GADOLINIUM OVERVIEW & NSF or NFD

Gadolinium-Based Contrast Agents (GBCA) are intravenous drugs used in diagnostic imaging procedures to enhance the quality of magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA).

There are some cases during an MRI scan that requires a contrast agent injected into the patient. A contrast MRI agent (or dye) is a substance that is more susceptible to the magnetic fields of produced during the scan, hence, producing a better image. Of the different contrast dyes, gadolinium is the most well known.

Gadolinium is a metal with very strong paramagnetic properties. In other words, it aligns very easily with an external magnetic field, which allows for the MRI to scan your body much more efficiently. Gadolinium can be very deadly to humans as an ion, so to make it safe to use it must go through chelation - a process that will bind gadolinium to other molecular compounds. There are currently five FDA approved gadolinium contrast agents:

- Magnevist
- Omniscan
- OptiMARK
- MultiHance
- ProHance

Fortunately, under most circumstances, there is no potential danger of being injected with gadolinium. The concentrations are kept low to prevent any side effects and the kidneys will be able to flush out the dye in time.

The real problem is for people without properly functioning kidneys. There is evidence that links gadolinium contrast agents to the cause of NSF, or nephrogenic systemic fibrosis. NSF is a potentially fatal disease that causes excessive fibrous tissue to grow. Consequently, your skin can become very tight and painful and your joint mobility can become extremely limited. If your kidneys are not able to purge the dye from your body, you are at great risk of being stricken with NSF.

What is gadolinium contrast medium?

When injected into the body, gadolinium contrast medium makes certain tissues, abnormalities or disease processes more clearly visible on a magnetic resonance imaging (MRI) scans. Gadolinium based contrast medium is sometimes called an MRI contrast medium or agent.

Gadolinium contrast medium contains complex molecules, that is, an arrangement of atoms (the smallest portion into which an element can be divided and retain its properties) held together by chemical bonds. The chemical bonds are made of a gadolinium ion (the MRI active part) and a carrier molecule. A carrier molecule is called a chelating agent, which modifies the distribution of gadolinium within the body, to overcome its toxicity while maintaining its contrast properties. It is injected intravenously (injected into a vein) as part of an MRI scan.

Gadolinium is a paramagnetic metal ion. Paramagnetic ions, such as gadolinium, move differently within a magnetic field.  This trait makes gadolinium useful for magnetic resonance imaging (MRI).

GBCAs are manufactured by a chelating process, a procedure in which large organic molecules form a stable complex around the gadolinium. The chelate reduces the chances of toxicity that could result from exposure to gadolinium. This stable complex is eliminated predominantly via the kidneys.
GBCAs are approved by FDA for use with MRI as a contrast agent to provide an improved image of body organs and tissues.
GBCAs are also used for magnetic resonance angiography (MRA), an imaging procedure used to evaluate blood vessels.  FDA has not approved GBCAs for use in MRA.

 Use of gadolinium contrast medium

Gadolinium contrast medium is used in up to 30% of MRI scans to improve the clarity of the scanned images or pictures of your body’s internal structures. This improves the diagnostic accuracy of the MRI scan. For example, it increases the visibility of inflammation, a tumour or growth, blood vessels, cardiac (heart) muscle scarring and assesses the blood flow to organs such as the brain and heart.

Usually, you will be advised before you have the MRI scan that part of the way through the scan, gadolinium contrast medium will be injected. The technologist who performs the MRI scan, a nurse or a radiologist (a specialist doctor) will give you the injection.

Sometimes, based on the notes provided by your doctor on your referral, it will not be expected that you require gadolinium but after some of the scanning is done, the radiologist may decide that gadolinium would help to make the images clearer. If you are told part of the way through your scan that gadolinium will be needed, you should not worry that this is an indication that something serious is wrong. Most often this is just being done to make the images clearer and therefore easier to interpret so that the diagnosis is more definite.

 Benefits of gadolinium contrast medium injections

MRI contrast agents (usually gadolinium based contrast medium) improve diagnostic accuracy in some conditions such as inflammation and infectious diseases of the brain, spine, soft tissues and bones by making it easier for the radiologist to see what and where the problem is. The nature and extent of some cancers and benign tumours is best seen and assessed using gadolinium contrast medium.

Angiography scans (showing the function of blood vessels as it is happening on a video screen) can be performed using gadolinium contrast medium and evaluation of many myocardial (heart) abnormalities can only be fully assessed using gadolinium contrast medium.

