What is nephrogenic systemic fibrosis

Nephrogenic systemic fibrosis (NSF) is a rare disease that affects different parts of the body, particularly the skin, mainly in people with advanced kidney failure with or without dialysis ¹. Nephrogenic systemic fibrosis may resemble skin diseases, such as scleroderma and scleromyxedema, with thickening and darkening developing on large areas of the skin. Symptoms of nephrogenic systemic fibrosis may include progressive swelling and tightening of the skin, sometimes resulting in contractures, and pruritis (itching). The skin findings are similar to those seen in patients with scleroderma. Nephrogenic systemic fibrosis can also affect internal organs, such as the heart, kidneys and lungs, and it can cause a disabling shortening of muscles and tendons in the joints (joint contracture).

Nephrogenic systemic fibrosis was first described in 1997 ². The exact pathogenesis of nephrogenic systemic fibrosis is unclear, but the disease has been linked with the use of gadolinium-based contrast agents during magnetic resonance imaging (MRI) testing, predominantly in patients with acute renal failure or end-stage renal disease ³. Recognition of this link has dramatically reduced the incidence of nephrogenic systemic fibrosis.

What causes nephrogenic systemic fibrosis?

The exact cause of nephrogenic systemic fibrosis isn’t fully understood. Exposure to gadolinium-containing contrast agents during magnetic resonance imaging (MRI) has been identified as a trigger for development of this disease. The Food and Drug Administration (FDA) recommends avoiding gadolinium-containing contrast agents in people with acute kidney injury or chronic kidney disease.

Other conditions that may lead to or promote the disease when severe kidney disease and exposure to gadolinium-containing contrast are present include:

• Use of high-dose erythropoietin (EPO), a hormone that promotes the production of red blood cells, often used to treat anemia
• Recent vascular surgery
• Blood-clotting problems
• Severe infection

Risk factors for nephrogenic systemic fibrosis

The highest risk of nephrogenic systemic fibrosis after gadolinium exposure occurs in people who:

• Have moderate to severe kidney disease
• Have had a kidney transplant, but have compromised renal function
• Are receiving hemodialysis or peritoneal dialysis
• Have acute kidney injury

This increased risk is thought to be related to the reduced ability of these people’s kidneys to remove the contrast agent from the bloodstream.

Nephrogenic systemic fibrosis symptoms

Nephrogenic systemic fibrosis can begin days to months after exposure to gadolinium-containing contrast. Some signs and symptoms of nephrogenic systemic fibrosis may include:

• Swelling and tightening of the skin
• Thickening and hardening of the skin, typically on the arms and legs and sometimes on the body, but almost never on the face or head
• Skin that may feel “woody” and develop an orange-peel appearance and darkening (excess pigmentation)
• Burning, itching or severe sharp pains in areas of involvement
• Skin thickening that inhibits movement, resulting in loss of joint flexibility
• Rarely, blisters or ulcers

In some people, involvement of muscles and body organs may cause:

• Muscle weakness
• Limitation of joint motion caused by muscle tightening (contractures) in arms, hands, legs and feet
• Bone pain
• Reduced internal organ function, including heart, lung, diaphragm, gastrointestinal tract, or liver, but direct evidence is often lacking
• Yellow plaques on the white surface (sclera) of the eyes
• Blood clots

Nephrogenic systemic fibrosis is generally long term (chronic), but some people may improve. In a few people, it can cause severe disability, even death.

Nephrogenic systemic fibrosis diagnosis

Diagnosis of nephrogenic systemic fibrosis is made by:

• Physical exam for signs and symptoms of the disease, and evaluation for a possible history of MRI using gadolinium when advanced kidney failure is present
• A sample of tissue (biopsy) taken from the skin and muscle
• Other tests as needed that may indicate involvement of muscles and internal organs

Nephrogenic systemic fibrosis treatment

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. And there is no cure for nephrogenic systemic fibrosis, and no treatment is consistently successful in halting or reversing the progression of the disease. Furthermore, nephrogenic systemic fibrosis only occurs rarely, making it difficult to conduct large studies.

Some doctors have experience with the following treatments for nephrogenic systemic fibrosis. More research is needed to determine if these treatments help, but they have shown limited success in some people:

• Hemodialysis. In people with severely reduced kidney function, performing hemodialysis immediately after receiving gadolinium-containing contrast may decrease the possibility of nephrogenic systemic fibrosis.
• Physical therapy. Physical therapy that helps stretch the involved limbs may help slow the progression of joint contractures and preserve movement.
• Kidney transplant. For people who are appropriate candidates, improvement in renal function because of a kidney transplant may help improve nephrogenic systemic fibrosis over time.
• Ultraviolet A phototherapy. Exposure of the skin to ultraviolet A light may reduce the skin thickening and hardening, but it’s unclear if the treatment penetrates deeply enough into the skin to be effective.
• Extracorporeal photopheresis. This treatment involves drawing the blood outside the body and treating the blood with a drug that sensitizes it to ultraviolet light. The blood is then exposed to ultraviolet light and returned to the body. Some people have shown improvement after receiving this therapy.
• Plasmapheresis. This procedure involves removing unwanted substances from the blood by separating solid blood cells from plasma, replacing plasma with donor plasma or albumin, then mixing it with the original solid blood cells and returning it to the body.

