Nephrogenic Systemic Fibrosis: [Print] - eMedicine Dermatology Page 1 of 19

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Nephrogenic Systemic Fibrosis

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
Shawn Cowper, MD, Director, NFD Registry Project, Associate Professor, Departments of Dermatology and Pathology, Yale University
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 noted[1 ]) 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 al[4 ]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 al[6 ]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. Saab[7 ]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 al[8 ]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

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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 al[10 ]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 al[11 ]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 al[12 ]

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 Barr[13 ]

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 al[14 ]and Ortonne et al[15 ]

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 al[16 ]

Kucher et al[16 ]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

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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 al[17 ]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 al[18 ]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 al[18 ]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 al[21 ]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 al[22 ]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 al[4 ]noted that more than 90% of proven nephrogenic systemic fibrosis cases are related to gadodiamide (Omniscan) and
some to gadopentetate (Magnevist).[5 ]

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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 al[27 ]noted generalized elastolysis following nephrogenic systemic fibrosis.

Kucher et al[28 ]noted nephrogenic systemic fibrosis with diaphragmatic involvement in a patient with respiratory failure.

Edward et al[29 ]noted cutaneous mucinosis associated with dermatomyositis and nephrogenic systemic fibrosis. They reported on
fibroblast hyaluronan synthesis and the effect on patients' serum.

Saenz et al[30 ]noted nephrogenic systemic fibrosis with involvement of the dura mater.

Naylor et al[31 ]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 al[34 ]noted nephrogenic systemic fibrosis with recurrence after allograft failure.

Wahba et al[1 ]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 al[35 ]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.

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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 al[36 ]noted nephrogenic systemic fibrosis mimicking inflammatory breast carcinoma.

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

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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 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.

Differential Diagnoses

Calciphylaxis Lichen Myxedematosus

Cellulitis Morphea
Dermatofibrosarcoma Protuberans Porphyria Cutanea Tarda
Eosinophilia-Myalgia Syndrome Systemic Sclerosis
Eosinophilic Fasciitis
Granuloma Annulare

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Other Problems to Be Considered

Fibroblastic rheumatism
Scleromyxedema
Beta2-microglobulin amyloidosis
Panniculitis
Sclerodermatous chronic graft versus host disease

Workup

Laboratory Studies
The following has been noted:

Scleromyxedemalike skin lesions occur without associated paraproteinemia. Serum protein electrophoresis and
immunoelectrophoresis results are negative.

Nephrogenic systemic fibrosis (NSF) occurs in the setting of renal disease. Thus, abnormal values of BUN and creatinine are
typically present.

Thyroid studies produce normal findings in patients with nephrogenic systemic fibrosis.

In rare cases, peripheral eosinophilia has been noted.

In some cases, a positive antinuclear antibody test result has been reported.

Some patients with nephrogenic systemic fibrosis have anticardiolipin or antiphospholipid antibodies.

Rheumatoid factor and other autoantibodies are typically absent.

Many patients have an associated hypercoagulable state.

Some patients have hepatitis B or C.

In summary, no particular laboratory abnormality is consistently linked to nephrogenic systemic fibrosis.

Imaging Studies
No imaging study is indicated to assess nephrogenic systemic fibrosis. However, although no imaging study is indicated to assess
nephrogenic systemic fibrosis, many authors have described soft tissue calcifications.

Other Tests
Abnormalities of nerve conduction have been described in some patients.

Thakral and Abraham[38 ]developed an automated quantitative scanning electron microscopy and energy dispersive x-ray spectroscopy
method for documenting gadolinium in tissue of patients with nephrogenic systemic fibrosis. They examined, under standardized
conditions, freshly cut tissue in paraffin block using the variable pressure mode. This allowed them to perform a random search of the
tissue area to conduct in situ detection and semiquantitative morphometric (volumetric) analysis of insoluble, higher–atomic number
features using backscattered electron imaging.

Thakral and Abraham detected gadolinium ranging from 1-2270 cps/mm2 in 57 cutaneous biopsy specimens of nephrogenic systemic
fibrosis. Gadolinium was associated with phosphate, calcium, and sodium in the tissues. This method reproducibly determines the
elemental composition, relative concentration, and spatial distribution of detected features within the tissue; however, they could not
detect features below their spatial resolution or concentrations below the detection limit of the scanning electron microscopy and energy
dispersive x-ray spectroscopy system.

