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Nephrogenic systemic fibrosis: a gadolinium-associated fibrosing disorder in patients with renal dysfunction
  1. J Kay
  1. Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts, United States
  1. Dr Jonathan Kay, Massachusetts General Hospital, Yawkey 2-174, 55 Fruit Street, Boston, MA 02114, USA; jkay{at}


Nephrogenic systemic fibrosis (NSF) is a debilitating fibrosing disorder that develops in patients with underlying kidney disease following exposure to gadolinium-containing contrast agents. NSF presents with cutaneous hyperpigmentation and induration and joint contractures, but fibrosis may also develop in other organs. NSF has been observed in up to 18% of patients receiving chronic haemodialysis and also may occur in individuals with stages 3 and 4 chronic kidney disease and, occasionally, in individuals who had experienced acute renal failure. Mortality is increased significantly among individuals with NSF. Although no medical treatment has been proved to be universally effective in patients with NSF, imatinib mesylate shows potential as a therapeutic agent and is currently being studied in these patients.

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Nephrogenic systemic fibrosis (NSF), originally named nephrogenic fibrosing dermopathy (NFD), was first observed in May 1997; by November 2000, eight (3%) of 265 renal transplant recipients at Sharp Memorial Hospital in San Diego, California, had been observed to develop cutaneous thickening and hyperpigmentation and flexion contractures, predominantly of their elbows and knees.1 In 2000, Cowper and colleagues reported 14 patients with chronic kidney disease, all of whom developed a condition that resembled scleromyxoedema, but that spared the face and was not associated with circulating paraproteins.2 These patients did not experience Raynaud’s phenomenon, as might individuals with scleroderma. Despite suffering severe pain and having flexion contractures of their elbows and knees, they had no evidence of arthritis. At the time of its original description, no visceral involvement had been identified.

Skin biopsies from these initial patients were reviewed by dermatopathologists at the University of California, San Francisco, who determined that these patients had a condition that was histologically distinct from other known skin diseases.3 Skin biopsies of patients with NSF are characterised by a hypercellular dermis with few inflammatory cells but with prominent dermal spindle cells that proliferate and intercalate among thickened and clefted collagen bundles. On their surface, these cells express CD34, CD45RO and type I procollagen: markers suggesting that these cells are derived from circulating fibrocytes that ultimately deposit in the skin. Prominent elastic fibres interweave among the dermal collagen bundles and mucin deposits in the interstitium of the superficial dermis. Dendritic cells expressing CD68 and factor XIIIa, as well as multinucleated giant cells, may also be present. In biopsies from some patients with NSF, calcium may be deposited around dermal blood vessels.4 Because the dermal changes of NSF are subtle in some patients and characteristic histological changes may also involve the interlobular septae, it is important to obtain a deep biopsy that includes both skin and subcutaneous fascia when evaluating a patient with suspected NSF.

The cutaneous features of NSF typically first involve the distal extremities and extend proximally as the disease progresses.5 6 Initially, patients may report itching or burning and may notice cutaneous erythema. As the disease progresses, red to violaceous or hypopigmented fixed plaques may develop in a reticular pattern on the extremities or trunk. The skin on the arms and legs usually becomes markedly indurated, such that it cannot be pinched between the thumb and forefinger, often with associated hyperpigmentation (see fig 1). The skin around hair follicles may be dimpled (peau d’orange change) and deep induration may create a cobblestone-like texture of the skin on the thighs, upper arms and trunk. Some patients may present with superficial changes of NSF, in which hypopigmented, pink or flesh-coloured macules or papules coalesce into patches or thin plaques, usually on the upper extremities. Many patients with NSF also have characteristic yellow scleral plaques on their eyes, nasal and temporal to the iris.