Risks of gadolinium contrast medium injections

Gadolinium contrast medium is generally very safe. Side effects or reactions are uncommon but may occur. The most common adverse reactions are brief headache, nausea (feeling sick) and dizziness for a brief time following the injection. This occurs in 1% to 5% of contrast injections. Infrequently, a feeling of coldness may occur at the injection site.

Allergic (anaphylactic) reactions to gadolinium contrast medium have occurred but are extremely rare.  These severe reactions, which may involve difficulty breathing and swelling of the lips and mouth, occur in about 1 in every 10,000 people who have gadolinium. These severe reactions generally respond very well to emergency drug treatment. This treatment is given while in the MRI department of the hospital or private radiology practice.

In patients with normal kidney function most of the gadolinium contrast medium injected is almost entirely passed out in the urine within 24 hours.

Gadolinium contrast medium should be avoided in patients with reduced kidney function or kidney failure (either chronic or acute), and hepatorenal syndrome (a condition involving reduced function of liver and kidneys).

Nephrogenic systemic fibrosis (NSF), a debilitating disease resulting in skin contractures (or localised skin thickening and tightening) and internal organ damage has occurred with some gadolinium based contrast agents in a minority of patients who had pre-existing severe kidney function abnormalities.

If you are pregnant or think you may be pregnant please inform your doctor prior to having the procedure so that your doctor can consider and talk to you about any risks and benefits of having gadolinium for you and your unborn baby.

If you are breast feeding it is safe to continue normal breast feeding after the gadolinium contrast medium has been given. There is no requirement to express and dispose of breast milk or to withhold breast feeding. The amount of gadolinium used is so small and rapidly passes out of the body that it does not represent any danger to your child.

If you have any concerns about the use of gadolinium, please discuss these with your referring doctor and the staff where you are having this procedure.

 SIDE EFFECTS OF GADOLINIUM

The most common side effects of headache, nausea and dizziness occur in a small minority of patients only but if they do occur they will be noticed within a few minutes of the injection. Allergic reactions will tend to occur immediately, within several minutes of the injection, when a patient is most likely in the scanner or still in the radiology practice or hospital.

Nephrogenic systemic fibrosis (NSF) is a rare condition associated with gadolinium contrast agents administered to patients with severe renal (kidney) disease. Its onset occurs days or weeks after administration of the agent with almost all cases occurring within six months of the last dose. The use of these agents is generally avoided in patients at risk of NSF.

 What is Nephrogenic Systemic Fibrosis (NSF)?


NSF was first described in the medical literature in 2000. The first case of NSF was identified in 1997. The cause of NSF is unknown but it has been reported only in patients who have severe kidney disease.  NSF causes fibrosis of the skin and connective tissues throughout the body. Patients develop skin thickening that may prevent bending and extending joints, resulting in decreased mobility of joints. NSF usually starts in the lower extremities. Fibrosis can also develop in the diaphragm, muscles in the thigh and lower abdomen, and lung vessels. Over time, NSF becomes worse and can cause death.
Nephrogenic systemic fibrosis (NSF) is also known as nephrogenic fibrosing dermopathy (NFD). With this disorder, patients generally experience a painful hardening of the skin and underlying muscles, especially in the arms and legs. The skin will often take on a "woody" or "orange peel" appearance. In addition to the skin hardening, contracture of joints such as ankles, knees, hips, elbows, wrists, and fingers also can occur, which in turn severely limits range of motion and leads to disability. It is now known that the same fibrosis that NSF causes in the skin and underlying muscles also can be found in the heart, lungs, and other internal organs. NSF is diagnosed by the patient having a "punch" biopsy, which is typically performed by a dermatologist.

Pathophysiology

The speculative pathophysiology for the induction of NSF is based on the patient's duration and concentration of free gadolinium in the 3+ valence state.

Patients with normal renal function clear gadolinium in 2 hours. If renal function is impaired gadolinium remains with tissues for a longer period of time. The risk of NSF has been attributed partially to the severity of pre-existing renal disease.

National Kidney Foundation K/DOQI

Stage GFR

CKD Stage 3 30-60 mL/min

CKD Stage 4 15-30 mL/min

CKD Stage 5 <15 mL/min

The worse the patient's glomerular filtration rate (GFR) the longer the biological half-life of the free gadolinium. Vascular trauma and endothelial dysfunction allow free Gd3+ to enter tissues more easily where it is phagocytosed by macrophages and a profibrotic response occurs.

