Magnetic resonance imaging (MRI) was first used for human body imaging in the early 1980s. It was not long before the first contrast agent, based on gadolinium – which of all the tested ions gave the best results – was introduced.
The gadolinium ion – a rare earth metal with no known metabolic role – is, by itself, highly toxic to humans, so it is bound to a ligand that protects the body from the toxic ion. Two types of ligands are used: a linear DTPA-based ligand and a cyclic DOTA-based ligand.
Recently, new agents have been introduced that can be used in smaller doses, due to their protein binding properties, to produce similar results to high-dose extracellular agents. These are called high-relativity agents; their uptake in the hepatocytes of the liver varies. The extracellular agents stay in the extracellular phase and are excreted via the kidneys.
In 1994, the benefits of structurally preorganised and rigid metal chelates – such as DOTA macrocycles, with their high kinetic and thermodynamic stability – as MRI contrast agents were established. DTPA-based agents are kinetically labile, raising the possibility of in vivo transmetallation with endogenous metal ions.
In the body, other ions, such as calcium, iron, zinc and copper, compete with gadolinium to bind to the ligand. This process of transmetallation may liberate gadolinium, and the poorer the binding process the higher the risk is that gadolinium will remain free. It has now been established that free gadolinium triggers the development of a newly diagnosed disease: nephrogenic systemic fibrosis (NFS). The disease is seen in patients with reduced renal function or those on dialysis. In such patients the contrast agents hang around for longer than they do in patients with normal renal function. Its prevalence is greater with the least stable agents and lower with the stable agents.
The world’s first NSF case was identified in 1997 and presented in 2000. Initially the disease was called scleromyxoedema-like cutaneous disease of renal dialysis patients, before being given a specific name: nephrogenic fibrosing dermopathy. Later it was demonstrated that the disease was systemic and affected several tissues, including striated muscles and visceral organs, and that other groups of patients with renal insufficiency could be affected, not just dialysis patients. As a result,
in 2005, the disease was renamed nephrogenic systemic fibrosis.
Since 1997 a growing number of NSF cases have been identified, and today almost 1,000 people suffer from the condition. Cases are mainly found in clusters of more than ten, indicating that the condition may be caused by a hospital-specific activity (a diagnostic procedure, drug prescription or treatment modality, for example). However, the primary causative agent, gadolinium, was not identified until 2006.
So why did it take so long to connect gadolinium contrast media with NSF? Generally contrast agents, in particular MRI agents, have been considered to be safe, inert drugs. It was almost nine years after the diagnosis of the first NSF case before it was realised that the disease was associated with exposure to the less stable gadolinium-based contrast agents.
There were several reasons for this delay. One reason was that uremic patients were exposed to many drugs during the progress of their disease, so the link with gadolinium has been obscured. Also NSF is a delayed reaction that mainly occurs weeks after the patient has received the contrast medium, it does not occur in all stage four or five chronic kidney disease patients (with a glomerular filtration rate of less than 30ml/min/1.73m²) and to date has only occurred after the use of the less stable gadolinium-based contrast agents, according to the peer-reviewed literature.
Access to MRI has increased considerably since the beginning of the century, and new techniques, such as step-wise angiography, based on a single contrast injection, have become available.
Another reason is that, until recently, most physicians did not know about NSF. Only severe skin changes, which have led to significant disability, have been noticed, while mild skin changes, on the lower extremities, for example, have sometimes gone undiagnosed. The histological skin lesions are not unique, and it requires some experience to spot them. The problem is worsened by the fact that patients
at risk suffer from many other skin lesions.
Under such circumstances, it is not surprising that it took time for the connection between NSF and some contrast agents to be recognised.
The discovery of a correlation between NFS and gadolinium-based contrast agents, in particular gadodiamide, shocked the radiologic community. Many publications had stated that gadolinium-based agents were safe, even in end-stage renal failure, and they were considered to be safer than iodine-based contrast agents in radiography.
This led some radiologists to recommend the use of gadolinium-based agents for radiography despite the fact that high doses are required to obtain adequate diagnostic images. Nevertheless, both acute renal and non-renal adverse reactions have been reported over the years after both radiographic and MRI doses.