These medications have been shown to help some people, but side effects limit their use:

• Pentoxifylline (Pentoxil). There is limited success with this medication, which theoretically decreases the thickness and stickiness (viscosity) of blood, aiding circulation.
• Imatinib (Gleevec). Although this treatment shows some promise in reducing skin thickening and tightening, more research is needed.
• Sodium thiosulfate. Possible benefit has been shown using this medication, but more research is needed.

A favorable response to medical intervention is anecdotal. Of all treatments, extracorporeal photopheresis seems to provide the best, albeit mild and extremely expensive, treatment modality for nephrogenic systemic fibrosis. In one patient, extracorporeal photopheresis resulted in some improvement in skin texture ⁴.

In 2011, Elmholdt ⁵ noted that low-dose oral imatinib mesylate slightly improved skin texture but not joint mobility in patients with nephrogenic systemic fibrosis.

In 2005, Schmook et al ⁶ reported on successful treatment of nephrogenic systemic fibrosis with photodynamic therapy in a kidney transplant recipient.

In 2004, Kafi et al ⁷ found that UV-A1 phototherapy improves nephrogenic systemic fibrosis.

Läuchli et al ⁸ 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 extracorporeal photopheresis.

Also in 2004, Chung and Chung ⁹ found that nephrogenic systemic fibrosis responded to high-dose intravenous immunoglobulin.

Wahba et al ¹⁰ 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 oral once daily) 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 ¹¹ noted 8 patients with nephrogenic systemic fibrosis, 5 of whom were treated with extracorporeal photopheresis 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 ¹² 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 ¹³ found limited effects of UV-A1 phototherapy in 3 patients with nephrogenic systemic fibrosis.

Nephrogenic systemic fibrosis prognosis

In most patients, nephrogenic systemic fibrosis is a chronic, progressive condition. Many patients report stabilization and marginal improvement after years with the condition. Rare cases of partial-to-complete spontaneous resolution is described in some reports in the absence of specific therapy, typically coincident with improved/resolved renal disease ¹⁴. 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 ¹⁵ 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.

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.

References

1. Nephrogenic systemic fibrosis. https://www.mayoclinic.org/diseases-conditions/nephrogenic-systemic-fibrosis/symptoms-causes/syc-20352299
2. Sweeney S, Cropley TG. Cutaneous Changes in Renal Disorders. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, eds. Fitzpatrick’s Dermatology in General Medicine. Vol 2. 6th ed. United States: The McGraw-Hill Companies, Inc.; 2003: 1623.
3. Cheong BY, Muthupillai R. Nephrogenic systemic fibrosis: a concise review for cardiologists [published correction appears in Tex Heart Inst J. 2011;38(1):104]. Tex Heart Inst J. 2010;37(5):508–515. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2953218
4. Kintossou R, D’Incan M, Chauveau D, et al. [Nephrogenic fibrosing dermopathy treated with extracorporeal photopheresis: role of gadolinium?]. Ann Dermatol Venereol. 2007 Aug-Sep. 134(8-9):667-71.
5. Elmholdt TR, Buus NH, Ramsing M, Olesen AB. Antifibrotic effect after low-dose imatinib mesylate treatment in patients with nephrogenic systemic fibrosis: an open-label non-randomized, uncontrolled clinical trial. J Eur Acad Dermatol Venereol. 2011 Dec 20.
6. Schmook T, Budde K, Ulrich C, Neumayer HH, Fritsche L, Stockfleth E. Successful treatment of nephrogenic fibrosing dermopathy in a kidney transplant recipient with photodynamic therapy. Nephrol Dial Transplant. 2005 Jan. 20(1):220-2.
7. Kafi R, Fisher GJ, Quan T, et al. UV-A1 phototherapy improves nephrogenic fibrosing dermopathy. Arch Dermatol. 2004 Nov. 140(11):1322-4.
8. Lauchli S, Zortea-Caflisch C, Nestle FO, Burg G, Kempf W. Nephrogenic fibrosing dermopathy treated with extracorporeal photopheresis. Dermatology. 2004. 208(3):278-80.
9. Chung HJ, Chung KY. Nephrogenic fibrosing dermopathy: response to high-dose intravenous immunoglobulin. Br J Dermatol. 2004 Mar. 150(3):596-7.
10. Wahba IM, White K, Meyer M, Simpson EL. The case for ultraviolet light therapy in nephrogenic fibrosing dermopathy–report of two cases and review of the literature. Nephrol Dial Transplant. 2007 Feb. 22(2):631-6.
11. Richmond H, Zwerner J, Kim Y, Fiorentino D. Nephrogenic systemic fibrosis: relationship to gadolinium and response to photopheresis. Arch Dermatol. 2007 Aug. 143(8):1025-30.
12. Yerram P, Saab G, Karuparthi PR, Hayden MR, Khanna R. Nephrogenic systemic fibrosis: a mysterious disease in patients with renal failure–role of gadolinium-based contrast media in causation and the beneficial effect of intravenous sodium thiosulfate. Clin J Am Soc Nephrol. 2007 Mar. 2(2):258-63.
13. Kreuter A, Gambichler T, Weiner SM, Schieren G. Limited effects of UV-A1 phototherapy in 3 patients with nephrogenic systemic fibrosis. Arch Dermatol. 2008 Nov. 144(11):1527-9.
14. Nephrogenic systemic fibrosis. https://emedicine.medscape.com/article/1097889-overview
15. Todd DJ, Kagan A, Chibnik LB, Kay J. Cutaneous changes of nephrogenic systemic fibrosis: predictor of early mortality and association with gadolinium exposure. Arthritis Rheum. 2007 Oct. 56(10):3433-41.