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NDT Advance Access originally published online on July 7, 2007
Nephrology Dialysis Transplantation 2007 22(11):3097-3101; doi:10.1093/ndt/gfm430
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org


Nephrogenic systemic fibrosis—the need for a multidisciplinary approach

Joëlle L. Nortier1,2 and Véronique del Marmol1,2

1Department of Nephrology and 2Department of Dermatology, Erasme Hospital, Université Libre de Bruxelles, B-1070 Brussels, Belgium

Correspondence and offprint requests to: Joëlle L Nortier, MD, PhD, Nephrology, Dialysis and Renal Transplantation, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik, 808, Brussels, Belgium, Email: jnortier{at}ulb.ac.be

Keywords: dialysis; gadolinium-based contrast agents; gadodiamide; nephrogenic fibrosing dermopathy; nephrogenic systemic fibrosis; severe renal dysfunction



   Introduction
Top
 Introduction
Definition and diagnosis
 Physiopathological aspects
 Gadodiamide-related NSF
 Proposed mechanisms of...
 Therapeutic strategies
 Conclusion and recommendations
 References
 
The emergence of a new type of fibrosing dermopathy in advanced CKD patients is currently changing the cooperation between nephrologists and rheumatologists, dermatologists and radiologists. Many aspects of the pathophysiology of this clinical entity, initially called ‘nephrogenic fibrosing dermopathy’ (NFD) and now replaced by the term ‘nephrogenic systemic fibrosis’ (NSF), are still unknown, as regards a potential systemic involvement of the fibrosis process. This Editorial Comment summarizes the characteristics of the disease and the proposed aetiological mechanisms, focusing on the relationship between NSF and exposure to gadolinium-based MR contrast agents, as reported by Marckmann et al. in the present issue. The recommendations made by the Food and Drug Administration and the guidelines released by the European Society of Urogenital Radiology together with the UK Commission on Human Medicines are updated.



   Definition and diagnosis
Top
 Introduction
 Definition and diagnosis
Physiopathological aspects
 Gadodiamide-related NSF
 Proposed mechanisms of...
 Therapeutic strategies
 Conclusion and recommendations
 References
 
Reported for the first time in 1997 and recognized a few years later [1–5], NFD is a rare disorder characterized by widespread skin and possibly other tissue fibrotic processes (lungs, skeletal muscle, heart, liver, diaphragm and oesophagus). Although the precise cause of NSF is unknown, it only occurs in patients with renal failure, acute or chronic, particularly in those with CKD stage 4 or stage 5 requiring dialysis [6,7]. Patients who have had, or who are awaiting, liver transplantation are also thought to be at an increased risk of developing the disease [8]. A few paediatric cases have been reported [9].

The clinical course of the disease is highly variable. Usually, patients present with cutaneous thickening, hardening, swelling and hyperpigmentation of the extremities and/or the abdomen (Figure 1). Head and neck are spared. Painful contractures of the joints may progressively result in reduced mobility, and may be associated with paresthesiae and/or severe pruritus. Spontaneous remissions are not the rule, although improvement has been observed if a rapid correction of renal function can be obtained by medical or surgical means. Five percent of the patients have a rapidly progressive fulminant course. Further detailed information can be found at the International Center for Nephrogenic Fibrosing Dermopathy Research website (http://www.icnfdr.org). This international NSF registry at Yale University (New Haven, Conn.) maintains records on over 215 patients worldwide.


Figure 1
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  		Fig. 1. (A) and (B) Skin thickening resembling an orange-peel texture is a typical clinical finding in early stage NSF, observed on both arms of a kidney transplant recipient 11 months after exposure to gadodiamide. Contractures followed, resulting in painful and significantly limited joint movement.

 
Diagnosis of NFD/NSF is made by a full-thickness skin biopsy of the affected area. Typically, reticular dermal bundles of collagen are observed with spindle cells staining positive for both CD34 and procollagen (Figure 2). This CD34+ immunostaining profile is actually characteristic of ‘circulating fibrocytes’, i.e. circulating cells of bone marrow origin expressing markers of both connective tissue cells and circulating leucocytes [10]. Mucin deposition is often seen between the collagen bundles but inflammatory cells are usually absent.


Figure 2
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  		Fig. 2. Punch biopsy of an involved site (haematoxylin and eosin stain; magnification 100x) showing widening of subcutaneous septae with thick collagen bundles in (A) the deep dermis, (B) the subcutaneum and (C) positivity in dendritic cells (CD34 stain, haematoxylin counterstain; magnification 100x).

 
The differential diagnosis includes scleromyxedema, systemic sclerosis, eosinophilic fasciitis, eosinophilia–myalgia syndrome, toxic oil syndrome, calciphylaxis, etc. [11–14] (Table 1).


