When gadolinium is in the bloodstream, medical imaging devices produce clearer, more defined images of the patient’s blood vessels. Since gadolinium is extremely toxic to human tissue, it must first be coated with a benign chemical before being injected into the patient. Over the course of time, the body expels the metal through the kidneys.

Patients with poor kidneys, however, experience a buildup of the toxic metal in their body. The protective coating on the gadolinium eventually breaks down and the patient begins to experience the symptoms of Nephrogenic Systemic Fibrosis (NSF).

Currently, 391 lawsuits have been filed in state and federal courts against manufacturers of the gadolinium based contrast dyes. 287 cases pending in Multidistrict Litigation are now moving forward in the U.S. District Court for the Northern District of Ohio. The remaining 104 NSF lawsuits are pending in state courts. The U.S. Judicial Panel on Multidistrict Litigation designated the Northern District of Ohio to handle all NSF lawsuits pending in federal courts. Last week, the presiding judge established ground rules for the consolidated cases now moving forward.

Defendants named in the suits are GE Healthcare, Bayer Healthcare Pharmaceuticals, Bracco Diagnostics, and Mallinckrodt.

The very first cases of NSF were identified in 1997. NSF is a debilitating disease for which there is currently no known cure. Symptoms include fibrosis of the skin, eyes, joints, and internal organs, hardened skin, limited movement, high blood pressure, dark patches, redness, itchiness, burning, and swelling of skin, soreness of hips and ribs, muscle weakness and limited movement. Progression of the disease can lead to severe rigidity in the joints and death.

NSF (sometimes called Nephrogenic Fibrosing Dermopathy or NFD) was first seen in patients in 1997, and it wasn’t mentioned in medical literature until 2000. NSF leads to excessive formation of connective tissue in the skin and internal organs. It is characterized by high blood pressure, burning, itching, swelling and hardening of the skin. Other symptoms include red or dark patches on the skin; pain deep in the hip bones or ribs and muscle weakness. NSF can progress to the point of causing severe stiffness in joints, and it can lead to death.

There is currently no cure for NSF and no one understands its specific cause. However, the evidence that Gadolinium MRI contrast agents play a role in its development is fast becoming irrefutable. Researchers at Yale University have reported that 95-percent of those with NSF had an MRI that involved a Gadolinium MRI contrast dye two to three months before their symptoms appeared. Researchers at Massachusetts General Hospital also have found that kidney patients who had undergone MRIs with Gadolinium MRI contrast dyes were 10 times more likely to develop NSF than patient who had not been exposed to such agents.

Gadolinium contrast dyes are used in MRI because they make it far easier for a diagnostician to differentiate between normal and abnormal tissue. While the tests can be done without the Gadolinium based contrast agent, they are nowhere near as effective. The FDA has warned that patients with kidney problems not be given Gadolinium based MRI contrast dyes unless it is absolutely necessary because of their association with NSF. Unfortunately, there are not yet any alternatives to gadolinium based MRI contrast agents.

The CDC study of the St. Louis NSF cases only reinforces the link between NSF and Gadolinium. According to the CDC, in May 2006, nephrologists at the St. Louis hospital reported a cluster of NFS among patients treated in their dialysis units. The CDC conducted an investigation to determine the number of affected patients and identify risk factors for NFS. Of the 19 patients eventually included in the study, only five had no identified gadolinium exposure within 1 year preceding NFS diagnosis. However, of these, four had gadolinium exposure from 16 to 68 months preceding diagnosis. Thirteen patients had multiple gadolinium-containing contrast exposures during the preceding year.

According to the CDC, the study indicated that exposure to Gadolinium-containing contrast agents during MRI studies was linked with the development of NFS. The CDC cautioned that clinicians should be aware of the potential for NFS, and when possible, should avoid use of Gadolinium-containing contrast agents in patients with advanced kidney disease.

January 31st, 2008 by Staff with NewsInferno.com

NSF/NSD is a rare disease that so far has affected only people with pre-existing kidney problems. The first case of NSF/NSD was reported in 1997, and it wasn’t mentioned in medical literature until 2000. NSF/NSD leads to excessive formation of connective tissue in the skin and internal organs.

