Nephrogenic Systemic Fibrosis (NSF): A Rodent Model for Therapeutic Intervention

描述（由申请人提供）：本R01申请关注一种新出现的疾病——肾源性系统性纤维化（NSF），它影响严重肾功能损害患者。NSF是一种进行性、衰弱性疾病，发病率和死亡率增加，与磁共振成像（MRI）中使用的钆（Gd）造影剂暴露有关。2007年FDA关于所有钆基造影剂在NSF发展中的风险的方框警告可能会影响大量患者（例如，仅在美国2007年估计就进行了2750万例MRI手术，其中43%使用钆基造影剂作为成像程序的一部分）。目前，放射科医生对于给任何程度肾功能损害的患者使用任何类型的Gd造影剂都犹豫不决，这使得临床医生难以获得肾功能不全患者的高分辨率成像。很少有研究依靠动物模型来研究Gd造影剂如何引发NSF，但研究中使用的肾功能正常的大鼠不能代表肾功能衰竭的患者，肾功能衰竭是大多数NSF病例的预先存在条件。目前，NSF没有有效的治疗方法，因此唯一推荐的行动是血液透析，以去除血液中的Gd造影剂。然而，缺乏血液透析疗效的证据。我们提出的工作是创新的，因为它将利用慢性肾衰竭（CRF）大鼠模型来研究Gd类造影剂引发的NSF，然后应用我们基于先进功能材料的新型脱孔方法从动物体内去除Gd类造影剂。具体来说，一旦腺嘌呤给药产生慢性肾衰竭（CRF）大鼠模型，这些动物的NSF疾病将作为Gd基造影剂的剂量依赖性和化学结构的功能以及其他天然金属的参与进行研究。将研究Gd基造影剂的药代动力学，以优化新型脱孔和血液透析方法的去除策略。两种方法的效果将从降低动物血液和组织中Gd含量和预防NSF发生的角度进行评估。这项研究直接响应了PA-08-251：医学中的金属，因为它涉及“合成无机配合物与生命系统及其组分的相互作用”以及“金属配合物和金属螯合剂的诊断和治疗应用”。通过与太平洋西北国家实验室（PNNL）领先的无机化学家、物理学家和毒理学家以及俄勒冈健康与科学大学（OHSU）的皮肤病理学和肾脏病学专家的合作，我们的研究团队具有独特的研究NSF机制和预防方法的能力。提议的工作也与国家普通医学科学研究所（NIGMS）的使命相一致，即“支持作为疾病诊断、治疗和预防基础的研究”。

DESCRIPTION (provided by applicant): This R01 proposal focuses on a new emerging disease, Nephrogenic Systemic Fibrosis (NSF), which affects patients with severe renal impairment. NSF is a progressive, debilitating disease with increased morbidity and mortality and has been linked to exposure to gadolinium (Gd) based contrast agents used in Magnetic Resonance Imaging (MRI). The 2007 FDA's box warning regarding the risk of all gadolinium-based contrast agents in developing NSF may affect a large number of patients (e.g., an estimated 27.5 million MRI procedures were performed in 2007 in the U.S. alone and 43 percent used Gd based contrast agents as part of the imaging procedure). At present, radiologists are hesitant to administer any type of Gd based contrast agents to patients with any level of renal impairment, which makes it difficult for clinicians to obtain high resolution imaging for patients with renal insufficiency. Few studies have relied on animal models to study how Gd based contrast agents trigger NSF, but rats with normal kidney function used in the studies fail to represent patients with renal failure, a pre-existing condition for most NSF cases. Currently, there is no effective treatment for NSF, thus the only recommended action is hemodialysis to remove the Gd contrast agent from the blood. However, proof of hemodialysis efficacy is lacking. Our proposed work is innovative because it will utilize a chronic renal failure (CRF) rat model to study NSF that is triggered by Gd based contrast agents, followed by applying our new decorporation method based on advanced functional materials to remove the Gd contrast agent from the animals. Specifically, once the chronic renal failure (CRF) rat model is produced by adenine dosing, NSF disease in these animals will be studied as a function of dose-dependency and chemical structures of Gd based contrast agents as well as involvement of other indigenous metals. Pharmacokinetics of the Gd based contrast agent will be studied in order to optimize the removal strategies by both novel decorporation and hemodialysis methods. The efficacy of both methods will be assessed in terms of the reduction of blood and tissue Gd content and the prevention of NSF incidence in the animals. This research is directly responsive to PA-08-251: Metals in Medicine, since it involves "the interactions of synthetic inorganic complexes with living systems and their components" as well as "diagnostic and therapeutic applications of metal complexes and of metal chelators." Through the collaboration among leading inorganic chemists, physicist, and toxicologist at the Pacific Northwest National Laboratory (PNNL) and experts in dermatopathology and nephrology at the Oregon Health & Science University (OHSU), our research team is uniquely capable of studying both NSF mechanism and prevention approaches. The propose work also aligns well with the mission of National Institute of General Medical Sciences (NIGMS), which is "Supporting research that is the foundation for disease diagnosis, treatment, and prevention." PUBLIC HEALTH RELEVANCE: This project aims at understanding how a new emerging disease, Nephrogenic Systemic Fibrosis (NSF), is triggered by gadolinium (Gd) based contrast agents used in Magnetic Resonance Imaging (MRI), and how to effectively prevent it with a novel blood decorporation method, thus allowing for the continued use of Gd based contrast MRI in patients with renal insufficiency.