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Observation |

Nephrogenic Systemic Fibrosis Relationship to Gadolinium and Response to Photopheresis FREE

Heather Richmond, BA; Jeffrey Zwerner, MD, PhD; Youn Kim, MD; David Fiorentino, MD, PhD
[+] Author Affiliations

Author Affiliations: Department of Dermatology, Stanford University School of Medicine, Palo Alto, California.


Arch Dermatol. 2007;143(8):1025-1030. doi:10.1001/archderm.143.8.1025.
Text Size: A A A
Published online

ABSTRACT

Background  Nephrogenic systemic fibrosis (NSF), previously known as nephrogenic fibrosing dermopathy, is an idiopathic condition seen in patients with renal disease that is characterized by cutaneous sclerosis that can often result in contractures, pain, and functional disability as well as systemic complications. Recent reports have suggested a possible link with exposure to gadolinium, a commonly used radiocontrast agent. No current therapy has clearly demonstrated efficacy for NSF, although case reports suggest that extracorporeal photopheresis (ECP) may be of benefit. The purpose of this study was to explore the plausibility of a gadolinium linkage with NSF as well as to assess the efficacy of ECP in the treatment of a cohort of patients with NSF.

Observations  We report our experience with 8 consecutive patients with NSF seen at the Stanford Medical Center, Palo Alta, California, from 2004 to 2006. Of the 8 patients, 6 had a history of arterial or venous thrombotic disease and 7 had a documented exposure to gadolinium within 1 week to several months prior to the onset of NSF. Specifically, all patients were exposed to gadodiamide. We treated 5 of the patients with ECP. After a mean number of 34 treatment sessions over a mean of 8.5 months, 3 patients experienced a mild improvement in skin tightening, range of motion, and/or functional capacity.

Conclusions  Our data support the hypothesis that exposure to gadolinium, perhaps specifically gadodiamide, plays a role in the pathogenesis of NSF. Larger epidemiologic studies will be needed to confirm this association. In addition, our experience suggests that, if used for extended periods, ECP might have some mild benefit for patients with NSF. Larger, randomized, placebo-controlled trials of ECP should be performed to more specifically assess the benefit of ECP in the treatment of NSF.

Nephrogenic systemic fibrosis (NSF), previously called nephrogenic fibrosing dermopathy, is an acquired, progressive, systemic fibrosing disorder of unknown etiology that develops in the setting of renal disease.1,2 Nephrogenic systemic fibrosis is clinically characterized by plaquelike, woody induration of the skin that frequently initially manifests with peau d’orange surface changes and may involve the deeper underlying tissues including the subcutis, fascia, and even skeletal muscle.1 Systemic sites of involvement that have been reported include skeletal muscle (including myocardium and diaphragm), pericardium, lung, and dura mater, as well as dystrophic calcification of other organs such as the kidneys and testes.1,35 Symptoms include burning pain, pruritus, weakness, and joint contractures that can impair range of motion and limb function.

There are approximately 200 cases that have been reported to the international NSF Registry to date (http://www.icnfdr.org),6 and data from an analysis of 175 of these patients demonstrate a male-female ratio of 1:1. Nephrogenic systemic fibrosis has been shown to affect all ages, ranging from 8 to 87 years, including at least 10 cases in the pediatric age range.7,8 This disease has been reported worldwide and has been described in white, Indian, Middle Eastern, Asian, Hispanic, and African American subjects.1,8

To our knowledge, no case has been identified prior to 1997, and the first case series was published in 2000.9 The fact that this disease appeared within the past 10 years suggests that the etiology of NSF may be linked to a factor that was not present before that time, such as a new medication, chemical, or infectious agent.1 Potentially associated factors have been implicated, including recent surgery or other vascular procedures, local trauma, thrombotic events, hypercoagulable states, pulmonary fibrosis, hepatic disease, and high-dose erythropoietin.2,10,11 One current model for the development of NSF involves a blood-borne cell of bone marrow origin, the circulating fibrocyte, which is involved in the normal wound healing process and is thought to be recruited to the sites of involvement and to subsequently cause the fibrotic changes that are associated with this disease.1 Cowper and colleagues12 suggest that recruitment of circulating fibrocytes to the tissues is a normal occurrence in patients with NSF, representing a physiologic response to stimuli that trigger a normal wound healing response (ie, clotting and endothelial injury) or possible passively in some cases (ie, secondary to edema). The authors contend that preexisting deposition of allergens, medications, or radiographic contrast agents might then serve as surrogate targets for these cells, resulting in their activation and initiation of the fibrotic process.1,12 Consistent with this notion, gadolinium, the contrast agent used for magnetic resonance imaging (MRI), has been implicated as an associated agent in 2 case series.1315