It is characterized by high blood pressure, burning, itching, swelling and hardening of the skin. Other symptoms include red or dark patches on the skin; pain deep in the hip bones or ribs and muscle weakness. NSF/NSD can progress to the point of causing severe stiffness in joints, and it can lead to death.

There is currently no cure for NSF/NSD, and no one understands its specific cause. However, it is widely believed that gadolinium based MRI contrast agents play a role in the development of this devastating disorder. Researchers at Yale University have reported that 95-percent of those with NSF/NSD had an MRI that involved a gadolinium based contrast agent two to three months before their symptoms appeared. Several other studies have also found a link between NSF/NSD and gadolinium based MRI contrast agents.

The connection between gadolinium and NSF/NSD is so strong that earlier this year, the Food & Drug Administration (FDA) requested that that the manufacturers of gadolinium based contrast agents update their products’ labels to include a black box warning regarding the risk of NSF/NSD in patients with kidney problems. The FDA also started a monitoring program to track the frequency of NSF/NSD related to gadolinium contrast agents.

Gadolinium based MRI contrast agents are used in MRIs because they make it far easier for a diagnostician to differentiate between normal and abnormal tissue. While the tests can be done without the gadolinium based contrast agent, they are nowhere near as effective. The FDA has warned that patients with kidney problems not be given gadolinium based MRI contrast agents unless it is absolutely necessary. Unfortunately, there are not yet any alternatives to gadolinium based MRI contrast agents.

For patients with NSF/NSD, life can become a living hell. Their skin can become so hardened that it resembles marble, while joints stiffen to the point that movement becomes impossible. The disease can also affect the heart, lungs and liver, and NSF/NSD can lead to death. Unfortunately, there are no effective treatments for NSF/NSD, although some patients have improved following a kidney transplant.

November 9th, 2007

The 38-year-old Santa Barbara resident said what happened to her is “devastating.”

The issue involves magnetic resonance imaging scans that include the use of a contrast dye containing gadolinium.

For people with healthy, functioning kidneys, the risk of using the element gadolinium to pinpoint potential health problems in MRI scans is zero.

“Gadolinium is extremely safe,” said neuroradiologist David Seidenwurm at Radiological Associates of Sacramento.

But, for people with kidney disease, the use of gadolinium poses a significant health risk. The risk is so significant that the Food and Drug Administration issued a warning for gadolinium this year.

Dr. Philip LeBoit of the University of California, San Francisco first discovered this problem. The disease is called nefrogenic systemic fibrosis, or NSF.

“It can have severe toxic effects,” LeBoit said.

The concern is that the chemicals that surround the gadolinium and make it safe for use in the human body are in some cases breaking down. For those patients with weakened kidneys, they cannot sufficiently rid the body of the gadolinium. That has led to toxic effects for an estimated 500 to 1000 people so far.

Dr. Shawn Cowper of Yale University estimates the risk of contracting the disease at 5 percent for kidney patients.

To date, there is no known treatment for NSF. The disease can lead to a debilitating hardening of the skin.

For Sarah Fracella, the skin on her hands has hardened so much that she cannot open a bottle on her own. She also has trouble sitting and walking. In more extreme cases, NSF has attacked internal organs. NSF has also proven fatal.

KCRA3 has learned that the Burg Simpson law firm in Denver, Colo., is already investigating dozens of potential lawsuits.

Attorney Peter Burg alleges that GE Healthcare, the manufacturer of OMNISCAN, one of the most widely used gadolinium-based dyes, “knew or should have known that this product was inherently dangerous and ultrahazardous to humans.”

When contacted, GE Healthcare said it does not comment on pending litigation.

As for Fracella, she said she is telling her story as a warning to others. She wants to make sure anyone with weakened kidneys is aware of the risk of this disease before they accept the use of a gadolinium-based dye in their body.

“It’s been the hardest thing I’ve ever had to deal with in my life,” she said.

