VisR Ultrasound for Noninvasively Monitoring Renal Allograft Health

VisR 超声用于无创监测同种异体肾移植健康

• 批准号: 9234516
• 负责人: Caterina M Gallippi
• 金额: $ 65.38万
• 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 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9234516
• 关键词: Acoustics; Adult; Affect; Allografting; American; Anisotropy; Antibodies; Biological Markers; Biopsy; Characteristics; Chronic Kidney Failure; Chronic rejection of renal transplant; Clinical; Clinical Trials; Creatinine; Data; Dependence; Detection; Diagnostic; Disease; Early Intervention; Early identification; End stage renal failure; Event; Failure; Family suidae; Feasibility Studies; Fibrosis; Functional disorder; Glomerular Filtration Rate; Goals; Graft Survival; Health; Hematuria; Heterogeneity; Histologic; Image; Individual; Inflammation; Intervention; Kidney; Kidney Transplantation; Measures; Mechanics; Methods; Monitor; Morbidity - disease rate; Operative Surgical Procedures; Outcome; Patients; Perfusion; Postoperative Care; Prognostic Marker; Property; Proteinuria; Protocols documentation; Radiation; Receiver Operating Characteristics; Renal function; Renal glomerular disease; Renal pelvis; Research; Risk; Sensitivity and Specificity; Serum; Structure of renal vein; Surrogate Markers; Techniques; Technology; Testing; Time; Tissues; Transducers; Transplant Recipients; Transplantation; Ultrasonography; Ureter; Urine; Validation; Variant; Vascular Diseases; base; cost; cost effective; effective therapy; graft failure; graft function; imaging modality; improved; in vivo; indexing; kidney allograft; mechanical force; novel; pre-clinical; pressure; prevent; public health relevance; renal artery; response; urinary; viscoelasticity

 DESCRIPTION (provided by applicant): Renal transplantation is the most desirable and cost effective treatment for end stage renal disease, but 20- 30% of allografts fail in living recipient by 10 years, and prolonging graft health is one of the major unmet needs for transplant patients. Although graft health is extended by preemptive treatments that prevent irreversi- ble damage, intervention is inadequately motivated by current transplant monitoring methods. Noninvasive methods, including changes in serial serum creatinine levels, lack sensitivity and specificity. In the absence of reliable noninvasive biomarkers, invasive biopsy remains the standard for assessing transplant health, but sur- veillance or "protocol" biopsies are associated with morbidity and cost and are therefore controversial in stable, unsensitized patients. The lack of a demonstrated, noninvasive biomarker for allograft health - one that identi- fies early graft degeneration with sufficient sensitivity and specificity to motivate appropriate biopsy and enable timely intervention - represents a major gap in renal transplant management. To fill this gap, the proposed re- search aims to demonstrate Viscoelastic Response (VisR) ultrasound, a novel acoustic radiation force (ARF)- based technology that noninvasively interrogates the viscoelastic properties of tissue, for monitoring renal allo- graft health. Alternative mechanical ultrasound approaches have shown correlation between renal fibrosis and measured stiffness, but these approaches are inhibited by the heterogeneity and anisotropy of the kidney as well as renal perfusion and urinary pressure. Unlike these methods, VisR estimates viscoelastic property by observing ARF-induced displacements in only the ARF region of excitation, so the disturbing mechanical force is focally distributed, and shear wave disturbances from heterogeneity are not confounding. Further, our pre- liminary data show that a symmetric ARF focal configuration obviates the angle dependence of VisR outcomes in anisotropic tissue. Our preliminary data also demonstrate that VisR delineates fibrosis and inflammation, the presence of which one-year post transplantation has been shown to predict later decline in kidney function and graft failure. Finally, we have demonstrated VisR's potential to impact renal transplant monitoring in a pilot clini- cal feasibility study, which illustrates that VisR distinguishes glomerular disease, moderate-to-severe vascular disease, and chronic allograft nephropathy (CAN) in renal transplant patients undergoing clinically indicated biopsy for suspected graft dysfunction versus control renal transplant recipients not undergoing biopsy. Our body of preliminary data suggests that VisR has strong potential to improve noninvasive monitoring of renal transplant health. We hypothesize that in vivo VisR ultrasound delineates renal allograft dysfunction earlier and with greater sensitivity and specificity than serum creatinine concentration in renal allograft recipients. To test this hypothesis, we will pursue the following specific aims: 1) Demonstrate which VisR outcome metrics are independent of renal pressure and tissue orientation in normal, inflamed and fibrotic pig kidneys; 2) Deter- mine which VisR outcome metrics detect renal allograft dysfunction clinically; and 3) Compare serial VisR and serum creatinine outcomes in terms of ability to detect renal allograft dysfunction and the timeliness of detec- tion. We anticipate that this approach will allow the individual parts of the project to be synergistic withut being interdependent. At the completion of this project, VisR imaging will be poised for a follow-on, larger-scale clini- cal trial to substantiate its usefulness for monitoring renal transplants.

