The relatively new medical device is gadolinium-based contrast agent (GBCA or gadolinium) used during certain MRI or similar procedures. The new kidney related disease that is little more than a decade old is called Nephrogenic Systemic Fibrosis (NSF). Caretakers inject the GBCA into the bloodstream just before patients undergo certain types of Magnetic Resonance Imaging (MRI).
Here is an example of how NSF might occur:
Patients undergo an MRI, MRA, or CT scan. As part of the procedure, doctors inject the patient with a contrast solution containing a rare earth metal called gadolinium. There are different commercial names for gadolinium-based contrast marker: Omniscan (General Electric), Magnavist (Bayer Healthcare), OptiMark (Mallinckrodt), MultiHance (Bracco), and ProHance (Bracco).
After being injected, the Gadolinium dissipates throughout the body. Ordinarily, gadolinium is extremely toxic to human tissues, and manufacturers have to chelate or coat gadolinium with benign chemicals to make it safe for use as an internal marker. Once the chelated gadolinium disperses in the body, doctors can use MRI to obtain a sharper image than they might have obtained without using gadolinium.
Once the MRI procedure is complete, there is no longer a need for chelated gadolinium to be circulating in the bloodstream or to be bound to other body tissue, and the kidneys usually remove the coated gadolinium from the blood. However, patients who have poor kidney function have less capacity to remove gadolinium from the body. This incapacity to remove gadolinium at a preferred rate leads to persistently high levels of residual gadolinium in body tissue. Compromised kidneys’ lack the “speed” necessary to remove gadolinium, and this failure to eliminate the gadolinium leads to a more dangerous situation.
The chelated gadolinium that remains behind in the bodies of patients with poor kidney function then goes through a further process where the protective chelate breaks off of the gadolinium, and free, very toxic, gadolinium remains. Lack of kidney function permits greater amounts of free gadolinium to circulate in the body. And gadolinium toxicity then begins to manifest in vital organs located outside the circulatory system.
For example, after free gadolinium reaches the skin, it forms deposits that cause the skin to become less elastic, patchy and discolored. Skin changes include blackening of tissue and scarring, which deforms and hardens the skin. The hardening and deformation of the skin leads to substantial pain and loss of flexibility while moving the arms and walking. Muscle tissue also absorbs the toxic gadolinium, causing further pain and weakness, with notable hip involvement.
Free gadolinium also deposits in the eyes, and in vital organs, such as the lungs, heart, and liver. Gadolinium deposits in vital organs often result in fatal organ failure.
Once again symptoms of gadolinium poisoning include:
Hardening and darkening of the skin;
Dark patches on the skin;
Painful joints and stiffness;
Difficulty straightening the arms, legs and feet;
Yellow patches on the eyes; and
Next we might ask why gadolinium escaped detection as a potential hazard for a good number of patients undergoing MRI.
Before March 1997 no doctor had ever heard of NSF. However, a few medical authors had suggested that a new diagnostic technique or agent might be responsible for the abrupt occurrence of this new disease. Unfortunately, three years passed before investigators first described NSF in the medical literature.
In February 2008, a Denver Colorado based ABC News station ran a story on NSF, explaining the progression of the disease and how it affected one patient who had fallen victim to gadolinium contrast medium.
Sometimes alternate sources of information, such as patents or patent applications tend to shed some light on issues surrounding a new invention. As a matter of course during the patent application process, the US Patent and Trademark Office mandates disclose of the best possible version of what will become the patented invention. Therefore, obtaining and reviewing a copy of a patent for a gadolinium-based contrast agent is a good way to get a feel for issues surrounding gadolinium and its use a contrast agent.
An attached special chelate substance keeps the gadolinium safe while it is being used in the bloodstream during an MRI. Without the chelating material, gadolinium in its pure and highly toxic, rare earth form would pass rapidly through the bloodstream, and remain within in the surrounding tissues, becoming toxic to the body.
