The Biological Fate of Gadolinium-based MRI Contrast Agents: a Call to Action for Bioinorganic Chemists

Gadolinium-based contrast agents (GBCAs) are widely used with clinical magnetic resonance imaging (MRI), and 10 s of millions of doses of GBCAs are administered annually worldwide. GBCAs are hydrophilic, thermodynamically stable and kinetically inert gadolinium chelates. In clinical MRI, 5-10 millimoles of Gd ion is administered intravenously and the GBCA is rapidly eliminated intact primarily through the kidneys into the urine. It is now well-established that the Gd3+ ion, in some form(s), is partially retained in vivo. In patients with advanced kidney disease, there is an association of Gd retention with nephrogenic systemic fibrosis (NSF) disease. However Gd is also retained in the brain, bone, skin, and other tissues in patients with normal renal function, and the presence of Gd can persist months to years after the last administration of a GBCA. Regulatory agencies are restricting the use of specific GBCAs and inviting health care professionals to evaluate the risk/benefit ratio prior to using GBCAs. Despite the growing number of studies investigating this issue both in animals and humans, the biological distribution and the chemical speciation of the residual gadolinium are not fully understood. Is the GBCA retained in its intact form? Is the Gd3+ ion dissociated from its chelator, and if so, what is its chemical form? Here we discuss the current state of knowledge regarding the issue of Gd retention and describe the analytical and spectroscopic methods that can be used to investigate the Gd speciation. Many of the physical methods that could be brought to bear on this problem are in the domain of bioinorganic chemistry and we hope that this review will serve to inspire this community to take up this important problem.