Noninvasive evaluation of the intrarenal microvasculature in ADPKD

常染色体显性遗传性多囊肾病(ADPKD)是一种破坏性的全身性疾病，是一种主要的 肾功能衰竭的原因。其特点是双侧肾囊肿持续发展和增大， 但许多导致肾损害和肾功能衰竭的病理生理机制仍不清楚。 在ADPKD中，血管重塑被认为在其发展过程中起重要作用。然而， 了解肾损伤和功能下降的确切原因，以及最佳治疗策略 由于缺乏工具，无法定量和非侵入性评估 肾内微血管构筑。显然，一种非侵入性和直接的方法评估肾内微血管 是必要的。成像研究，如微型CT、MRI和对比增强超声，已经尝试 在临床前模型中提供肾内微血管的非侵入性评估。然而，每一个 这些模式在转化为人类时有重要的限制，包括低空间分辨率。 超分辨超声(Sru)成像技术的引入克服了固有的空间限制。 超声波的分辨率。通过使用无肾毒性的造影剂微泡来突破衍射极限 超声波，以及利用超快帧速率的超声定位显微镜的引入 成像重建超分辨率合成图像，SRU提供了一种范式转换工具 组织微血管的结构和功能评价。然而，在活体人体成像中，以及在 尤其是肾脏成像，在器官深度和运动方面提出了重大挑战。要克服这些障碍 限制，我们的团队实施了先进的过滤和微气泡定位和跟踪技术， 它只提取微泡信号，并可靠地定位每个微泡的中心。组合在一起 使用这些自动化和后处理工具的SRU产生了前所未有的微观成像 临床相关穿透深度的分辨率，同时使超声更定量，使用更少- 依附的。这一提议背后的工作假设是，SRU成像与高级 过滤和微气泡定位跟踪后处理技术将可靠和可重复性 评估早期ADPKD患者的肾内微血管构筑。我们会 追求三个具体目标：目标1：将介绍和评估SRU成像以及高级职位 用于评估早期ADPKD患者和对照组肾内微血管的处理技术。 目标2：将确定超声诊断者间和观察者间微血管的可重复性 参数。目标3：将确定对照组微血管参数的日常变异性范围， 以及ADPKD患者之间的变异性。成功的研究将引入一个强大的工具来解释 肾内微血管损害在ADPKD进展中的作用 靶点和微血管参数作为评估疾病严重程度和进展的成像生物标记物。

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a devastating systemic disorder and a leading cause of renal failure. It is characterized by continuous development and enlargement of bilateral renal cysts, but many pathophysiological mechanisms contributing to renal damage and failure remain poorly understood. In ADPKD, vascular remodeling has been proposed to play an important role in its progression. However, knowledge on the precise contribution to renal injury and function decline, and optimal therapeutic strategies have been hampered by the lack of tools enabling the quantitative and noninvasive assessment of the intrarenal microvasculature. Clearly, a noninvasive and direct method to assess the intrarenal microvasculature is needed. Imaging studies, such as microCT, MRI, and contrast-enhanced ultrasound, have attempted to provide noninvasive assessment of the intrarenal microvasculature in pre-clinical models. However, each of these modalities have important limitations when translating into humans, including low spatial resolution. Super-resolution ultrasound (SRU) imaging was introduced to overcome the limitation of inherent spatial resolution of ultrasound. With the use of non-nephrotoxic contrast microbubbles to break the diffraction limit of ultrasound, and the introduction of ultrasound localization microscopy which utilizes ultrafast frame rate imaging to reconstruct a super-resolved composite image, SRU has provided a paradigm-shifting tool for structural and functional evaluation of tissue microvasculature. However, in vivo human imaging, and in particular kidney imaging, poses significant challenges related to organ depth and motion. To overcome these limitations, our team implemented advanced filtering and microbubble localization and tracking techniques, which extract only microbubble signals and reliably pinpoint the center of each microbubble. The combination of SRU with these automation and post processing tools results in unprecedented microscopic-level imaging resolution at clinically relevant penetration depths, while rendering ultrasound more quantitative and less user- dependent. The working hypothesis underlying this proposal is that SRU imaging coupled with advanced filtering and microbubble localization-tracking post processing techniques would reliably and reproducibly assess the intrarenal microvasculature in patients with ADPKD from early stages of the disease. We will pursue three specific aims: Aim 1: Will introduce and evaluate SRU imaging coupled with advanced post processing techniques to assess the intrarenal microvasculature in patients with early ADPKD and controls. Aim 2: Will determine the inter-sonographer and inter-intra-observer reproducibility of microvascular parameters. Aim 3: Will determine the range of day-to-day variability of microvascular parameters in controls, and of patient-to-patient variability in ADPKD. Successful studies will introduce a powerful tool to elucidate the role of intrarenal microvascular damage in the progression of ADPKD, the microvasculature as therapeutic target, and microvascular parameters as imaging biomarkers to assess disease severity and progression.