VisR Ultrasound for Monitoring Antibody-Mediated Rejection in Renal Transplant Patients

项目总结 对于美国786,000名患有终末期肾病(ESRD)的患者，治疗 选择是肾移植。虽然移植的寿命在过去的15年里微妙地增加了，但十年的移植 已故供者的存活率只有28%，活体供者的存活率只有46%。贪污的主要原因是 第一年后的失败是抗体介导的排斥反应(AMR)，其有害影响是 再加上并发的纤维化。因此，有一种迫切但尚未得到满足的需求，即通过以下方式延长移植物的寿命 在广泛的纤维化改变和其他严重的、不可逆的移植物损伤之前修复AMR。治疗性的 治疗AMR的干预措施没有得到FDA的批准或临床标准化，因为它们不一致 往往表现不佳。有希望的治疗方案正在开发中，但它们转化为 临床试验将需要对AMR反应的频繁监测，而目前的 评估标准是有创活组织检查，因为它存在相关的安全风险。一种更安全的替代方案是跟踪 替代血清和尿液生物标志物，但这些标志物是非特异性的，诊断阈值不明确， 并且其值的可测量波动可能发生在潜在的病变之后很久 异体移植。活组织检查的另一种安全选择是成像，最常见的是超声波，它也表明AMR 不明确地说。缺乏一种非侵入性和特异性的方法来检测AMR并常规监测其 肾移植患者对治疗的反应是延长移植肾寿命的主要差距。为了填满这个 GAP，我们团队在该奖项的第一个五年周期中一直在开发非侵入性粘弹性 反应(VISR)超声监测肾移植状态。我们的研究表明，在活体内 VISR评估延髓和皮质的弹性和粘性差异，以及延髓和 皮质弹性和粘性各向异性，描绘了猪模型中的肾脏炎症和纤维化。此外，在 先导临床可行性研究，我们的研究表明，活体VisR与活检证实的 从植入时起连续成像的人类患者同种异体移植物中的肾小管间质纤维化。这个 到目前为止，我们调查的成功推动了VISR技术的进一步进步，并将其扩展到 无创性检测和监测AMR。具体地说，我们将增强在 第一个资金周期，采用新的各向异性测量方法(角度内插)和新的成像 提高检测灵敏度和特异度的方法(DoPIo) 炎症，AMR的一个特征。我们将应用先进的VISR和DoPIo方法来识别AMR和 监测其对人类肾移植患者的治疗反应。我们假设高级VISR 在人类肾移植中，DOPIo超声描绘了与AMR相关的经活检证实的炎症 患者体内，这与无创性监测AMR治疗的反应有关。

PROJECT SUMMARY For the 786,000 people in the United States living with end stage renal disease (ESRD), the treatment of choice is kidney transplantation. While transplant life has subtly increased over the last 15 years, ten-year graft survival rates are only 28% for deceased-donor and 46% for living-donor grafts. The primary cause of graft failure after the first year is antibody-mediated rejection (AMR), the detrimental impacts of which are compounded by concurrent fibrosis. Thus, there is an urgent yet unmet need to prolong graft life by remediating AMR prior to extensive fibrotic changes and other severe, irreversible graft damage. Therapeutic interventions to remediate AMR are not FDA approved or clinically standardized due to their inconsistent and often suboptimal performances. Promising treatment protocols are in development, but their translation to clinical trials will require frequent monitoring of AMR response that cannot be supported by the current evaluation standard, invasive biopsy, due to its associated safety risks. A safer alternative involves tracking surrogate serum and urine biomarkers, but these markers are nonspecific with unclear diagnostic thresholds, and measurable fluctuations in their values may occur well after underlying pathological changes to the allograft. Another safe alternative to biopsy is imaging, most often ultrasound, which also indicates AMR nonspecifically. The lack of a noninvasive and specific method for detecting AMR and routinely monitoring its response to treatment in renal transplant patients represents a major gap in prolonging graft life. To fill this gap, our group has spent the first five-year cycle of this grant award developing noninvasive Viscoelastic Response (VisR) ultrasound for monitoring renal transplant status. Our research has demonstrated that in vivo VisR assessments of elastic and viscous differences across the medulla and cortex, as well as medullary and cortical elastic and viscous anisotropy, delineate renal inflammation and fibrosis in a pig model. Further, in a pilot clinical feasibility study, our research has shown that in vivo VisR differentiates biopsy-confirmed tubulointerstitial fibrosis in the allografts of human patients imaged serially from time of implantation. The success of our investigations thus far motivates further advancement of VisR technology and its extension to noninvasively detecting and monitoring AMR. Specifically, we will augment the VisR methods developed in the first funding cycle with a new approach to anisotropy measurement (angle interpolation) and a new imaging method (Double Profile Intersection (DoPIo) ultrasound) to improve the sensitivity and specificity of detecting inflammation, a hallmark of AMR. We will apply the advanced VisR and DoPIo methods to identifying AMR and monitoring its response to treatment in human renal transplant patients. We hypothesize that advanced VisR and DoPIo ultrasound delineate biopsy-confirmed inflammation associated with AMR in human renal transplant patients, in vivo, which is relevant to noninvasively monitoring response to AMR treatment.