Treatment of patients with this disease is challenging, and even among the few patients who regain normal kidney function, many do not experience resolution of their symptoms. Many treatments under investigation include plasmapheresis, extracorporeal photopheresis (ECP), systemic and topical steroids, topical calcipotriene, selective histamine blockade, thalidomide, psoralen-UV-A (PUVA) light, cyclophosphamide, cyclosporine, methotrexate, interferon alfa, intravenous immunoglobulin, oral retinoids, and aggressive physical therapy.2 Unfortunately, none of these has been shown to be broadly efficacious, and many patients do not improve with these therapies. Extracorporeal photopheresis has been reported to be effective in reversing some of the symptoms of NSF in affected patients even in the face of persistent renal insufficiency.7,16,17

The purpose of our study was to document our data pertaining to gadolinium exposure as well as the effects of ECP in our patients with NSF.

METHODS

Between January of 2004 and October of 2006, we treated 8 patients with NSF who had been seen at the Stanford Medical Center, Palo Alto, California. Diagnostic criteria included the presence of renal insufficiency at the time of onset of the disease, a biopsy finding consistent with NSF (hypercellular dermis with an increase in CD34+, spindle-shaped, fibroblastlike cells and dermal histiocytes, thickened collagen bundles, and a variable increase in mucin deposition), and characteristic clinical distribution of lesions over the distal extremities and trunk with sparing of the head and neck. With 1 exception (see “Results” section), the patients did not have paraproteinemia, anticentromere antibodies, anti-Scl antibodies, Raynaud phenomenon, any known underlying malignancy, or a history of an allogeneic transplant. These data made the following diagnoses unlikely: scleromyxedema, scleroderma, paraneoplastic systemic sclerosis, and sclerodermoid graft-vs-host disease. During laboratory evaluation, 1 patient (patient 8) was found to have a monoclonal gammopathy consisting of IgG-λ. The patient's clinical presentation and onset of cutaneous disease shortly after acute onset renal failure, however, were more consistent with NSF. This conclusion was also reached by multiple clinicians at a second academic institution (Department of Dermatology Grand Rounds, University of California, San Francisco, June 2005).

Extracorporeal photopheresis is an immunomodulatory therapy that involves ex vivo treatment of a patient's leukocyte rich plasma with a photosensitizing agent and UV-A radiation followed by reinfusion of the treated blood product. The ECP treatment was performed in an outpatient setting using the UVAR XTS photopheresis machine with UVADEX (Therakos Inc, Exton, Pennsylvania) according to standard procedures in the manufacturer's guidelines. Four of the patients were treated with 1 cycle consisting of 2 treatments on consecutive days. Cycles were repeated every 2 to 3 weeks. One patient (patient 7), who was receiving peritoneal dialysis, was given a single ECP treatment every week to avoid undesired excess volume with each treatment.

The degree of response to treatment was determined by using a global physician assessment that took into account quantitative skin induration (using a modified Rodnan score of affected areas),18 range of motion (when applicable), and patient perception of disability. All patients were assessed by the same physician (Y.K.) to assure consistency in response measurement. The patients' disease (compared with baseline) was scored as worsened, stable, mildly improved, or markedly improved.