November 26th, 2007

Fracella is one of as many as 1,000 people worldwide who have contracted a debilitating, incurable and sometimes fatal disease called nephrogenic systemic fibrosis, or NSF, from the dye that is used in millions of magnetic resonance imaging scans every year.

For most people, dyes based on gadolinium - the magnetic ion blamed for the condition - are safe, said David Seidenwurm, a neuroradiologist with Radiological Associates of Sacramento. But for people with severe kidney problems, the ion can poison the patient by causing collagen to build up in tissues.

The Food and Drug Administration asked manufacturers in May to include a so-called black-box warning on gadolinium-based products, saying patients with kidney problems could develop NSF after a single exposure. In addition to severe thickening of the skin, leading to immobility, the disease is also known to affect the liver, the lungs and the heart.

Few alternatives to dye for MRIs

The specific cause of NSF is not yet understood, but researchers at Yale University reported that in more than 95 percent of the cases they had surveyed, patients were exposed to a gadolinium-based dye two to three months before the onset of the disease.

Shawn E. Cowper, a dermatologic pathologist at Yale who first identified the condition with Philip LeBoit of the University of California-San Francisco, said as many as 1 in 20 kidney patients could be at risk of contracting NSF after undergoing an MRI using gadolinium.

Gadolinium-based dyes latch into specific tissue types in the body, making them easy to contrast from other tissues on an MRI. The tests can be administered without a contrasting agent, but they are considered to be significantly less useful.

Complicating the problem is that gadolinium is the only contrasting agent approved for use in most MRIs. Two others, Feridex I.V. and Teslascan, are limited to use only in examinations of specific liver problems.

NSF has been confirmed in children and the elderly, but it tends to affect the middle-aged most commonly, according to the International Center for Nephrogenic Fibrosing Dermopathy Research. It affects men and women equally.

The FDA recommended that all patients with serious kidney problems ask their doctors not to use contrasting agents in MRI exams, unless there is no alternative.

‘Hardest thing I’ve ever had to deal with’

Numerous lawsuits have been filed against GE Healthcare, a division of General Electric Co., which manufactures gadodiamide, the type of gadolinium implicated in a large majority of the cases known to date. GE Healthcare said that the company does not comment on pending litigation but that in general, it believes it has “a number of meritorious defenses.”

For Fracella, the skin on her hands has hardened so much that she cannot open a bottle on her own. She also has trouble sitting and walking.

“It’s been the hardest thing I’ve ever had to deal with in my life,” she said.

Fracella’s mother, Susan, said her daughter’s condition was “terrifying.”

“It’s agonizing to watch your child suffer,” she said. “… I mean, knowing this now, would you want any of your children to have an MRI?”

November 8th, 2007

But the use of gadolinium in a procedure call Magnetic Resonance Angiography (MRA) could put these patients at an even greater risk of developing NSF/NSD, because these procedures often use far more gadolinium than a typical MRI. The use of gadolinium contrast agents in MRAs is a growing practice, even though the Food Drug Administration (FDA) never approved gadolinium for MRAs.

An MRA is a variation of a traditional MRI that is used to provide pictures of blood vessels inside the body. In many cases, an MRA can provide information that cannot be obtained from an X-ray, ultrasound, or computed tomography (CT) scan. An MRA is often used to detect aneurysms, blood clots or narrowing caused by plaque buildup in the blood vessels leading to the brain, and it is also used to find similar narrowing in the vessels leading to the lungs, kidneys and legs.

Currently, five gadolinium based contrast agents are approved for use by the FDA. These are Omniscan, Optimark, Magnevist, Multihance and Prohance. Gadolinium contrast agents are used during MRAs for the same reason they are used in MRIs, to help differentiate between normal and abnormal tissue. The gadolinium based contrast agent is injected into the bloodstream right before an individual undergoes an MRA. However, in order to be effective in an MRA, the gadolinium contrast agent must be administered at three times the approved dose. What’s more, this constitutes an off-label use of gadolinium based contrast agents - that is these agents were never approved by the FDA to be used with MRAs.

