Indecent exposure: exploring the relationship between GBCA and NSF

Nephrogenic systemic fibrosis (NSF) was first described in medical literature in 2000. It is a systemic fibrosing disease, primarily involving the skin and subcutaneous tissues, but can affect other organs such as the lung, oesophagus, heart and skeletal muscles. It can cause contractures and joint immobility and, in some patients, prove fatal, while in others, symptoms can be relatively mild.

It is also recognised to occur predominantly in patients with end-stage chronic kidney disease (CKD), particularly those on dialysis. In 2006, a strong association was first noted between gadolinium-based contrast agent (GBCA) and administration in those with advanced renal disease. This year, the American College of Radiology (ACR) made clear in its latest guidance that "it is now generally accepted that GBCA exposure is a necessary factor in the development of NSF".

The drawbacks of GBCA

There is still much that's relatively unknown, unclear or not completely understood about the precise relationship between NSF and the different formulation of GBCA, however. According to Dr Archana Laroia, clinical assistant professor in cardiovascular and pulmonary imaging at the University of Iowa Hospitals and Clinics' department of radiology, and a member of the ACR Committee on Drugs and Contrast Media, this means education, communication and best practice around procedure and processes - for physicians and patients - are key tools in the management and reduction of the incidence of this troublesome disease.

"Since the 1980s, some two million MRI contrast media injections have been administered in the US, so it is a frequent way of imaging these days," she points out.

When, in 2005-06, the association between GBCA and NSF began to emerge, Laroia explains, the industry began to become aware that they were facing a serious issue. The FDA then became involved and now has more than 500 cases on its database. The scale of the problem worldwide is less clear, she admits, but is estimated to have between 2 and 6% prevalence.

"Typically, it is not seen in people whose renal function is normal; it has almost always been reported in association with chronic or late chronic kidney disease, especially among those who are on dialysis," says Laroia. "Almost all patients who have developed NSF had chronic kidney disease and about 80% of these had at some point received GBCAs - so it was relatively easy to put two and two together.

"The good news is that, since this has been recognised as an issue and people have become much more vigilant, the incidence rate has been going down. But have we pinpointed the exact causal relationships? No, we have not," she cautions.

"What is clear is that gadolinium-based contrast media is an issue when a patient's kidney function is not working regularly. Normally, a chemical-collating component is incorporated into the contrast media to ensure that the gadolinium is not released into the body and can be excreted easily in a non-toxic way through the normal renal function.

"But when a kidney is functioning at a low or sub-optimal level, or there is a high severity of kidney disease, the gadolinium can get disassociated from the collating agent and released into the body," she adds.

Proceed with caution

This is where screening comes into the mix, especially screening a patient for their renal function, testing their blood and carrying out an estimated glomerular filtration rate (eGFR) test. If this shows a level of around 30 or more (the ACR recommends 30-40ml/min/1.73m2) - showing stage three CKD or higher - then the patient should not receive GBCA.

"But, of course, clinical science is not black and white," acknowledges Laroia. "In some cases, it will be a question of the whole team - the radiologist, the treating surgeon and so on - sitting down and discussing what the options are. If there is no other option, then a gadolinium-based contrast media MRI screening may still be considered, ensuring the lowest possible dose is given.

"Another key element to the management of this issue is obtaining informed consent from the patient, with the emphasis being very much on 'informed'," she stresses. "So it is imperative that the patient knows and understands what is being proposed: the potential risks and, also, the potential benefits.

"It is important to treat the patient as an equal party, and only go ahead once they have agreed," she advises.

The FDA issued a safety statement in 2010, along with a comprehensive list of approved GBCAs. It also cautioned that contrast dosages not be repeated in the same study.

The treatment of NSF

The best way to tackle NSF is through prevention, particularly as the condition's course is so hard to predict and treat once acquired, emphasises Laroia.

"It is a disease that is very unpredictable in its course. Various treatment approaches have been tried - even kidney transplants - but so far we have only achieved mixed results," she says.

"If we do not have a good way to treat it then our top priority is to make sure we are preventing it, particularly through screening, best practice and education," she continues. "If, for example, the patient is on dialysis and does need a contrast agent MRI scan, then it is important to ensure they receive the lowest possible dose and are dialysed within 24 hours of the scan having taken place. It is about trying to help patients rid their bodies of the gadolinium through artificial means."

Another important factor, she reiterates, is education about MRI, contrast media and NSF in the form of training programmes at all levels.

"The practising radiologist needs to be aware of what they are doing in this context, of course, but so does the technologist administering and delivering the contrast agent, and any nurses involved. It is a question of constant vigilance," Laroia recommends. "Here at the University of Iowa, for example, we run education programmes around four times a year. We do an enormous amount of imaging at this hospital and so it is important we keep communicating and educating. We also go out into the community and give seminars to ensure patients understand contrast agents," she adds.

Laroia emphasises that the industry does not yet know everything about this evolving issue, and must keep raising awareness, educating people and monitoring what is happening around the world.

"We, for instance, now have well-recognised and systematic protocols in place in the US and Western healthcare systems, but elsewhere in the world, awareness is less prevalent," she says.

"This is a problem that appears to be decreasing, however, and our hope, of course, is that this trend will continue; we need to bring incidences down to the bare minimum possible. We are also optimistic that, at some point, a treatment for NSF will become available," Laroia concludes.