A new risk for patients with chronic kidney disease
From the May ACP Observer, copyright © 2007 by the American College of Physicians.
In 1997, a few physicians began noticing a new skin disorder among renal transplant recipients. This previously unrecognized disease was named nephrogenic fibrosing dermopathy, but little was known about it except that it occurred only in patients with chronic kidney disease.
Last year, researchers uncovered a definitive link between the disease and exposure to gadolinium, a common contrast agent in magnetic resonance imaging (MRI) studies. The discovery prompted the FDA to issue a public health advisory in June warning physicians about the risks of using gadolinium in patients with chronic kidney disease. The CDC followed, publishing an investigation and recommendation in February.
Mark A. Perazella, FACP, is an expert on the disease, now known as nephrogenic systemic fibrosis (NSF). As an associate professor of medicine at Yale University, he works with researchers who are collecting cases in the NSF Registry and trying to uncover more information about this new, debilitating disease. He recently shared some of his insights with ACP Observer.
It's a very horrendous disease with no effective therapy, and it is associated with extensive morbidity and mortality.
Q: What is NSF?
A: NSF is characterized by severe dermal fibrosis, which is associated with joint contractures and limitations in mobility that often cause a wheelchair-dependent or bed-bound state. It's also been known to involve systemic organs, hence the name NSF. It's a very horrendous disease with no effective therapy, and it is associated with extensive morbidity and mortality.
The vast majority of patients that develop NSF are dialysis-dependent, although it has also been described in patients with advanced CKD [chronic kidney disease] not yet on dialysis—stage 4 and 5 CKD—and those with acute kidney injury sometimes requiring dialysis.
Q: How common is it?
A: It's not that common. In the U.S., we probably have over 400,000 patients on dialysis, and if you add everything up, there are probably over 200 to 300 cases [of NSF], but I think the greater concern is that it's such a devastating complication that is currently not treatable.
The scary part is that it's occurring with an increased frequency. Now whether there's a bias because more physicians are recognizing it or in fact that gadolinium exposure has increased or some combination thereof, it's hard to know for sure.
Q: What evidence is there linking NSF to gadolinium?
A: There have been a total of 35 cases published in the medical literature. The NSF registry at Yale, with over 215 patients, confirms the association of gadolinium exposure to development of NSF, as all patients with data available for analysis received this contrast agent prior to development of the disease.
Prolonged tissue exposure to gadolinium, a common MRI agent, can lead to a skin and tissue damage in patients with chronic kidney disease, whose kidneys are less able to excrete the toxic element.
Three recent studies have documented free gadolinium levels in the tissue of patients with NSF. One of these notes that concentrations are 35- to 150-fold higher than the level of gadolinium retained in the bone of healthy volunteers with normal kidney function. These data also strongly support the association.
Q: What precautions should physicians take in ordering MRIs for patients with kidney disease?
A: MRI studies without gadolinium entail no risk of NSF. MRI studies with gadolinium engender no risk for NSF if the patient has normal kidney function.
End-stage renal disease patients on either hemo- or peritoneal dialysis are at highest risk and should avoid exposure to gadolinium if at all possible. Non-gadolinium options should be explored and employed when feasible. If an ESRD [end-stage renal disease] patient must receive gadolinium, use the lowest dose possible and avoid gadodiamide.
Patients with acute kidney injury and advanced stage 5 CKD who are not on dialysis are probably also at high risk. My opinion is to avoid gadolinium exposure. In those with moderately severe kidney disease [stage 4], the risk of NSF is currently unknown, but certainly not zero.
Q: What alternative procedures do you recommend?
A: Other modalities of study like ultrasounds, MRI without contrast and CT scan without iodinated radiocontrast are potential options. But often a CT scan with iodinated radiocontrast is required to visualize certain structures. In ESRD patients already on some form of dialysis, a CT scan with iodinated radiocontrast is preferred over gadolinium.