In 2006, evidence began to emerge that gadolinium based MRI contrast agents were linked to the development of NSF/NSD. NSF/NSD is a debilitating disease that affects people with pre-existing kidney disease. The first case of NSF/NSD was reported in 1997, and it wasn’t mentioned in medical literature until 2000.

NSF/NSD leads to excessive formation of connective tissue in the skin and internal organs. It is characterized by high blood pressure, burning, itching, swelling and hardening of the skin. Other symptoms include red or dark patches on the skin; pain deep in the hip bones or ribs and muscle weakness. NSF/NSD can progress to the point of causing severe stiffness in joints, and it can lead to death. Unfortunately, for many patients with NSF/NSD, the only way to improve kidney function is with a transplant.

October 31st, 2007

Only about 215 cases have been reported worldwide, all involving people with kidney disease. No cures have been reported but some patients have seen improvement after treatment to improve their kidney function, according to the International Center for Nephrogenic Fibrosing Dermopathy Research.

Gerber’s lawsuit claims that people with impaired kidney function can’t properly eliminate the gadolinium from their system.

Last year, the U.S. Food and Drug Administration issued an advisory that patients with moderate to “end-stage” kidney disease should avoid having medical scans that use gadolinium-based contrast dyes, such as magnetic resonance images and magnetic resonance angiographies. If the imaging is done, “prompt dialysis” following the procedure should be considered, the FDA said.

Gerber had such imaging before he underwent a kidney transplant.

His lawsuit, filed Friday in San Francisco Superior Court, names medical centers and companies involve in making, distributing and using the dyes, including Bayer Healthcare Pharmaceuticals Inc. and GE Healthcare Inc.

Both companies have added warning labels to their dyes.

“Mr. Gerber was never warned that there was any kind of risk associated with gadolinium, let alone NSF,” Gerber’s attorney, Lawrence J. Gornick, told the Los Angeles Daily Journal. “Because of that, he developed a life-threatening disease that will most likely take his life in a horrible way.”

“There is only one identified cause of NSF, and that’s gadolinium,” Gornick said. “And there is only one way gadolinium gets into the human body, and that’s through these contrasting agents.”

Gornick said he expected to seek millions of dollars in damages.

Bayer spokeswoman Marcy Funk said Tuesday that the company could not comment on pending litigation.

“There are warning labels on the product,” she said. “Patient safety is always the No. 1 priority of the company and we’re working with the health authorities … on this particular issue.”

GE Healthcare spokesman Brian McKaig said in a written statement that a “definitive causal relationship” between NSF and the use of gadolium-based dyes has not been established.

“GE Healthcare does not comment about ongoing lawsuits but the company is concerned for patients diagnosed with NSF “and continue to emphasize our commitment to patient care and safety,” he wrote..

Gerber’s is one of only a handful of lawsuits filed by people with the rare disease.

October 30th, 2007

Early reports noted that NSF closely resembled scleromyxedema, but had a number of differentiating features. The entity was initially termed nephrogenic fibrosing dermopathy, and a case definition was established based on its characteristic clinical and histopathologic features. The name was later changed to NSF in view of the systemic nature of the disorder and recognition of the role circulating fibrocytes play in mediating NSF.

Underlying renal impairment is a prerequisite for the diagnosis of NSF, and 90% of patients with NSF have end-stage renal disease (ESRD). The age of the patients with NSF has ranged from 8-87 years with equal gender distribution. Cases of NSF have been reported in many countries and no race predilection has been observed. In a recent case-control study of 19 patients with NSF, 58% and 32% received hemodialysis and peritoneal dialysis respectively in the six months preceding the diagnosis.

Clinical, histologic features

NSF is associated with cutaneous lesions that are typically distributed in a symmetrical fashion on the limbs and trunk; the face is usually spared. The primary lesions consist of skin-colored to erythematous papules coalescing into brawny patches with a peau d’orange surface appearance.

The patient’s involved skin typically becomes markedly thickened and develops a woody texture. Yellow scleral plaques have been observed in some patients with NSF. Intense pain and pruritis are commonly reported in affected areas.

