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.

项目概要 对于美国 786,000 名终末期肾病 (ESRD) 患者来说，治疗 选择是肾移植。虽然移植寿命在过去 15 年中略有增加，但十年移植寿命 已故捐赠者的存活率仅为 28%，活体捐赠者移植物的存活率为 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式延长移植物寿命： 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修复 AMR。治疗性 补救 AMR 的干预措施尚未获得 FDA 批准或临床标准化，因为它们的不一致和 经常表现不佳。有希望的治疗方案正在开发中，但它们的转化 临床试验将需要频繁监测 AMR 反应，而当前的技术无法支持这一点。 评估标准为侵入性活检，因为其存在相关的安全风险。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， 在潜在的病理变化之后，它们的值可能会发生可测量的波动。 同种异体移植物。活检的另一种安全替代方法是成像，最常见的是超声检查，这也表明 AMR 非具体地。缺乏检测 AMR 并对其进行常规监测的非侵入性特异性方法 肾移植患者对治疗的反应代表了延长移植物寿命的主要差距。为了填补这个 差距，我们的小组在该拨款的第一个五年周期中开发了非侵入性粘弹性 用于监测肾移植状态的反应 (VisR) 超声。我们的研究表明，在体内 VisR 评估髓质和皮质的弹性和粘性差异，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，描绘猪模型中的肾脏炎症和纤维化。进一步地，在一个 试点临床可行性研究，我们的研究表明，体内 VisR 可以区分活检证实的 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 迄今为止我们研究的成功推动了 VisR 技术的进一步发展及其扩展到 无创检测和监测 AMR。具体来说，我们将增强 VisR 方法中开发的 第一个资助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（双轮廓相交（DoPIo）超声）以提高检测的灵敏度和特异性 炎症，AMR 的一个标志。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治疗的反应。我们假设先进的 VisR 和 DoPIo 超声描绘了人肾移植中活检证实的与 AMR 相关的炎症 患者体内，这与无创监测 AMR 治疗的反应有关。