Nephrogenic systemic fibrosis (NSF) is an iatrogenic fibrosing disorder that primarily affects individuals with chronic kidney disease (CKD) following exposure to gadolinium-based contrast agents (GBCAs) during imaging procedures. NSF is characterised by skin thickening, tethering and hyperpigmentation; flexion contractures of joints; and extracutaneous fibrosis. This article reviews the history, clinical manifestations, epidemiology, histopathology and pathophysiology of this disabling disease.
Nephrogenic systemic fibrosis (NSF) is an iatrogenic fibrosing disorder that primarily affects individuals with chronic kidney disease (CKD) following exposure to gadolinium-based contrast agents (GBCAs) during imaging procedures. NSF is characterised by skin thickening, tethering and hyperpigmentation; flexion contractures of joints; and extracutaneous fibrosis. It is chronic, often progressive and has no cure. In this review, we address the most commonly asked questions regarding NSF.
How was NSF first recognised?
NSF was first observed in 1997 at Sharp Memorial Hospital in San Diego, California. Between May 1997 and November 2000, 8 of 265 renal transplant recipients at that hospital developed flexion contractures, hyperpigmentation and ‘brawny induration’ of their skin . In 2000, 14 patients with stage 5 CKD who developed a scleromyxoedema-like skin disease, but without facial involvement or circulating paraproteins, were described in a published case series . Dermatopathologists at the University of California, San Francisco, analysed skin biopsies from these patients and noted a novel histopathologic appearance that was distinct from scleromyxoedema and other known fibrosing diseases . In 2001, this scleromyxoedema-like skin disease was termed nephrogenic fibrosing dermopathy (NFD) . NFD was later renamed nephrogenic systemic fibrosis (NSF), when involvement of tissues other than skin was recognised .
What are the clinical manifestations of NSF?
NSF typically presents with rapidly progressive skin thickening, tethering and hyperpigmentation, principally involving the extremities . Skin changes usually appear first on the distal lower legs and feet and then progress cephalad to involve the thighs, hands, forearms and upper arms. The skin on the chest, abdomen and back is affected much less often than that on the extremities.
Early in the course of NSF, affected skin may be erythematous and oedematous, lacking hyperpigmentation. These early skin lesions may be pruritic and can be mistaken for an allergic reaction. As cutaneous fibrosis progresses, however, the skin becomes significantly indurated and tethered to the point where it cannot be pinched. It commonly appears shiny with brawny hyperpigmentation ( Fig. 1 ). These established skin lesions are typically extremely painful.
Patterned plaques are another cutaneous manifestation of NSF. These thin, fixed plaques are red to violaceous in colour and have a polygonal or reticular appearance . Patients may also have superficial, hypopigmented pink or flesh-coloured macules with irregular borders that eventually coalesce into patches or thin plaques . Later in the course of NSF, patients may develop epidermal atrophy and hair loss, follicular dimpling (peau d’orange), ‘cobblestoning’, and hyperkeratosis with scaling .
Patients with advanced NSF commonly develop flexion contractures of the fingers, elbows and knees as a result of periarticular skin tightening ( Fig. 2 ). These flexion contractures can severely impair physical function . Patients may also develop extracutaneous fibrosis of skeletal muscle, diaphragm, lymph nodes, heart, lungs, pleura, oesophagus, liver, thyroid, genitourinary tract, sclera and dura mater .
What are the clinical manifestations of NSF?
NSF typically presents with rapidly progressive skin thickening, tethering and hyperpigmentation, principally involving the extremities . Skin changes usually appear first on the distal lower legs and feet and then progress cephalad to involve the thighs, hands, forearms and upper arms. The skin on the chest, abdomen and back is affected much less often than that on the extremities.
Early in the course of NSF, affected skin may be erythematous and oedematous, lacking hyperpigmentation. These early skin lesions may be pruritic and can be mistaken for an allergic reaction. As cutaneous fibrosis progresses, however, the skin becomes significantly indurated and tethered to the point where it cannot be pinched. It commonly appears shiny with brawny hyperpigmentation ( Fig. 1 ). These established skin lesions are typically extremely painful.