RESULTS

All patients had renal insufficiency or renal failure of varying causes at the time of disease onset, and all patients received some form of dialysis (Table 1). Of the 8 patients, 6 had a history of arterial or venous thrombotic disease. Of the 4 patients undergoing evaluation for a hypercoagulable state, 3 were found to have elevated homocysteine levels, and 1 patient was also positive for anticardiolipin antibodies (Table 2). Two patients had possible extracutaneous disease: 1 patient (patient 4) had pleural nodularity on chest radiography (without diagnostic biopsy) and a second patient (patient 1) had yellow scleral plaques, a finding previously documented in NSF.19

Table Graphic Jump LocationTable 1. Clinical Features of Patients With Nephrogenic Systemic Fibrosis (NSF)
Table Graphic Jump LocationTable 2. Thrombosis History in Patients With Nephrogenic Systemic Fibrosis

In light of recent data implicating gadolinium exposure with NSF, we attempted to obtain complete documentation regarding gadolinium exposure in our cohort. Of 8 patients, 7 had documented radiographic imaging using gadolinium contrast prior to the onset of symptoms, and all received gadodiamide (Table 1). Patients 1, 2, 3, 7, and 8 received the contrast agent during MRI. Patient 6 was exposed to gadodiamide during a concurrent head MRI/magnetic resonance angiography. Patient 4 developed symptoms consistent with NSF shortly after a radiology-directed liver biopsy in which gadodiamide was used. For the 5 patients with available records, the mean time to onset of symptoms was 3 to 4 weeks (range, 1-8 weeks) following gadodiamide exposure. Records regarding the exact date of onset of symptoms were not obtainable for 2 patients with documented gadolinium exposure, but the onset of symptoms occurred within months of the specified procedure. One patient (patient 4) had transient acute renal failure that lasted only 10 days, during which time she was given gadodiamide contrast. Although her renal failure subsequently resolved, she developed NSF within 8 weeks of gadodiamide exposure but continues to slowly improve without therapy. Another patient (patient 3) underwent a successful renal transplantation in 2004 and, despite normal renal function, continued to experience stable cutaneous disease (for over a year) before therapy.

We treated 5 of our patients with ECP (Table 3). At the time of treatment, all of these patients had progressive disease (based on patient history and physician global assessment of skin sclerosis) that had been present for a mean of 2.75 years. After a mean number of 34 treatment sessions (17 courses) over a mean of 8.5 months, 3 patients experienced mild improvement in both skin tightening and/or objective range of motion despite persistent renal insufficiency (Table 3; data not shown). The mean number of treatments before improvement was observed was 20 (range, 6-30). These patients were able to perform activities limited to them before ECP treatment, such as walking without mechanical assistance (patients 2 and 7) or climbing a flight of stairs unassisted (patient 3), leading to a significant improvement in their quality of life.

Table Graphic Jump LocationTable 3. Details of Patients Treated With ECP

COMMENT

We report our experience with NSF in a cohort of 8 patients at the Stanford Medical Center. Consistent with other reports, all of our patients had renal insufficiency or failure (1 transient and 7 chronic), and as in the majority of documented cases, all were receiving some form of dialysis.1 Consistent with previously published data on this disease process, improvement in renal function does not necessarily result in remission of NSF; of our patients who had transient renal failure (patient 4), significant improvement in renal function (patient 8), or a successful renal transplantation (patient 3), all continue to manifest symptoms of NSF. Only 1 of these patients (patient 4) demonstrated improvement without therapy.

Interestingly, 6 of 8 patients had a history of arterial or venous thrombosis. This has been described in patients with NSF,10 and circulating anticardiolipin antibodies were a consistent finding in at least 1 cohort,20 although this is not a consistent finding.21,22 Of the 4 patients in this series evaluated for anticardiolipin antibodies, only 1 was found to have a detectable level. Serum homocysteine level, another risk factor for thrombosis, was elevated in 3 of the 4 patients tested. This result is not surprising, since multiple reports have linked even mild renal disease with elevated homocysteine levels, and the prevalence of hyperhomocysteinemia in hemodialysis patients is between 80% and 100%.23,24 It is unclear if a hypercoagulable state is associated with NSF or simply represents the known association with renal failure.25,26 It is tempting to speculate that some form of endothelial damage might play a role in the pathogenesis of NSF, perhaps leading to the physiologic recruitment of circulating fibrocytes to the skin.1,12

Our data are consistent with a potential causative link between gadolinium contrast and NSF. All patients for whom we have a definitive set of complete records demonstrated a temporal association between the administration of gadolinium contrast and the development of cutaneous symptoms. The patient without documented gadolinium exposure is deceased, although there are no hospital records at our institution of any procedures in which the gadolinium was administered. Of note, this patient received care outside of our institution and had multiple medical problems for which an MRI/magnetic resonance angiography may have been administered. A discussion with the patient's family members, primary care physician, and nephrologist, however, failed to uncover records of any such procedure.

