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 对于美国有786,000人患有末期肾脏疾病（ESRD）的人 选择是肾脏移植。在过去的15年中，移植寿命略有增加，但十年的移植物 死者持有人的存活率仅为28％，而活人脱子移植物的存活率仅为46％。移植的主要原因 第一年之后的失败是抗体介导的排斥反应（AMR），其有害影响是 由并发纤维化复合。因此，紧急但未满足的需要延长嫁接寿命 在发生广泛的纤维化变化和其他严重的不可逆移植物损害之前对AMR进行修复。治疗性 由于其不一致，并且 通常表现出色。有希望的治疗方案正在开发中，但它们的转化为 临床试验将需要经常监测AMR响应，而当前无法支持 评估标准，侵入性活检，由于其相关的安全风险。更安全的替代方案涉及跟踪 替代血清和尿液生物标志物，但这些标记是非特异性的，诊断阈值不明确， 并且其值的可测量波动可能会在病理学变化对 同种异体移植。活检的另一个安全替代方法是成像，最常见于超声波，这也表明AMR 非特定于。缺乏用于检测AMR并常规监视其的无创和具体方法 肾移植患者对治疗的反应是延长移植寿命的主要差距。填写这个 GAP，我们的小组已经度过了该赠款奖的第一个五年周期，开发了非侵入性粘弹性 响应（VISR）超声检查以监测肾移植状态。我们的研究表明，体内 对髓质和皮质的弹性和粘性差异的VESR评估，以及髓质 猪模型中的皮质弹性和粘性各向异性，描绘肾脏炎症和纤维化。此外， 飞行员临床可行性研究，我们的研究表明，体内VIVO VISR分化了活检确认 从植入时间开始串行成像的人类同种异体移植物中的肾小管间质纤维化。这 到目前为止，我们的调查的成功激发了Visr技术的进一步发展及其扩展到 非侵入性检测和监测AMR。具体来说，我们将增加在 第一个融资周期，采用新的各向异性测量方法（角度插值）和新成像 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的标志。我们将应用高级Visr和Dopio方法来识别AMR和 监测其对人肾移植患者治疗的反应。我们假设先进的Visr 和Dopio超声划定与AMR相关的人类肾移植中的活检证实的炎症 患者在体内与非侵入性监测对AMR治疗的反应有关的患者。