eMedicine Specialties > Dermatology > Internal Medicine

Nephrogenic Systemic Fibrosis

Author: Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Private Practice
Coauthor(s): Shawn Cowper, MD, Director, NFD Registry Project, Associate Professor, Departments of Dermatology and Pathology, Yale University
Contributor Information and Disclosures

Updated: Sep 16, 2009

Introduction

Background

Nephrogenic systemic fibrosis (NSF), also known as nephrogenic fibrosing dermopathy (NFD), is a disease of fibrosis of the skin and internal organs reminiscent but distinct from scleroderma or scleromyxedema.

Nephrogenic systemic fibrosis always occurs (with the exception of one report in 2 transplant patients whose organ donors’ histories were not noted1 ) in patients with renal insufficiency who have had imaging studies (eg, magnetic resonance angiography) with gadolinium, a contrast agent used in imaging studies. Gadolinium can be found in tissue samples of nephrogenic systemic fibrosis. Evidence for a link between nephrogenic systemic fibrosis and gadolinium was first described in a case series of 13 patients, all of whom developed nephrogenic systemic fibrosis after being exposed to gadolinium.2

Nephrogenic systemic fibrosis resembles scleroderma and eosinophilic fasciitis clinically and scleromyxedema histopathologically. Patients with nephrogenic systemic fibrosis may develop large areas of indurated skin with fibrotic nodules and plaques. Flexion contractures with an accompanying limitation of range of motion also can occur. Although most patients with nephrogenic systemic fibrosis have undergone hemodialysis for renal failure, some have never undergone dialysis and others have received only peritoneal dialysis.

Histopathologically, nephrogenic systemic fibrosis resembles scleromyxedema in that it manifests with a proliferation of dermal fibroblasts and dendritic cells, thickened collagen bundles, increased elastic fibers, and mucin deposition.

Pathophysiology

The pathophysiology of nephrogenic systemic fibrosis is related to the exposure of patients with renal insufficiency to gadolinium in association with imaging studies. Evidence for a link between nephrogenic systemic fibrosis and gadolinium was first described in a case series of 13 patients, all of whom developed nephrogenic systemic fibrosis after being exposed to gadolinium.2 The mechanism by which this occurs in not known, but it seems to involve a cell termed a circulating fibrocyte that is stimulated by gadolinium.3

Thomsen et al4 noted that more than 90% of proven nephrogenic systemic fibrosis cases are related to gadodiamide (Omniscan) and some to gadopentetate (Magnevist).5

The relationship between epoetin alfa (Epogen) and nephrogenic systemic fibrosis has engendered controversy. Whether epoetin alfa is related to nephrogenic systemic fibrosis or if severe renal impairment merely sets the stage for nephrogenic systemic fibrosis remains unclear. Goveia et al6 noted in their case control study that 100% of patients with nephrogenic systemic fibrosis (n = 8) were treated with recombinant epoetin after undergoing renal transplantation versus only 6% of control subjects (n = 24). They theorized that epoetin, through its ability to promote endothelial cell proliferation and augment fibrin-induced wound healing, could play a role in the pathogenesis of nephrogenic systemic fibrosis. Saab7 challenged this conclusion and noted the following:

88% of patients with nephrogenic systemic fibrosis had a serum creatinine greater than 5 mg/dL as compared with only 21% of control subjects. The fact that these patients had significantly worse renal function as compared with most of the control subjects puts them at higher risk for requiring recombinant epoetin therapy for management of anemia. Because nephrogenic systemic fibrosis is only seen in patients with severe renal insufficiency, the epoetin requirement in this group may simply be a manifestation of decreased renal function.
Gadolinium can be deposited in almost any tissue in the body after its use for imaging studies. Gibson et al8 noted 2 reports with apparent multiorgan fibrosis with involvement of skeletal muscle, myocardium, the lungs, the kidneys, and the testes. Of interest, a condition that resembles nephrogenic systemic fibrosis is eosinophilia-myalgia syndrome, which is also caused by an exogenous substance.