There are 5 different gadolinium-based contrast agents that are approved by the Food and Drug Administration (FDA) for medical use in the United States including gadopentetate dimeglumine (Magnevist; Bayer HealthCare Pharmaceuticals Inc, Wayne, New Jersey), gadoteridol (ProHance; Bracco Diagnostic Inc, Princeton, New Jersey), gadodiamide (Omniscan; Nycomed Inc, Princeton), gadoversetamide (OptiMARK; Mallinckrodt, Hazelwood, Missouri), and gadobenate dimeglumine (MultiHance; Bracco Diagnostics Inc). These were approved by the FDA in 1988, 1992, 1993, 1999, and 2004, respectively, for use in MRI.

Interestingly, all of our patients were exposed specifically to gadodiamide. This is consistent with previous studies.13,14,27 Gadodiamide is a nonionic chelate of gadolinium and diethylenetriaminepentaacetic acid bis-(methylamide),28 and is characterized by having excess chelate and being less stable. This is due to the high propensity for this particular substance to undergo transmetallation with endogenous ions.29 It is possible that either free gadopentetate ion or the chelate itself could bind to endogenous ions in the tissues.30 This ion is poorly soluble and it can form salt precipitates with phosphates and other anions that are frequently elevated in patients with renal failure, which may lead to increased tissue deposition and inflammation.13 Indeed, gadolinium has been detected in the skin of patients with NSF, most likely in intracellular deposits.15,30 This is consistent with the hypothesis that this might be a trigger for resident CD34+ cells to synthesize extracellular matrix components, including collagen. According to the FDA Web site, NSF has been associated with 3 of the 5 FDA-approved gadolinium-containing agents, and they warn that all of the available agents might have the potential for this association.27

Case reports suggest that ECP might be an effective treatment for some patients with NSF. In one report of 3 patients, all demonstrated significant improvement in terms of joint mobility and both objective and subjective skin softening following at least 4 cycles of ECP. One patient developed complete resolution of symptoms after 16 cycles of treatment.16,17 Auron et al7 report 1 case of a pediatric patient who experienced symptomatic improvement following 1 year of 2-day sessions occurring every other week. Finally, although the report by Gilliet et al17 suggests that significant improvement can be seen as early as 8 weeks, other patients have required much longer treatment periods to show benefit. Although none of our patients had as dramatic a response as those in the previous reports, results were encouraging. Of the 5 patients treated with ECP, 3 had some form of objective response. In all of the responding patients, the decreased sclerosis was primarily seen in the upper extremities. Such “minor” objective improvement can offer significant hope and benefit in the quality of life of patients, since all patients had a notable improvement in function. The 2 patients without objective improvement demonstrated stabilized disease while receiving ECP; because the disease was progressive before therapy, this might also indicate a therapeutic benefit. It is unclear whether technical differences in the ECP treatment are responsible for the varied outcomes between our cohort and those previously reported. In addition, the time lapse between disease onset and the start of ECP treatment was not mentioned in the previous reports. Our patients had a mean disease duration of 2.75 years before they received ECP. It is possible that patients treated early in their disease course, before extensive sclerosis has developed, would benefit most from this therapy. It should also be noted that acitretin therapy was used as adjuvant therapy in many of our patients, based on positive personal experience from the authors (Y.K. and D.F.) in other sclerosing disorders of the skin, such as scleromyxedema and chronic graft-vs-host disease (and limited data in NSF2). For 2 of our patients responding to ECP (patients 2 and 7), the contribution of the retinoid cannot be discounted.

ARTICLE INFORMATION

Correspondence: David Fiorentino, MD, PhD, Department of Dermatology, Stanford University, 900 Blake Wilbur Dr, Stanford, CA 94305 (fiorentino@stanford.edu).

Financial Disclosure: None reported.

Accepted for Publication: April 20, 2007.

Author Contributions: Dr Fiorentino had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Ms Richmond and Dr Zwerner contributed equally to this work. Study concept and design: Richmond, Kim, and Fiorentino. Acquisition of data: Richmond, Zwerner, Kim, and Fiorentino. Analysis and interpretation of data: Richmond, Zwerner, Kim, and Fiorentino. Drafting of the manuscript: Richmond. Critical revision of the manuscript for important intellectual content: Zwerner, Kim, and Fiorentino. Administrative, technical, and material support: Richmond, Zwerner, and Fiorentino. Study supervision: Kim and Fiorentino.