As NSF progresses, patients may experience significant decrease in the function of their hands and feet, with the development of joint contractures. Some may require wheelchair use and assistance with activities of daily living. Severe disability and mortality have been reported in patients with NSF.

NSF is a clinical and histopathological diagnosis. Lesions show an increase in dermal spindle cells which are bland and have long dendritic processes. Most of these spindle cells are immunohistochemically positive for CD34 and procollagen I. This immunologic profile is identical to circulating fibrocyte, a bone-marrow derived leukocyte. Thick collagen bundles with surrounding clefts are also prominent findings with a variable amount of mucin and elastic fibers noted.

Etiology

No etiologic agent or intervention has been identified as causing or being associated with NSF until recently. The observations that vascular surgery and thrombotic episodes were common preceding events prompted speculation that NSF may be triggered by an imaging contrast agent. Five out of nine ESRD patients in an Austrian dialysis center who underwent MR angiography with gadodiamide had developed NSF two to four weeks later. Gadolinium was thought to be a trigger for NSF under certain conditions based on above observations. This theory was further supported by the findings of a study of 13 confirmed cases of NSF, all of whom had been exposed to gadodiamide before the onset of NSF. The odds ratio was calculated at 32.5 with these 13 NSF cases identified among 370 ESRD patients exposed to gadolinium-based contrast agents (GBCA) and none among 430 non-exposed ESRD patients. The time lag from gadodiamide exposure to the first sign or symptom of NSF was 2-75 days (median, 25 days). Of the 13 patients, seven (54%) became severely disabled and one died at 21 months after gadodiamide exposure. Subsequent case-control series found the odds ratio to range from 8.97 to 22.33 for prior exposure to gadodiamide or other GBCA in ESRD and acute kidney injury (AKI) patients.

Prevalence of NSF has ranged between 3.5% to 4% in ESRD patients exposed to GBCA. Yearly incidence was reported as 4.6% for a population of hospitalized patients whose (GFR) was less than 60 mL/min/1.73m2 and had a pro-inflammatory event. Incidence was calculated to be 4.3 cases per 1000 patient-years in a stable outpatient (ESRD) population. Each radiologic study using (GBCA) presented a 2.4% absolute risk for NSF in the same recent series.

Risk factors

NSF cases have been reported in patients with AKI or CKD and in renal or liver transplant recipients with compromised renal function. All patients with documented NSF had renal impairment with either ESRD, AKI, or CKD with an estimated glomerular filtration rate (GFR) below 30 mL/min per 1.73m2. Patients with ESRD appear to be at the highest risk for NSF, and those with CKD Stage 4 also appeared to be at elevated risk. Peritoneal dialysis appears to be associated with a greater risk for NSF compared to hemodialysis.

Risk for NSF appears to increase with repeated administration with an odds ratio of 2.618.10,11 Risk for NSF appears to increase with use of double-dose (0.2 mmol/kg) compared with single-dose (0.1 mmol/kg) gadodiamide administration with an odds ratio of 12.19. Acidosis was initially reported as a risk factor favoring NSF occurrence with mean bicarbonate level of 19.5 ± 1.7 mmol/L versus 22.95 ± 0.58 mmol/L in unaffected cases. Mean bicarbonate level was 22.5 mmol/L, 23.5 ± 1.1 mmol/L and 22.3 ± 2.74 in three subsequent reports with no association found with NSF. Higher rHuEpo doses have been reportedly in cases with NSF but this could be a result of inflammation and resistance to rHuEpo.4,6,12 ACE inhibitors were thought to be protective but this was not consistently observed. Pro-inflammatory state may be a predisposing factor.

Treatment

Given the significant morbidity and mortality associated with NSF, the FDA has stated that the benefits and risks associated with using a GBCA upon recommending or performing an MRI or MRA should be carefully weighed in light of recent reports of NSF observed following administration of these agents. Alternative imaging methods and/or contrast agents should be used whenever possible. A total of five GBCA (Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance) are currently approved for use in the United States.

