With new research coming out, and many unknowns still remaining, finding the answer to contrast agent questions proves elusive.

The 2008 European Congress of Radiology (ECR), which took place in Vienna in early March, provided fresh occasion for debate over the contrast agent problem, with three new studies examining the relationship between gadolinium-based contrast agents and nephrogenic systemic fibrosis (NSF). Though all three studies hypothesized a correlation between administration of the contrast agents and the occurrence of NSF in patients with renal insufficiency, the breadth and severity of the issue are still in question.

“The only thing that’s clear at this point is that there’s still a lot of ambiguity and a lot of unknowns,” said Jeffrey Weinreb, MD, director of medical imaging, chief of body imaging, and chief of MR imaging at Yale University School of Medicine, New Haven, Conn. “It’s very hard under those conditions to create guidelines or standards. As information comes in, we have to be flexible.”

New Data on NSF

One of the ECR studies examined medical records of dialysis patients who received treatment at Emory University Hospital, Atlanta, over a 4-year period. The retrospective study identified nine patients with NSF, representing 2.6% of all dialysis patients who were exposed to gadolinium at some point during the 4-year time span. The only gadolinium-based contrast agent in use at Emory at the time was Omniscan from GE Healthcare, Waukesha, Wis.

“Not every patient who gets gadolinium develops NSF,” noted Thomas Lauenstein, MD, assistant professor of research at Emory and the study’s lead author. “Only patients with renal insufficiency are in question, but even those patients do not all develop NSF.”

That’s why one of the Emory study’s key goals was the identification of other factors that could contribute to NSF development. “We compared the medical history of our NSF patients to the medical history of the renal insufficiency patients without NSF and tried to determine whether there was a difference,” Lauenstein said. “We only found one factor that was more profound or more present in our NSF group, and that was the so-called anion gap, a parameter for the acidosis of the blood. The anion gap in our NSG group was higher; their blood was more acidic compared to our reference group. So this could be a factor or cofactor in the development of NSF.”

A similar retrospective study conducted at the Vienna General Hospital, however, found no correlation between gadolinium and the development of NSF in patients with chronic renal failure. Seven gadolinium-based contrast agents were used over the 10-year reach of the study, and the only agent that showed a slight risk factor for NSF was gadodiamide (used in Omniscan). Beyond that, significant clinical cofactors included a history of thrombosis or recent surgery. Acidosis has been shown to be a predisposing factor for thrombosis.

Finally, results from the Fibrose Nephrogenique Systemique (FINEST) study were presented. FINEST involved the analysis of 308 patients with renal insufficiency who underwent MRI with or without gadolinium in nine French nephrology departments over a 1-year period. The study’s presenter, Vincent Launay-Vacher, MD, of Pitie-Salpetriere Hospital, Paris, reported that no incidences of NSF were discovered by the researchers.

New Help for CIN

Meanwhile, research continues in the area of contrast-induced nephropathy (CIN), the acute kidney injury caused by iodinated contrast material administered for CT imaging. Recent data show that the incidence of CIN is linked to the chemical structure of iodinated agents, though risk stratification remains difficult.

“CIN occurs predominately in people who have reduced kidney function,” noted Richard Soloman, MD, professor of medicine at the University of Vermont School of Medicine, Burlington. “And cofactors could include anything else that will make the contrast hang out longer in the kidney, including reduced blood flow in patients who have had heart failure. Depending on the various risk factors, the incidence of CIN ranges from 5% to 50%. There isn’t one simple answer.”

Sanjay Saini, MD, professor of radiology at Harvard Medical School, Boston, recommends using an estimated glomerular filtration rate (GFR) to determine renal function as opposed to the more traditional method of creatinine measurement. “The best way to identify high-risk patients is through history and the measurement of GFR,” he said, noting that online databases—complete with calculators—are available to translate creatinine measurements into GFRs. (See http://mdrd.com/ for one such tool.)

Meanwhile, new devices are emerging to help minimize the risk of CIN development. Dual-headed contrast injectors can chase contrast with 20 cc of saline, reducing the total amount of iodinated agent in the kidney and helping to flush the agent through. “If someone administers 100 cc of contrast, then the last 20 cc or so are still sitting in the arm,” notes Saini. “Use injectors with a saline push at the end of the injection for an equivalent image.”

PLC Systems Inc, Franklin, Mass, has developed a device called Renal Guard, currently in FDA trials; Renal Guard measures the amount of fluid leaving the body as urine and replaces it with an equal amount of fluid in the veins, resulting in no net fluid gain or loss for the patient. “Giving fluids is the best strategy,” said Solomon, who was involved in Renal Guard’s development. “The fluid stimulates urine production, making patients flush out the contrast faster. The Renal Guard is an interesting approach.”