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  		Table 1. Main differential diagnoses for nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis (NFD/NSF)

 


   Physiopathological aspects
Top
 Introduction
 Definition and diagnosis
 Physiopathological aspects
Gadodiamide-related NSF
 Proposed mechanisms of...
 Therapeutic strategies
 Conclusion and recommendations
 References
 
Although more questions than answers remain regarding the aetiology of NSF, it appears that circulating fibrocytes, initially described in the context of wound repair, are the cells which are aberrantly stimulated and synthesize collagen, resulting in thickening of the skin [10]. This process, in a context of renal failure and associated with an upregulation of transforming growth factor (TGF)-β, has been correlated with specific situations such as thrombotic events or hypercoagulable states (over 10% of individuals with NSF), high doses of erythropoietin and the lack of use of angiotensin-converting enzyme inhibitors acting as potent inhibitors of TGF-β [15–18]. A persistent inflammatory syndrome, possibly reflecting a sustained ‘endothelial stress’, has also been suggested as an enhancement factor. Indeed, a major tissue injury (surgical procedure, ischaemic limb) has been linked with NSF in many reports. However, the cause of skin targeting is still unknown. Cowper et al. have proposed that the key pathogenetic mechanism of NSF includes the pre-existence of renal dysfunction and concurrent tissue injury. This proinflammatory milieu may then cause the release of cytokines, which recruit circulating fibrocytes from the bone marrow. These cells deposit in the skin and joints and release more cytokines, growth and neoangiogenic factors, resulting in fibrosis [19].



   Gadodiamide-related NSF
Top
 Introduction
 Definition and diagnosis
 Physiopathological aspects
 Gadodiamide-related NSF
Proposed mechanisms of...
 Therapeutic strategies
 Conclusion and recommendations
 References
 
The fact that renal dysfunction is a common factor to all cases suggests the presence of some endogenous or exogenous substances susceptible to trigger NSF. Grobner [20] was the first to propose a possible causal link between NSF and a gadolinium (Gd)-containing magnetic resonance imaging (MRI) contrast agent, gadodiamide (Omniscan®) in patients with end-stage renal failure (ESRF) and documented metabolic acidosis. Several months later, Marckmann et al. [21] reported 13 CKD patients who underwent MRI with gadodiamide contrast agent prior to the development of NSF. No other common exposure/event could be identified. The delay from exposure to first sign of the disease was 2–75 days (median 25 days). The odds ratio for acquiring the disease after gadodiamide exposure was 32.5 (95% CI: 1.9–549.2) (P < 0.0001). Half of these patients became severely disabled and one died <2 years after exposure. Already in 2004, Evenepoel et al. [22] reported two cases of severe NSF. The common factor in these three reports was that all 20 patients had been exposed to gadodiamide. According to the official site of the NFS registry, the majority of cases had been exposed to gadolinium within 2–8 weeks prior to clinical symptoms. Gadodiamide was the most frequent contrast agent involved [23].

In this issue, Marckmann et al. [24] report the results of a case-control study performed on 19 histologically proven NSF cases and 19 sex- and age- matched controls. Interestingly, the authors identified four risk factors for developing gadodiamide-related NFS: a high cumulative gadodiamide exposure, biological parameters particularly of most importance in stage 5 CKD patients (high serum concentrations of ionized calcium and phosphate) and high dose of epoietin-β treatment.



   Proposed mechanisms of gadolinium-based contrast agents triggered NSF
Top
 Introduction
 Definition and diagnosis
 Physiopathological aspects
 Gadodiamide-related NSF
 Proposed mechanisms of...
Therapeutic strategies
 Conclusion and recommendations
 References
 
Around 200 million patients have had injections of a Gd-based contrast agent since the early 1980s. These contrast agents are actually aqueous solutions containing the rare earth metal Gd. Because Gd is highly toxic, it is reversibly held in a complex structure with other molecules (called a chelate) in the contrast-agent solution. Eight agents have been authorized for use in the European Union since the late 1980s. Among them, Omniscan®, the brand name of gadodiamide, is used in MRI examinations of the brain, spine and other parts of the body, and is also used to detect coronary artery disease and peripheral arterial disease. Omniscan® is given by intravenous injection, and the recommended dose for adults is 0.1 mmol/kg body weight.

Because NSF develops only in patients with advanced renal failure, it is important to realize that gadodiamide is almost exclusively excreted renally. Therefore, its total body clearance is dramatically slower in renal failure (the elimination half-life increases from 1.3 h in healthy volunteers to 34.3 h in stage 5 CKD patients) [25].

The mechanisms by which some gadolinium-containing contrast agents are more likely to trigger NSF than others have been related to their different physicochemical properties susceptible to affect the release of free Gd ions (Gd3+) [26]. The agents Omniscan® and OptiMARK® (only available in the US) carry no molecular charge and are arranged in a linear structure with excess chelate (DTPA-BMA 12 mg/ml for gadodiamide) facilitating the release of free Gd3+ into the body by transmetallation of the excess chelate with endogenous ions. Contrast agents with a linear structure but carrying a molecular charge (e.g. Magnevist®, Multihance®, Primovist®, and Vasovist®), and those free of molecular charge but with a cyclical structure (e.g. Gadovist® and ProHance®) seem to be less likely to release free Gd3+ into the body. Dotarem has a molecular charge and a cyclical structure, and is least likely to release free Gd3+ into the body (Tables 2 and 3). Actually, transmetallation is more likely to occur when Gd-agents remain inside the body for a long period as is the case in renal failure. Deposition of free Gd ions in tissues and organs from NSF patients has been reported [27,28]. Although the exact mechanism of such deposition is unknown, it is thought to stimulate NSF through induction of fibrosis [19]. Up till now, most NSF cases have been associated with the agents Omniscan® and OptiMARK®, while a small number of cases have been associated with Magnevist®.