Patterned plaques are another cutaneous manifestation of NSF. These thin, fixed plaques are red to violaceous in colour and have a polygonal or reticular appearance . Patients may also have superficial, hypopigmented pink or flesh-coloured macules with irregular borders that eventually coalesce into patches or thin plaques . Later in the course of NSF, patients may develop epidermal atrophy and hair loss, follicular dimpling (peau d’orange), ‘cobblestoning’, and hyperkeratosis with scaling .
Patients with advanced NSF commonly develop flexion contractures of the fingers, elbows and knees as a result of periarticular skin tightening ( Fig. 2 ). These flexion contractures can severely impair physical function . Patients may also develop extracutaneous fibrosis of skeletal muscle, diaphragm, lymph nodes, heart, lungs, pleura, oesophagus, liver, thyroid, genitourinary tract, sclera and dura mater .
What is the differential diagnosis of NSF?
First and foremost, the clinician must suspect that a patient may have NSF. NSF is a clinical diagnosis that can be misidentified as one of several other fibrosing disorders, including scleromyxoedema, scleroedema diabeticorum and diffuse cutaneous or limited cutaneous systemic sclerosis ( Table 1 ). There are, however, several important clinical and historical features that aid the clinician in distinguishing NSF from other fibrosing disorders. A key clinical feature that distinguishes NSF from systemic sclerosis and scleromyxoedema is the nearly universal absence of facial skin involvement in NSF . Moreover, patients with NSF may have slightly raised, yellow plaques on the sclera of their eyes, adjacent to the iris, that are often accompanied by conjunctival injection ( Fig. 3 ). Raynaud’s phenomenon, periungual capillary dilatation and dropout and telangiectasias, which are commonly present in patients with systemic sclerosis, are not features of NSF. In addition, patients with NSF do not develop acroosteolysis.
| Fibrosing disorder | Clinical and historical features | Laboratory assessment and studies, if applicable |
|---|---|---|
| Lipodermatosclerosis / chronic venous stasis | Lesions of induration/dyspigmentation typically confined to the leg below the knee, without joint contractures Varicosities present proximal to lesions of induration | Venous duplex ultrasound with reflux testing |
| Scleromyxedema (lichen myxoedematous) | Numerous, minute (2–3 mm), firm, closely spaced papules on hands, arms, upper aspect of trunk, and/or face and neck Papules often arranged in linear pattern May show glabellar furrowing | Serum protein electrophoresis and serum immunofixation or immunoelectrophoresis for monoclonal gammopathy |
| Eosinophilic fasciitis | Symmetric cutaneous induration Joint stiffness | Complete blood cell count with white blood cell differential count Absolute eosinophil count |
| Systemic sclerosis (limited cutaneous and diffuse cutaneous) | Limited form with cutaneous involvement limited to face and skin distal to elbows and knees Diffuse form with cutaneous involvement that includes extremities proximal to elbows and knees as well as trunk May show diffuse hyperpigmentation or salt/pepper dyspigmentation (sparing or hypopigmentation around hair follicles) of forehead or in shawl distribution on trunk Sclerodactyly More likely to show induration of areas not typical of NSF (trunk and face, decreased oral aperture) Periungual dilated capillary loops Raynaud’s phenomenon Telangiectasias Ischaemic and traumatic digital ulcerations Acral osteolysis | Antinuclear antibody titre and pattern Anti-centromere antibodies Anti-topoisomerase 1 (Scl-70) antibodies Anti-RNA polymerase III antibodies Nailfold capillaroscopy |
