Improving Gadolinium-based Contrast Safety

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It is clear that gadolinium-based contrast agents (GBCA) for MRI improve detection (sensitivity), characterization (specificity), disease staging, and diagnostic confidence levels. It has also become clear that nephrogenic systemic fibrosis (NSF) is associated with their use in patients with preexisting kidney disease. For radiology, the challenge is to minimize the risk of NSF while retaining, when appropriate, the advantages of GBCA use.

GBCA Characteristics
GBCAs consist of an active element (gadolinium chelate), an added safety measure (an extra chelating agent) in some products, and a solvent (water). GBCAs increase reliability and may decrease examination times; this is particularly true in MR angiography. Increased signal (enhancement) on T1-weighted images is the result of GBCA’s ability to shorten the T1 relaxation time of nearby water protons.

GBCAs are administered intravenously at an injection rate of 1 to 5 mL per second, with the dose depending on the specific application, but typically 0.1 mmol/kg. This total dose of 15 to 30 mL is sometimes increased for MR angiography, for multiple examinations, or for imaging patients with brain metastases or multiple sclerosis.

On administration, GBCAs initially circulate in intravascular spaces, but they quickly leak through pores of vessels into extracellular spaces. They do not cross the normal blood-brain barrier. They are excreted primarily through the kidneys by glomerular filtration and have a half-life of about two hours in patients who have normal renal function; most are eliminated completely within a day.

GBCAs were commonly used in patients with kidney problems because they are less harmful to the kidneys (at standard doses) than the iodinated contrast used for CT. Patients in this category include those with renal insufficiency, diabetes, or vasculopathies, as well as the elderly (and, of course, dialysis patients).

In the United States, none of the GBCAs on the market have been approved for use in imaging the heart, breast, or musculoskeletal system, nor are they approved for intra-articular use, CT, or angiography (whether MR or conventional). Off-label use is permitted, as usual, if there are no explicit warnings or contraindications associated with the intended use and if that use meets the community standard of care.

The NSF Connection
NSF is a systemic disorder first recognized in 1997. Through skin swelling and tightening, NSF limits motion, leading to contractures and resulting in falls (with fractures and clotting complications). Burning, itching, and severe pain are among the symptoms, and the lungs, heart, muscles, and other tissues may become involved. Several deaths have been reported, and no effective therapy has been documented. The disease may develop over a protracted period, but about 5% of patients experience rapid progression.

As of May 2007, more than 250 cases of NSF had been reported to the FDA; by October 2007, 262 cases had been reported to the International NSF Registry at Yale University. The worldwide total of known cases is approximately 500.

It is important to bear in mind, when considering these figures, that millions of contrast-enhanced MRI procedures have been performed. In 2005, for example, about a third of the 31 million MRI procedures that were performed used GBCAs.

It appears that the individuals who experience NSF have serious kidney disease before they undergo imaging using GBCAs. Approximately 2% to 5% of patients with severe or end-stage renal disease who have received GBCAs have developed NSF, by most estimates (with one recent report1 indicating a much higher percentage). NSF has not been shown to be related to the cause or duration of patients’ serious kidney disease.

Almost all patients who have developed NSF have been exposed to high doses or repeated doses of GBCAs. The disorder appears to be distributed worldwide, with no incidence differences based on sex or race. Patients have ranged in age from 8 to 87 years. To date, six pediatric cases have been reported, although there have been no reports of NSF in neonates or infants.

In May 2007, an FDA request for a boxed warning to appear on GBCAs was issued to manufacturers. The agency noted that no cases of NSF had been reported in patients without serious underlying kidney disorders. The warning states that GBCAs should be avoided in imaging patients with estimated glomerular filtration rates (eGFRs) of less than 30 mL/minute/1.73 m2, with acute