Funding/Support: Dr Fiorentino is partially supported by a Career Development Award from the Dermatology Foundation.

This article was corrected for typographical errors on 10/10/2007.

REFERENCES

Cowper  SEBoyer  PJ Nephrogenic systemic fibrosis: an update. Curr Rheumatol Rep 2006;8 (2) 151- 157
PubMed Link to Article
DeHoratius  DMCowper  SE Nephrogenic systemic fibrosis: an emerging threat among renal patients. Semin Dial 2006;19 (3) 191- 194
PubMed Link to Article
Kucher  CSteere  JElenitsas  RSiegel  DLXu  X Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis with diaphragmatic involvement in a patient with respiratory failure. J Am Acad Dermatol 2006;54 (2) ((suppl)) S31- S34
PubMed Link to Article
Gibson  SEFarver  CFPrayson  RA Multiorgan involvement in nephrogenic fibrosing dermopathy: an autopsy case and review of the literature. Arch Pathol Lab Med 2006;130 (2) 209- 212
PubMed
Saenz  AMandal  RKradin  RHedley-Whyte  ET Nephrogenic fibrosing dermopathy with involvement of the dura mater. Virchows Arch 2006;449 (3) 389- 391
PubMed Link to Article
Cowper  SE Nephrogenic fibrosing dermopathy. NFD/NSF Web site; 2001-2006 http://www.icnfdr.orgAccessed August 1, 2006
Auron  AShao  LWarady  BA Nephrogenic fibrosing dermopathy in children. Pediatr Nephrol 2006;21 (9) 1307- 1311
PubMed Link to Article
Scheinfeld  N Nephrogenic fibrosing dermopathy a comprehensive review for the dermatologist. Am J Clin Dermatol 2006;7 (4) 237- 247
PubMed Link to Article
Cowper  SERobin  HSSteinberg  SMSu  LDGupta  SLeBoit  PE Scleromyxoedema-like cutaneous disease in renal-dialysis patients. Lancet 2000;356 (9234) 1000- 1001
PubMed Link to Article
Cowper  SE Nephrogenic fibrosing dermopathy: the first 6 years. Curr Opin Rheumatol 2003;15 (6) 785- 790
PubMed Link to Article
Swaminathan  SAhmed  IMcCarthy  JT  et al.  Nephrogenic fibrosing dermopathy and high-dose erythropoietin therapy. Ann Intern Med 2006;145 (3) 234- 235
PubMed Link to Article
Cowper  SEBucala  RLeboit  PE Fibrosing dermopathy/nephrogenic systemic fibrosis—setting the record straight. Semin Arthritis Rheum 2006;35 (4) 208- 210
PubMed Link to Article
Grobner  T Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006;21 (4) 1104- 1108
PubMed Link to Article
Marckmann  PSkov  LRossen  K  et al.  Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 2006;17 (9) 2359- 2362
PubMed Link to Article
Boyd  ASZic  JAAbraham  JL Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol 2007;56 (1) 27- 30
PubMed Link to Article
Läuchli  SZortea-Caflisch  CNestle  FOBurg  GKempf  W Nephrogenic fibrosing dermopathy treated with extracorporeal photopheresis. Dermatology 2004;208 (3) 278- 280
PubMed Link to Article
Gilliet  MCozzio  ABurg  GNestle  FO Successful treatment of three cases of nephrogenic fibrosing dermopathy with extracorporeal photopheresis. Br J Dermatol 2005;152 (3) 531- 536
PubMed Link to Article
Furst  DEClements  PJSteen  VD  et al.  The modified Rodnan skin score is an accurate reflection of skin biopsy thickness in systemic sclerosis. J Rheumatol 1998;25 (1) 84- 88
PubMed
Streams  BNLiu  VLiegeois  NMoschella  SM Clinical and pathological features of nephrogenic fibrosing dermopathy. J Am Acad Dermatol 2003;48 (1) 42- 47
PubMed Link to Article
Mackay-Wiggan  JMCohen  DJHardy  MAKnobler  EHGrossman  ME Nephrogenic fibrosing dermopathy (scleromyxedema-like illness of renal disease). J Am Acad Dermatol 2003;48 (1) 55- 60
PubMed Link to Article
Swartz  RDCrofford  LJPhan  SHIke  RWSu  LD Nephrogenic fibrosing dermopathy: a novel cutaneous fibrosing disorder in patients with renal failure. Am J Med 2003;114 (7) 563- 572
PubMed Link to Article
Ting  WWStone  MSMadison  KCKurtz  K Nephrogenic fibrosing dermopathy with systemic involvement. Arch Dermatol 2003;139 (7) 903- 906
PubMed
van Guldener  CRobinson  K Homocysteine and renal disease. Semin Thromb Hemost 2000;26 (3) 313- 324
PubMed Link to Article
Wollesen  FBrattstrom  LRefsum  HUeland  PMBerglund  LBerne  C Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus. Kidney Int 1999;55 (3) 1028- 1035
PubMed Link to Article
Nampoory  MRDas  KCJohny  KV  et al.  Hypercoagulability, a serious problem in patients with ESRD on maintenance hemodialysis, and its correction after kidney transplantation. Am J Kidney Dis 2003;42 (4) 797- 805
PubMed Link to Article
Molino  DDe Lucia  DGaspare De Santo  N Coagulation disorders in uremia. Semin Nephrol 2006;26 (1) 46- 51
PubMed Link to Article
US Food and Drug Administration, Public health advisory: update on magnetic resonance imaging (MRI) contrast agents containing gadolinium and nephrogenic fibrosing dermopathy. http://www.fda.gov/cder/drug/advisory/gadolinium_agents_20061222.htmAccessed April 6, 2007
Joffe  PThomsen  HSMeusel  M Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Acad Radiol 1998;5 (7) 491- 502
PubMed Link to Article
Thomsen  HS Nephrogenic systemic fibrosis: a serious late adverse reaction to gadodiamide. Eur Radiol 2006;16 (12) 2619- 2621published online ahead of print October24 2006;
PubMed Link to Article
High  WAAyers  RAChandler  JZito  GCowper  SE Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 2007;56 (1) 21- 26
PubMed Link to Article

