Endogenous Urea CEST MRI (urCEST): pH and urea gradient mapping in human kidney

 描述（由申请人提供）：肾脏疾病影响着美国和世界各地数百万人。这些包括但不限于慢性肾病（CKD）、肾结石、肾癌和急性肾损伤。目前全球检测肾功能不全的“金标准”是通过肾小球滤过率（GFR）降低结合尿液分析（蛋白尿、化学、显微镜检查）。也使用成像（MRI、CT和US），但主要限于评估解剖结构而不是功能。 今天用于评估肾脏健康的测试要么提供全球输出信息（GFR，化学和尿液分析），要么解决解剖学（成像）。功能和代谢变化可能先于解剖学或全局标记。此外，功能变化可能是异质性的;仅影响肾脏的某些区域，或仅影响一个肾脏，而GFR，尿分析和大体解剖学表现正常。 肾脏的主要功能之一是排泄尿素。在正常的肾脏中， pH值和尿素的径向梯度维持良好（髓质深部较高）。未能维持这些梯度反映了肾功能的缺陷。因此，pH和尿素空间分布的非侵入性映射将提供关于肾功能的敏感功能信息。在此，我们打算开发这样的检测方法。 化学交换饱和转移是一种磁共振成像对比机制，其依赖于化学交换质子的选择性预饱和以及由于饱和质子与水交换而观察到随后的水信号降低。CEST效应固有地对pH敏感，因为化学交换的速率通常依赖于pH。同时，CEST效应也依赖于交换基团的浓度。内源性尿素是一种天然的CEST试剂：它具有两个带有质子的胺基，可与水进行化学交换。因此，CEST使用这些内源性基团（urCEST）可以提供尿素浓度以及细胞外pH值的读数。我们的假设：定量urCEST提供了肾脏中pH值分布和尿素浓度的空间图。我们采用先进的技术，如：高（3 T）场强，时间交织并行射频发射，最先进的 后期处理我们将所谓的Omega-plot CEST定量方法扩展到尿素，允许独立测定尿素浓度和交换率（与pH值一一对应）。该假设将在含有尿素水溶液和琼脂糖凝胶以及含有各种尿素浓度和pH值的尿液样本中进行验证。随后将在正常志愿者中进行不同受控生理挑战的体内实验。使用MRI与尿液分析在膀胱中测定的pH值和浓度的比较将作为验证和表征所开发方法的“金标准”。

 DESCRIPTION (provided by applicant): Kidney ailments affect millions of people in the US and worldwide. These include, but not limited to chronic kidney disease (CKD), kidney stones, renal cancers, and acute kidney injury. The current "gold standard" to globally detect renal dysfunction is through the reduction in glomerular filtration rate (GFR) coupled with the analysis of the urine (proteinuria, chemistry, microscopic examination). Imaging (MRI, CT and US) is also used, but is restricted mainly to assessing anatomy and not function. The tests used today to assess kidneys health either provide global output information (GFR, chemistry and urinalysis) or address anatomy (imaging). Functional and metabolic changes may precede anatomical or global markers. Moreover, the functional changes can be heterogenous; affecting only certain areas of the kidney, or only one kidney, while GFR, urinalysis and gross anatomy appear normal. One of the main functions in the kidney is excretion of urea. In a normal kidney, there is a well-maintained radial gradient for pH and urea (higher in the deep medulla). Failure to maintain these gradients reflects defects in renal function. Thus non-invasive mapping of pH and urea spatial distribution will provide sensitive functional information about kidney function. Here, we intent to develop such detection method. Chemical Exchange Saturation Transfer is an Magnetic Resonance Imaging contrast mechanism that relies on the selective pre-saturation of the chemically exchanging protons and observation of the subsequent water signal decrease due to exchange of the saturated protons with water. The CEST effect is inherently sensitive to pH, since the rate of chemical exchange is often pH dependent. At the same time the CEST effect is also dependent on the concentration of the exchanging group. Endogenous urea is a natural CEST agent: it possesses two amine groups with protons in chemical exchange with water. Thus, the CEST using these endogenous groups (urCEST) can provide a read-out of urea concentration as well as extracellular pH. Our hypothesis: quantitative urCEST provides spatial maps of pH distribution and the urea concentration in kidneys. We employ technological advances such as: high (3T) field strength, time-interleaved parallel RF transmit, state-of-the-art post-processing. We expand the so-called Omega-plot CEST quantification method to urea, allowing independent determination of the urea concentration and exchange rate (which has one-to-one correspondence to pH). The hypothesis will be validated in phantoms containing aqueous urea in water solutions and agarose gels as well as in the urine samples containing various urea concentrations and pH. These will be followed by in-vivo experiments in normal volunteers undergoing different controlled physiological challenges. Comparison of the pH and concentration determined in bladder using MRI vs urine analysis will serve as the "gold standard" to validate and characterize the methods developed.