 描述（申请人提供）：肾移植是终末期肾病最理想且最具成本效益的治疗方法，但 20-30% 的同种异体移植物在活体受者体内 10 年后会失败，而延长移植物健康是移植患者未满足的主要需求之一。尽管通过预防不可逆转的损害的预防性治疗可以延长移植物的健康，但目前的移植物监测方法并不能充分激发干预作用。非侵入性方法，包括连续血清肌酐水平的变化，缺乏敏感性和特异性。在缺乏可靠的非侵入性生物标志物的情况下，侵入性活检仍然是评估移植健康的标准，但监测或“方案”活检与发病率和费用相关，因此在稳定、不敏感的患者中存在争议。缺乏一种经证实的、非侵入性的同种异体移植物健康生物标志物——一种能够以足够的敏感性和特异性识别早期移植物退化的生物标志物，以促进适当的活检并实现及时干预——是肾移植管理中的一个主要差距。为了填补这一空白，拟议的研究旨在展示粘弹性响应（VisR）超声，这是一种基于声辐射力（ARF）的新型技术，可无创地询问组织的粘弹性特性，用于监测同种异体移植肾的健康状况。替代机械超声方法已显示肾纤维化和测量的硬度之间的相关性，但这些方法受到肾脏的异质性和各向异性以及肾灌注和尿压的抑制。与这些方法不同，VisR 通过仅在 ARF 激励区域观察 ARF 引起的位移来估计粘弹性特性，因此干扰机械力集中分布，并且来自异质性的剪切波干扰不会混淆。此外，我们的初步数据表明，对称的 ARF 焦点配置消除了各向异性组织中 VisR 结果的角度依赖性。我们的初步数据还表明，VisR 描绘了纤维化和炎症，移植后一年的存在已被证明可以预测随后的肾功能下降和移植失败。最后，我们在一项试点临床可行性研究中证明了 VisR 影响肾移植监测的潜力，该研究表明 VisR 可以区分因疑似移植物功能障碍而接受临床指示活检的肾移植患者与未接受活检的对照肾移植受者的肾小球疾病、中重度血管疾病和慢性同种异体移植肾病 (CAN)。我们的初步数据表明 VisR 具有改善肾移植健康无创监测的巨大潜力。我们假设体内 VisR 超声比同种异体肾移植受者的血清肌酐浓度更早地描述同种异体移植肾功能障碍，并且具有更高的敏感性和特异性。为了检验这一假设，我们将追求以下具体目标： 1) 证明哪些 VisR 结果指标独立于正常、发炎和纤维化猪肾脏的肾压和组织方向； 2) 确定哪些 VisR 结果指标可在临床上检测肾同种异体移植功能障碍； 3) 在检测肾同种异体移植功能障碍的能力和检测的及时性方面比较连续 VisR 和血清肌酐结果。我们预计这种方法将使项目的各个部分能够协同作用而不相互依赖。该项目完成后，VisR 成像将准备进行后续更大规模的临床试验，以证实其在监测肾移植方面的有用性。