Figures

Tables

Table Graphic Jump LocationTable 1. Clinical Features of Patients With Nephrogenic Systemic Fibrosis (NSF)
Table Graphic Jump LocationTable 2. Thrombosis History in Patients With Nephrogenic Systemic Fibrosis
Table Graphic Jump LocationTable 3. Details of Patients Treated With ECP

References

Cowper  SEBoyer  PJ Nephrogenic systemic fibrosis: an update. Curr Rheumatol Rep 2006;8 (2) 151- 157
PubMed Link to Article
DeHoratius  DMCowper  SE Nephrogenic systemic fibrosis: an emerging threat among renal patients. Semin Dial 2006;19 (3) 191- 194
PubMed Link to Article
Kucher  CSteere  JElenitsas  RSiegel  DLXu  X Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis with diaphragmatic involvement in a patient with respiratory failure. J Am Acad Dermatol 2006;54 (2) ((suppl)) S31- S34
PubMed Link to Article
Gibson  SEFarver  CFPrayson  RA Multiorgan involvement in nephrogenic fibrosing dermopathy: an autopsy case and review of the literature. Arch Pathol Lab Med 2006;130 (2) 209- 212
PubMed
Saenz  AMandal  RKradin  RHedley-Whyte  ET Nephrogenic fibrosing dermopathy with involvement of the dura mater. Virchows Arch 2006;449 (3) 389- 391
PubMed Link to Article
Cowper  SE Nephrogenic fibrosing dermopathy. NFD/NSF Web site; 2001-2006 http://www.icnfdr.orgAccessed August 1, 2006
Auron  AShao  LWarady  BA Nephrogenic fibrosing dermopathy in children. Pediatr Nephrol 2006;21 (9) 1307- 1311
PubMed Link to Article
Scheinfeld  N Nephrogenic fibrosing dermopathy a comprehensive review for the dermatologist. Am J Clin Dermatol 2006;7 (4) 237- 247
PubMed Link to Article
Cowper  SERobin  HSSteinberg  SMSu  LDGupta  SLeBoit  PE Scleromyxoedema-like cutaneous disease in renal-dialysis patients. Lancet 2000;356 (9234) 1000- 1001
PubMed Link to Article
Cowper  SE Nephrogenic fibrosing dermopathy: the first 6 years. Curr Opin Rheumatol 2003;15 (6) 785- 790
PubMed Link to Article
Swaminathan  SAhmed  IMcCarthy  JT  et al.  Nephrogenic fibrosing dermopathy and high-dose erythropoietin therapy. Ann Intern Med 2006;145 (3) 234- 235
PubMed Link to Article
Cowper  SEBucala  RLeboit  PE Fibrosing dermopathy/nephrogenic systemic fibrosis—setting the record straight. Semin Arthritis Rheum 2006;35 (4) 208- 210
PubMed Link to Article
Grobner  T Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006;21 (4) 1104- 1108
PubMed Link to Article
Marckmann  PSkov  LRossen  K  et al.  Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 2006;17 (9) 2359- 2362
PubMed Link to Article
Boyd  ASZic  JAAbraham  JL Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol 2007;56 (1) 27- 30
PubMed Link to Article
