Nephrogenic Systemic Fibrosis 

Updated: May 22, 2018
Author: Noah S Scheinfeld, JD, MD, FAAD; Chief Editor: Dirk M Elston, MD 

Overview

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. It is caused by gadolinium exposure used in imaging in patients who have renal insufficiency.

Nephrogenic systemic fibrosis almost always occurs  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, and alternative contrast agents are being sought.[1, 2, 3]

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.[4]  Sometimes articles are published that state a patient with renal impairment developed nephrogenic systemic fibrosis, but these are likely instances when an inadequate history has been taken.[5] One case of nephrogenic systemic fibrosis developed 10 years after gadolinium exposure.[6]  Newer contrast agents like gadobenate dimeglumine carry a lower risk.[7, 8]

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. The chelated forms of the less stable gadolinium chelates might have a significant role, but it appears that dissociated gadolinium's gradual release is pivotal in the development of nephrogenic systemic fibrosis and its sometimes delayed onset.[9]

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.[4] 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.[10] Endothelin-1/endothelin receptor signaling plays a role in the calcification and fibrosis of nephrogenic systemic fibrosis.[11]

Toll-like receptors (TLR), in particular TLR4 and TLR7, play a role in the development of nephrogenic systemic fibrosis.[12]

Thomsen et al[13] noted that more than 90% of proven nephrogenic systemic fibrosis cases are related to gadodiamide (Omniscan) and some to gadopentetate (Magnevist).[14] As such, gadoversetamide (OptiMARK) and gadopentetate dimeglumine (Magnevist) should not be used for imaging in patients with renal impairment. MultiHance and ProHance, similar brands, should also likely not be used.

The safety of gadopentetate linear product might be no different from macrocyclic preparations such as gadodiamide (Omniscan), but guidelines should be followed in all gadolinium products.[15]

The macrocyclic contrast agents gadobutrol (Gadovist/Gadavist) and gadobenate dimeglumine (MultiHance) should be used only following guidelines. It is possible that Gadovist, Dotarem, and Prohance are safer, but this does not justify changing guidelines.[16]

While evidence data showing a benefit for prompt hemodialysis after gadolinium imaging are lacking, this is a justified precaution. Similar guidelines from the FDA and the American College of Radiology (ACR) state that gadolinium use with an approximate glomerular filtration rate of 30-44 mL/min per 1.73 m2 should be used with extreme caution.

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[17] 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[18] challenged this conclusion and noted that 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[19] 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.[20]

Parsons et al[21] 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[22] 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. Metformin use might influence nephrogenic systemic fibrosis, but this is not proven.[23]

Iron metabolism shapes the development of nephrogenic systemic fibrosis in a mouse model.[24]

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[25]

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[26]

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[27] and Ortonne et al[28]

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[29]

Kucher et al[29] 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.

Etiology

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).[30] Metformin use might influence nephrogenic systemic fibrosis, but this is not proven.[23]

Gadolinium-based contrast agents (Ablavar, Eovist, 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.

On September 9, 2010, the FDA announced it is requiring that gadolinium-based contrast agents (GBCAs) carry new warnings on their labels about the risk for nephrogenic systemic fibrosis and its association when administered to certain patients with kidney disease. The FDA's review of the safety of the most widely used GBCAs determined that Magnevist, Omniscan, and Optimark are associated with a greater risk for nephrogenic systemic fibrosis than other GBCAs. These 3 agents will be contraindicated for use in certain patients with kidney disease, while other gadolinium contrast agents will carry a warning. Data suggest that nephrogenic systemic fibrosis may follow the administration of any GBCA, and the FDA continues to assess the safety of each GBCA to better estimate its nephrogenic systemic fibrosis risks.[31]

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.

Epidemiology

Frequency

United States

Nephrogenic systemic fibrosis is an uncommon condition. Since 1997, hundreds of cases have been reported to the NFD Registry. Few cases have occurred since guidelines have been instituted by the ACR, FDA, and EU regulatory authorities; however, this author has heard at meetings that a few sporadic cases have occurred. These cases do not seem to have been reported the NSF Registry at Yale. That is, even with guidelines in place, in 2010, 2011, 2012, 2013, a handful of new cases of were reported but many fewer than before gadolinium was defined as the cause. Some of these cases likely involve exposure to gadolinium used before the guidelines were put in place and involve delayed onset of the disease.

