Mystery Solved

Peculiar disease linked to MR contrast agent

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A mysterious fibrosing disorder, nephrogenic systemic fibrosis (NSF) can be detrimental to a variety of bodily organs. But, when kidney disease patients began developing NSF after exposure to a certain MR contrast agent, physicians knew that they had to solve the mystery – before it was too late.

Does Your Patient Have NSF?

Some physical symptoms that should alert medical professionals about the possibility of NSF include:

• Burning, itching, reddened or darkened patches in the skin
• Skin swelling, hardening and/or tightening
• Yellow raised spots on the whites of the eyes
• Stiffness in the bones, joints and muscles
• Limited range of motion in

the arms, hands, legs or feet

Pain deep in the hipbone or ribs

General muscle weakness

—J.P.L.

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Physicians, including Preethi Yerram, MD, resident physician in the department of internal medicine at the University of Missouri-Columbia, examined the patient and noted that her lower legs appeared to be hairless, shiny and woody, with bluish-brown discolorations.

Both upper and lower extremities showed clubbing, a condition that involves thickening of the skin under finger and toenails that is often the result of decreased blood oxygen levels.

Treatments aimed at alleviating pain were only minimally successful. Due to this, and because the patient presented with large arterial calcifications on her X-ray, the team started her on intravenous sodium thiosulfate (STS). STS has antioxidant and chelating properties, which means that it bonds to metallic ions.

Within a month, the patient saw improvement. Her skin discoloration, pain and joint stiffness were significantly better, and her need for pain mediations was greatly reduced. When the patient underwent a skin biopsy, she was diagnosed with nephrogenic systemic fibrosis (NSF).

What could have caused the appearance of this mysterious disease? A retrospective review of the patient's medical record turned up a clue: She had undergone multiple MRIs as well as an MR venogram prior to developing NSF. And since the contrast agent used included gadolinium, it served as a clue to the development of a potentially deadly disease.

Identifying NSF

NSF is a fibrosing disorder predominantly involving the skin; as such, it was previously known as nephrogenic fibrosing dermopathy. "It was initially thought that the skin was the only organ affected, but the nomenclature was changed after its systemic involvement was noted," says Yerram.

Upon discovery that the condition can also affect organs, such as liver, heart, lungs, diaphragm and skeletal muscles, the name was changed to NSF to more accurately reflect the progression of the condition.

Physicians first identified the condition in 1997, although more than 200 cases have been reported. In addition to fibrosis of the skin, NSF can affect the connective tissue of the body, inhibiting movement of the joints and resulting in contractures.

Fibrosis of other organs is also a possibility; however, a definitive diagnosis can be made after skin biopsy. Unfortunately, the disease is progressive and can be fatal.

Although the exact cause of NSF remains a mystery, the patients affected all have some sort of underlying kidney dysfunction. According to an editorial in the Clinical Journal of the American Society of Nephrology by Mark A. Perazella, MD, of the department of medicine, section of nephrology at Yale University School of Medicine in New Haven, Conn., "approximately 90 percent of patients in the [NFD/NSF] registry have ESRD and are on either hemodialysis or peritoneal dialysis."

The remainder of the patients suffered from chronic kidney disease or an acute kidney injury.

Clearly, compromised kidney function is key to the development of NSF.

In a normal, healthy patient, circulating fibrocytes enter the tissues of wounds and help with scar formation, the body's normal attempt to begin healing.

In a patient with NSF, however, these circulating fibrocytes begin this process without there being a wound present, which results in their entry into normal tissue and the beginnings of fibrosis. It is thought that the environment created by kidney disease may supply abnormal signals, which encourage this process.

However, NSF does not occur spontaneously in all patients with compromised kidney function. The problem is seen after patients undergo an MR exam with the use of a gadolinium-based contrast agent. The contrast agent gadodiamide, approved by the U.S. FDA for use in MRI, is one such agent.

Part of the problem appears to be the speed with which gadodiamide can be cleared from the body. In a healthy person, the normal elimination half-life of gadodiamide is about 90 minutes.

In patients with ESRD, however, the period can be as long as 10 to 60 hours, meaning that the gadodiamide will linger much longer in the body. Perazella reports that gadolinium is eliminated from the body almost entirely by the kidneys, and that patients with compromised renal function are at a distinct disadvantage.

In addition, Perazella says, in patients with ESRD, hemodialysis requires three treatments to ultimately remove 95 percent or more of the gadolinium from the body; peritoneal dialysis is even less effective.

Moreover, gadolinium is a chelating agent, which means it binds with metallic ions. In gadodiamide, the gadolinium ion is bound to a ligand, a molecule that binds the metal.

In the body, the gadolinium can be separated from its ligand, leaving it free to bind to other metals in the body. This, in turn, can lead to the creation of salts formed by chelating with phosphate, carbonate and hydroxyl, which can be deposited into tissues such as liver, bone, skin and muscle.

The elevated levels of phosphate in the bodies of patients with renal failure can contribute to this process. The instability of gadodiamide is another factor.

Overall, it is a situation in which all of the worst problems can combine to induce NSF. Patients with compromised renal function cannot remove the gadolinium from their system as rapidly as do healthy individuals, so their bodies are exposed to the element for much longer than normal.

