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First published online March 28, 2007
British Journal of Radiology (2007) 80, 73-76
© 2007 British Institute of Radiology
doi: 10.1259/bjr/17111243
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Commentary

Nephrogenic systemic fibrosis following the administration of extracellular gadolinium based contrast agents: is the stability of the contrast agent molecule an important factor in the pathogenesis of this condition?

S K Morcos, FRCS, FFRRCSI, FRCR

Department of Diagnostic Imaging, Sheffield Teaching Hospitals NHS Foundation Trust, Northern General Hospital, Sheffield S5 7AU, UK

Correspondence: Professor Sameh K Morcos, Consultant Radiologist, Department of Diagnostic Imaging, Northern General Hospital, Herries Road, Sheffield S5 7AU, UK. E-mail: sameh.morcos{at}sth.nhs.uk

Nephrogenic systemic fibrosis (NSF) was first described in 1997 in patients with end-stage renal disease (ESRD) [1]. It is characterised by scleroderma-like skin changes that mainly affect the limbs and trunk. The induration of the skin can progress to cause flexion contracture of the joints. The fibrotic changes may also affect other organs such as muscles, heart, liver and lungs [1–7]. The disease can be aggressive in some patients, leading to serious physical disability or even death [1].

Recently, it has been suggested that extracellular gadolinium based contrast agents (Gd-CA) might have a causal relation with NSF [4–7]. According to a recent editorial there are more than 150 patients who have developed NSF following administration of Gd-CA. Strikingly, the overwhelming majority (~90%) followed administration of the non-ionic agent gadodiamide (only 15% of all Gd-CA injections worldwide are gadodiamide) [7]. This was completely unexpected considering the good safety records of all Gd-CA, including gadodiamide [8]. According to the manufacturer (GE Healthcare, Waukesha, WI) gadodiamide has been administered to about 30 million patients since its introduction for clinical use in 1993 without high incidence of important adverse effects [6]. Hence, this recently observed strong association between NSF and gadodiamide requires an explanation.

Currently, there are seven extracellular Gd-CA available for clinical use (Table 1Go). They are all chelates containing the Gd ion (Gd+++). The configuration of the molecules is either linear or cyclic. They are available as ionic or non-ionic preparations (Table 1Go). The important difference between these agents that could be of relevance to patients with advanced renal impairment (GFR <30 ml min–1) and a factor in the development of NSF is the stability of the chelate molecule [6]. Gd-CA are eliminated from the body through the kidneys and biological half-life in patients with normal renal function is 1.5 h. In patients with advanced renal impairment, elimination half-life can be prolonged to 30 h or more [9]. Patients on haemodialysis would require three consecutive dialysis sessions over 6 days to remove 97% of the administered dose of Gd-CA from the body. Continuous ambulatory peritoneal dialysis for 20 days eliminates 69% of the injected dose of Gd-CA [10]. Transmetallation is likely to occur when the Gd-chelate remains in the body for a long period, as is the case in patients with ESRD, including those on dialysis. Transmetallation of Gd-CA leads to release of free gadolinium through replacement of the Gd+++ within the chelate molecule by body cations such as zinc or copper [11]. Free gadolinium is highly toxic and animal studies showed that it can cause splenic degeneration, central lobular necrosis of the liver and a variety of haematological abnormalities [9, 12]. Therefore, it is crucially important that Gd+++ should be strongly attached to a chelate to avoid its toxic effects. Understanding the synthesis of metal chelates is somewhat difficult, especially for those of us who have no deep knowledge in chemistry. However, the author of the article attempted to present some of the chemical principles involved in the production of Gd-chelate in a simplified manner, hopefully without important compromise of scientific accuracy. The gadolinium ion has nine coordination sites (coordination sites represent the number of atoms or ligands directly bonded to the metal centre such as Gd+++ . A ligand is a molecule or atom that is bonded directly to a metal centre. The bonding between the metal centre (Gd+++) and the ligands is through valent bonds in which shared electron pairs donated to the metal ion by the ligand). In the ionic linear molecule such as Gd-DTPA, Gd+++ is coordinated with five carboxyl groups and three amino nitrogen atoms. The remaining vacant site is coordinated with a water molecule, which is important in enhancing the signal by the contrast agent in T1 weighted MR imaging (Figure 1Go) [12]. In the non-ionic linear molecule such as gadodiamide and gadoversetamide, the number of carboxyl groups are reduced to three as the other two carboxyl groups have been replaced by non-ionic methyl amide (Figure 2Go) [12]. Although both amide carbonyl atoms are directly coordinated to Gd+++, the binding is weaker in comparison to that of carboxyl groups [13]. This will result in a weakening of the grip of the chelate on the Gd+++ and a decrease in the stability of the molecule [13]. The other feature which influences the binding between the Gd+++ and the chelate is the configuration of the molecule; the cyclic molecule offers a better protection and binding to Gd+++ in comparison with the linear structure [9, 11–13].


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  		Table 1. Physico-chemical characteristics of clinically available extracellular gadolinium based contrast agents [9, 11]

 

Figure 1
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  		Figure 1. The chemical structure of gadopentetate(Gd-DTPA, an ionic linear molecule). Gadolinium ion (Gd+++ ) in the chelate has nine coordination sites (dotted lines), five with carboxyl groups and three with amino nitrogen atoms. The remaining vacant site is coordinated with a water molecule (H2O).