Deo et al[32] 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[33] 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.[34] Additional cases have been reported in Germany and Switzerland.

For example, delayed-onset nephrogenic systemic fibrosis was reported in a Korean person with renal failure who demonstrated a "reverse superscan" on bone scintigraphy at age 19 years who had been exposed to gadolinium at age 14 years.[35]

A study in Denmark found a rate of 12 cases of nephrogenic systemic fibrosis per million, which may be the highest prevalence worldwide.[36]

In France, after new guidelines for use of gadolinium were instituted, a study of patients from 2009-2011 found that no cases of nephrogenic systemic fibrosis occurred.[37]

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,[38] 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; persons of any age exposed to gadolinium may 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[39] reported on 2 pediatric cases. A series from England noted a patient in her 20s with the disease.

Children are generally not less able to develop nephrogenic systemic fibrosis. However, since new guidelines have been implemented, children who receive gadolinium have not developed nephrogenic systemic fibrosis.[40]

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[41] noted a case of nephrogenic systemic fibrosis after 5 days of hemodialysis.

Prognosis

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

Nephrogenic systemic fibrosis appears linked to increased morbidity and mortality. Todd et al[33] 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.

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).

 

Presentation

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[13] noted that more than 90% of proven nephrogenic systemic fibrosis cases are related to gadodiamide (Omniscan) and some to gadopentetate (Magnevist).[14]

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.[42] 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.[34]

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.[43]

Involvement of skeletal muscle in dialysis-associated systemic fibrosis (nephrogenic systemic fibrosis) has been noted.[44]

Nephrogenic systemic fibrosis has been described in a renal transplant recipient with tubulointerstitial nephritis and uveitis.[45]

Glaich et al[46] noted generalized elastolysis following nephrogenic systemic fibrosis.

Kucher et al[47] noted nephrogenic systemic fibrosis with diaphragmatic involvement in a patient with respiratory failure.

Edward et al[48] 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[49] noted nephrogenic systemic fibrosis with involvement of the dura mater.

Naylor et al[50] 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.[51]

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.[52]

Goddard et al[53] noted nephrogenic systemic fibrosis with recurrence after allograft failure.

Metformin use might influence nephrogenic systemic fibrosis, but this is not proven.[23]

Wahba et al[2] 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[54] 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.

Gathings et al in 2014 noted that GAP appeared as erythematous plaques, with a diameter of 0.5-2.5 cm. One patient experience pruritus and the other did not. Histopathologically, these plaques demonstrated eosinophilic, collagenous, ovoid or round bodies (sclerotic bodies) in a variety of calcification. Previously, these sclerotic bodies were thought to be pathognomonic for nephrogenic systemic fibrosis, which required chronic renal insufficiency and imaging with gadolinium; this was not the case in these two patients.[55]

Ross in 2014 noted nephrogenic systemic fibrosis in a gadolinium-naïve woman that was treated successfully with oral sirolimus.[56]

It has been found that in patients with chronic liver disease, the incidence of nephrogenic systemic fibrosis after gadolinium exposure is roughly equal to controls.[57]

Perforating osteoma cutis has been noted in a patient with long-standing nephrogenic systemic fibrosis.[58]

Physical Examination

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 al[59] noted nephrogenic systemic fibrosis mimicking inflammatory breast carcinoma.

Note the images below.

Nephrogenic fibrosing dermopathy on the abdomen, d Nephrogenic fibrosing dermopathy on the abdomen, demonstrating a peau d'orange appearance.
Nephrogenic systemic fibrosis on the abdomen, demo 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, demonstr Nephrogenic systemic fibrosis on the leg, demonstrating a bound-down and sclerotic appearance and texture.

Complications

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

 

DDx

Diagnostic Considerations

Also consider the following:

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

Differential Diagnoses

 

Workup

Laboratory Studies

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[60] 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.

Paraffin-embedded tissue, lesional, nonlesional, and fresh tissue, as well as serum, can all show elevated levels of gadolinium in nephrogenic systemic fibrosis.[61]

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

In 2001, Cowper et al[38] 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.[62]

In 2011, Elmholdt noted that low-dose oral imatinib mesylate slightly improved skin texture but not joint mobility in patients with nephrogenic systemic fibrosis.[63]

In 2005, Schmook et al[64] reported on successful treatment of nephrogenic systemic fibrosis with photodynamic therapy in a kidney transplant recipient.