There is no consistently successful treatment for NSF. It is not known if hemodialysis post-exposure prevents it. A current recommendation is to initiate hemodialysis within two to three hours of a GBCA administration, followed by a second session within 24 hours. Treatments that have been used with some success and continue to be investigated include oral steroids, plasmapher-esis, extracorporeal photopheresis and sodium thiosulfate. Additional information on NSF is available on the InternationalCenter for Nephrogenic Fibrosing Dermopathy Research Web site (www.icnfdr.org).

October 29th, 2007

The Scottish gadolinium MRI contrast agent study looked at 1,826 patients who underwent renal replacement therapy at two Glasgow hospitals between January 1, 2000 and July 1, 2006. Of those patients, 421 underwent an MRI that involved the use of a gadolinium based contrast agent. Fourteen were diagnosed with NSF/NFD, and of those, 13 had been exposed to gadolinium during an MRI. The researchers also found that the patients with NSF/NFD had received far higher doses of gadolinium than those patients who were exposed to gadolinium but did not develop the disorder.

The Scottish study was the second published this month that confirmed the link between NSF/NFD and gadolinium based contrast agents. A study conducted by researchers at Massachusetts General Hospital, which was published in the October issue of the Journal of Arthritis & Rheumatism, found that kidney patients who had undergone MRIs with gadolinium based contrast agents were 10 times more likely to develop NSF/NFD than patient who had not been exposed to such agents.

For several years now, gadolinium based contrast agents have been a prime suspect in the sudden appearance of NSF/NFD. The first case of NSF/NFD was not even reported in 1997, and it wasn’t mentioned in medical literature until 2000. In 2006, Dutch researchers first linked gadolinium contrast agents to the onset of NSF/NFD. That same year, the Food & Drug Administration (FDA) warned health care professionals about the link between gadolinium contrast agents and the occurrence of NSF/NFD. Then in 2007, the FDA requested that the manufacturers of gadolinium based contrast agents update their products’ labels to include a black box warning regarding the risk of NSF/NFD in patients with kidney problems. The FDA also started a monitoring program to track the frequency of NSF/NFD related to gadolinium contrast agents.

NSF/NFD, a disease that affects people with pre-existing kidney disease, leads to excessive formation of connective tissue in the skin and internal organs. It is characterized by high blood pressure, burning, itching, swelling and hardening of the skin. Other symptoms include red or dark patches on the skin; pain deep in the hip bones or ribs and muscle weakness. NSF/NFD can progress to the point of causing severe stiffness in joints, and it can lead to death.

In their report, the Scottish researchers noted that the link between NSF/NFD and gadolinium based contrast agents has been accepted by most of the worldwide medical establishment. They suggest that gadolinium contrast agents be avoided altogether or at least in patients with pre-existing kidney problems. And in cases where gadolinium is the only alternative, the lowest possible dose should be used.

October 24th, 2007

The FDA’s move on Friday finalizes its announcement in May that it would add the labeling warning to the MRI contrast agents.

The final warning notes that the agent boosts the risk of a potentially fatal side effect in patients with certain kidney and liver conditions. The skin disease called nephrogenic systemic fibrosis, or NSF, can occur in some patients, the companies said in a joint letter to health-care professionals, posted on the FDA’s Web site on Friday.

Such gadolinium-based imaging agents are made by Bayer AG’s Bayer Schering Pharma, General Electric Co’s GE Healthcare, Tyco International Ltd.’s Mallinckrodt unit, and Bracco Diagnostics Inc.

The FDA has said there have been no reports of nephrogenic systemic fibrosis among patients with normal kidney function or those with mild-to-moderate kidney insufficiency.

Agency officials first alerted doctors to the potential risk in 2006, following reports that patients who received the injectable agents developed NSF.

Although the risk of NSF from any one agent is unknown, the letter cited a study that found an estimated risk in patients with severe renal insufficiency at 4 percent.

The condition triggers thickening of the skin, organs and other tissues that makes it difficult to move and can lead to broken bones. There is no effective treatment.

Patients should be screened for kidney problems before use of such agents, the letter said, adding that the recommended dose should not be exceeded.

October 18th, 2007