Nephrogenic Systemic Fibrosis
NSF, a new disorder
Nephrogenic Systemic Fibrosis is a serious disorder of the skin and internal organs which was first reported in 1997. It has been described in the medical literature as "a devastating complication of severe renal failure." Casey Gerry pharmaceutical attorney Gayle Blatt has followed the development of this little-understood condition. As recently as 2003, Shawn Cowper MD of Yale University School of Medicine, a leading expert in the condition, described it as a "newly recognized scleroderma-like fibrosing skin condition," and wrote that the cause of this condition was not understood.
Since 2003, a number of research studies have demonstrated that patients with a history of renal failure who have undergone Contrast Magnetic Resonance Imaging (MRI) or Magnetic Resonance Angiography (MRA) study have a significant risk of developing NSF. Contrast MRI and MRA are non-invasive diagnostic procedures for evaluating the condition of internal organs (MRI), and arteries (MRA). Before the procedure, a gadolinium based contrast agent, GBCA, a fluid containing gadolinium, is swallowed or injected, depending on the structure to be examined. The gadolinium contrast agent causes the tissue that has absorbed it to display in bright contrast, enabling the radiologist to see the condition of the organ or vessels. Although the mechanisms by which the GBCA causes NSF is not understood, for patients with kidney failure the correlation having used a gadolinium based contrast agent in a magnetic imaging study and developing NSF is very strong.
NSF affects women and men in roughly equal numbers. Cases of NSF have been reported in the elderly, and in children, but the majority of its victims are middle-aged. The disorder has been identified in patients from a variety of races and ethnic backgrounds, and the diagnosis has been made in patients from Asia, North America, and Europe. The persistent common factor shared by all patients who develop NSF is a history of kidney failure symptoms. Kidney failure symptoms predispose a person to NSF, and the exposure to a gadolinium contrast agent triggers the onset of the condition.
Symptoms of NSF appear as rapidly as 2 days after the MRI or MRA where the gadolinium-containing contrast agent was used, to as long as 18 months later. Many of those who develop symptoms received a high dose of the GBCA, but some received only a single dose.
The FDA monitored the mounting evidence of a correlation between Gadolinium Based Contrast Agents and the development of NSF among patients with renal failure who had had an MRI or MRA. In May of 2007 the FDA required all manufacturers of Gadolinium Based Contrast Agents to include a new black box warning on their product labeling. A black box warning, in which the warning text is surrounded by a heavy black line, is the strongest warning the FDA requests.
Here is the black box warning that is now part of the package insert for all Gadolinium Based Contrast Agents:
Gadolinium-based contrast agents increase the risk for Nephrogenic Systemic Fibrosis (NSF) in patients with: Acute or chronic severe renal insufficiency (glomerular filtration rate < 30 mL/min/1.73m2), or Acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period. In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI).
NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a sufficient period of time for elimination of the agent from the body prior to any readministration.
In addition to the black box warnings, the FDA requested the following New Warnings be added to the information provided to physicians:
Additional New Warnings:
- Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA.
- For patients receiving hemodialysis, healthcare professionals may consider prompt hemodialysis following GBCA administration in order to enhance the contrast agent's elimination. However, it is unknown if hemodialysis prevents NSF.
- Determine the renal function of patients by obtaining a medical history or conducting laboratory tests that measure renal function prior to using a GBCA.
- The risk, if any, for developing NSF among patients with mild to moderate renal insufficiency or normal renal function is unknown.
- Post-marketing reports have identified the development of NSF following single and multiple administrations of Gadolinium Based Contrast Agents. These reports have not always identified a specific agent. Where a specific agent was identified, the most commonly reported agent was Omniscan, followed by Magnevist and OptiMARK.
- NSF has also developed following the sequential administration of Omniscan and MultiHance and Omniscan and ProHance. The distribution of the number of reports for the individual Gadolinium Based Contrast Agents may relate to multiple factors, including more limited use of some Gadolinium Based Contrast Agents, under-reporting of NSF, characteristics of the agent and a lack of patients’ complete GBCA exposure history.