Title: Gadolinium deposition in nephrogenic fibrosing dermopathy
Abstract: There is growing recognition of the association between the use of gadolinium-containing radiocontrast agents for magnetic resonance imaging and the serious dermal and systemic disease nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis (NFD/NSF). The pathogenesis of this entity remains unclear; however, our recent observations suggest a likely mechanism for the initial dermal manifestations of this gadolinium toxicity. There is growing recognition of the association between the use of gadolinium-containing radiocontrast agents for magnetic resonance imaging and the serious dermal and systemic disease nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis (NFD/NSF). The pathogenesis of this entity remains unclear; however, our recent observations suggest a likely mechanism for the initial dermal manifestations of this gadolinium toxicity. In 2000, Cowper et al1Cowper S.E. Robin H.S. Steinberg S.M. Su L.D. Gupta S. LeBoit P.E. Scleromyxedema-like cutaneous diseases in renal-dialysis patients.Lancet. 2000; 356: 1000-1001Abstract Full Text Full Text PDF PubMed Scopus (778) Google Scholar reported a series of 14 hemodialysis patients with thickening and hardening of the skin and scleromyxedema-like features. None of the patients, however, demonstrated a monoclonal gammopathy. Clinically, the lesions presented as hyperpigmented patches and plaques on the extremities. The following year, the same group of investigators described in greater detail the pathologic changes associated with this disease and termed the condition nephrogenic fibrosing dermopathy (NFD).2Cowper S.E. Su L.D. Bhawan J. Robin H.S. LeBoit P.E. Nephrogenic fibrosing dermopathy.Am J Dermatopathol. 2001; 23: 383-391Crossref PubMed Scopus (422) Google Scholar Systemic involvement has been subsequently reported, leading to the suggestion that this entity be called nephrogenic systemic fibrosis.3Grobner T. Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?.Nephrol Dial Transplant. 2006; 21: 1104-1108Crossref PubMed Scopus (1477) Google Scholar As NFD appeared to be a recently occurring phenomenon, it was postulated that exposure to some insult or new clinical practice may be responsible. Grobner3Grobner T. Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?.Nephrol Dial Transplant. 2006; 21: 1104-1108Crossref PubMed Scopus (1477) Google Scholar and Marckmann et al4Marckmann P. Skov L. Rossen K. Dupont A. Damholt M.B. Heaf J.G. et al.Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging.J Am Soc Nephrol. 2006; 17: 2359-2362Crossref PubMed Scopus (1102) Google Scholar described separate case series of patients administered gadolinium (Gd)-containing radiocontrast materials during magnetic resonance imaging (MRI) studies who subsequently developed NFD and proposed that this metal may be responsible for the disease. Until now, the presence of Gd in cutaneous biopsies from patients with NFD has not been reported. A 68-year-old white female presented to the Vanderbilt University Dermatology Clinic in June 2006 with a 3-week history of thickened skin on her extremities which began as painful soft tissue swellings and rapidly became indurated. Her past history was significant for chronic hepatitis C infection–induced hepatic failure for which she received a liver transplant in 1995. Cyclosporine therapy–induced renal failure necessitated hemodialysis in January 2006. Three weeks later she underwent an in-patient MRI heart scan using Gd-containing contrast material (gadodiamide-DTPA-BMA). During this hospitalization she was consistently hypocalcemic, hyperphosphatemic, and acidotic. Her medications included cyclosporine, metoprolol, coumadin, and amiodarone. She has been exposed to no other radiocontrast materials subsequently. On physical examination, her bilateral arms and forearms, calves, and shins demonstrated woody induration without appreciable color changes. A punch biopsy from the left posterior arm demonstrated diffuse dermal fibroplasia with spindle cells extending into the subcutaneous tissues, mild interstitial mucin deposition, and minimal inflammation, features consistent with NFD. Scanning