Several years ago, Herb had an MRI as part of his ongoing evaluation and treatment of renal failure and related illnesses. Dye was given during the MRI, and because this had been done many times before, he thought nothing of it. Herb had been on dialysis for years.
Herb began to notice his skin began to thicken and tighten around her hands and feet, and, it seemed to spread up his arms and legs. He also experienced severe pain that was different than anything he had previously experienced. Only long acting opiates offered any relief, though brief it was. Over time, because of the skin tightening and joint contractures, Herb became increasingly crippled, and eventually required a walker to navigate in and out of her home. His doctors were at a loss and did not know the cause of Herb’s increasing disability.
A dermatologist was called to perform a skin biopsy. Herb was diagnosed with NSF.
History of NSF
In 1997, a number of renal dialysis patients developed thickening of their skin for which no explanation could be found. Biopsies of the skin were obtained and the tissue resembled a rare disorder known as scleromyxedema. Because of that resemblance, the disease was called “scleromyxedema” disorder.
Over the next several years the disease was seen at multiple centers in the United States, and in 2001 the disease was reclassified as “nephrogenic fibrosing dermopathy.” Most of the patients who had this disease were on dialysis or had undergone a kidney transplant, and all had severely impaired renal function.
Originally, the investigators thought the disease was being caused by something involved with the transplant procedure or dialysis itself or some associated inflammatory condition. However, over time the common risk factor in all patients with NSF was redefined as significant kidney disease at the time of an MRI with dye. There has been no case of NSF in a person with normal renal function at the time the MRI with dye was performed.
Clinical Presentation
Nephrogenic systemic fibrosis (NSF) is a very dramatic disease with profound symptoms and physical changes. It is a painful, often progressive disease involving the skin, underlying fascia as well as muscle. NSF usually begins on the hands and feet and progresses toward the trunk, in a proximal manner, and is associated with skin that is as hard as wood, swelling, orange peel appearance and brawny dark color changes that can have irregular geographic appearing borders. The joints of the fingers, elbows, ankles and knees often are contracted, or drawn up, and there can be significant tethering of the skin making it difficult to extend the elbows or knees. In addition, it is often difficult to place the palms flatly together because of the inability to straighten the fingers. We now know NSF can affect the internal organs as well with almost every major organ having been found to be affected by the fibrosing process of NSF.
Obvious disability due to NSF is easily detected but many patients with milder symptoms may go undetected. Examination of patients with renal failure does not usually involve a detailed examination of the skin of the legs, so it is possible many patients have gone undetected, leading to incorrect predictions about the number of patients who have the disease. The diagnosis is made clinically, based on physical examination, as well as by skin biopsy.
Cause of Nephrogenic Systemic Fibrosis
It is believed gadolinium contained in MRI dye causes NSF. Gadolinium is a “rare earth” metal that is not rare at all but exists in nature in a form that is not readily absorbed by the human body. It is a “paramagnetic” ion that has the ability to enhance the images obtained with MRI. It has been known for many years that gadolinium in its free state is extremely toxic to humans and it has been detected in the skin of patients with NSF as long as 11 months after exposure.
In January 2006, Dr. Thomas Grobner, of Austria, described nine renal patients who were exposed to gadolinium based dye, and five of those patients developed NSF. All of the patients with NSF received Omniscan, a gadolinium based dye and all developed the symptoms of NSF within two to four weeks of exposure. Dr. Grobner was the first to theorize the gadolinium in the dye might be breaking apart from its protective cover, triggering the onset of NSF.
There have been many studies looking for specific cause of NSF, and every study found a significant increased risk or association between the exposures to a gadolinium based contrast agent (GBCA) and NSF. The association is so strong the FDA and other public health agencies have issued warnings about the use of GBCAs in patients with kidney disease.
Once in the human body, gadolinium remains for many years where it has the potential of leaching into bone and enzyme systems causing as yet undetermined long term damage. For example, gadolinium interferes with calcium and calcium is an important component of many enzymes.
When patients without renal failure were given GBCAs, gadolinium was found in their bone in significant quantities.
Treatment of NSF
Many different treatments have been attempted with limited success and there is no consistently successful treatment of NSF. Improvement of renal function does often slow the progression of the disease, and in some cases reverses the symptoms. Among the treatments that have been tried are oral steroids, topical creams, extracorporeal photospheresis, plasmapheresis, Thalidomide, physical therapy, pentoxifulline, high dose intravenous Ig therapy and renal transplantation. A clinical trial is being conducted at Johns Hopkins to investigate the use of Gleevec as a potential treatment. Vera has found that her treating physicians are unable to offer a specific treatment and they seem reluctant to discuss the disease.
The Future
Nephrogenic systemic fibrosis (NSF) is a new disease, barely more than 10 years old. There are no long term epidemiologic studies of the natural course of the disease, effective treatments or cures. NSF is seen more frequently from 5-30 percent after the use of certain GBCAs and eliminating the use of those agents in patients with severe kidney disease may reduce the incidence of new cases of NSF.
NSF is a man-made disease and we can eliminate new causes of NSF with careful study and the use of safer alternative GBCAs in patients with kidney disease. Although Herb didn’t live to see a cure, he had the comfort of knowing his family would be financially healed for after Steven M. Goldberg and his associates recovered a large, confidential award of money for Herb’s harms and losses.
