NSF: Still relevant

In 2006, the overwhelming majority of radiologists including myself were shocked by the news that a contrast agent, that most of us believed was very safe, could cause nephrogenic systemic fibrosis (NSF). NSF is a delayed adverse contrast reaction which may cause severe disability and even death. Within two years, it became clear that 1) patients at risk were those with reduced renal function (particularly in patients with a glomerular filtration rate [GFR] below 15 mL/min 1.73 m2 or on dialysis) 1, 2; 2) gadodiamide was the agent that had been used in most cases of NSF (∼85%) 3, 4; 3) the severity varies (from a plaque to nearly universal fibrosis (the head is spared)) 1, 5; 4) the incidence was between 3 and 18% (low figures: based on figures from registries 1, 2, 6; high figures: based on direct inspection of the patient's skin, particularly the lower extremities) 1, 2, 7; 5) this side effect was dose-related, but has occasionally been described following a single dose 2, 8. Around 1600 cases have been reported to the Food and Drug Administration (FDA) as of the date of publication. Four percent came from Denmark and 93% from the U.S. These 1600 cases, however, likely only represent the tip of the iceberg. Denmark is the only country in the world where a national investigation is looking after living patients with NSF. The incidence was 20 patients per 1 million inhabitants 9. If this figure is extended to Europe and North America, the figure for patients suffering from NSF is probably close to 10,000 patients when all degrees of NSF are included 10. The use of gadolinium-based contrast agents decreased quickly, and restrictions on use, particularly in patients with reduced renal function, was introduced. "Nothing" became the most frequently used agent in patients with a GFR below 30 mL/min 1.73 m2 and at some institutions a cutoff level for use of gadolinium-based contrast was even set at 60 mL/min 1.73 m2. Despite the increased knowledge regarding NSF, the greater frequency of non-enhanced studies has continued (according to the number of raised hands as a response to various questions at scientific meetings). Even in Europe, where the authorities contraindicated the use of gadodiamide, gadovertisamide, and gadopentetate dimeglumine in patients with reduced renal function in 2007 11, and stated that they should only be used with caution in patients with moderately reduced renal function, "nothing" is still a frequently used drug. The three high-risk agents are also contraindicated in neonates and pregnant women 11. In Europe, it is also cumbersome to use the three agents, as you must measure the renal function by laboratory measurements prior to administration, but they are still used in some European countries. In Denmark—the country with the highest number of NSF cases (∼100 cases plus those patients who died between 1997 and 2009 without having the diagnosis established in a population of 5.5 million)—no high-risk agent has been used since 2008; even gadopentetate dimeglumine and gadovertisamide are no longer available on the Danish market. Have we seen the last case of NSF? Probably not. No cases where the patient got gadolinium-based contrast medium have been published after 2009 in the peer-reviewed literature yet, but outside the meeting rooms there is often one who knows a case. A patient can develop NSF many years after exposure to a less stable agent 2; it is not fair to report such cases as "new" cases. It is well known that less stable agents might be used by mistake in patients with poor renal function despite the fact that they are contraindicated. In a French study, six patients received a contraindicated product 12. If a patient develops NSF when the agent was not used properly by accepted guidelines, the marketing authorization holder (MAH) and the local authority have no responsibility. A radiologist who has used a contraindicated agent will be held legally responsible. Will he or she follow the patient or just hope for the best? Will the nephrologist think of NSF when the patient complains about a skin lesion? The best way to avoid the risk of NSF is to not have high-risk agents at the department. Contrast-induced nephropathy after exposure to iodine-based contrast media has been known for more than 60 years, but despite several experimental and clinical studies, the pathophysiology of contrast-induced nephropathy is still unclear: chemotoxic effects on the tubular cells, balance between vasoconstrictors and vasodilators, etc. There are still several theories 13. For NSF the same is not the case. Here the world is divided into two groups: 1) an overwhelming majority who believe that transmetallation has a major role, if not the pivotal role in the development of NSF 1, 2; 2) a much smaller minority who still believe that NSF is a result of exposure to both ion and ligand 14. That ions from the lathanide group in the periodic table could change the collagen was reported in 1982 15, the toxicity of all lathanides was well described in a book published in 1989 16, the fact that gadodiamide caused lesions which were not found after exposure to gadopentetate dimeglumine 17, and transmetallation was mentioned for the first time in 1988 18. So if somebody had sat down and looked at the puzzle at the end of the last century, we might have avoided several cases of NSF. Although there were warnings, they came only to the attention of a very small group of researchers. There are several things to learn from that history, particularly for the authorities, so we can avoid a repetition. It is our mission to provide safe diagnostic examinations that can rule out the suspicion of an abnormal lesion or confirm its presence, not to injure or disable our patients. The editor of this prestigious journal asked me "NSF: still relevant?" My opinion is not shared by all, for sure, but in my opinion the answer to the question is yes, if we stop stocking the higher-risk agents, and follow the ESUR recommendation: "in all patients use the smallest amount of contrast medium necessary for a diagnostic result." We should never deny a patient a clinically well-indicated enhanced-magnetic resonance imaging (MRI) examination independent of renal function. And, finally, do not forget, "always record the name and dose of the contrast agent used in the patient records." It will be helpful, as cases of NSF might show up in the distant future due to small accumulations of gadolinium from the least stable agents. Recently, environmentalists reported increasing amounts of gadolinium in water from large cities 19. It seems like the last word has not been said in the gadolinium debate. On the other hand, no other ion has yet been shown to be as effective (cause most relaxivity per ion at 1.5T) for enhancement during MRI. Henrik S.