The amount of gadolinium needed to induce aberrant production of hyaluronic acid seems to be minimal. According to an abstract presented by Dr. Susie Mukherjee reported at the 2007 annual meeting of the British Association of Dermatologists, only tiny concentrations of gadolinium are needed to stimulate hyaluronan synthesis by fibroblasts. Both 10-mmol/L and 1-mmol/L concentrations of gadolinium caused a 2.3-fold increase in hyaluronan synthesis.9

Parsons et al10 performed immunohistochemical studies using antibodies to transglutaminase-2, factor XIIIa, transglutaminase isopeptide, and the histiocyte marker CD68 on 5 archived skin biopsy specimens of nephrogenic systemic fibrosis. Parsons et al found that dermal fibroblasts and histiocytes of nephrogenic systemic fibrosis expressed transglutaminase-2, CD68, factor XIIIa, and transglutaminase isopeptide. They posited that this represented increased expression, activation, or concomitant activation and expression of transglutaminases in nephrogenic systemic fibrosis.

Edward et al11 found that fibroblasts derived from skin affected by nephrogenic systemic fibrosis synthesize elevated levels of sulphated glycosaminoglycans, in particular hyaluronan, compared with normal control samples, while serum from the one patient with dermatomyositis and from the 2 patients with nephrogenic systemic fibrosis stimulated sulphated glycosaminoglycans synthesis, including hyaluronan synthesis, by both control and patient fibroblasts.

Historical theories on the etiology of nephrogenic systemic fibrosis
The following discussion is interesting more for historical purposes, because, since the identification of the nephrogenic systemic fibrosis–gadolinium link in 2006, the understanding of nephrogenic systemic fibrosis has changed radically.

Mackay-Wiggan et al12

In 2003, Mackay-Wiggan et al found that all patients in their series had anticardiolipin or antiphospholipid antibodies detected on testing. This implied a role for these antibodies in the development of nephrogenic systemic fibrosis. Mackay-Wiggan et al suggested that although these antibodies occur in 10-29% of patients with end-stage renal disease, the antibodies are more common in patients with nephrogenic systemic fibrosis.

Mackay-Wiggan et al also suggested that the lipid molecule of the antiphospholipid or anticardiolipin antibody may interact with a lipid substance in the dialysis procedure. How it interacts is uncertain. Possibly, it interacts with the dialysis machine's filter or the tubing to stimulate fibroblast or mucin production. This cause would not explain the occurrence of nephrogenic systemic fibrosis in the small subset of end-stage renal disease patients with an onset of the disorder before beginning hemodialysis.

Another theory of Mackay-Wiggan et al is that an accumulated substance intrinsic to acute or chronic renal failure may interact with the antiphospholipid antibody. Yet another theory of Mackay-Wiggan et al is that sudden, severe edema may trigger a fibrotic and mucinous cutaneous reaction that results in this progressive scleromyxedemalike illness. They speculate that perhaps edema coupled with immunosuppression in patients with antiphospholipid antibodies stimulate a physiologic response, resulting in the proliferation of fibroblastlike cells and mucin deposition in the dermis.

McNeill and Barr13

In 2002, McNeill and Barr hypothesized that patients with hepatitis C who were undergoing hemodialysis would be at increased risk for this disorder because of increased levels of basic fibroblast growth factor, transforming growth factor-beta1, or both.

Jiménez et al14 and Ortonne et al15

In 2004, Jiménez et al reported on their histopathologic studies. These studies of patients with nephrogenic systemic fibrosis indicated that the fibrotic process of nephrogenic systemic fibrosis affected the subcutaneous tissue, fascia, striated muscles, lungs, and myocardium, in addition to the dermis. The skin contained large numbers of CD68+/factor XIIIa+ dendritic cells and increased expression of transforming growth factor-beta1.

Also in 2004, Ortonne et al suggested the presence of CD45RO+ CD34+ cells with collagen synthesis activity as part of the etiology of nephrogenic systemic fibrosis.

