Cell Injury Involving Transmetallation of Gadolinium Based MRI Contrast Agents
EMSL Project ID
40115
Abstract
This EMSL user proposal is directly responsive to Biological Interactions and Dynamics Science Theme. The work involves the fundamental studies on the heterogeneity in cell composition and response to alterations in cell conditions as a result of introduction of important chemicals to a rodent model. Such chemicals are gadolinium based contrast agents, commonly used in magnetic resonance imaging (MRI) procedures. Gadolinium based contrast agents have recently been linked to an emerging fetal disease Nephrogenic Systemic Fibrosis (NSF), which affect patients with renal impairment. NSF is a progressive, debilitating disease with increased morbidity and mortality. In 2007, the FDA issued a box warning regarding all gadolinium-based contrast agents to inform consumers about the risk of developing NSF in patients with severe kidney insufficiency, liver transplant patients (both before and after), or those with chronic liver diseases. This warning has affected 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 less enthusiastic to administer any type of Gd based contrast agents to patients with any level of renal impairment. This makes it difficult for clinicians to obtain high resolution imaging for patients with renal insufficiency. Thus, NSF has become an important problem to the U.S. and around the world. The mechanism of how exposure to gadolinium based contrast agents triggers the development of NSF is not clear, but NSF appears to be associated with the gadolinium ion rather than a specific Gd based contrast agent. Gd based contrast agents are chelates of Gd which protects against the toxicity of free Gd when injected into the vascular tree. With normal renal function, the half-life of Gd is ~2 hours, with loss of renal function the half-life is prolonged reaching extremes of 34 hours in CKD stage 5 patients. The combination of a prolonged half-life plus the identification of free Gd in skin and other organ tissues has lead to a proposed mechanism of tissue injury which involves transmetallation. Basically, transmetallation would involve the displacement of Gd from it chelate by competing cations, especially zinc (Zn2+) and iron (Fe3+ ), although other metals like calcium (Ca2+) and copper (Cu2+) have not been ruled out. In order to understand how the cell injury of NSF disease is linked to the transmetallation processes in cells, the EMSL's Electron Microscopy resource along with the expertise of EMSL staff (Ms. Alice Dohnalkova) is requested to augment our recently funded NIH project. The parent project, entitled 'Nephrogenic Systemic Fibrosis: A Rodent Model for Therapeutic Intervention', and R01 project funded from 2010-2014 (PI: Yantasee) by the National Institute of General Medical Sciences (NIGMS).
Project Details
Project type
Large-Scale EMSL Research
Start Date
2010-10-12
End Date
2011-10-16
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Chouyyok W, RJ Wiacek, K Pattamakomsan, T Sangvanich, RM Grudzien, GE Fryxell, and W Yantasee. 2010. "Phosphate Removal by Anion Binding on Functionalized Nanoporous Sorbents." Environmental Science & Technology 44(8):3073-3078. doi:10.1021/es100787m
Yantasee W, GE Fryxell, GA Porter, K Pattamakomsan, V Sukwarotwat, W Chouyyok, V Koonsiripaiboon, J Xu, and KN Raymond. 2010. "Novel sorbents for removal of gadolinium-based contrast agents in sorbent dialysis and hemoperfusion: preventive approaches to nephrogenic systemic fibrosis ." Nanomedicine 6(1):1-8. doi:10.1016/j.nano.2009.05.002