It has been known for years that patients with reduced renal function have an increased risk of – mainly temporary – reduced renal function (contrast-induced nephropathy (CIN)) followed by increased morbidity and mortality. As a result, these patients have been referred for enhanced MRI, where fewer contrast molecules are used and the risk of CIN is reduced. Now these patients face an increased risk, NSF as well as CIN.
SEEKING A SOLUTION
Recent developments have led some radiologists to deny patients with reduced renal function proper imaging (enhanced MRI). However, such patients need the best imaging when they show signs or symptoms of disease. Sub-optimal imaging may overlook lesions that may be treatable.
Prior to the recommendation of any imaging, an individual medical technology assessment should be done. Factors that should be considered in this assessment include:
- The diagnostic quality of imaging (compared with enhanced MRI)
- Procedural complications
- The morbidity and mortality of haemodialyses in untrained patients
- Acute non-renal adverse reactions
- Acute renal adverse reactions
- Delayed reactions
In most cases, the conclusion will be reached that the risk of doing an alternative examination is higher than the risk of NSF after exposure to a macrocyclic agent in MRI-approved doses. Physicians are well advised to continue to use macrocyclic agents when the examination is clinically well indicated, but avoid the most unstable agents, such as gadodiamide. If a physician wants to use unstable agents in healthy patients, they should store these far away from stable agents, so that an unstable agent is not injected into in a patient with reduced renal function. Such mistakes have occurred.
The first law suits in Europe and in the Americas have been launched against the manufacturers of the most unstable agents, including, it is believed, one of the largest and wealthiest companies in the world: General Electric. General Electric produced one of the most unstable agents, which has caused the majority of NSF cases. Law suits against other companies have also been launched.
In the early 1990s, the academic literature reported the instability of gadodiamide and suggested the use of DOTA-cyclic agents instead. However, DOTA-cyclic agents are more expensive to produce than DTPA-ligands, so there was some reluctance to use them, while many radiologists misinterpreted the literature warning about the potential consequences of using unstable non-ionic linear agents such as gadodiamide.
The health authorities in Europe and in the Americas also failed to heed these warnings. The European authorities have now taken note of the consequences of this failure and contraindicated the use of the least stable agents in patients with reduced renal function. However, in the US the FDA has only issued a ‘black box’ warning on all the agents available in the US market.
To date no specific adverse reactions to gadolinium-based contrast agents in patients with normal renal function have been reported. However, experience with patients with reduced renal function has raised concern over the use of these agents. A further worry is that they seem to have a cumulative effect, with the prevalence and severity of the disease increasing with multiple dosing.
The use of MRI and enhanced MRI is increasing all over the world as MRI capacity increases. An examination that was extremely rare ten years ago has become routine. It is even recommended now for breast cancer screening in high-risk groups. As a result, more patients are now being exposed to MR contrast agents and more are receiving multiple injections. Their use is no longer restricted to severely diseased patients.
Bone from patients with normal renal function has been found to contain up to four times more free gadolinium when the most unstable agents are used than when the most stable agents are used. Each time the patient has an injection of gadolinium-based agent more free gadolinium accumulates in the body.
The least stable agents cause the highest levels of free gadolinium, so, theoretically, the patient can have many more (well-indicated) injections of a stable agent than an unstable one before the same amount of free gadolinium has accumulated in the body.
But will this accumulation have an impact on patient health in the long run? We don’t know. Experience based on patients with reduced renal function suggests the possibility can’t be excluded – there is probably a threshold before the toxic effects of free gadolinium occur, although this threshold is unknown. Also a patient could develop uremia, which could then lead to NSF, or the turnover in a patient’s bone could change – as a result of osteoporosis, for example – liberating free gadolinium into circulation in toxic amounts. Such a scenario was seen many years ago with lead.
A patient should never be denied a clinically indicated enhanced MRI examination. However, it is of the utmost importance that patient exposure to free gadolinium is minimised. This can be achieved by using the smallest amount of contrast agent necessary to obtain a diagnosis and by avoiding the use of the most unstable agents.