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（由适用提供）：肾移植是终末期肾脏疾病的最理想和成本效益的治疗方法，但20-30％的同种异体移植失败了10年，延长移植物健康是移植患者的主要未满足需求之一。尽管通过预先治疗可预防反转损害的先发治疗方法扩大了移植健康，但干预措施的动机不足，目前的移植监测方法的动机不足。非侵入性方法，包括序列血清创造水平的变化，缺乏灵敏度和特异性。在没有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，但是射波或“方案”活检与发病率和成本有关，因此在稳定，未敏感的患者中存在争议。缺乏针对同种异体健康健康的表现出的无创生物标志物 - 鉴定早期移植性变性具有兼容的敏感性和特异性，以融合适当的活检并实现及时干预 - 代表了肾脏移植管理的主要差距。为了填补这一空白，提出的搜索旨在证明粘弹性响应（Visr）超声，这是一种基于新的声学辐射力（ARF）的技术，无创顾问组织的粘弹性特性，用于监测肾脏同藻健康。替代的机械超声方法已经显示出肾纤维化与测量的刚度之间的相关性，但是这些方法受肾脏的异质性和各向异性以及肾脏灌注和尿压的抑制。与这些方法不同，VISR仅在ARF的兴奋区域观察ARF诱导的位移来估计粘弹性特性，因此干扰的机械力是局部分布的，而异质性引起的剪切波扰动也不令人困惑。此外，我们的二元前数据表明，对称ARF焦点构型消除了各向异性组织中VISR结局的角度依赖性。我们的初步数据还表明，VISR描述了纤维化和炎症，已显示移植后一年的存在可以预测肾脏功能和成绩衰竭后来的下降。最后，我们证明了Visr在一项试验临床可行性研究中影响肾脏移植监测的潜力，该研究表明VISR区分了肾小球疾病，中度至重度血管疾病以及慢性同种异体移植肾病（CAN CAN）在接受临床指示的临床临床培训者的肾脏差异对手中的肾脏转移患者中受到临床指示的培养基对照群体的侵害，而对肾脏的生物疾病则无关。我们的初步数据表明，Visr具有改善肾移植健康无创监测的强大潜力。我们假设体内Vivo visr超声描绘了早期的肾脏同种异体功能障碍，并且比肾合金受体中血清肌酐浓度更高的灵敏度和特异性。为了检验这一假设，我们将追求以下特定目的：1）证明哪些VISR结果指标与正常，发炎和纤维化的猪肾脏中的肾压和组织取向无关； 2）确定哪种visr结果指标在临床上检测肾合金功能障碍； 3）在检测肾脏同种异体功能障碍和检测率的及时性方面，比较串行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与相互依存相同。该项目完成后，Visr成像将被毒化以进行后续大规模的诊所CAL试验，以证实其在监测肾脏移植物中的有用性。