Läuchli  SZortea-Caflisch  CNestle  FOBurg  GKempf  W Nephrogenic fibrosing dermopathy treated with extracorporeal photopheresis. Dermatology 2004;208 (3) 278- 280
PubMed Link to Article
Gilliet  MCozzio  ABurg  GNestle  FO Successful treatment of three cases of nephrogenic fibrosing dermopathy with extracorporeal photopheresis. Br J Dermatol 2005;152 (3) 531- 536
PubMed Link to Article
Furst  DEClements  PJSteen  VD  et al.  The modified Rodnan skin score is an accurate reflection of skin biopsy thickness in systemic sclerosis. J Rheumatol 1998;25 (1) 84- 88
PubMed
Streams  BNLiu  VLiegeois  NMoschella  SM Clinical and pathological features of nephrogenic fibrosing dermopathy. J Am Acad Dermatol 2003;48 (1) 42- 47
PubMed Link to Article
Mackay-Wiggan  JMCohen  DJHardy  MAKnobler  EHGrossman  ME Nephrogenic fibrosing dermopathy (scleromyxedema-like illness of renal disease). J Am Acad Dermatol 2003;48 (1) 55- 60
PubMed Link to Article
Swartz  RDCrofford  LJPhan  SHIke  RWSu  LD Nephrogenic fibrosing dermopathy: a novel cutaneous fibrosing disorder in patients with renal failure. Am J Med 2003;114 (7) 563- 572
PubMed Link to Article
Ting  WWStone  MSMadison  KCKurtz  K Nephrogenic fibrosing dermopathy with systemic involvement. Arch Dermatol 2003;139 (7) 903- 906
PubMed
van Guldener  CRobinson  K Homocysteine and renal disease. Semin Thromb Hemost 2000;26 (3) 313- 324
PubMed Link to Article
Wollesen  FBrattstrom  LRefsum  HUeland  PMBerglund  LBerne  C Plasma total homocysteine and cysteine in relation to glomerular filtration rate in diabetes mellitus. Kidney Int 1999;55 (3) 1028- 1035
PubMed Link to Article
Nampoory  MRDas  KCJohny  KV  et al.  Hypercoagulability, a serious problem in patients with ESRD on maintenance hemodialysis, and its correction after kidney transplantation. Am J Kidney Dis 2003;42 (4) 797- 805
PubMed Link to Article
Molino  DDe Lucia  DGaspare De Santo  N Coagulation disorders in uremia. Semin Nephrol 2006;26 (1) 46- 51
PubMed Link to Article
US Food and Drug Administration, Public health advisory: update on magnetic resonance imaging (MRI) contrast agents containing gadolinium and nephrogenic fibrosing dermopathy. http://www.fda.gov/cder/drug/advisory/gadolinium_agents_20061222.htmAccessed April 6, 2007
Joffe  PThomsen  HSMeusel  M Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Acad Radiol 1998;5 (7) 491- 502
PubMed Link to Article
Thomsen  HS Nephrogenic systemic fibrosis: a serious late adverse reaction to gadodiamide. Eur Radiol 2006;16 (12) 2619- 2621published online ahead of print October24 2006;
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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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