 INDICATIONS FOR NSF

• Skin and eyes
• Swelling, hardening and tightening of your skin
• Reddened or darkened patches on the skin
• Burning or itching of your skin
• Yellow raised spots on the whites of your eyes
• Bones and muscles
• Stiffness in your joints; problems moving or straightening arms, hands, legs, or feet
• Pain deep in your hip bones or ribs
• Muscle weakness

Gadolinium-based MRI contrast agents and Nephrogenic Systemic Fibrosis

Contrast-enhanced MRIs are a relatively common medical procedure, but several of the contrast agents used with MRIs have been linked to a severe condition called nephrogenic systemic fibrosis (NSF). Gadolinium is a highly toxic heavy metal that is contained in MRI contrast agents. The toxicity of gadolinium in these contrast agents is designed to be neutralized by binding it to a chemical called a chelator. However, if the chelator does not securely hold the gadolinium throughout the time it is in the body, the toxic gadolinium is released and causes NSF. Because renal failure patients take longer to excrete the drug, it is this population of patients who are most commonly affected with NSF.

What MRI contrast agents are associated with NSF?

There are five FDA approved gadolinium contrast agents; however, only three of these contrast agents have been credibly implicated in cases of nephrogenic systemic fibrosis. These three gadolinium MRI contrast agents are Omniscan (GE Healthcare), Optimark (Covidien/Mallinckrodt), and Magnevist (Bayer Healthcare). All three of these contrast agents share a common linear design for their chelator that is intended to bind the gadolinium. Other contrast agents use a safer chelator design that builds a "cage" around the gadolinium. These "macrocyclic" contrast agents have not been linked to cases of NSF. In fact, the only proven cause of NSF is exposure to one of these three contrast agents with the linear design.

Five gadolinium-based contrast agents are approved by the FDA for use during an MRI. The trade names for these products are:

• Omniscan
• OptiMARK
• Magnevist
• ProHance
• MultiHance

None of these agents are approved by the FDA for MRA. The dose of gadolinium-based contrast agent given to patients undergoing an MRA is often higher (up to three times) than the approved dose for MRI.

gadodiamide (OmniScan)*

gadopentetate dimeglumine (Magnevist)*

gadoversetamide (OptiMARK)*

gadobenate dimeglumine (MultiHance)

gadoteridol (ProHance)

* these agents have shown a higher risk association with NSF

Less stable contrast gadolinium agents have shown to have a higher association with NSF. Gadodiamide (OmniScan) is one of the least stable agents. The higher the thermodynamic stability constant for the contrast agent the higher the stability.

- Gadoversetaminde (OptiMARK) 16.6

- Gadodiamide (Omnisan) 16.9

- Gadobutrol (Gadovist) 21.8

- Gd-DTPA (Magnevist) 22.1

- Gadobenate (Multihance) 22.6

- Gadoteridol (Prohance) 23.8

- Gd-DOTA (Dotarem) 25.8

Identifying At Risk Patients

Patients at risk for NSF include those with the following:

Altered renal function

Gad MRI studies

Tissue injury (surgery, thrombosis, ischemic limb)

Cumulative Gad doses

Metabolic acidosis

Erythropoietin

IC iron

Hypophosphatemia

Zinc Loss

Phosphate binders

Seeking compensation if you have NSF

If you have been diagnosed with nephrogenic systemic fibrosis, you may be eligible to collect money damages. The gadolinium attorneys at Spangenberg, Shibley & Liber have been leaders in the court litigation against the pharmaceutical companies whose MRI contrast agents have been linked to NSF. Spangenberg, Shibley & Liber partners Peter J. Brodhead and William Hawal have been appointed to serve as Plaintiffs' Liaison Counsel for all of the Federal Court litigation, which is centered here in Cleveland, Ohio. Mr. Brodhead and Mr. Hawal also are actively participating in the taking of evidence in these cases.

To find out if you have a case Call 1-888-633-0360 or Contact one of these a gadolinium lawyers.


NSF: indurated plaques




NSF: cachexia and contracture

There is believed to be a strong association between impaired renal function, gadolinium contrast enhanced MRI studies and tissue injury resulting in vascular damage (ie. surgery, thrombosis, ischemic limb).

Early symptomatology include: swelling of lower extremities, pain, paresthesias, pruritus

firm, erythematous and indurated plaques.

Later symptomatology include: skin becomes thickened, coarse and hard, predominantly involves extremities, can lead to joint immobility