Gadolinium-based Magnetic Resonance Contrast Agents and Nephrogenic Systemic Fibrosis
The skin fibrosis of NSF patients varies from minor islets of hardened skin (plaques, papules and nodules) to large areas of confluent skin fibrosis with calcifications (see Figure 1). In the latter type of cases, patients are usually severely disabled and dependent on wheelchairs and personal assistants for most, if not all types of daily activities. Although skin fibrosis is the major problem in most NSF patients, it is important to recognise the existence of extracutaneous symptoms. In some patients, these symptoms predominate.
Skin Histology
As part of the diagnostic approach to patients thought to have NSF, it is essential to obtain a deep skin biopsy from regions with skin changes. In many cases, the histology may be characteristic and almost pathognomonic of NSF: dermis and subcutis are sites of extraordinary fibrosis with thick bands of collagen penetrating the subcutis and eventually involving the underlying muscles. Between collagen strands, CD34+ fibrocytes are a characteristic finding, whereas inflammation is usually absent. However, skin histology may be different, with foreign body reactions, panniculitis-like changes or signs of lymphocytic vasculitis in the early stages, and with unspecific fibrosis in the late stages of NSF. Therefore, skin histology does not always bring the diagnosis, but rather helps exclude certain differential diagnoses. Readers are referred to other papers for more details on the characteristics of NSF histology.11,16,23
Nephrogenic Systemic Fibrosis Epidemiology The first known NSF case was found in 1997.7
According to statistics
from the Danish Medicines Agency, the US Food and Drug Administration (FDA) and scientific reports, the number of suspected and confirmed NSF cases is now probably approaching 2,000. However, many more cases may have died without having been correctly diagnosed, and many living cases – in particular cases with mild or atypical symptoms – are probably still undiagnosed. The true number of NSF victims might be as high as 10,000 patients. The timing of the case reports in scientific papers and registries demonstrates that NSF has occurred as a global epidemic, with a peak incidence in 2005–2006.24–27
Today, the incidence has come
close to zero due to the change in clinical practices following the recognition of the causative agent(s).28–30
NSF has only been diagnosed among individuals with renal insufficiency (see Table 3). The large majority (>95 %) of cases are patients with chronic kidney disease (CKD) stage 5, either pre-dialytic or dialysed patients. However, NSF has also been reported in CKD4 patients and in patients with acute renal failure.31,32
There seems to be
no predilection for gender, race or age. Several paediatric cases have been reported.33
Link between Gadolinium-based Contrast Agents and Nephrogenic Systemic Fibrosis Until 2006, researchers had been unsuccessful in identifying the agent(s) causing NSF. Most agreed that the causative factor would be found in relation to newly introduced clinical practices. Intravenous iron, certain antibiotics, thrombotic events, surgery and septicaemia were suggested. However, none of these or other putative causal factors could be convincingly confirmed.
In the Department of Nephrology at Copenhagen University Hospital Herlev, Denmark, we were concerned when we realised that we were experiencing an NSF epidemic in 2005.24
EUROPEAN NEPHROLOGY
The skin of both legs from toes to high on the thighs is hardened and inflexible and has led to contractures of toes, ankles, knees and hips, and total dependency on a wheelchair. The skin is hairless and has a shiny appearance in some areas, whereas other areas show hyperpigmentation and scaling. Photograph: Fie Sløk, Plastic Surgery Department, Copenhagen University Hospital Herlev, Denmark.
at least 10 NSF cases among our CKD patients after not diagnosing any such cases in earlier years. In our search for a causative factor, we considered Gd toxicity caused by our frequent use of one particular GdBCA, Omniscan, for magnetic resonance (MR) angiograms in transplant candidates. In January 2006, we could conclude that, besides renal failure, GdBCA/Omniscan exposure was the only factor common to all of our NSF cases. Our suspicion about a causal link between GdBCA/Omniscan and NSF was confirmed when the Austrian nephrologist Thomas Grobner published his seminal report online on 23 January 2006.34
He observed that five of
nine haemodialysis patients developed NSF within a few weeks of GdBCA exposure. Our initial observations on 13 confirmed NSF cases were published in August 2006.35
In March 2006, we reported
our findings to the Danish Medicines Agency. Despite these efforts, it took almost a year before the European Medicines Agency (EMA) and FDA finally, in early 2007, signaled that GdBCAs should be abandoned or used with caution in patients with severe renal insufficiency.
Nephrogenic Systemic Fibrosis Risk Varies Between Individual Gadolinium-based Contrast Agents
Since 2006, the relationship between GdBCA exposure and NSF has been verified by several researchers worldwide, from the US to Europe and Japan.13,27,31,32,36–40
By August 2005, we counted
Most NSF cases have occurred after exposure to Omniscan (gadodiamide), one of the GdBCAs with the poorest stability profile (see Table 1). Even when market shares are taken into account, Omniscan is associated with over five times more NSF cases than most other GdBCAs. Only OptiMark® (gadoversetamide), which has a
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Figure 1: Patient with Severe Late Symptoms of Nephrogenic Systemic Fibrosis
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