Nephrogenic Systemic Fibrosis
Gadolinium-based Magnetic Resonance Contrast Agents and Nephrogenic Systemic Fibrosis
Peter Marckmann
Professor and Consultant Nephrologist, Department of Nephrology, Odense University Hospital, and Institute of Clinical Research, University of Southern Denmark
Abstract
The first contrast agents for magnetic resonance imaging (MRI) based on the highly toxic heavy metal gadolinium (Gd) were developed almost 30 years ago and, from the early 1990s, they were introduced into clinical practice. The first case of nephrogenic systemic fibrosis (NSF) was identified in 1997. Since then, a global epidemic of NSF has unfolded, with a peak incidence of the disease in 2005–2006. The total number of cases may range from 2,000 to 10,000 patients. The causal association between certain Gd-based contrast agents (GdBCAs) and NSF was first suggested in 2006. Numerous studies from different areas of research have substantiated that causal link. NSF only occurs in patients with severe renal insufficiency, primarily in pre-dialysis and dialysis patients. The renal excretion of GdBCAs explains this finding. NSF ranges from mild to totally disabling forms with hardening and inflexibility of the skin, primarily of the extremities. Extracutaneous manifestations probably explain the increased mortality of NSF patients. There is no known medical cure for NSF; prevention is essential.
Keywords Kidney disease, dialysis, diagnosis, clinical findings, epidemiology, history
Disclosure: The author has no conflicts of interest to declare. Received: 7 November 2010 Accepted: 14 February 2011 Citation: European Nephrology, 2011;5(2):121–5 Correspondence: Peter Marckmann, Clinical Research Unit, Department of Nephrology, Odense University Hospital, Klovervanget 12B, DK-5000 Odense C, Denmark. E:
peter.marckmann@
dadlnet.dk
Gadolinium (Gd)-based contrast agents (GdBCAs) are composed of one Gd atom in complex with a ligand, forming a chelate. The Gd atom is what gives the GdBCA its unique paramagnetic properties, which are exploited in magnetic resonance imaging (MRI). The chelation of the Gd atom is necessary for its use in medicine, because free Gd atoms are highly reactive and toxic. The severe toxicity of Gd has been known for several decades.1,2
One of the mechanisms behind the
toxic effects of Gd is its capability to replace calcium in membranes and enzymes due to its biophysical similarities with calcium.3
The possible toxicity problems arising from the instability of GdBCAs were recognised before their introduction into clinical medicine, and some researchers warned about this problem very early.5
Nevertheless, the medical community and
authorities became confident that GdBCAs were safe, and gradually introduced their use from the early 1990s in countries worldwide.
© TOUCH BRIEFINGS 2011
GdBCAs for MRI were developed in the 1980s; at least nine GdBCAs are available on the market. According to the physico-chemical nature of the chelate, GdBCAs are divided into linear and cyclic agents, and into ionic and non-ionic agents (see Table 1). They were all designed to possess sufficient chemical stability to avoid Gd liberation in human use. However, total stability does not exist, and the GdBCAs may be divided into different categories of thermodynamic and kinetic instability. The thermodynamic instability of a given GdBCA is an indicator of the extent to which free Gd will be present in the steady state, whereas the kinetic instability is an indicator of the speed with which the steady state is reached.4
From the mid- to late-1990s, GdBCAs were increasingly used for renally impaired patients.
The excretion of GdBCAs is mainly or exclusively renal, except for Primovist® (gadoxetate disodium), where hepatic excretion accounts for around half of the clearance. Accordingly, GdBCAs stay in the body of patients with renal insufficiency for prolonged periods of time. The elimination half-life of a GdBCA such as Omniscan® is around 1.5 hours in patients with normal renal function, but increases gradually with decreasing glomerular filtration rate (GFR), and exceeds 24 hours in patients with renal failure (GFR less than 15 ml/minute/1.73 m2) and in patients on peritoneal dialysis.6
During
haemodialysis, the half-life is around 2.5 hours. The prolonged presence of GdBCAs in the body of renally impaired patients is associated with an increased risk for Gd liberation from the GdBCA. Even GdBCAs with a relatively low kinetic instability may become problematic in patients with renal insufficiency.
Nephrogenic Systemic Fibrosis
Nephrogenic systemic fibrosis (NSF) was first described by the US dermatopathologist Shawn Cowper and colleagues in a letter to the editor in The Lancet in 2000.7
They reported that a hitherto unknown
skin disorder had been identified in 15 renal dialysis patients between 1997 and 2000. The disease had several similarities with scleromyxoedema, but differed from it by the absence of monoclonal plasma protein and extracutaneous mucin deposits. Cowper initially named the disease ‘scleromyxoedema-like
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