INVESTIGATION OF GADOLINIUM CONTRAST AGENT TOXICITY BY X-RAY FLUORESCENCE MICROS

Stanford University, Stanford CA

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Abstract

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. Nephrogenic systemic fibrosis, or NSF, is a relatively new disease that experts have linked to the use of gadolinium-based contrast agents. The Food and Drug Administration first alerted the medical community and public about this link in June 2006, then again in December. In May 2007, the agency asked that the labeling of gadolinium-based MRI dyes be updated to include the risk of NSF in patients with kidney disease or insufficiencies. NSF is a highly debilitating and sometimes fatal scleroderma-like disease that occurs within patients with severe or end-stage renal failure. Though the molecular origin of the disease is currently not known, the connection between NSF and gadolinium MRI contrast agents lies in the observation that appreciable amounts of Gd have been found deposited in various organs, including the heart, kidneys, and liver (1), and in skin lesions (2) of NSF patients. Many hypotheses have been put forward regarding the mechanism of Gd toxicity in these patients (3) and the majority proposes the release of Gd3+ from its organic chelating ligand and subsequent interactions with Gd3+ the surrounding milieu. Preexisting renal failure may facilitate these processes by delaying the excretion of the Gd contrast agents. A fundamental understanding of how Gd interacts with tissues of NSF patients will be crucial in determining the role Gd plays in the molecular origins of this disease. A critical first step towards understanding the mechanism of Gd- induced NSF is understanding the detailed distribution of Gd.