Nephrogenic systemic fibrosis: a serious adverse reaction to gadolinium – 1997–2006–2016. Part 1

The first magnetic resonance (MR) scanners for imaging the human body became commercially available in the early 1980s. Early in the development of magnetic resonance imaging (MRI) it was believed that contrast medium would not be necessary because of the good soft-tissue discrimination obtained, but before long it became obvious that contrast agents could provide additional diagnostic information. Currently, up to nine gadolinium-based agents are available in most countries (Table 1). Six agents are distributed in the extracellular fluid and are excreted by glomerular filtration. The remaining three agents are so-called organspecific, protein-binding, or high relaxivity agents. The currently available gadolinium-based contrast media are only approved for intravenous injection, not for intra-arterial or intra-cavitary injection. Because MRI has better soft tissue resolution than computed tomography (CT), the extracellular MR contrast agents are on average only used in one-third of the MR examinations whereas iodine-based contrast media are used for around two-thirds of CT examinations. Also the molar dose used for an average MR examination is approximately eight times lower than for CT. Since gadolinium-based contrast agents were introduced, there have been rapid developments, both in MR techniques and in the use of these agents, which could not have been foreseen when most of the agents were developed and underwent testing (phase I to III trials). In the early 2000s gadolinium-based contrast agents were considered to be one of the safest drugs on the market and were used rather liberally, even in patients with poor renal function. However, like all drugs, gadolinium-based contrast media may cause adverse events. Adverse events are divided into acute (within 60min the exposure to the contrast agent), late (from 1h to 7 days), and very late (occurring more than 7 days after the exposure to the agent) (1). Acute adverse events can be either generalized (systemic) or renal reactions. Generalized reactions may be mild, moderate, or severe. Moderate and severe reactions requiring medical treatment are infrequent (<0.2%) (2). Renal adverse reactions, often called contrast-induced nephropathy (CIN), are rarely seen after gadoliniumbased contrast media in the doses used for MRI (3). In 2006, it became apparent that some gadoliniumbased contrast media were responsible for a very late adverse reaction, nephrogenic systemic fibrosis (NSF) (4,5). In North America and Western Europe, NSF appears to have been eliminated by no longer using less stable gadolinium-based contrast agents in patients with reduced renal function, or, in some countries, by not using less stable agents at all. I have not been able to find any reports of NSF in the peer-reviewed literature, where the patient received the agent after 2009; however, the lack of cases in the peer-reviewed literature does not exclude that there are cases (5). The aim of this review is to bring the reader up to date on this devastating very late adverse reaction, which, up until now, is estimated to have affected around 10,000 patients with reduced renal function since 1997 (6).