Kucher et al16

Kucher et al16 reviewed 9 biopsy specimens positive for a nephrogenic systemic fibrosis diagnosis and 7 biopsy specimens positive for a scleromyxedema diagnosis.

Immunohistochemical staining for CD34, factor XIIIa, CD31, smooth muscle actin, CD68, and colloidal iron were similar for both conditions. Procollagen-I showed increased expression in scleromyxedema. The significance of this is unclear.

Frequency

United States

Nephrogenic systemic fibrosis is an uncommon condition. Since 1997, hundreds of cases have been reported to the NFD Registry.

Deo et al17 studied a population of patients with end-stage renal disease in and around Bridgeport, Connecticut over an 18-month period. The incidence of nephrogenic systemic fibrosis was 4.3 cases per 1000 patient-years. Each radiologic study using gadolinium presented a 2.4% risk for developing nephrogenic systemic fibrosis.

Todd et al18 found that exposure to gadolinium-containing contrast was associated with an increased risk of developing cutaneous changes of nephrogenic systemic fibrosis (odds ratio, 14.7; 95% confidence interval, 1.9-117.0) compared with patients who were not exposed to gadolinium.

International

Nephrogenic systemic fibrosis is an uncommon condition. Several case series from Europe have been reported. Four cases were described in a report in the British Journal of Dermatology in March 2003.19 Additional cases have been reported in Germany and Switzerland.

Mortality/Morbidity

Nephrogenic systemic fibrosis appears linked to increased morbidity and mortality. Todd et al18 found that 24-month mortality rates following examination were 48% and 20% in patients with and those without cutaneous changes of nephrogenic systemic fibrosis, respectively (adjusted hazard ratio, 2.9; 95% confidence interval, 1.4-5.9).

Within weeks of disease onset, many patients become dependent on a wheelchair because of contractures. Several patients have died because of complications from fractures after falls triggered by their mobility problems. Additionally, many patients report maddening pruritus and/or causalgia. Finally, some patients experience flexion contractures if the disorder occurs over a joint.

Race

No racial predisposition is reported. Whites, Hispanics, African Americans, and Asians have all been reported with this condition.

Sex

No sexual predilection is recognized. Data from the NFD Registry indicate a male-to-female ratio of 1:1. However, in the 2001 article by Cowper et al,20 the male-to-female ratio in patients with biopsy-proven disease was 9:5.

Age

Nephrogenic systemic fibrosis has been reported in all age groups; it seems likely that persons of any age exposed to gadolinium can develop nephrogenic systemic fibrosis. The first group of persons reported with nephrogenic systemic fibrosis were adults whose ages ranged from 31-74 years. Data from the nephrogenic systemic fibrosis Registry indicate a range of ages from 8-87 years at the time of disease onset, with a mean age of 46.4 years. In 2003, Jan et al21 reported on 2 pediatric cases. A series from England noted a patient in her 20s with the disease.

The development of nephrogenic systemic fibrosis is not correlated with the duration of renal failure, and it can occur early as well as later. Hancox et al22 noted a case of nephrogenic systemic fibrosis after 5 days of hemodialysis.

Clinical

History

All patients with nephrogenic systemic fibrosis have a history of renal insufficiency of varying severity and duration and gadolinium exposure (with the exception of one report involving transplant recipients in which the donor exposure to gadolinium was not reported). A few have primarily liver disease. Most patients have had treatments that include hemodialysis, peritoneal dialysis, or renal transplantation. However, neither dialysis nor transplantation is a prerequisite for nephrogenic systemic fibrosis.

