Since 2006, when the association of gadolinium-based contrast agents (GBCAs) with nephrogenic systemic fibrosis (NSF) was first recognised, there has been a restructuring of the practices within the radiologic community as it has attempted to identify a means of preventing the development of this disease. During these past three to four years, the radiologic community has seen certain opinions, ideas, and practices come and go.

Some initial thoughts have proven incorrect, while others have been almost uncannily on the mark.

The past

Since 2006 much has been published regarding the role of GBCAs and the development of NSF in patients with significant renal disease. It has been noted for some time that there were more NSF-related research studies than cases of NSF.

However, all recognised that, rare as it is, NSF was a serious disease with no reliable known cure. It was known it can involve the entire body, including the skin, heart, diaphragm, testes, dura, etc., but, interestingly, seemed to spare the brain parenchyma itself – as if, perhaps, the blood brain barrier offered some sort of protection.

NSF seemed almost always to be associated with a prior GBCA administration, while higher doses were recognised as being associated with a greater likelihood of NSF development.

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“It appears there have been very few if no new cases of NSF diagnosed worldwide in roughly two years.”

It was known the disease was found in patients with severe or end-stage chronic kidney disease (CKD), and that most, but not all, were dialysis patients. Initially it was believed the disease was linked only with Omniscan, but within a year there were also cases connected with prior Magnevist and Optimark administration. Some were concerned the disease was a class association, and might be associated with any GBCA at possibly equivalent likelihoods, while others felt the links with Omniscan and possibly Optimark were far greater than with any of the other agents.

The American College of Radiology (ACR), through its ACR Guidance Document for Safe MR Practices: 2007, took the initiative and recommended screening patients who were at greater risk of renal disease. When significant renal disease was identified, it was recommended that reconsideration be given as to whether GBCAs were actually required at all.

If it was deemed clinically desirable to administer a GBCA, it was recommended to use the lowest dose absolutely required – e.g. half dose – to attain the diagnostic objective.

It was recommended that Omniscan – and some felt Optimark and perhaps even Magnevist – should not be used in patients with significant renal disease, and that macrocyclics or possibly lower dose Multihance (with its higher relaxivity) be used instead.

It was recommended that hemodialysis patients who were administered GBCAs undergo immediate hemodialysis following the MR examination for which the GBCA had been administered, and that this be repeated daily for the next few days.

In Europe and in other locations, Omniscan, Optimark, and Magnevist were outright contraindicated in patients with severe renal disease.

In the meantime, hundreds of lawsuits have been filed by patients, almost entirely against the pharmaceutical firms who produced these agents.

The present

It is accepted that between 10-20% of all NSF cases are in patients who were in acute renal failure, and not just those with CKD. Furthermore, although the vast majority of NSF cases in CKD patients are in those with end-stage renal disease (i.e. CKD stage 5), NSF can also be found in patients with CKD stage 4, and even in patients with CKD stage 3.

As the vast majority of diseases manifest bell-shaped population distribution curves, it would be unlikely there would be a sharp estimated glomerular filtration rate (eGFR) cut-off above which the disease incidence precipitously drops to zero.

Initial reports of patients with NSF yet with no history of prior GBCA administration were followed by reports of high gadolinium levels in the tissue biopsy of these patients. Considering that prior GBCA administration history is nearly ubiquitous in NSF patients, this lent even further strength to the argument that GBCA administration was indeed necessary – but not sufficient – for the development of NSF.

Today’s recommendations and practices almost universally acknowledge an increased risk of developing NSF in renal disease patients who receive linear GBCAs as compared to those who receive macrocyclic ones. The US Food and Drug Administration (FDA) has chosen to treat all the (FDA-approved) GBCAs equally, and has provided a black box warning (which indicates a drug may cause serious adverse effects) clarifying a perceived risk of developing NSF after the administration of any GBCA, with no black box content differentiation whatsoever in regards to frequency on NSF development following administration of the various GBCAs.

(Their 23 May 2007 Public Health Advisory on this issue does mention that when a specific agent had been named, more cases had received Omniscan, then Magnevist, then Optimark. Also the author is not aware of any regulatory agency or scientific/societal body in the world that has agreed with this opinion, and has even gone so far as to publish in the peer-reviewed literature a commentary strongly disagreeing with the FDA’s approach that attempts to suggest that the NSF-related risks among the various GBCAs is equivalent.)

Meanwhile, there appears to be biopsy-confirmed cases of NSF developing after prior isolated administrations of Omniscan, Magnevist or Optimark (in order of frequency), yet no biopsy-confirmed cases of NSF reported in the world with a history of isolated prior Dotarem, Gadovist, Multihance, Primovist, Prohance, or Vasovist administration.

If, today, it is felt necessary to administer a GBCA to a patient who is perceived to be at higher risk for NSF, the vast majority seem to be given macrocyclic GBCAs (Dotarem, Gadovist, or Prohance) or lower dose Multihance, taking advantage of its higher relaxivity.

Most importantly, however, it appears there have been very few if any new cases of NSF diagnosed worldwide in roughly two years.

“To this day we still have no actual proof what causes NSF and the role GBCAs play.”

This suggests that in less than two years since the initial association of NSF with GBCA it has been possible to alter practices sufficiently to almost, if not entirely, preclude the development of new cases. This is a strong testament to the ability of the medical community to rapidly disseminate new information, which is in no small part attributable to the power of the internet today.

