Gadolinium chelate-associated nephrogenic systemic fibrosis.

Correspondence to: Dr Kei Pin Lin Tel: (65) 6222 3322 Fax: (65) 6326 5242 Email: binglin8@ yahoo.com.sg Nephrogenic systemic fibrosis (NSF) is a rare multisystem disease characterised by widespread tissue fibrosis. It is recognised for its epidemiological association in patients with chronic renal failure, after administration of gadolinium-chelate magnetic resonance (MR) contrast agent, particularly gadodiamide (Omniscan, GE Health Diagnostic, Amersham, United Kingdom). Gadoliniumbased contrast agents (GBCAs) are used for MR imaging because of gadolinium’s ability to increase the T1 relaxivity of soft tissue, increasing the contrast between normal tissue and pathology. As gadolinium, in its free form (Gd3+), can result in a toxic reaction in vivo, it exists in a form of water-soluble gadolinium chelate complex for use in medical imaging. Several brands of gadoliniumbased contrast agents exist, differing from each other by the chelate which binds to the gadolinium ion. The clinical features of NSF were first observed in 1997 and formally documented in 2000.(1,2) By January 2006, Grobner first proposed a possible causal relation between gadolinium-based contrast media and NSF. In that paper, Grobner observed that five of nine haemodialysis patients exposed to a GBCA (gadodiamide in this instance) developed NSF within 2–4 weeks of an MR imaging examination.(3) Since then, more than 80 related papers have been published, strengthening the epidemiological association between GBCAs and the development of NSF. Based on currently available data, the estimated incidence for the development of NSF in the patients with chronic renal failure, and who have had GBCA, is in the range of 3%–5%.(4-6) NSF has not been described in patients with normal renal function. The disease was originally named nephrogenic fibrosing dermopathy (NFD) for its more obvious dermatological clinical manifestations; it was later renamed nephrogenic systemic fibrosis in recognition of its systemic effects.(7) In spite of this, NSF remains a misnomer as it is not a kidney disease, but rather, it seems to occur in patients with severe renal failure who have received GBCAs. The estimated time between onset of symptoms and the contrast-enhanced MR imaging examination is about two to several months.(6,8) The skin manifestation is often the most obvious feature, although it can mimic scleromyxoedema, cellulitis or lymphoedema.(1) The skin thickening is usually insidious, but it can develop rapidly and confine the patient to a wheelchair within weeks. There is a predilection for the extremities, but torso involvement has been described. NSF typically spares the face and lacks the serological markers for scleroderma, such as antinuclear antibodies, anti-Scl 70 antibodies and anticentromere antibodies.(8) Autopsy series have shown fibrosis of skeletal muscles, bones, lungs, pleura, pericardium, oesophagus and kidneys.(7,9,10) The diagnosis is confirmed on skin biopsy. Histologically, there is increased tissue deposition of collagen bundles separated by cleft and proliferation of distinctive dermal spindle cells that stain positive for both CD 34 and procollagen. The precursors for these spindle cells exist in circulation as free “circulating fibrocytes”. In NSF, these “circulating fibrocytes” are thought to leave the circulation and differentiate into terminal fibroblast cells that are ultimately responsible for systemic fibrosis.(11) What triggers these circulating fibrocytes to differentiate into terminal fibroblast cells is unclear, but current thinking suggests Gd3+ may play a major role in the development of NSF. Recent reports have found gadolinium in skin biopsy of patients with NSF on electron dispersion spectroscopy.(12,13) While this is not a proof of causation, it is nevertheless supportive of epidemiological association between exposure to GBCA and development of NSF. Fig. 1a Chemical structure of a typical macrocyclic contrast agent: Dotarem.