Procedures
A skin biopsy is indicated for this condition. A deep biopsy, such as an incisional biopsy or a deep punch biopsy, should be performed. A
sample of dermis, subcutaneous fat, and fascia should be obtained, if possible.

Histologic Findings

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In 2001, Cowper et al[20 ]described the unique histopathologic features of nephrogenic systemic fibrosis, specifically, thickened collagen
bundles with surrounding clefts, mucin deposition, and a proliferation of fibroblasts and elastic fibers.

Early lesions (within 20 wk of clinic onset) demonstrate reticular, dermal, large, and epithelioid or stellate spindle cells. These cells can
extend into and widen the subcutaneous fat lobule septa. The spindle cells are diffusely arranged among thickened collagen bundles.

Clefts can encompass some spindle cells. Most of the spindle cells are CD34/procollagen dual-positive cells that form a dense
interconnecting network.

Because this condition is not commonly reported, diagnostic errors abound. Spindle cell proliferation can be confused with
dermatofibrosarcoma protuberans or even spindle cell melanoma. Alcian blue, mucicarmine, or Movat pentachrome stains can be used
to detect variable amounts of mucin. Thick elastic fibers oriented parallel to collagen bundles are usually present.
Some cases of nephrogenic systemic fibrosis have manifested with a scant superficial and deep lymphocytic infiltrate, although
inflammation is usually absent, and this finding should prompt consideration of an alternative diagnosis. Multinucleated cells positive for
CD68 and factor XIIIa–positive cells are commonly present.

Late lesions (>20 wk of clinical onset) typically have less prominent clefting, less mucin, and fewer CD34/procollagen–positive cells.
Calcification, which is described in some patients and which has been interpreted as dystrophic in nature, can be present.

Treatment

Medical Care
Nephrogenic systemic fibrosis (NSF) is usually a chronic, progressive condition. Rare cases of partial-to-complete spontaneous
resolution have been reported in the absence of specific therapy, with the return of renal function. A favorable response to medical
intervention is anecdotal. Of all treatments, extracorporeal photopheresis (ECP) seems to provide the best, albeit mild and extremely
expensive, treatment modality for nephrogenic systemic fibrosis.

In one patient, ECP resulted in some improvement in skin texture.[39 ]

In 2005, Schmook et al[40 ]reported on successful treatment of nephrogenic systemic fibrosis with photodynamic therapy in a
kidney transplant recipient.

In 2004, Kafi et al[41 ]found that UV-A1 phototherapy improves nephrogenic systemic fibrosis.

Lãuchli et al,[42 ]in 2004, described the case of a 40-year-old woman with renal insufficiency who was treated with hemodialysis
and who had undergone kidney transplantation. Two years after transplantation, she developed sclerodermiform brownish
plaques on her extremities. The induration improved significantly after 4 cycles of ECP.

Also in 2004, Chung and Chung[43 ]found that nephrogenic systemic fibrosis responded to high-dose intravenous immunoglobulin.

Wahba et al[44 ]suggest that UV light therapy has a role in the treatment of nephrogenic systemic fibrosis, based on 2 cases with
which they were involved.

Another report noted that patients had no benefit from plasma exchange, intralesional triamcinolone, or intralesional methotrexate.

A trial of localized psoralen plus UV-A treatment in one patient produced no improvement. Oral prednisone (60 mg PO qd) has
been effective in several cases, but it has been discontinued in some patients because of its adverse effects.

In 1 of 2 patients, intralesional alpha interferon (3 MU 3 times weekly) improved the skin, although in both patients, it had to be
discontinued because of its adverse effects. In another patient, this therapy was associated with a worsening of lesions.

A small series of patients with dual liver/kidney transplants showed marked improvement with plasmapheresis. As renal function
had improved posttransplant, the contribution of plasmapheresis to the improvement of cutaneous findings is not clear.

Cyclophosphamide has shown no efficacy in several patients.

Topical calcipotriene (Dovonex) under occlusion has resulted in subjective improvement in 2 patients. Calcipotriene plus
betamethasone dipropionate (Taclonex) seemingly might have a role in topical treatment for nephrogenic systemic fibrosis.

Richmond et al[45 ]noted 8 patients with nephrogenic systemic fibrosis, 5 of whom were treated with ECP for a mean number of 34
treatment sessions over a mean of 8.5 months. Mildly improved skin tightening, range of motion, and/or functional capacity were

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achieved.