| Scleredema diabeticorum | Primarily involves upper aspect of back with induration/erythema | Serum glucose (fasting) Haemoglobin A1c |
| Morphea / lichen sclerosis et atrophicus | Linear or guttate lesions of induration/dyspigmentation, typically paucilesional and asymmetric | |
| Chronic graft-versus-host disease | More likely to show lichenoid papules, erosive indurated plaques Involvement of trunk | |
| Dupuytren contracture | Lesions confined to palms/ hands, with subcutaneous bands of fibrosis on palms resulting in digital contractures | |
| Pruritus of renal disease / neuropathy | Lesions primarily secondary to chronic scratching, e.g., erosions/ulcers | Electromyography Nerve conduction studies |
| β 2 -Microglobulin amyloidosis | More likely to exhibit subcutaneous masses around shoulders and wrists and on palms of hands, without cutaneous lesions | |
| Stiff skin syndrome / congenital fascial dystrophy | Childhood onset Buttocks and thighs with bound-down skin Contractures of knees and hips commonly Hypertrichosis over involved areas Sharp demarcation at inguinal crease | |
| Sclerodermoid porphyria cutanea tarda | Tense, photodistributed bullae and vesicles Subtle facial hypertrichosis Shiny, firm, bound-down plaques of photoexposed and unexposed skin | Quantitation of uroporphyrinogen I in urine In anuric patients, stool isocoproporphyrin III and plasma uroporphyrin levels |
| Eosinophilia-myalgia syndrome | Caused by ingestion of l -tryptophan contaminated with 1,1′-ethylidenebis- l -tryptophan | |
| Spanish toxic oil syndrome | Caused by olive oil adulterated with denatured rapeseed oil |
Laboratory testing may support a clinical diagnosis of NSF by demonstrating the absence of antibodies that are present in some patients with other fibrosing disorders. Autoantibodies, such as antinuclear antibodies, anti-centromere antibodies, anti-topoisomerase I (Scl-70) antibodies and anti-RNA polymerase III antibodies may be present in patients with systemic sclerosis but are usually absent in patients with NSF. The absence of a circulating paraprotein can help to distinguish NSF from scleromyxoedema.
Which patients are at risk for developing NSF?
Grobner first posited an association between NSF and GBCA exposure in 2006, when he observed five of nine haemodialysis patients develop skin changes of NSF within 2–4 weeks after receiving an intravenous infusion of gadodiamide (Omniscan ® ) . Since this landmark publication, several studies have confirmed the association between administration of GBCA to individuals with CKD and the subsequent development of NSF ( Table 2 ) . This association fulfils most of the Bradford-Hill criteria for causality ( Table 3 ). Although multiple and higher cumulative doses of GBCA confer an increased risk of developing NSF, this fibrosing disorder can develop after only a single dose of a GBCA .
| Study (location) | Year published | Type | GBCA exposure | NSF cases/ total patients | NSF cases/GBCA-exposed patients |
|---|---|---|---|---|---|
| Marckmann et al. (Denmark) | 2006 | Retrospective | Gadodiamide | N/A | 13/370 (3.5%) |
| Broome et al. (Loma Linda, CA) | 2007 | Retrospective | Gadodiamide | 10/168 (6%) | N/A |
| Collidge et al. (Scotland) | 2007 | Retrospective | Gadodiamide | 14/1826 (0.8%) | 13/421 (3.1%) |
| Deo et al. (Bridgeport, CT) | 2007 | Retrospective | Gadodiamide | 3/467 (0.6%) | 3/87 (3.4%) |
| Lauenstein et al. (Atlanta, GA) | 2007 | Retrospective | Gadodiamide | N/A | 8/312 (2.6%) |
| Othersen et al. (Charleston, SC) | 2007 | Retrospective | Gadodiamide | 4/849 (0.5%) | 4/261 (1.5%) |
| Todd et al. (Boston, MA) | 2007 | Cross-sectional and prospective | Gadopentetate dimeglumine | 25/186 (13.4%) | 16/54 (29.6%) |
