INVESTIGATION OF GADOLINIUM CONTRAST AGENT TOXICITY BY XAS

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 中心，但不一定是研究者所在的机构。 由于它们的顺磁性质，有机钆络合物和钆化合物的溶液被用作静脉内放射性造影剂以增强医学磁共振成像中的图像。 钆已在美国、欧洲和日本的成人和儿童中使用多年，数千名患者没有出现任何严重并发症。FDA在1988年宣布钆可安全用于MRI。然而，可能会出现一些副作用，如轻度头痛、恶心和局部烧灼感。 Caravan及其同事最近发现，严重肾功能不全的患者如果接受钆基MR造影剂，则易患“肾源性全身性纤维化”。 他们的结果表明，在人类受试者中，肾脏和心脏中的Gd含量特别丰富。Gd如何与这些组织相互作用的基本理解将是至关重要的，在确定这些患者中的Gd毒性的分子起源。我们认为，使用XANES和EXAFS测量心脏和肾脏组织区域中的Gd是这个独特实验机会中最合适的第一步，这可能对转化研究产生巨大影响。 我们希望从尸检样本中确定Gd在组织中的局部配位环境，并将这些结果与可能的生物Gd模型（如Gd磷酸盐、Gd硫酸盐和有机Gd造影剂）进行比较。 根据这些数据，我们将能够清楚地确定Gd造影剂在肾脏和心脏组织中是否以及如何发生化学变化。 Gd配位和/或氧化态的变化可能导致在Caravan实验室中观察到的不良反应。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Because of their paramagnetic properties, solutions of organic gadolinium complexes and gadolinium compounds are used as intravenous radiocontrast agents to enhance images in medical magnetic resonance imaging. Gadolinium has been used for years in adults and children in the United States, Europe and Japan, without any serious complications in thousands of patients. The FDA declared Gadolinium safe for use in MRI in 1988. However, a few side effects, such as mild headache, nausea and local burning can occur. Caravan and colleagues have recently found that patients with severe kidney dysfunction are susceptible to "nephrogenic systemic fibrosis" if they get gadolinium based MR contrast. Their results indicate that in human subjects, Gd is particularly rich in the kidney and heart. A fundamental understanding of how Gd interacts with these tissues will be crucial in determining the molecular origin of Gd toxicity in these patients. We believe that surveying Gd in regions of heart and kidney tissue using XANES and EXAFS is the most appropriate first step in this unique experimental opportunity, which could potentially have a large impact on translational research. We wish to determine the local coordination environment of Gd in tissue from autopsy samples and compare these results to likely biological Gd models, such as Gd phosphate, Gd sulfate, and the organic Gd contrast agent. From these data, we will be able to clearly determine if and how the Gd contrast agent is chemically altered in kidney and heart tissue. Changes in Gd coordination and/or oxidation state could potentially lead to the adverse effects observed in the Caravan lab.