electron microscopy and energy dispersive x-ray spectroscopy (SEM/EDS) demonstrated Gd detected only in areas of calcium phosphate deposition in blood vessels (Fig 1). The patient is currently undergoing extracorporeal photophoresis for her condition and has experienced modest improvement. NFD is a recently described entity occurring almost exclusively in patients undergoing hemodialysis for end stage renal disease (ESRD); while the instance is rare, patients have developed this condition while performing peritoneal dialysis.2Cowper S.E. Su L.D. Bhawan J. Robin H.S. LeBoit P.E. Nephrogenic fibrosing dermopathy.Am J Dermatopathol. 2001; 23: 383-391Crossref PubMed Scopus (422) Google Scholar Beginning as swelling of the hands and feet, the skin becomes progressively thickened with a peau d'orange appearance.5Mendoza F.A. Artlett C.M. Sandorfi N. Latinis K. Piera-Velazquez S. Jimenez S.A. Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature.Semin Arthr Rheum. 2006; 35: 238-249Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar This progression appears to proceed at a variable rate, with some patients describing rapid advancement of the indurated areas while others note a much slower course. Most patients describe the lesions as painful or pruritic and significantly debilitating. Involvement of the trunk and buttocks may ensue, but the head and neck are rarely affected. The skin hardening resembles scleroderma or morphea with joint contractures, sclerodactyly, and limitation of motion ultimately occurring in most patients.2Cowper S.E. Su L.D. Bhawan J. Robin H.S. LeBoit P.E. Nephrogenic fibrosing dermopathy.Am J Dermatopathol. 2001; 23: 383-391Crossref PubMed Scopus (422) Google Scholar, 5Mendoza F.A. Artlett C.M. Sandorfi N. Latinis K. Piera-Velazquez S. Jimenez S.A. Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature.Semin Arthr Rheum. 2006; 35: 238-249Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar Systemic involvement of the lungs, myocardium, striated muscles, and diaphragm have also been reported.6Ting W.W. Stone M.S. Madison K.C. Kurtz K. Nephrogenic fibrosing dermopathy with systemic involvement.Arch Dermatol. 2003; 139: 903-909Crossref PubMed Scopus (256) Google Scholar No specific laboratory findings have been described, although C reactive protein and erythrocyte sedimentation rate are often elevated.5Mendoza F.A. Artlett C.M. Sandorfi N. Latinis K. Piera-Velazquez S. Jimenez S.A. Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature.Semin Arthr Rheum. 2006; 35: 238-249Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar Importantly, monoclonal gammopathies have not been reported. The histologic features of cutaneous biopsies vary depending on the age of the lesion. When biopsied early in the disease, the changes may be subtle, with only a scant proliferation of spindled fibroblasts and minimal evidence of collagen production appreciated. Older lesions, however, demonstrate more florid numbers of fibroblasts and collagen deposition in the reticular dermis and subcutis.2Cowper S.E. Su L.D. Bhawan J. Robin H.S. LeBoit P.E. Nephrogenic fibrosing dermopathy.Am J Dermatopathol. 2001; 23: 383-391Crossref PubMed Scopus (422) Google Scholar, 6Ting W.W. Stone M.S. Madison K.C. Kurtz K. Nephrogenic fibrosing dermopathy with systemic involvement.Arch Dermatol. 2003; 139: 903-909Crossref PubMed Scopus (256) Google Scholar The subcutaneous septae may be expanded by this fibrotic process. Mildly increased amounts of stromal mucin may also be noted but inflammation is typically absent. CD34+ dermal dendrocytes are abundant, and factor XIIIa+ and CD68+ monocytes and multinucleated cells are found in increased numbers. Mendoza et al5Mendoza F.A. Artlett C.M. Sandorfi N. Latinis K. Piera-Velazquez S. Jimenez S.A. Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature.Semin Arthr Rheum. 2006; 35: 238-249Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar have also noted increased numbers of these cells in early lesions. The patient with fatal NFD and systemic involvement reported by Ting et al6Ting W.W. Stone M.S. Madison K.C. Kurtz K. Nephrogenic fibrosing dermopathy with systemic involvement.Arch Dermatol. 