In 2004, Kafi et al[65] found that UV-A1 phototherapy improves nephrogenic systemic fibrosis.

Läuchli et al,[66] 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[67] found that nephrogenic systemic fibrosis responded to high-dose intravenous immunoglobulin.

Wahba et al[68] 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[69] 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 achieved.

Yerram et al[70] 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.[71]

Inpatient care

Nephrogenic systemic fibrosis 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.

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.

Prevention

Guidelines have vastly decreased the number of cases of NSF. These guidelines include (1) limiting gadolinium-based contrast agents to a maximum dose of 0.1 mmol/kg, (2) dialyzing renally impaired patients undergoing dialysis rapidly following gadolinium-based contrast agents use, (3) delaying gadolinium-based contrast agents in acute renal failure by waiting until renal function improves or dialysis is started, and (4) not using nonionic linear GBCA in patients with renal failure, in particular when proinflammatory conditions are coincident.[72]

Long-Term Monitoring

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

 

Medication

Medication Summary

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.[73]

 

Questions & Answers

Overview

What is nephrogenic systemic fibrosis (NSF)?

What was the Jiménez theory of the pathogenesis of nephrogenic systemic fibrosis (NSF)?

What is the pathophysiology of nephrogenic systemic fibrosis (NSF)?

What is the role of epoetin alfa (Epogen) in the pathogenesis of nephrogenic systemic fibrosis (NSF)?

What is the role of gadolinium in the pathogenesis of nephrogenic systemic fibrosis (NSF)?

Which antibodies may have a role in the pathophysiology of nephrogenic systemic fibrosis (NSF)?

What was the Macay-Wiggan et al theory of the pathogenesis of nephrogenic systemic fibrosis (NSF)?

What was the McNeill and Barr theory of the pathogenesis of nephrogenic systemic fibrosis (NSF)?

What was the Kucher theory of the pathogenesis of nephrogenic systemic fibrosis (NSF)?

What causes nephrogenic systemic fibrosis (NSF)?

What is the prevalence of nephrogenic systemic fibrosis (NSF) in the US?

What is the global prevalence of nephrogenic systemic fibrosis (NSF)?

What are the racial predilections of nephrogenic systemic fibrosis (NSF)?

What is the sexual predilection in nephrogenic systemic fibrosis (NSF)?

Which age groups are at highest risk for nephrogenic systemic fibrosis (NSF)?

What is the prognosis of nephrogenic systemic fibrosis (NSF)?

What is included in patient education about nephrogenic systemic fibrosis (NSF)?

Presentation

Which clinical history findings are characteristic of nephrogenic systemic fibrosis (NSF)?

Which physical findings are characteristic of nephrogenic systemic fibrosis (NSF)?

What are the possible complications of nephrogenic systemic fibrosis (NSF)?

DDX

Which conditions should be included in the differential diagnoses of nephrogenic systemic fibrosis (NSF)?

What are the differential diagnoses for Nephrogenic Systemic Fibrosis?

Workup

What is the role of lab testing in the workup of nephrogenic systemic fibrosis (NSF)?

What is the role of imaging studies in the workup of nephrogenic systemic fibrosis (NSF)?

How are nerve conduction abnormalities assessed in the workup of nephrogenic systemic fibrosis (NSF)?

What is the role of biopsy in the workup of nephrogenic systemic fibrosis (NSF)?

Which histologic findings are characteristic of nephrogenic systemic fibrosis (NSF)?

Treatment

What is included in the inpatient care for nephrogenic systemic fibrosis (NSF)?

How is nephrogenic systemic fibrosis (NSF) treated?

What is the role of surgery in the treatment of nephrogenic systemic fibrosis (NSF)?

Which specialist consultations are beneficial to patients with nephrogenic systemic fibrosis (NSF)?

Which activity modifications are used in the treatment of nephrogenic systemic fibrosis (NSF)?

How is nephrogenic systemic fibrosis (NSF) prevented?

What is included in the long-term monitoring of patients with nephrogenic systemic fibrosis (NSF)?

Medications

What is the role of medications in the treatment of nephrogenic systemic fibrosis (NSF)?