 

Figure 2
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  		Figure 2. The chemical structure of gadodiamide(Gd-DTPA-BMA, a non-ionic linear molecule). In this molecule, the carboxyl groups are reduced to three as the other two carboxyl groups have been replaced by non-ionic methyl amide (CONHC3). Both amide carbonyl atoms are directly coordinated to Gd+++, but the binding is weaker in comparison with that of the carboxyl groups. A coordination site with a water molecule (H2O) is present.

 
The following measurements are used to assess the stability of the chelate molecules; thermodynamic stability constant, conditional stability and kinetic stability (dissociation half-life under very acidic conditions [pH 1]). The higher the value of these measurements, the higher the stability of the molecule. In addition, the presence of excess chelate in the Gd-CA preparation is an indirect marker of the low stability of the molecule [11]. The excess chelate is included in the preparation to ensure the absence of free Gd+++ in the solution [9, 11]. The addition of excess chelate dramatically reduces the acute toxicity of non-formulated preparations (no excess chelate) by a factor of 2.5, as demonstrated by acute toxicity studies (intravenous LD50) [9]. Considering the different stability measurements and other characteristics of Gd-CA, it becomes clear that the most stable molecule is the ionic cyclic chelate (Figure 3Go). No excess chelate is required in the commercial preparation of this type of Gd-CA, which has the highest stability values and the longest dissociation half-life (Table 1). In contrast, the least stable preparations are the non-ionic linear Gd-chelates, which have the lowest thermodynamic and constant stability values, and the highest amount of excess chelate in comparison to the other types of Gd-CA (Table 1Go) [9, 11–13]. Transmetallation is more likely to occur with these preparations even in patients with normal renal function. According to one report, gadodiamide (a non-ionic linear chelate) leaves 2–4 times more Gd+++ in the bone than gadoteriodol (non-ionic cyclic chelate) in patients with normal renal function [14]. However, the differences in the stability between the commercially available Gd-CA have not so far shown important differences in the safety of these agents [8]. Nevertheless, the recently observed strong association between gadodiamide and NSF suggests that it is probable that the stability of the chelate and transmetallation is clinically relevant in patients with marked renal impairment. In addition, both transmetallation between endogenous zinc and Gd+++ and the presence of excess chelate in the non-ionic linear chelate preparations that can bind to zinc in serum can lead to an increase in zinc excretion in urine and a decrease in its serum level. These changes were not significant with endogenous copper. [9, 15, 16]. Animal and human studies have shown that gadodiamide caused a large increase in zinc excretion that was higher by a factor of almost three in comparison with the zincuria induced by the ionic linear molecule Gd-DTPA [9, 15, 16]. A decrease of 32% of plasma zinc has been reported after one single gadodiamide injection in healthy volunteers [16]. On the other hand, the ionic cyclic Gd-DOTA had no significant effect on zinc excretion [9, 15, 16]. It is of interest to note that animal studies in rats and monkeys demonstrated that repeat administration of high doses (3–5 mmol kg–1) of non-ionic linear Gd chelates (gadoversetamide and gadodiamide) for 28 days produced skin ulceration and testicular atrophy [9]. These lesions are similar to those described with zinc deficiency [17]. Much higher cumulative doses were required to produce similar lesions with the ionic agents Gd-DTPA and Gd-DOTA [9].


Figure 3
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  		Figure 3. The chemical structure of gadoterate(Gd-DOTA, an ionic cyclic molecule). In this molecule, Gd+++ in the centre of the chelate has coordination sites with four carboxyl groups and four amino nitrogen atoms. The remaining vacant site is coordinated with a water molecule (H2O).

 
In summary, if Gd-CA, particularly the non-ionic linear chelates, are responsible for the development of NSF in patients with ESRD, then the stability of the Gd chelate is likely to be an important factor in the pathogenesis of this condition. The least stable molecules are the non-ionic linear chelates as they have the lowest stability values and the largest amounts of excess chelates [9, 11–13]. It is reasonable to hypothesise that free Gd+++ or ligands resulting from transmetallation might deposit in the dermis or other organs, attracting free fibrocytes which are present in the circulation to these sites to initiate the process of fibrosis. In addition, transmetallation and excess chelate can cause some depletion of endogenous zinc, which might be another factor in the pathogenesis of NSF.

Finally, more data are needed to establish the epidemiology of NSF and the threshold GFR above which this condition does not occur. Further studies are also required to explain the mechanisms responsible for this debilitating disease and elucidate the role of Gd-CA in triggering its development. Meanwhile, it is probably prudent at this stage of our understanding to avoid the administration of non-ionic linear chelates in patients with advanced renal impairment (GFR <30 ml min–1) including those on dialysis. A more stable Gd-CA such as ionic cyclic Gd-chelate might prove less hazardous if contrast enhanced MRI examination is thought to be necessary in such a group of patients.

Received for publication November 14, 2006. Revision received November 24, 2006. Accepted for publication December 4, 2006.


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