Thomsen et al4 noted that more than 90% of proven nephrogenic systemic fibrosis cases are related to gadodiamide (Omniscan) and some to gadopentetate (Magnevist).5

  • Many patients with nephrogenic systemic fibrosis have calcium pathology. Traumatic calcinosis cutis in a dialysis patient with nephrogenic systemic fibrosis has been reported. Osseous metaplasia in the setting of nephrogenic systemic fibrosis has been noted.23 A variant of nephrogenic systemic fibrosis with osteoclastlike giant cells, which has been termed a syndrome of dysregulated matrix remodeling, has been noted. Calciphylaxis and metastatic calcification associated with nephrogenic systemic fibrosis has also been reported.19
  • Patients may have a history of a tightening or a thickening of the skin. Stiffening of the hands and flexion contractures can also occur.
  • Some patients may have a history of preceding episodes of severe anasarca, recent vascular surgery, or hypercoagulability.
  • Some patients have known concurrent liver disease and/or neoplasia. A history of liver problems may be present. Some patients may have chronic hepatitis C.
  • The disease can develop days, months, or years after undergoing dialysis or after renal failure starts.
  • Patients may report that their skin is shiny.
  • This condition can develop slowly.
  • Pain or pruritus can be a prominent feature in many patients and can be a major component of their disability.
  • Some patients may have taken immunosuppressive medications.
  • Nephrogenic systemic fibrosis has been reported in 2 patients with systemic lupus erythematosus.24
  • Involvement of skeletal muscle in dialysis-associated systemic fibrosis (nephrogenic systemic fibrosis) has been noted.25
  • Nephrogenic systemic fibrosis has been described in a renal transplant recipient with tubulointerstitial nephritis and uveitis.26
  • Glaich et al27 noted generalized elastolysis following nephrogenic systemic fibrosis.
  • Kucher et al28 noted nephrogenic systemic fibrosis with diaphragmatic involvement in a patient with respiratory failure.
  • Edward et al29 noted cutaneous mucinosis associated with dermatomyositis and nephrogenic systemic fibrosis. They reported on fibroblast hyaluronan synthesis and the effect on patients' serum.
  • Saenz et al30 noted nephrogenic systemic fibrosis with involvement of the dura mater.
  • Naylor et al31 reported on a 65-year-old woman with nephrogenic systemic fibrosis with septal panniculitis whose biopsy specimen demonstrated unique histologic features of septal panniculitis with lymphocytic aggregates and Miescher radial granulomas mimicking erythema nodosum.
  • Neuromuscular involvement can occur in nephrogenic systemic fibrosis, and it can be documented by electromyography/nerve conduction studies. These findings may be difficult to appreciate clinically because of joint and skin fibrosis.32
  • Nephrogenic systemic fibrosis has been reported in a 14-year-old-girl with new-onset systemic lupus erythematosus and acute lupus nephritis after gadolinium exposure.33
  • Goddard et al34 noted nephrogenic systemic fibrosis with recurrence after allograft failure.
  • Wahba et al1 noted 2 organ transplant recipients who they stated had had no gadolinium exposure and yet developed nephrogenic systemic fibrosis. This report is of uncertain significance because (1) the nephrogenic systemic fibrosis tissue was not examined for gadolinium in the manner of High et al35 and (2) the history of the apposite organ donors was not obtained; thus, gadolinium may have been present in the bodies of the patients reported by Wahba et al.

Physical

  • Nephrogenic systemic fibrosis manifests with induration, thickening, and hardening of the skin with brawny hyperpigmentation. Distinct papules and subcutaneous nodules can also be seen. Cellulitis is commonly suspected.
  • The skin can have a peau d'orange appearance, and plaques may have an amoeboid advancing edge.
  • The skin is often shiny and hard to the touch. A woody consistency is typical.
  • The extremities are the most common areas of involvement, followed by the trunk. The face is almost never involved.
  • Yellow palmar papules resembling cutaneous calcinosis have been reported. In addition, yellow scleral plaques have been reported in patients with nephrogenic systemic fibrosis.
  • Solomon et al36 noted nephrogenic systemic fibrosis mimicking inflammatory breast carcinoma.
Nephrogenic fibrosing dermopathy on the abdomen, ...

