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

描述(由申请人提供)：这份R01提案侧重于一种新出现的疾病，肾源性系统性纤维化(NSF)，它影响严重肾损害的患者。NSF是一种进行性、衰弱的疾病，发病率和死亡率增加，并与磁共振成像(MRI)中使用的基于Gd的造影剂的暴露有关。2007年FDA关于所有基于Gd的造影剂在发展NSF过程中的风险的盒子警告可能会影响大量患者(例如，2007年仅在美国就进行了大约2750万次MRI手术，其中43%使用基于Gd的造影剂作为成像程序的一部分)。目前，放射科医生对任何程度的肾损害患者都不愿使用任何类型的Gd造影剂，这使得临床医生很难为肾功能不全患者提供高分辨率的成像。很少有研究依赖动物模型来研究基于Gd的造影剂如何触发NSF，但研究中使用的肾功能正常的大鼠无法代表肾功能衰竭的患者，这是大多数NSF病例的一种预先存在的疾病。目前，NSF还没有有效的治疗方法，因此唯一推荐的行动是血液透析，从血液中去除Gd造影剂。然而，缺乏血液透析疗效的证据。我们提出的工作具有创新性，因为它将利用慢性肾功能衰竭(CRF)大鼠模型来研究基于Gd的造影剂引发的NSF，然后应用我们基于先进功能材料的新去孔法从动物体内去除Gd造影剂。具体地说，一旦通过腺嘌呤剂量建立了慢性肾功能衰竭(CRF)大鼠模型，将研究这些动物的NSF疾病与剂量依赖关系、基于Gd的造影剂的化学结构以及其他本土金属的参与。将研究基于Gd的造影剂的药代动力学，以便通过新的去孔法和血液透析方法来优化去除策略。这两种方法的有效性将从降低血液和组织中的Gd含量以及预防动物的NSF发病率方面进行评估。这项研究直接回应了PA-08-251：医药中的金属，因为它涉及“合成无机络合物与生命系统及其成分的相互作用”，以及“金属络合物和金属螯合剂的诊断和治疗应用”。通过太平洋西北国家实验室(PNNL)的领先无机化学家、物理学家和毒理学家与俄勒冈健康与科学大学(OHSU)的皮肤病理学和肾脏病专家的合作，我们的研究团队具有研究NSF机制和预防方法的独特能力。这项拟议的工作也与国家普通医学科学研究所(NIGMS)的使命很好地一致，NIGMS的使命是“支持作为疾病诊断、治疗和预防基础的研究”。 公共卫生相关性：该项目旨在了解磁共振成像(MRI)中使用的基于Gd的造影剂是如何引发一种新的新兴疾病-肾源性系统性纤维化(NSF)的，以及如何通过一种新的血液去孔法有效地预防它，从而使基于Gd的造影剂能够继续用于肾功能不全患者。

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.