2003; 139: 903-909Crossref PubMed Scopus (256) Google Scholar demonstrated similar findings in the skin as well as “large zones of calcium deposition within the collagen bundles without vessel calcification.” At autopsy, the patient's diaphragm and psoas muscle showed significantly increased fibrous tissue with vascular and interstitial calcium deposits. Other internal organs including the heart, lungs, kidneys, and rete testes also demonstrated calcium deposition. Similar findings have been reported by others.5Mendoza F.A. Artlett C.M. Sandorfi N. Latinis K. Piera-Velazquez S. Jimenez S.A. Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature.Semin Arthr Rheum. 2006; 35: 238-249Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar The pathogenesis of this condition is unclear, with coagulation abnormalities, angiotensin-converting enzyme inhibitor administration, recent vascular surgery, or intervention and the presence of antiphospholipid antibodies having been proposed.3Grobner T. Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?.Nephrol Dial Transplant. 2006; 21: 1104-1108Crossref PubMed Scopus (1477) Google Scholar The early infiltration of the dermis by factor XIIIa+/CD68+ cells may represent a host response to noxious stimuli.5Mendoza F.A. Artlett C.M. Sandorfi N. Latinis K. Piera-Velazquez S. Jimenez S.A. Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature.Semin Arthr Rheum. 2006; 35: 238-249Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar In situ hybridization studies of affected skin, muscle, and fascia have demonstrated increased expression of transforming growth factor β1 mRNA.5Mendoza F.A. Artlett C.M. Sandorfi N. Latinis K. Piera-Velazquez S. Jimenez S.A. Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature.Semin Arthr Rheum. 2006; 35: 238-249Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar It is possible that these dermal dendrocytes may be responsible for the production of this growth factor and the ensuing fibrosis. A more attractive hypothesis involves bone marrow–derived cells involved in normal wound repair termed circulating fibrocytes.7Cowper S.E. Bucala R. LeBoit P.E. Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis—setting the record straight.Semin Arthr Rheum. 2005; 35: 208-210Abstract Full Text Full Text PDF Scopus (78) Google Scholar These cells stain for CD34, CD45RO, and type 1 collagen, are recruited into the skin where they are involved in wound repair and fibrotic processes, and have been described in NFD patient biopsies.8Ortonne N. Lipsker D. Chantrel F. Boehm N. Grosshans E. Cribier B. Presence of CD45RO+ CD34+ cells with collagen synthesis activity in nephrogenic fibrosing dermopathy; a new pathogenic hypothesis.Br J Dermatol. 2004; 150: 1050-1052Crossref PubMed Scopus (87) Google Scholar Ortonne et al8Ortonne N. Lipsker D. Chantrel F. Boehm N. Grosshans E. Cribier B. Presence of CD45RO+ CD34+ cells with collagen synthesis activity in nephrogenic fibrosing dermopathy; a new pathogenic hypothesis.Br J Dermatol. 2004; 150: 1050-1052Crossref PubMed Scopus (87) Google Scholar postulated that “a recently introduced material, possibly a contrast agent, medication, or other allergen” might be deposited in the tissues and serve as a surrogate target for circulating fibrocytes. Grobner3Grobner T. Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?.Nephrol Dial Transplant. 2006; 21: 1104-1108Crossref PubMed Scopus (1477) Google Scholar reported 5 patients with ESRD on hemodialysis who developed NFD 2 to 4 weeks after undergoing a Gd-EDTA enhanced MRI scan. He noted that affected patients had been on dialysis longer and were experiencing metabolic acidosis at the time of their scans compared to similarly evaluated patients without NFD. Marckmann et al4Marckmann P. Skov L. Rossen K. Dupont A. Damholt M.B. Heaf J.G. et al.Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging.J Am Soc Nephrol. 2006; 17: 2359-2362Crossref PubMed Scopus (1102) Google Scholar described 13 patients with ESRD on hemodialysis affected by NFD an average of 25 days following their exposure to Gd, but failed to associate their condition with metabolic acidosis. NFD without prior Gd exposure was not observed and no cases have developed since suspending the use of Gd-containing contrast agents. Gd-DTPA-BMA (gadodiamide) was introduced in 1993 as a paramagnetic contrast agent for use in MRI scans and was believed to be safe for patients with impaired renal function.3Grobner T. Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?.Nephrol Dial Transplant. 2006; 21: 1104-1108Crossref PubMed Scopus (1477) Google Scholar Free Gd ions can form precipitates with anions, such as phosphate, because of its poor solubility, and it is considered highly toxic in its ionic form.8Ortonne N. Lipsker D. Chantrel F. Boehm N. Grosshans E. Cribier B. Presence of CD45RO+ CD34+ cells with collagen synthesis activity in nephrogenic fibrosing dermopathy; a new pathogenic hypothesis.Br J Dermatol. 2004; 150: 1050-1052Crossref PubMed Scopus (87) Google Scholar Marckmann et al4Marckmann P. Skov L. Rossen K. Dupont A. Damholt M.B. Heaf J.G. et al.Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging.J Am Soc Nephrol. 2006; 17: 2359-2362Crossref PubMed Scopus (1102) Google Scholar have posited that NFD may result from liberated Gd ions deposited in the tissues. These molecules are known to be extremely toxic and to produce deposits of Gd with calcium phosphates in the tissues of rodents.9Spencer A. Wilson S. Batchelor J. Reid A. Rees J. Harpur E. Gadolinium chloride toxicity in the rat.Toxicol Pathol. 1997; 25: 245-255Crossref PubMed Scopus (118) Google Scholar The US Food and Drug Administration has recently issued a public health advisory regarding these agents, citing “a possible link between NSF/NFD and exposure to gadolinium-containing contrast agents.”10Center for Drug Evaluation and Research. US Food and Drug Administration Web site. Public health advisory: Gadolinium-containing contrast agents for magnetic resonance imaging (MRI): Omniscan, OptiMARK, Magnevist, ProHance, and MultiHance (June 8, 2006). Available at: http://www.fda.gov/cder/drug/advisory/gadolinium_agents.htm. Accessed October 30, 2006.Google Scholar Calcification was not appreciated in tissue sections stained with hematoxylin–eosin or von Kossa (calcium) in our patient, and Gd deposition was restricted to areas with concomitant calcium phosphate deposition in the reported patient as well as in biopsies evaluated from additional patients with NFD (Table I). Gd deposition along eccrine sweat gland basal lamina was also noted in patient 4 (Fig 2). Calcium phosphate deposits are common in cutaneous biopsies taken from patients undergoing hemodialysis, presumably secondary to altered calcium and phosphate metabolism. We believe cutaneous Gd deposition may serve as a nidus for the development of NFD. Gadolinium deposition at sites other than those associated with discernable calcium phosphate deposition cannot be excluded, as only retained, insoluble Gd is detectable in our tissue samples with SEM/EDS methodology. Whether Gd deposition precedes or follows tissue calcification is unknown. Additionally, whether the presence of elevated circulating and/or tissue calcium and phosphate induce release of the (toxic) free Gd from the contrast agent is unclear.Table IClinical characteristics of the patients studiedPatient 1Patient 2Patient 3Patient 4Age (y)/Sex68/F31/F41/F46/MCause of renal failureCyclosporine toxicitySystemic lupus erythematosusInsulin-dependent diabetes mellitusPolycystic kidney diseaseLength of time on dialysis3 weeks8 months43 months14 monthsAmount of Gd administered3.8 gm5.8 gmUnknownUnknownTime to development of symptoms5 months5 monthsUnknown6 monthsSerum calcium at time of MRI (normal, 8.5-10.5 mg/dl)7.2 mg/dl9.0 mg/dlUnknownUnknownSerum phosphate at time of MRI (normal, 2.5-4.5 mg/dl)6.6 mg/dl5.2 mg/dlUnknownUnknownAcidosisYesNoUnknownUnknownTreatmentECPRetransplantedECPECPCurrent statusAliveAliveAliveDeceasedECP, Extracorporeal photophoresis; Gd, gadodiamide; MRI, magnetic resonance imaging. Open table in a new tab ECP, Extracorporeal photophoresis; Gd, gadodiamide; MRI, magnetic resonance imaging.
Publication Year: 2007
Publication Date: 2007-01-01
Language: en
Type: review
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 379
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