Nephrogenic fibrosing dermopathy on the abdomen, demonstrating a peau d'orange appearance.

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Nephrogenic fibrosing dermopathy on the abdomen, ...

Nephrogenic fibrosing dermopathy on the abdomen, demonstrating a peau d'orange appearance.


Nephrogenic systemic fibrosis on the abdomen, dem...

Nephrogenic systemic fibrosis on the abdomen, demonstrating a peau d'orange appearance. A keloid from a previous surgery is present.

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Nephrogenic systemic fibrosis on the abdomen, dem...

Nephrogenic systemic fibrosis on the abdomen, demonstrating a peau d'orange appearance. A keloid from a previous surgery is present.


Nephrogenic systemic fibrosis on the leg, demonst...

Nephrogenic systemic fibrosis on the leg, demonstrating a bound-down and sclerotic appearance and texture.

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Nephrogenic systemic fibrosis on the leg, demonst...

Nephrogenic systemic fibrosis on the leg, demonstrating a bound-down and sclerotic appearance and texture.


Causes

  • The cause of nephrogenic systemic fibrosis is the connexation of renal insufficiency and gadolinium exposure from imaging studies. The exact degree of renal insufficiency that sets up the development of nephrogenic systemic fibrosis is not known. Risk factors include advanced chronic kidney disease (stages 4 and 5) and acute or chronic inflammatory insults. The US Food and Drug Administration (FDA) has updated its public health advisory to include patients with moderate renal insufficiency (chronic kidney disease stage 3).37
  • Gadolinium-based contrast agents (Magnevist, MultiHance, Omniscan, OptiMARK, ProHance) have recently been linked to the development of nephrogenic systemic fibrosis. The disease has occurred in patients with moderate- to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or magnetic resonance angiography. As of late December 2006, the FDA had received reports of 90 such cases. Worldwide, the FDA has reported more than 200 cases.
  • Nephrogenic systemic fibrosis is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.

More on Nephrogenic Systemic Fibrosis

Overview: Nephrogenic Systemic Fibrosis
Differential Diagnoses & Workup: Nephrogenic Systemic Fibrosis
Treatment & Medication: Nephrogenic Systemic Fibrosis
Follow-up: Nephrogenic Systemic Fibrosis
Multimedia: Nephrogenic Systemic Fibrosis
References
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References

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Further Reading

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Keywords

nephrogenic systemic fibrosis, NFS, nephrogenic fibrosing dermopathy, NFD, scleromyxedemalike illness of renal disease, scleromyxedemalike illness of hemodialysis, atypical lichen myxedematosus, scleroderma, scleromyxedema, dermatofibroma protuberans

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Contributor Information and Disclosures

Author

Noah S Scheinfeld, MD, JD, FAAD, Assistant Clinical Professor, Department of Dermatology, Columbia University; Consulting Staff, Department of Dermatology, St Luke's Roosevelt Hospital Center, Beth Israel Medical Center, New York Eye and Ear Infirmary; Private Practice
Noah S Scheinfeld, MD, JD, FAAD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Optigenex Consulting fee Independent contractor

Coauthor(s)

Shawn Cowper, MD, Director, NFD Registry Project, Associate Professor, Departments of Dermatology and Pathology, Yale University
Disclosure: Nothing to disclose.

Medical Editor

Carrie L Kovarik, MD, Assistant Professor of Dermatology, Dermatopathology, and Infectious Diseases, University of Pennsylvania School of Medicine
Carrie L Kovarik, MD is a member of the following medical societies: Alpha Omega Alpha
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey J Miller, MD, Associate Professor of Dermatology, Penn State University College of Medicine; Staff Dermatologist, Penn State Milton S Hershey Medical Center
Jeffrey J Miller, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Association of Professors of Dermatology, North American Hair Research Society, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania
Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology
Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds None; Genentech Consulting fee Consulting; Centocor Consulting fee Consulting; Centocor Grant/research funds None; Covance Consulting fee Consulting; Shire  Consulting

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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