| Prince et al. (New York, NY) | 2008 | Retrospective | Gadodiamide, gadopentetate dimeglumine, gadobenate dimeglumine, gadoteridol | N/A | 11/398 (2.8%) |
| Rydahl et al. (Denmark) | 2008 | Retrospective | Gadodiamide | N/A | 18/102 (17.6%) |
| Chen et al. (Taiwan) | 2009 | Retrospective | Gadodiamide | N/A | 1/127 (0.8%) |
| Chrysochou et al. . (United Kingdom) | 2009 | Retrospective | Gadodiamide, gadopentetate dimeglumine, gadofosveset trisodium | N/A | 1/81 (1.2%) |
| Heinz-Peer et al. (Austria) | 2009 | Retrospective | Gadodiamide, gadopentetate dimeglumine, gadoterate meglumine, gadobutrol, gadoteridol, gadobenate dimeglumine, gadoxetate disodium | 6/552 (1.1%) | 6/367 (1.6%) |
| Hope et al. (Northern California) | 2009 | Retrospective | Gadopentetate dimeglumine | N/A | 1/530 (0.2%) |
| Lee et al. (Rochester, MN) | 2009 | Retrospective | Gadodiamide, gadopentetate dimeglumine, gadobenate dimeglumine, gadoteridol, gadoxetate disodium | N/A | 8/827 (1.0%) |
| Janus et al. (France) | 2010 | Retrospective | Gadodiamide, gadopentetate dimeglumine, gadoterate meglumine, gadobenate dimeglumine | 0/165 (0%) | N/A |
| Lemy et al. (Belgium) | 2010 | Retrospective | Gadodiamide, gadoterate, meglumine | 6/705 (0.9%) | 5/33 (15.2%) |
| Martin et al. (Atlanta, GA) | 2010 | Retrospective | Gadodiamide, gadobenate dimeglumine | N/A | 8/1096 (0.7%) |
| Chow et al. (Los Angeles, CA) | 2011 | Retrospective | Gadodiamide, gadopentetate dimeglumine | N/A | 1/97 (1.0%) |
| Kendrick-Jones et al. (New Zealand) | 2011 | Retrospective | Gadodiamide, gadopentetate dimeglumine, gadobutrol, gadobenate | N/A | 5/522 (1.0%) |
| Alhadad et al. (Sweden) | 2012 | Retrospective | Gadodiamide, gadopentetate dimeglumine, gadoterate meglumine, gadobenate dimeglumine, gadoxetate disodium, gadoteridol | N/A | 0/129 (0%) |
a This table includes results compiled from the listed studies only for patients with GFR < 15 mL/min. Broome et al. calculated a disease prevalence per GBCA exposure but not per GBCA-exposed patient.
| Criterion | Supporting evidence |
|---|---|
| Strength | Haemodialysis patients exposed to GBCA had an increased risk of developing cutaneous changes of NSF compared to haemodialysis patients not exposed to GBCA (OR 14.7) |
| Consistency | Multiple studies in different parts of the world have suggested an association between gadolinium exposure and the development of NSF |
| Specificity | All patients with NSF have had prior GBCA exposure or detectable gadolinium in tissue. (The four reported cases of NSF without prior GBCA exposure did not assay tissue from these patients to confirm the absence of detectable gadolinium.) |
| Temporality | NSF developed within 3 months after the last Magnevist ® dose in 66% of 36 patients with stage 5 CKD and biopsy-proven NSF . |
| Biological gradient | The likelihood of developing NSF was greater with higher cumulative and total GBCA doses (OR 1.2) . |
| Plausibility | NSF appeared only after GBCAs were used at higher doses in patients with stage 5 CKD for MR angiography just prior to renal transplantation surgery. The incidence of NSF decreased markedly after GBCA use was restricted in patients with stage 5 CKD . |
| Coherence | Gadolinium has been detected and quantified in the skin and other tissues of patients with NSF . |
| Experiment | Gadolinium has been detected and quantified in the skin of rats, which previously had been subjected to 5/6 nephrectomy, after the intravenous administration of a GBCA . |
| Analogy | Environmental exposures, such as to contaminated l -tryptophan or to rapeseed oil, have caused other fibrosing disorders among exposed individuals . |
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