The gadolinium, which is easily released from its chelating agent, is free to roam the body. It escapes from abnormal blood vessels made more delicate from irregularities, such as vascular trauma, endothelial dysfunction and chronic edema, and the element is deposited in the patient's tissues.

Once in the tissues, macrophages containing the gadolinium produce profibrotic cytokines that attract circulating fibrocytes; they then begin the process of fibrosis. And, consequently, NSF is born.

Recommendations and Treatment

To determine the scope of the problem linking gadolinium-based contrast agents to the development of NSF, Shawn E. Cowper, MD, of the departments of dermatology and pathology at New Haven, Conn.-based Yale University School of Medicine, along with colleagues, designed a study. The team looked at the population of patients with ESRD in and around the Bridgeport, Conn., area during an 18-month period.

Overall, Cowper and colleagues found the risk of dialysis patients developing NSF is 4.3 cases per 1,000 dialysis patients per year, or a risk of 2.4 percent for each time a patient with advanced kidney disease is exposed to gadolinium.

This, in turn, means that about one in 40 MRI scans using gadolinium-based contrast agents resulted in the patient developing NSF.

What's more, no risk was found when the scans were done without the gadolinium-based contrast agent, and there have been no reported cases of NSF in patients whose kidney function was not compromised.

In Cowper's paper in the Clinical Journal of the American Society of Nephrology, he reports a "highly significant association between patient exposure to gadolinium and the subsequent development of NSF in this ESRD population." In addition, some evidence suggests that development of NSF is linked to dose-related toxicity of gadolinium exposure.

For instance, Yerram points to reports of development of NSF after MR angiography involving the use of gadodiamide; this procedure uses "gadodiamide at a dosage three times higher than the dosage approved by the FDA for MRI in healthy patients," she says.

However, Yerram's 26-year-old patient did not undergo MR angiography. Instead, she was exposed to gadolinium repeatedly through multiple MRI exposures. This leads Yerram and colleagues to hypothesize "a dosage-dependent effect of the association of gadodiamide with the development of NSF."

Practical Applications

So, what can radiology professionals take away from these findings? First is the realization that patients with kidney disease should reduce, or eliminate, the occasions of exposure to gadodiamide or gadolinium.

"Dialysis patients are clearly at risk and should avoid [gadolinium] at all costs," Perazella writes. In addition, he says, "for the time being, it is best to avoid administration of [gadolinium] to patients with AKI and stage 4/stage 5 CKD (including transplant patients) and those who are on dialysis."

Healthcare professionals have long favored gadodiamide because of its characteristic as a non-radioactive contrast agent. However, the possibility of developing NSF from single or repeated exposure makes the risk from any alternative radioactive agent seem more palatable.

Perazella says, "If MRI with [gadolinium] is to be avoided, then iodinated radiocontrast-based imaging may be the only alternative when other noninvasive studies are insufficient. One is left to ponder whether the potential risk for NSF (and its devastating consequences) from [gadolinium] is more dangerous than radiocontrast-induced neuropathy (and its mortality risk) in patients with advanced kidney disease."

Nevertheless, Perazella concludes that the jury is still out. Still, he says, because the neuropathy is generally reversible while NSF is not, "exposure to radiocontrast is probably preferable."

The irreversibility of NSF may not be a certainty, however. For Yerram's patient, the use of sodium thiosulfate, which was given to treat calcium deposits in the blood vessels, led to a dramatic improvement into the patient's NSF.

"It was basically an accidental finding; [STS] was not intended to treat NSF," she says. However, this accidental finding raises hope that the mysterious disease of NSF may have a treatment that could halt or slow its progression.

Currently, knowledge is power when treating patients who may be at risk from gadolinium exposure, especially those who may have poor renal function.

Yerram tells radiologists and RTs that "going through the patient's history would help" them identify the possibility of problems with gadolinium-based contrast agents. As always, the RT can play an active role in looking for potential problems and bringing them to the physician's attention. "Once you think they are at risk, ask," urges Yerram.

Patients, too, should take an active role in managing their health and being on the lookout for the symptoms of NSF, especially patients with compromised renal function who have been exposed to a gadolinium-based contrast agent.

At presstime, both the FDA and the company that makes gadodiamide, the gadolinium-based contrast agent, have issued warnings about using this product in patients with advanced kidney disease.

And, in an update from last December, the FDA urged using an alternative imaging method or contrast agent in patients with moderate- to end-stage renal disease.

The FDA also suggested that this population undergo dialysis promptly after they have been imaged with gadolinium-based contrast agents, in the hopes that dialysis will remove the circulating contrast agent more quickly.

This information is of critical importance to health professionals, as millions of Americans have chronic kidney disease or other renal problems that may put them at risk from gadolinium-based contrast agents.

But until more is known about NSF and the potential link to gadolinium exposure, Yerram advises a conservative approach. "Be very cautious in the use [of gadolinium] in patients with renal disease," she says. "It is the right way to go until we have more evidence."

—Jennifer Patterson Lorenzetti is an Ohio-based freelance writer and the owner of Hilltop Communications. Questions and comments can be directed to editorial@rt-image.com.