Yerram et al[46 ]reported on a patient who had nephrogenic systemic fibrosis and had multiple previous exposures to gadolinium
(Gd3+)–based MRI studies and experienced a substantial decrease in pain and skin changes after a trial of intravenous sodium
thiosulfate.

In 2008, Kreuter et al found limited effects of UV-A1 phototherapy in 3 patients with nephrogenic systemic fibrosis.[47 ]

Surgical Care
Surgical care has no role in the treatment of this condition. Although surgical care has no direct role in the treatment of nephrogenic
systemic fibrosis, patients who have undergone successful kidney transplantation may show resolution of the lesions. Nephrogenic
systemic fibrosis is not a contraindication to transplantation; however, because of reports of associated thrombotic events and early graft
loss, evaluation for hypercoagulability should be performed.

Consultations

A dermatologist should assess the patient. The consultation is usually referred by a nephrologist.

A dermatopathologist should be requested to review the biopsy material, and the suspicion of nephrogenic systemic fibrosis
should be clearly indicated on the accession form.

Activity
This disease can result in limited movement. Although the role for physical therapy has not been studied, it would appear intuitive to be
useful in patients who are affected.

Medication

Some medications have shown a benefit in small numbers of patients. Nephrogenic systemic fibrosis lesions may be treatable earlier in
the disease course, becoming recalcitrant after significant fibrosis has occurred. Prednisone and calcipotriene have been used with
marginal success (see Medical Care). Alfa interferon has been used, but its effects on the disease are unclear. Methotrexate,
cyclophosphamide, and psoralen plus UV-A light have been used without effect.

In 2008, Marckmann et al found possibly enhanced gadolinium excretion in dialysate, but they did not observe major clinical benefits with
3-5 months of treatment with sodium thiosulfate in patients in the late stages of nephrogenic systemic fibrosis.[48 ]

Follow-up

Further Inpatient Care

Nephrogenic systemic fibrosis (NSF) does not require inpatient care. No inpatient or outpatient treatment has been particularly
successful in treating this condition. Plasmapheresis has shown some promise and is still being evaluated for its efficacy in persons who
have not undergone transplantation.

Further Outpatient Care

Because nephrogenic systemic fibrosis may restrict mobility, physical therapy might be helpful for some patients with this condition.

Deterrence/Prevention
No preventive actions for this disease are known. Unlike many of the other complications of uremia, kidney transplantation has not been
shown to be beneficial, and, in fact, it may contribute to nephrogenic systemic fibrosis development. Others believe that kidney
transplantation may have beneficial effects in some patients.

Complications
Nephrogenic systemic fibrosis can be disabling and restrict the patient's range of motion. Falls are not uncommon, and fractures
frequently result.

Prognosis
Spontaneous resolution is described in some reports, typically coincident with improved/resolved renal disease. In most patients,

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nephrogenic systemic fibrosis is a progressive condition. Many patients report stabilization and marginal improvement after years with
the condition. Whether nephrogenic systemic fibrosis is a localized or systemic disease is not yet clear.

Patient Education
Patients need to understand that nephrogenic systemic fibrosis in not a life-threatening disease and that it lacks effective treatment.
Patients should also be warned about the increased risk of falls and subsequent fractures. Patients can be directed to the NFD Registry
Web page for updated information (NFD/NSF Registry).

Miscellaneous

Medicolegal Pitfalls

Confusing NFD with scleromyxedema, which is a paraneoplastic condition, and either overtreating or undertreating the disease at
hand is a pitfall.

Confusing NFD with scleroderma and not properly educating the patient regarding his or her actual disease and perhaps
instituting improper therapy are pitfalls. See Scleroderma.

Confusing NFD histopathologically with dermatofibrosarcoma protuberans is a pitfall that could lead to inappropriate surgery.
See Dermatofibrosarcoma Protuberans.

Multimedia

Media file 1: Nephrogenic fibrosing dermopathy on the abdomen, demonstrating a peau d'orange appearance.

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Media file 2: Nephrogenic systemic fibrosis on the abdomen, demonstrating a peau d'orange appearance. A keloid
from a previous surgery is present.

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Media file 3: Nephrogenic systemic fibrosis on the leg, demonstrating a bound-down and sclerotic appearance and
texture.

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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

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.

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Nephrogenic Systemic Fibrosis: [Print] - eMedicine Dermatology Page 19 of 19

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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