Until last year, few side effects had been reported with Gadolinium-based contrast agents for MRI. In consequence, they were considered among the safest agents used in humans. However, in August of 2006 that changed. Then, a disease called Nephrogenic Systemic Fibrosis (NSF), which was first recognized in 1997, was reported to have developed in patients with impaired renal function who had received one of the MR contrast agents in common use, Gadodiamide.

Thus, it was only in 2006 that a connection between NSF and gadolinium contrast agents was established. This is an observation of interest and importance to patients with VHL given the frequent use of contrast enchanced MRI in their management. Although all the answers are not yet here we will present some of the questions surrounding NSF and the risks associated with it in patients receiving MRI contrast agents.

What is NSF?

NSF is a disease process that produces progressive fibrosis. Most commonly it involves the skin in which it produces sites of skin thickening that can be painful or itchy. If it occurs around the joints it can cause joint stiffening which can be disabling. In some cases, the fibrosis can involve the internal organs . In about 5% of cases this can lead to death due to progressive organ failure. Thus, when it occurs, NSF can be a serious condition.

Who is at risk for NSF ?

Most VHL patients who receive Gadolinium contrast agents are NOT at risk for NSF. This is because most patients with VHL have normal or nearly normal renal function and because NSF seems to occur almost exclusively in patients with very impaired renal function or who are on dialysis. In about 3-5% of patients with severely impaired renal function, NSF appears to develop within a few weeks to months after the administration of a Gadolinium contrast agent.

The gadolinium agent most frequently (90% of cases so far) associated with NSF has been gadodiamide or Omniscan made by GE Healthcare (formerly Amersham). However, reports are emerging of NSF occurring with other agents (Magnevist, Berlex Labs, Optimark, Mallinckrodt Labs) although as of this writing no cases have been associated with ProHance or MultiHance (Bracco); however, according to what is known now- it is important that a patient having an MRI scan be aware of the potential risk for NSF with any brand of gadolinium-based contrast agent.

How was the link between NSF and Gadolinium contrast agents discovered?

Reports began to emerge in 2006 about a link between gadodiamide and NSF. NSF was noted first in patients who were on dialysis and who received double or triple doses of gadodiamide for MR angiography studies, however, as attention was drawn to NSF, physicians started reporting NSF in patients who had received only a single dose of one of several gadolinium contrast agents.

What causes NSF ?

At this point, the cause of NSF following injection of Gadolinium contrast agents is unknown. One theory is that the Gadolinium ion may become separated from the rest of the contrast agent molecule to which it is bound and that the resulting “free”, unbound Gadolinium induces fibrosis. Indeed, some investigators have found “free” Gadolinium in the tissues of patients with NSF but this is only indirect evidence of the cause of NSF. Impaired renal function increases risk according to this theory since the kidney is the primary means by which gadolinium contrast agents are eliminated. Patients with impaired renal function take longer to clear Gadolinium contrast agents from their body once they are injected; the prolonged residence time of the agent in the body increases the chances of creation of “free” Gadolinium. This theory is plausible but there is little hard evidence to support it.

What levels of renal impairment predispose to NSF?

Patients on dialysis due to renal failure are at highest risk for NSF. Patients with impaired renal function not requiring dialysis may be at risk as well. The worse the renal function the higher the risk. The serum Creatinine value is a common measure of renal function and is common use, however most kidney specialists rely on the Glomerular Filtration Rate or GFR to define the level of renal function. This involves the collection of timed blood and urine samples. An estimate of GFR can be calculated from the serum Creatinine value by including patient age and weight. The official National Kidney Foundation system classifies “moderate” chronic kidney disease as a GFR between 30 and 59 ml/min/1.73 m 2, “severe” chronic renal disease as a GFR between 15 and 29 ml/min/1.73 m 2 and “end stage” chronic renal disease as a GFR < 15 ml/min/1.73 m 2 or on dialysis.

