection, the non-invasive longitudinal monitoring of disease, therapeutic efficacy of new drugs and for prognostication.