The chosen chelate must also be able to selectively bind the gadolinium(symbol, Gd) to a specific site found on human serum albumin (HSA). This binding process is convenient because HSA travels along with blood cells in the circulatory system. As a result, it is the union between the selected chelate and the blood albumin that allows the attached gadolinium to remain in the bloodstream long enough to be effective during an MRI procedure.
In reading the background and description sections in the ‘953 patent, we see that before 1999, clinicians were familiar with a group of gadolinium products that contained a less desirable chelating agents. Reportedly, those chelating agents allowed the gadolinium to remain indefinitely in surrounding tissue. Therefore, using then available chelating agents to manufacture gadolinium-based contrast agent tended to result in undesirable physiological side effects.
Mallinckrodt’s 1999 invention used a new chelating agent with gadolinium, and that combination was supposed to cause a substantial reduction in undesirable toxic side effects associated with free gadolinium. Mallinckrodt’s new invention employed a low molecular weight chelate known for its ability to bind the gadolinium to HSA, to keep it there for a reasonable time, and to keep the gadolinium “coated” and safe to use during an MRI or like procedure.
As mentioned above, once gadolinium does its job, the body should be able to (and must) eliminate it. Usually, a healthy body has no problem doing just that. Since the kidney is the organ that does most of the work to rid the system of used gadolinium, patients with severely compromised kidneys do not have the capacity to eliminate coated gadolinium from their bodies before the protective coating disassociates.
Let’s take a closer look at some of the problems associated with using gadolinium.
According to the FDA, the first report of a problem associated with using gadolinium appeared on May 29, 2006 in a Danish Medicines Agency press release, and there was also an April 2006 Grobner report in Nephrology, Dialysis and Transplantation.
In addition, Marckmann had published a retrospective study in the Journal of the American Society of Nephrology that included 370 patients with severe renal insufficiency, who became exposed to gadolinium during MRI procedures. These studies showed that exposure to gadolinium had a connection with a unique skin disease, and that there was an increased risk of NSF.
In December 2006 the FDA received information that patients with only moderate renal insufficiency were at risk for developing NSF. However, after further investigation, the FDA determined that those moderately compromised patients originally had severe renal impairment when they received gadolinium for their MRI procedures. The FDA also confirmed that patients with no impairment or even moderate renal insufficiency were not at risk. The report stated further that all five commercially available gadolinium markers were suspect in causing severe medical problems for renally compromised patients.
As a result of gaining this newly acquired information about gadolinium, the following occurred:
The FDA required that all gadolinium manufacturers include a new Boxed Warning, and a new Warnings section in labels, describing risks of developing NSF. Additionally, the FDA required manufacturers to collect data on patients with varying degrees of renal insufficiency that would be exposed to gadolinium. This data would allow a more accurate determination of the relative risk.
Lastly, it is important to know what manufacturers and the medical community knew about gadolinium’s risks, before the FDA approved gadolinium-based contrast agents.
Between 1988 and 2004, the FDA approved five versions of gadolinium-based contrast agents. Reportedly, the five gadolinium manufacturers studied the effects of the contrast agent on 3,000 patients, combined. Those studies revealed that some patients developed various skin conditions (including facial swelling, rash, itching and hives), irritated veins, and blood clots. The most common side effect after gadolinium administration was an allergic reaction, usually mild, but sometimes leading to fatalities.
Amazingly, those clinical studies included very few patients with compromised kidney function, or more severely impaired dialysis patients. This lack of attention to including higher risk patients in studies occurred, despite manufacturers’ knowledge that the kidney was the main excretory organ in the body for eliminating gadolinium. Therefore, gadolinium manufacturers knew just how dangerous and highly toxic gadolinium rare earth was to begin with, and that the coating must not dissociate from the toxic metal. Yet they all ignored the reality of testing a broad spectrum of patients more likely to require gadolinium enhanced MRI procedures. Those compromised patients would be the ones most likely to run the risk of leaving “naked,” toxic gadolinium in their bodies.