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  		Table 2. Currently marketed gadolinium contrast agents associated with NFD/NSF cases (according to [26])

 

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  		Table 3. Currently marketed gadolinium contrast agents not associated with NFD/NSF cases (according to [26])

 


   Therapeutic strategies
Top
 Introduction
 Definition and diagnosis
 Physiopathological aspects
 Gadodiamide-related NSF
 Proposed mechanisms of...
 Therapeutic strategies
Conclusion and recommendations
 References
 
A large panel of dermatological treatments, usually used in sclerodermal processes, has been proposed for the treatment of NSF, with varying degrees of success. No single treatment has proven effective. However, improvement in renal function seems to stop or reverse the process. Therapeutic approaches including steroids, plasmapheresis, extracorporeal photopheresis, intravenous immunoglobulin, ultraviolet light therapy, physical therapy, renal transplantation and pentoxifylline have shown some promise [29–32]. The use of ACEIs has also been proposed [16], but in the case control study by Marckmann et al. (see this issue), a similar proportion of controls took these drugs.



   Conclusion and recommendations
Top
 Introduction
 Definition and diagnosis
 Physiopathological aspects
 Gadodiamide-related NSF
 Proposed mechanisms of...
 Therapeutic strategies
 Conclusion and recommendations
References
 
NSF is to be considered as a serious late adverse reaction in stages 4 or 5 CKD patients. A possible causal relationship between gadodiamide and NSF has recently been established, but the effective involvement of other Gd-based contrast agents in the disease remains to be assessed. In view of all available data, the Food and Drug Administration (FDA) issued a warning on 8 June 2006, on the risk of using gadodiamide in patients with advanced renal dysfunction (http://www.fda.gov). In February 2007, after several meetings of European experts, the UK Commission on Human Medicines, together with the European Pharmacovigilance Working Party of the Committee for Medicinal Products for Human Use, proposed the following recommendations:

  • Do not use Omniscan® (gadodiamide) in patients with a glomerular filtration rate <30 ml/min/1.73 m2) or in patients who have had, or who are awaiting, liver transplantation. Gadodiamide should only be used in neonates and infants up to 1 year of age after careful consideration.
  • Careful consideration should be given to the use of other Gd-containing MRI contrast agents in patients with severe renal impairment (glomerular filtration rate <30 ml/min/1.73 m2).
  • There is not enough evidence to advice initiation of dialysis in patients at risk of NSF after use of a Gd-containing contrast agent. In a recent study, dialysis of 10 patients within 2 days of gadodiamide administration did not prevent these patients from developing NSF [33].

It should be noted that Omniscan® has been used in more than 30 million patients worldwide since it was first licensed. As no cases of NSF have been observed in patients with normal renal function, its use in these patients is considered safe.

Suspected adverse drug reactions should be reported to the Medicines and Healthcare products Regulatory Agency (MHRA) by use of a Yellow Card, which is available from MHRA, CHM Freepost, London SW8 5BP or electronically via the MHRA website (http://www.mhra.gov.uk). Additional information can also be found on the website of the European Society for Urogenital Radiology (http://www.esur.org).

Conflict of interest statement. None declared.

(See related article by J. B. Othersen et al. Nephrogenic systemic fibrosis after exposure to gadolinium in patients with renal failure. Nephrol Dial Transplant 2007; 22: 3179–3185.)

(See related article by P. Marckmann et al. Case-control study of gadodiamide-related nephrogenic systemic fibrosis. Nephrol Dial Transplant 2007; 22: 3174–3178.).



   References
Top
 Introduction
 Definition and diagnosis
 Physiopathological aspects
 Gadodiamide-related NSF
 Proposed mechanisms of...
 Therapeutic strategies
 Conclusion and recommendations
 References
 

  1. Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet (2000) 356:1000–1001.[CrossRef][ISI][Medline]
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  17. Swaminathan S, Ahmed I, McCarthy JT, et al. Nephrogenic fibrosing dermopathy and high-dose erythropoietin therapy. Ann Intern Med (2006) 145:234–235.[Free Full Text]
  18. Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor beta in human disease. N Engl J Med (2000) 342:1350–1358.[Free Full Text]
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  22. Evenepoel P, Zeegers M, Segaert S, et al. Nephrogenic fibrosing dermopathy: a novel, disabling disorder in patients with renal failure. Nephrol Dial Transplant (2004) 49:469–473.
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Received for publication: 28. 5.07
Accepted in revised form: 6. 6.07


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Related articles in NDT:

Case-control study of gadodiamide-related nephrogenic systemic fibrosis
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In this issue ...

NDT 2007 22: i. [Extract] [FREE Full Text]  




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