Nephrogenic systemic fibrosis and gadolinium exposure: Association and lessons for idiopathic fibrosing disorders

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In 1914, Bramwell reported cases of scleroderma in Scottish stone masons who appeared to have acquired the disease because of their occupational exposure to silicates (1). Since that time, there has been a periodic emergence of scleroderma-like syndromes in association with an environmental exposure. Vinyl chloride disease and organic solvent exposure (reported in the 1950s) (2), toxic oil syndrome (reported in 1981) (3), and eosinophilic myalgia syndrome (reported in 1989) (4) are examples of fibrosing disorders that resemble scleroderma, both in their cutaneous manifestations and in certain multisystem features (5).

Nephrogenic systemic fibrosis (NSF) is a recently recognized fibrosing disorder that develops in individuals with renal impairment, usually in those requiring dialysis. The disease was first described in 2000 and originally was termed nephrogenic fibrosing dermopathy (6); this name was changed recently to better acknowledge the systemic features of the disease (7, 8). Patients with NSF generally present with rapidly progressive thickening and hardening of the skin of the extremities. Although the skin changes may begin insidiously, the rapidity of progression can be striking, and patients who are affected can be immobilized and become wheelchair-bound in a matter of a few weeks. Histologically, there is increased cutaneous deposition of collagen and the presence of CD34+, spindle-shaped cells, or fibrocytes (9) (Figure 1). Inflammatory cells and eosinophilia are not observed, and the serologic features of scleroderma or autoimmunity are absent. Some patients show histologic involvement of the internal organs (lung, heart, esophagus, skeletal muscle, and diaphragm), but these manifestations are frequently subclinical. NSF may occasionally stabilize, and, in a few cases, renal replacement has led to remission and a reversal of disease (10).

Figure 1.

Double immunoperoxidase staining for CD34 (brown) and procollagen (red), showing abundant fibrocytes in the cutaneous lesions of nephrogenic systemic fibrosis. Staining for CD34 is most marked along the dendritic processes, while that for procollagen is localized to the cytoplasm.

With renal impairment a prerequisite for NSF and no cases evident before 1997, the first attention by investigators and the US Centers for Disease Control and Prevention was on the causative role of new, or reformulated, medications. In 2006, Grobner reported on 9 patients with end-stage renal disease who had received magnetic resonance (MR) angiography with gadodiamide; among these 9 patients, NSF developed in 5 (11). Subsequently, investigators from Denmark reported that among 370 patients with severe renal insufficiency who received a gadolinium-based MR contrast agent, NSF was later diagnosed in 13 patients (3.5%) (12). More recently, a study of 467 patients with end-stage renal disease who lived in Connecticut identified an incidence of NSF of 4.3 cases per 1,000 patient-years, with each gadolinium exposure conferring a 2.4% risk for disease (13). Results of a survey of the international NSF registry at Yale University that is currently under way now suggest that perhaps 95% of patients with NSF have received a gadolinium-based MR contrast agent within a 3-month period prior to disease onset (Cowper SE: unpublished observations). These cases, together with those reported to the US Food and Drug Administration MedWatch Web site (14), have led to the issuance of a Public Health Advisory urging caution in the use of MR contrast agents in patients with renal disease, and the prompt institution of dialysis in patients with renal insufficiency who have received gadolinium-based MR contrast agents (15, 16).

In this issue of Arthritis & Rheumatism, Todd and colleagues contribute to this evolving story with their finding of early cutaneous changes of NSF in as many as 30% (16 of 54) of hemodialysis patients with documented exposure to gadolinium-based contrast agents (17). These patients were followed up prospectively for 2 years, and the calculated odds ratio for developing clinical skin findings was 14.7. This high incidence of NSF-like skin changes may reflect the purely clinical criteria used in their study, which recorded skin hyperpigmentation, hardening, and tethering. This report nevertheless raises the possibility that reactive NSF-like skin changes may be more common in this patient group than presently considered and perhaps point to an early, or less severe, form of NSF. The authors also suggest a significantly increased risk of mortality for these patients (48% in those with the cutaneous changes of NSF versus 21% in those without such changes), which is significant given the already poor survival of patients requiring dialysis. These findings, if confirmed by a biopsy-proven study, will undoubtedly heighten concern about the risk of exposure to gadolinium-based MR contrast agents in dialysis patients and perhaps in patients with more mild renal insufficiency.

A causative relationship between gadolinium and NSF remains to be established, although the present data certainly point to such a relationship. Gadolinium is a paramagnetic rare earth metal in the lanthanide series that typically exists in a 3+ oxidation state. The various MR imaging contrast agents use different chelates to bind a single atom of gadolinium (Figure 2). The gadolinium chelates are rapidly cleared by the kidney or by various dialysis modalities (18). Free, unchelated gadolinium is highly toxic (19), and recent tissue biopsy studies have confirmed the retention of this element in the affected skin of patients with NSF, in some cases for many months after administration (20, 21).

Figure 2.

Chemical structure of a representative gadolinium (Gd) chelate (gadodiamide). Development of nephrogenic systemic fibrosis has been associated with several chemically different, chelated forms of gadolinium. Gd-DTPA-BMA = Gd–diethylenetriaminepentaacetic acid bismethylamide.

What may be said about the pathogenesis of NSF based on our current fund of knowledge? Why do only a small subset of patients with renal insufficiency—perhaps no more than 5% of a series of patients with biopsy-proven NSF—develop NSF? Does patient susceptibility reflect a genetic predisposition to gadolinium? Precisely how is gadolinium toxicity manifest in patients prone to development of the disorder? Are some gadolinium-based contrast agents more toxic than others, perhaps due to their clearance properties or to the intrinsic chemical stability of the gadolinium chelate (22)? Is there a role for concurrent disorders in metabolism, such as acidosis, or in calcium homeostasis that may promote chelate dissociation and the liberation of free, toxic gadolinium (23)? Calcium deposition occurs in the vascular wall and interstitium; perhaps these are mixed deposits of gadolinium and calcium phosphates (21). An increase in the thickness of the adventitial layer of small and medium-sized arterioles also has been reported, which may reflect a vasculopathic effect of gadolinium (24).

The presence in lesions of fibrocytes (25), which are presumably derived from the circulation, and the absence of mitotic figures suggest that these cells may have infiltrated from the circulation in response to activation or abnormal trafficking signals (9, 24, 26). Whether fibrocytes play a primary pathogenic role in NSF, as may be suggested by recent studies of these cells in patients with fibrosing disorders of the lung (27), liver (28), and kidneys (29), is unknown, but this question may be approached by studying the responses of these cells to gadolinium exposure. The ability to create molecular profiles, with high precision, of connective tissue cell responses offers a means to identify candidate disease pathways in patients who are and those who are not reactive to gadolinium exposure. Such information also could facilitate the development of MR contrast agents that have a less toxic response profile, and preserve the high clinical utility of MR as an imaging modality in patients with renal insufficiency.

Finally, the fact that scleroderma-like conditions arise rather frequently may highlight a dominant feature of the scleroderma phenotype in the systemic tissue response to injurious stimuli. A closer understanding of both the molecular and the individual basis for susceptibility to these “reactive” fibroses may prove instructive in uncovering the pathogenesis of not only NSF but also idiopathic scleroderma and other fibrosing disorders.

Acknowledgements

We are grateful to participants of the First Annual Scientific Symposium on Nephrogenic Systemic Fibrosis (New Haven, CT, May 4, 2007) for helpful discussions, and to Stephen Malawista for review of the manuscript.

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