Although NSF was initially identified as a skin disease (giving rise to its original name of NFD), prominent systemic involvement has become evident as more cases of NSF have appeared. Both striated and cardiac muscles are affected by NSF, with muscle fibre atrophy, perimysial and endomysial fibrosis, scattered interstitial chronic inflammation and occasional calcium deposition in muscle.7 Prominent fibrosis of the left ventricular myocardium, interventicular septum, atrioventricular node, pericardium and great vessels has been identified on postmortem examination of patients with NSF.8 Pleural and diaphragmatic fibrosis has also been observed.9 Interstitial pulmonary fibrosis has been identified in patients with NSF, as evidenced by decreased total lung capacity and single breath diffusion capacity of carbon monoxide on pulmonary function testing. The adventitia of small and medium sized pulmonary arterioles may be thickened with marked accumulation of fibrous tissue, perhaps contributing to the clinical presentation of pulmonary hypertension in some patients with NSF.10 NSF involvement of the central nervous system has manifested as dura mater thickening.11 12 Changes of NSF have also been found in liver, lymph nodes and the genitourinary tract.8 13 As more patients with NSF undergo detailed postmortem examinations, the clinical spectrum of systemic involvement by this condition will almost certainly expand.

All patients identified to date with NSF have had underlying renal dysfunction. Most have had stage 5 chronic kidney disease (CKD, glomerular filtration rate (GFR) <15 ml/min/1.73 m2 or are receiving dialysis) and most had been undergoing haemodialysis. However, cases of NSF have been reported in patients with stage 4 CKD (GFR 15–29 ml/min/1.73 m2) and several cases have been confirmed in patients with stage 3 CKD (GFR 30–59 ml/min/1.73 m2). NSF has also developed in individuals who had acute renal failure and then recovered, as well as in individuals with CKD after renal transplantation.14 Thus, whereas underlying kidney disease appears to be necessary for the development of NSF, it is not a complication of renal replacement therapy alone.

To assess the prevalence of cutaneous changes of NSF among patients at risk for developing this condition, we performed screening skin examinations on 186 adult patients who were receiving outpatient haemodialysis at five outpatient dialysis centres.15 The arms and legs of these patients were examined for characteristic skin changes of NSF: hyperpigmentation, hardening and tethering. We considered a patient to have clinical evidence of NSF if any two or all three of these skin findings were present. Of the 186 patients examined, 25 (13.4%) had at least two findings and 12 (6.5%) had all three findings. Skin biopsies available from four of these 25 patients demonstrated histological features diagnostic of NSF. Of the 25 patients who were identified as having cutaneous changes of NSF, 12 (48%) had changes involving either the skin of the upper and lower extremities or joint contractures on affected extremities. Thus, lipodermatosclerosis or chronic venous stasis change could be excluded as a confounding cause of these skin changes in at least half of the cases identified. Rydahl and colleagues in Denmark confirmed this high prevalence of NSF among individuals with stage 5 CKD, diagnosing NSF in 18% of a cohort of patients receiving haemodialysis.16

When we followed our cohort of patients with cutaneous changes of NSF over 24 months after the skin examination, we observed significantly decreased survival of those with skin changes compared to those without.15 Among patients with clinical evidence of NSF, 24-month mortality was increased significantly compared to those without (48% versus 20%, respectively). The hazard ratio (HR) for death, comparing those with skin changes to those without, was greatest at 6 months (HR 5.1, 95% CI 1.9 to 13.4) but remained significantly increased at 12, 18 and 24 months. When adjusted for sex, age group, duration of haemodialysis, race and presence of diabetes, the hazard ratios for death at each time point decreased only slightly and remained statistically significant. Of the demographic characteristics, only having diabetes was significantly associated with mortality (p = 0.04). Cardiovascular causes accounted for seven (58%) of 12 deaths in patients with cutaneous changes of NSF and for 16 (48%) of 33 deaths in patients without cutaneous changes of NSF, but no other single cause of death predominated in either group. Further study of larger numbers of patients will be necessary to ascertain the predominant cause of this increased observed mortality among patients with NSF.