The FDA has stated that caution should be exercised in administering Gadolinium contrast agents to patients with moderately impaired to end stage renal function. Many feel this guideline is too conservative based on what is known today. Until more is known, however, it is the only official guideline. Several journal articles have been published or will be published stating that severely impaired or end stage renal function would qualify for a caution. Under the FDA guidelines in excess of one out of four Americans over age 70 could be excluded from receiving Gadolinium contrast agents because of a glomerular filtration rate (GFR, a measure of kidney function) of less than 60cc/min, and roughly 7.7 million Americans have a GFR between 30 and 60 (National Kidney Foundation). All VHL patients with GFRs indicating “moderately” and “severely” impaired renal function should this issue with their doctor to determine whether it is appropriate to receive gadolinium contrast agents. Until more is known, you and your physician must balance the benefits of the study against the risk of NSF.

Should VHL patients at risk for NSF have MRI with Gadolinium?

For the patient with VHL the question of the use of Gadolinium with MRI is one of weighing the risk of developing NSF versus the benefit of the diagnostic information that the contrast-enhanced MR images provide. Approximately 3-5% of patients with renal dysfunction who receive gadolinium develop NSF according to what is known today (March 2007). Clearly, in some cases the benefit of the MRI (e.g. from detection and accurate depiction of a brain or kidney tumor) outweighs the small risk of NSF. However, since the benefit of contrast-enhanced MRI varies among patients, each patient at risk for NSF should discuss the risks, benefits, and alternatives with her or his physician before proceeding with the MRI.

Can the patient get a CT scan instead of a MRI?

Unfortunately, CT contrast agents have their own problems when it comes to renal function. In patients with impaired renal function, iodinated contrast agents can lead to further damage to the kidneys. Therefore, for most patients with impaired renal function, contrast enhanced CT is not an alternative to contrast enhanced MRI.

Another question to be addressed is whether the MRI exam can be performed without Gadolinium-based contrast media. This is not a viable option for many patients since much of the diagnostic information provided by the MRI is obtained only by virtue of use of the contrast agent. However, it is always worth exploring this possibility.

If an MRI with Gadolinium is performed in a patient at risk for NSF, what can be done to reduce that risk?

Currently two basic approaches are available: i.e., reduce the patient’s exposure to the contrast agent and avoid agents with known higher risk. Whatever agent is used, the least dose necessary to complete the study should be used (e.g. half dose) and double and triple dosing should always be avoided. If a contrast enhanced MRI is performed in a patient with severely impaired renal function, it is recommended that hemodialysis (not peritoneal dialysis) be performed immediately after the MRI scan. The use of Omniscan should be avoided (Omniscan has been banned for use in patients on dialysis patients in Europe). At this time (March 2007) there have been no reports of NSF with the gadolinium agent ProHance (Bracco); hence, until evidence to the contrary emerges, its use may be something to consider in the patient at risk for NSF (But it is a safe assumption that eventually all of the available agents will be implicated with some degree of risk for NSF.

The “NSF Story” is constantly evolving and patients are well advised to check the literature on the web about developments. Until firmer guidelines are established this will be a difficult time for patients with VHL and renal impairment who need contrast enhanced MRI scans.

What resources are available for patients and their doctors to consult?

There is a growing list of on-line publications concerning NSF. They are written by experts in the field and may be useful in helping you sort through this problem with your doctor.

FDA guidance on the use of Gadolinium contrast agents in patients with impaired renal function:

http://www.fda.gov/cder/drug/advisory/gadolinium_agents_20061222.htm

The International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR), a clearinghouse of information on the subject,

http://www.pathmax.com/dermweb/

2007 Radiology article on NSF entitled “Nephrogenic Systemic Fibrosis: Risk Factors and Incidence Estimation ””

http://radiology.rsnajnls.org/cgi/content/full/2431062144v1

2007 AJR article on NSF entitled Gadiodiamide-Associated Nephrogenic Systemic Fibrosis: Why radiologists should be concerned”

http://www.ajronline.org/cgi/reprint/188/2/586

As printed in the VHL Family Forum 15:2, May 2007. For permission to reprint, please contact VHL Family Alliance, editor@vhl.org. Further information is available from the VHL Family Alliance, info@vhl.org.