However, in patients with stage 4 and 5 CKD, the risk of radiocontrast nephropathy is significant. Realizing that you're weighing one problem against another, my approach is that in general the radiocontrast nephropathy is reversible and NSF is not, so I would recommend using low or iso-osmolar iodinated radiocontrast along with standard prophylactic measures such as intravenous fluids and N-acetylcysteine.
Q: The FDA advisory includes patients with moderate kidney disease. Should the same precautions apply to these patients?
A: In patients with moderate kidney disease [estimated GFR >30 ml/min <60 ml/min, CKD stage 3], the risk for NSF following gadolinium exposure is unknown. I think the FDA is basing the advisory on a handful cases that had an estimated GFR somewhere between 30 and 60, but those are really, really small numbers compared to the rest.
You can be very conservative and say we should not expose these patients. The problem is that's a huge number of patients and if we don't allow a gadolinium study we have excluded them from undergoing a potentially important test without truly knowing if there's a risk. I don't agree with the recommendation as there are not enough data to reach this conclusion. There's a little bit of controversy and non-agreement in the community about that statement.
Q: Is hemodialysis immediately after an MRI with gadolinium effective in preventing NSF?
A: Although hemodialysis after gadolinium exposure makes sense based on the pharmacokinetics of gadolinium, there are no data to support that it will prevent NSF. In fact, there are unpublished data that NSF has occurred after hemodialysis was performed following gadolinium exposure.
Hemodialysis effectively removes gadolinium, but requires three sessions to remove nearly 98% of the substance. Peritoneal dialysis poorly clears gadolinium. Unfortunately, there are no data to support that any form of dialysis will prevent development of NSF, making avoidance of exposure more critical for the time being.
Q: Is gadodiamide worse than other gadolinium agents?
A: That is unclear. The majority of NSF cases described have followed exposure to gadodiamide [brand name Omniscan]. However, gadodiamide was the only chelate used for MR studies by most of the NSF reporting centers, which makes it hard to compare NSF risk with other gadolinium preparations.
NSF has also been reported with other gadolinium-chelates-gadopenetetate, gadoversetamide, albeit at a much lower rate. All gadolinium formulations should be considered as having potential to cause NSF in patients with advanced kidney disease. However, gadodiamide is likely more risky.
Q: Have you uncovered why gadolinium causes NSF?
A: Not definitively, but we can speculate based on available associative data. One may speculate that underlying kidney disease predisposes to NSF by two mechanisms. The first factor is reduced excretion of gadolinium from impaired kidney function, which significantly prolongs tissue exposure to gadolinium in patients with advanced CKD. The second factor is endothelial dysfunction and leaky vascular endothelium allowing free gadolinium, which is released from its unstable chelate, to enter tissues.
Q: Why haven't any medical organizations issued guidelines regarding gadolinium use?
A: The association of NSF with gadolinium exposure has only come to light in the past six months. Cause and effect have not been proven. As the association has become stronger, the FDA has made recommendations and the CDC is putting out guidelines to regulate use of gadolinium in patients with kidney disease. Both U.S. and European radiology societies and the American Society of Nephrology are involved in this process.
Leading radiology and nephrology journals have published editorials on this subject. Many academic institutions including Yale, Johns Hopkins and the University of Pennsylvania have established guidelines for gadolinium use in patients with kidney disease.
Q: What is the next step is research on the subject?
A: The best way to follow this problem now is to examine the available data and see what are the potential cofactors. Continued observation of newly reported cases as they are recorded [in the NSF Registry at Yale, available online] and examination of potential factors is essential. It's clearly not just gadolinium. It's gadolinium plus something else. Just what the other factor is, it's not quite clear.
Researchers are in the process of creating an animal model, so they can actually test the various factors along with gadolinium to see what sets the fibrosing reaction of NSF into motion, which gadolinium agent causes it more often, and which cofactors are important.
An article on the link between gadolinium and NSF authored by Dr. Perazella was published in March Clinical Journal of the American Society of Nephrology, available online.
The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.
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