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

VisR 超声监测肾移植患者抗体介导的排斥反应

• 批准号: 10608688
• 负责人: Caterina M Gallippi
• 金额: $ 68.4万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608688
• 关键词: Allografting; Anisotropy; Antibodies; Award; B-Lymphocytes; Biological Markers; Biopsy; Blood Vessels; Chronic; Clinical; Clinical Trials; Creatinine; Detection; Development; Diagnostic; Early Diagnosis; Elasticity; End stage renal failure; Evaluation; Feasibility Studies; Fibrosis; Funding; Goals; Graft Survival; Grant; Human; Image; Immunosuppression; Inflammation; Intervention; Intravenous Immunoglobulins; Investigation; Kidney; Kidney Transplantation; Life; Living Donors; Measurable; Measurement; Measures; Mechanics; Mediating; Methods; Monitor; Non-Invasive Detection; Operative Surgical Procedures; Outcome; Pathologic; Patient imaging; Performance; Persons; Physiologic pulse; Plasmapheresis; Proteinuria; Protocols documentation; Public Health; Research; Research Design; Resistance; Risk; Risk Factors; Safety; Sampling; Sensitivity and Specificity; Serum; Standardization; Steroids; Surrogate Markers; Survival Rate; T-Lymphocyte; Technology; Therapeutic Intervention; Thinness; Time; Translations; Transplant Recipients; Transplantation; Treatment Protocols; Ultrasonography; United States; United States Food and Drug Administration; Urine; Variant; Viscosity; Work; antibody detection; antibody-mediated rejection; detection method; donor-specific antibody; graft dysfunction; graft failure; imaging modality; immunoregulation; implantation; improved; in vivo; in vivo Model; indexing; non-invasive monitor; novel strategies; porcine model; remediation; response; serial imaging; success; treatment choice; treatment response; ultrasound; viscoelasticity

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.

项目摘要 对于美国786，000名患有终末期肾病（ESRD）的患者， 选择是肾移植。虽然在过去的15年里，移植生命已经微妙地增加， 死亡供者的存活率仅为28%，而活体供者的存活率为46%。移植的主要原因 第一年后的失败是抗体介导的排斥反应（AMR），其有害影响是 并发纤维化因此，迫切需要通过以下方法来延长移植物寿命， 在广泛的纤维化变化和其他严重的、不可逆的移植物损伤之前补救AMR。治疗 补救AMR的干预措施没有获得FDA批准或临床标准化， 经常是次优性能。有希望的治疗方案正在开发中，但它们的翻译， 临床试验将需要频繁监测AMR反应，而目前的技术无法支持这一点。 评估标准，侵入性活检，由于其相关的安全性风险。一个更安全的选择是跟踪 替代血清和尿液生物标志物，但这些标志物是非特异性的，诊断阈值不清楚， 并且它们的值的可测量的波动可以在潜在的病理变化之后很久发生， 同种异体移植另一种安全的活检替代方法是成像，最常见的是超声，这也表明AMR 不具体缺乏一种非侵入性和特异性的方法来检测AMR并对其进行常规监测， 肾移植患者对治疗的反应是延长移植物寿命的主要差距。填补这一 间隙，我们的小组已经花了第一个五年的周期，这个赠款奖开发非侵入性粘弹剂 反应（VisR）超声监测肾移植状态。我们的研究表明， 整个髓质和皮质的弹性和粘性差异的VisR评估，以及髓质和皮质的弹性和粘性差异。 皮质弹性和粘性各向异性，描述猪模型中肾脏炎症和纤维化。此外，在A 试点临床可行性研究，我们的研究表明，在体内VisR分化活检证实， 从植入时间开始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。的 迄今为止，我们研究的成功激励了VisR技术的进一步发展， 非侵入性检测和监测AMR。具体来说，我们将增强在 第一个供资周期，采用新的各向异性测量方法（角度插值）和新的成像方法 方法（双剖面交叉（DoPio）超声），以提高检测的灵敏度和特异性 炎症，AMR的标志。我们将应用先进的VisR和DoPio方法来识别AMR， 监测其对人类肾移植患者治疗的反应。我们假设高级VisR 和DoPio超声描绘活检证实的与人类肾移植中AMR相关的炎症 患者，在体内，这是相关的非侵入性监测AMR治疗的反应。