The most important clue to understanding the pathogenesis of NSF came from the observation in 2006 by Grobner, a nephrologist in Wiener Neustadt, Austria, that five of nine patients receiving treatment in his dialysis unit “developed thickening and induration of the skin, starting on the lower extremities and eventually spreading to the trunk and upper extremities” within 2–4 weeks after undergoing magnetic resonance (MR) angiography with gadodiamide (Omniscan), a gadolinium-containing contrast agent.17 He noted that all of the patients who developed NSF after gadodiamide exposure had metabolic acidosis, whereas the four patients who did not had normal pH and bicarbonate levels. Based upon this observation, he suggested that gadodiamide “possibly plays a triggering role in the development of NFD under certain circumstances”. Later in 2006, Marckmann and colleagues from Herlev Hospital in Denmark, reported an additional 13 patients with stage 5 CKD who developed NSF a median of 25 days (range 2–75 days) after receiving gadodiamide contrast during MR imaging.18

We investigated the association of previous gadolinium exposure and the subsequent development of cutaneous changes of NSF in our cohort of patients with stage 5 CKD, all of whom had been examined for skin changes.15 Because the skin examination had been performed long before there had been any suggestion of an association between gadolinium-containing contrast exposure and NSF, we had not obtained a history of gadolinium exposure among all 186 patients. However, we were able to define a subcohort of 90 patients who had an active electronic medical record and who had obtained at least two radiographic studies within the Partners Healthcare system during the year before the skin examination. There was no statistical difference between the groups in the subcohort and those in the entire cohort with regard to age, gender, race, duration of haemodialysis, history of diabetes mellitus, or aetiology of renal disease. Among those with cutaneous changes of NSF, 16 (94%) had a record of undergoing a gadolinium-enhanced imaging study using gadopentetate dimeglumine (Magnevist) as the contrast agent; among the 73 without cutaneous changes of NSF, 38 (52%) had a record of a previous gadopentetate dimeglumine-enhanced imaging study. Thus, the odds ratio for clinical evidence of NSF was 14.7 (95% CI 1.9 to 117.0) for those patients who had previously undergone an imaging study with gadolinium-containing contrast. This implies a very strong association between previous gadolinium-containing contrast exposure and the presence of NSF and confirmed the hypothesis that gadolinium might trigger the development of NSF.

The association between gadolinium exposure and the development of NSF in patients with CKD is further supported by the detection of gadolinium in the skin of patients with NSF,19 20 but not in the skin of individuals with normal kidney function who had received gadolinium-containing contrast.21 High and colleagues detected gadolinium by field emission scanning electron microscopy (SEM) and identified elemental components by field electron dispersion spectroscopy (EDS) in skin biopsies from four of seven patients with NSF but not in one negative control.19 Boyd and colleagues detected gadolinium by SEM and EDS in areas of calcium-phosphate deposition in cutaneous blood vessels of another patient with NSF.20 We demonstrated systemic deposition of gadolinium in skin, lymph node, thyroid, kidney, adrenal gland, liver, lung and myocardium obtained from a patient with NSF at postmortem examination.8 The inability to detect gadolinium in tissue from a patient with NSF probably is due to the amount of gadolinium being below the sensitivity of the assay and not to the true absence of gadolinium. Although four patients are reported to have developed NSF without previous gadolinium exposure, tissue from these patients was not assayed to confirm the absence of detectable gadolinium in involved skin.2224

Gadolinium is a rare earth element of the lanthanoid series that, as a free cation, is highly toxic.25 Free gadolinium blocks voltage-gated calcium channels and inhibits physiological processes that depend upon calcium influx, inhibits phagocytosis by Kupffer cells and interferes with drug metabolism by decreasing cytochrome P450 content of hepatic microsomes. As a free cation, gadolinium can compete with other cations for physiological binding sites. Thus, gadolinium can displace co-factors such as zinc, iron or copper from their binding sites on enzymes and interfere with the catalytic activity of those enzymes. Gadolinium can also displace iron from binding proteins, resulting in increased circulating free iron.26

To reduce the acute toxicity of gadolinium, it may be chelated by polyamino-polycarboxylic ligands.27 These organic cages surround the gadolinium cation and minimise the amount of free gadolinium that is available for binding. Gadolinium-containing contrast agents consist of gadolinium cations surrounded by various chelates. Six gadolinium-containing contrast agents are approved by the US Food and Drug Administration (FDA) and eight are approved by the European Medicines Agency (EMEA) for use in MR imaging (table 1). However, none of the FDA-approved gadolinium-containing contrast agents are approved or indicated in the United States for MR angiography, in which a larger volume of contrast is used than in routine MR imaging. The toxicity of a gadolinium-chelate complex depends upon its ability to release free gadolinium cations. In general, the macrocyclic chelates are considered to be more stable than the linear chelates.25 However, the linear gadolinium-chelate complexes gadodiamide (Omniscan) and gadopentetate dimeglumine (Magnevist) have been the most frequently used gadolinium-containing contrast agents. We have demonstrated an inverse relation between the total amount of gadopentetate dimeglumine administered to a patient and the time to onset of NSF symptoms: the higher the total gadopentetate dimeglumine dose, the sooner the onset of NSF symptoms.28 This dose-response relation further supports the association of gadolinium-containing contrast administration with the development of NSF.