What has changed in the past few years that has resulted in this impressive near-eradication of new NSF cases? Polling the MR community reveals that there have been three major practice alterations since this GBCA-NSF association was first identified.

Interestingly, all three behavioural modifications undertaken by the MR community worldwide were those recommended in early 2007 in the American College of Radiology Guidance Document for Safe MR Practices: 2007. These include:

Prospective patient screening to determine eGFR calculations prior to GBCA administration.

Avoiding GBCA administration, or administering lower doses, to patients with significant renal disease.

Changing the administered GBCA brand from those perceived to be more associated with NSF to those that are perceived to be significantly less so associated.

It is not known which, or which combination, of the above has yielded this cut in observed new NSF cases since these modifications were clinically implemented worldwide in mid-2007. Indeed, it may specifically be the combination of these three that has specifically resulted in this near eradication of new NSF cases.

The future

There are some several possible outcomes for the future of the industry.

Some have already questioned whether we need to continue screening patients. After all, they claim, there are no new cases, so perhaps the disease has been eradicated.

This is akin to suggesting that anti-malarials are no longer required for those travelling to high-risk locales since those who have taken them in the past have not come down with the disease. Ordinarily, this suggestion would not be worthy of a response.

However, considering the present financial crisis and the attempts to rein-in costs, it has arisen from some otherwise quite reputable individuals. However, common sense should prevail, and while we might discover new ways to screen patients or methods of verbal screening that might prove as reliable as eGFR determinations, prospective patient screening is here to stay – as well it should be. Indeed, what is needed now is the development of a reliable means for screening patients with clinically undetected acute renal failure.

This population has been demonstrated to be able to develop NSF despite the lack of prior renal disease history and even with rapid renal function recovery within a few weeks following the GBCA administration.

Reliance on ‘CKD stage 3’ or ‘30 mL/min/1.73 m2’ as a sharp cut-off above which NSF cannot occur will finally be recognised as inappropriate. Nephrologists know that patients with eGFR values of 30 are quite different from those with 59, despite both being classified as CKD stage 3.

“10-20% of all NSF cases are in patients who were in acute renal failure.”

Radiologists are an intelligent lot, and will recognise the need to focus not on an artificially classified ‘stage’ but rather the measured eGFR for decision-making purposes.

Total prior cumulative dose monitoring might be deemed warranted for patients with significant renal disease.

Agent selection will continue to play a major role in NSF case development. Human nature being what it is, future cases of NSF could develop after administration of agents that are perceived to be at a greater risk for the development of NSF.

The resultant well-publicised lawsuits will almost certainly discourage future usage of these agents in the general population, not just those perceived to be at higher NSF associated risk.

Administered GBCA doses will continue to decline. While high-dose administration for specific patients can be defended where subtle pathologic processes need to be accurately detected and/or quantified, much of diagnostic imaging will suffice with decreasing doses.

This will be further potentiated by present and new higher relaxivity agents that produce similar levels of contrast enhancement and lesion detectability with smaller doses of administered gadolinium ion.

Finally, the number of lawsuits against pharmaceutical firms will decrease to zero as existent cases are settled. Physicians and sites will continue to increasingly become the targets of new lawsuits alleging malpractice in GBCA administration.

This is even more likely if NSF results after GBCA administration in the setting of clinically unrecognised acute renal failure, or if a perceived higher risk agent is accidentally administered to a patient with known significant renal disease, or if a site chooses to stop screening patients for renal disease and administers a perceived higher risk agent to a patient with significant CKD.

To this day we still have no actual proof as to what causes NSF and the role GBCAs play. Undeniably, however, a mainstream opinion has emerged as to the relationship between the two, and that is the theory of transmetallation/dissociation, the release of the gadolinium ion from its ligand molecule, and sequelae thereof.

“The US Food and Drug Administration (FDA) treats all the (FDA-approved) gadolinium-based contrast agents equally.”

Mainstream thinking certainly does not constitute any sort of proof per se.

Nevertheless, in this exceptionally litigious NSF environment (at least in the US), one would be well advised to have very clear and defendable reasons for not following commonly accepted practices and opinions should NSF develop after alternate practices were followed.

We have been most fortunate to see the near disappearance of NSF just a few years after its association with GBCAs was first recognised. This almost certainly resulted from significant modifications in how the MR community has approached GBCA administration to patients with potentially significant renal disease.

With intelligent continued application and refinement of these same guidelines, we may be able to proudly claim our share in helping to eradicate this rare but most serious disease.

Lawsuits target radiologists

The lawsuits filed today have a different target. As opposed to the initial battery of suits that were almost exclusively aimed at the pharmaceutical firms providing these GBCAs, more recent legal actions are now almost universally naming the radiologists and the sites who administered these agents. Since the issuance of warnings by the pharmaceutical firms and the black box warnings in all GBCA product labels in the US, the pharmaceutical companies can now clearly state that they have warned people about the risks. At this stage it would appear difficult to hold them responsible for any new NSF case that might develop. After all, it is now a recognised possible associated adverse event of which the prescribing physician must be aware in their risk-benefit analysis prior to administering these agents. Therefore, should a new case of NSF result today, it is quite clear the decision-making process as to why the agent was given, how much was given, and specifically which agent did the site elect to administer, will be held up to extreme scrutiny.