Saini says another route to adequate hydration of patients is simple: remove outdated restrictions on eating and drinking before an exam. “We used to restrict food intake for several hours prior to the CT, but now that we’re using low osmotic contrast agents, there’s no more nausea and vomiting,” he said. “You don’t need to guarantee that people aren’t dehydrated because normal fluid intake will ensure that they’re not dehydrated.”

Other potential solutions include catheterization of the renal artery, enabling direct infusion of protective drugs into the renal vasculature, or catheterization of the heart to remove contrast before it reaches the kidney. Both are currently being studied in early clinical trials. Finally, Saini notes that sometimes adjusting the kVp of the study can brighten the appearance of iodinated materials, reducing the need for contrast. “When you do that, you can get a much lower dose,” he said. “One study showed that lowering kVp could be used to cut contrast in half, from the 90 cc range to the 45 cc range.”

NSF Prevention

While no device exists to prevent the occurrence of NSF, some medical device manufacturers have made forays into creating alternatives to gadolinium administration. Prominent among these is Toshiba America Medical Systems Inc, Tustin, Calif, which has been marketing an array of software-based solutions to MRI image enhancement.

Experts are optimistic about the value of research to help address concerns about NSF and CIN cases associated with contrast agents.

“There are a number of techniques by which clinicians can evaluate both vascular and cardiac anatomy and physiology without the use of contrast material,” said John Hipple, product manager for Toshiba’s MR business unit. “There’s software that resides on our Vantage MR systems that allows users to do this with special pulse sequences. One of our techniques, Time-SLIP, allows us to get a very detailed evaluation of the renal arterial structure without the use of contrast.”

Hipple says that Toshiba has experienced a high level of interest in the techniques since the nascence of the NSF scare. “We’ve seen a dramatic increase in interest in these techniques, from both users and other vendors’ users,” he said. “Systems today have to have this capability.”

Lauenstein has a different idea. “If you go to the literature and have a look at all the studies that have been published so far about NSF patients, all of them have been exposed to linear gadolinium compounds,” he noted. Linear compounds are currently industry standard in the United States; there is only one FDA-approved cyclic compound on the market, ProHance (gadoteridol) from Bracco Diagnostics Inc, Princeton, NJ. “In Europe and Asia, cyclic compounds have been on the market for years, and they’re a considerable portion of the market share,” Lauenstein continued. “There should have been some NSF cases described in conjunction with them, but there’s not a single case.”

Chelate structure is important, explains Lauenstein, because it determines the stability of gadolinium. Agents like gadodiamide have low stability, leading to a certain percentage of free gadolinium in the blood following contrast injection. But agents with a cyclic chelate structure minimize the toxicity of gadolinium.

“Cyclic compounds have a much better safety profile than the old linear compounds,” said Lauenstein. “My hypothesis is that once those compounds have a higher market share in the United States, NSF will completely disappear. When you attend a congress in the year 2012, there won’t be any sessions about NSF anymore. Maybe that’s a little optimistic, but I’m pretty much convinced.”

Clinical Guidelines

In the meantime, when can the radiology community expect to see clear guidelines on the usage of gadolinium-based contrast agents? The American College of Radiology (ACR), Reston, Va, is currently in the process of developing a set of recommendations to address the gaps in current information.

“People are very confused,” said Weinreb, who helped organize the meeting of the ACR and the National Kidney Foundation where the new recommendations originated. “They’re getting all kinds of conflicting data, and it’s becoming a state of hysteria in some places, to the point where people are afraid to give gadolinium to patients with no risk at all.” Part of the problem, according to Weinreb, is the sheer volume of new data on the topic. “In the end, if we ever find out what’s going on, we’ll find that 90% of the stuff being published is either not correct or correct but irrelevant,” he said. “But everybody’s already changing their practices.”

Weinreb’s prescription, for now, is a dose of pragmatism chased by a grain of salt. “Anytime there’s a new disease, there’s initially great alarm because it’s something unknown,” he said. “It’s natural that people are surprised and shocked by this—it’s really something new. But even though we don’t have a complete picture of what’s going on, this is not that different than what we deal with on a daily basis. Every time we give contrast to people we know that there could be adverse events. You might say this problem is easier to deal with because we know which patients are at risk, whereas, with allergic reactions, a lot of times we don’t know who’ll have an adverse event.”

Of course, radiologists need to protect themselves against liability now that the ambulance chasers have found reason to sniff around their practices. “There are a huge number of lawsuits happening now,” said Weinreb. “I’m quite certain that a lot of them have nothing to do with NSF, but that’s the legal system and the country we live in.”

The best thing to do, he says, is look at each individual case—particularly cases involving patients with renal insufficiency—and determine whether the administration of gadolinium is justified. “The bright side of the story is that this appears to be a preventable disease, as long as you implement appropriate screening processes,” Weinreb said. “With NSF, we’re talking about a couple hundred documented cases out of 120 million doses of gadolinium. That’s a pretty safe drug.”

Cat Vasko is a contributing writer for Axis Imaging News. For more information, contact .