Table 1 Gadolinium-containing contrast agents

Although spontaneous resolution of NSF lesions has been reported in two patients who experienced normalisation of renal function,3 most patients with NSF experience relentlessly progressive disease. That NSF developed in patients with functioning renal allografts, who had received gadolinium-containing contrast during MR angiography performed before renal transplantation, demonstrates that restoration of normal renal function does not prevent the onset or progression of NSF. Acute haemodialysis after exposure to gadolinium-containing contrast has been proposed for patients with CKD.29 However, less than 80% of gadopentetate dimeglumine is removed in a single haemodialysis treatment30 and it is unclear that dialysis can be performed soon enough after the administration of gadolinium-containing contrast to prevent dissociation and tissue deposition of free gadolinium.

Most medical treatments attempted for NSF have been ineffective. These include potent topical corticosteroids, selective H2-blockers such as cimetidine and ranitidine, ciclosporin, prednisone, immunosuppressive agents, photopheresis and plasmapheresis.6 31 Several patients with very early skin changes of NSF demonstrated initial improvement when treated with thalidomide,32 but thalidomide has been ineffective in patients with more advanced NSF. Extracorporeal photopheresis with ultraviolet (UV) B has been reported to result in mildly decreased skin thickening in seven patients with NSF, three of whom exhibited improvement in ambulation.33 Another patient with NSF was observed to experience “slight reversal” of skin changes when treated with pentoxyphylline.17 However, there has been no universally effective medical treatment for NSF.

We have observed rapid improvement in skin induration in two patients with NSF treated with imatinib mesylate.34 In the patient who also had significant knee joint contractures, the contractures improved as his skin induration lessened. Compared to a pretreatment biopsy, there was less fibrosis and less immunohistochemical staining for type I procollagen in a skin biopsy obtained after 4 months of imatinib mesylate treatment. Distler and colleagues have demonstrated that imatinib mesylate strongly inhibits dermal fibroblast synthesis of type I collagen and fibronectin by inhibiting the c-Abl kinase activity of transforming growth factor beta (TGF-β) receptors and the tyrosine kinase activity of platelet-derived growth factor (PDGF) receptors and that imatinib mesylate pretreatment reduces extracellular matrix synthesis and accumulation in bleomycin-induced experimental dermal fibrosis.35 The mechanism of imatinib mesylate action in NSF probably involves similar pathways. An open-label trial of imatinib mesylate therapy in patients with NSF is ongoing ( identifier: NCT00677092).

Based upon these observations, the pathogenesis of NSF probably involves the production of profibrotic cytokines, such as TGF-β and PDGF, by monocytes or macrophages exposed to gadolinium-containing contrast agents or to free gadolinium that has been released from its chelate. These cytokines then stimulate extracellular matrix production by fibroblasts, which results in the clinical manifestations of systemic fibrosis. That imatinib mesylate allows for clinical improvement, despite the persistence of gadolinium in tissue, suggests that gadolinium may serve as a chronic stimulus for fibrosis in patients with NSF.34

In summary, NSF is an emerging epidemic among individuals with chronic kidney disease who have been exposed previously to gadolinium-containing contrast agents. Patients with NSF exhibit increased early mortality. Imatinib mesylate is a potential anti-fibrotic therapy for NSF and other fibrosing disorders and a clinical trial of imatinib mesylate in patients with NSF is ongoing. However, because no treatment has yet been demonstrated to cure this devastating condition, the use of gadolinium-containing contrast agents should be avoided in individuals with stages 4 and 5 CKD and possibly also in those with stage 3 CKD. Further study of the clinical manifestations and pathogenesis of NSF may enhance our understanding of other fibrosing diseases.



  • Competing interests: None.

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