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Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis.

In 2000, Cowper and colleagues published the first report of a new sclerosing skin disorder that was seen primarily in individuals with renal failure. From 1997 until 2000, they identified 15 patients on hemodialysis with characteristic thickening and hardening of the skin of the extremities. Due to its similarities to scleromyxedema and its occurrence only in patients undergoing dialysis, this new disorder was initially described as "scleromyxedema-like cutaneous disease of dialysis" (Cowper, 2003, p. 789). Clinically and histopathologically, however, the disorder is distinctly different from scleromyxedema and the term nephrogenic fibrosing dermopathy (NFD) was used to designate the disorder as a new clinical-pathological entity. Further reports have shown that NFD occurs in adults and children receiving hemodialysis, peritoneal dialysis, or even those that are predialysis. Unfortunately, the cause of NFD is unknown; however there are several theories as to possible triggers for its development.

Background

The first few cases of NFD were seen in 1997 in a renal transplantation center in southern California; additional cases were soon seen in Michigan, Ohio, and Mississippi. All patients were receiving hemodialysis at the time of disease onset and the majority of patients were kidney transplant recipients who had rejected, or were rejecting, their transplants (Cowper et at., 2000; Cowper, Su, Bhawan, Robin, & LeBoit, 2001; LeBoit, 2003). The "clustering of cases in specific dialysis centers initially suggested a possible infectious and/or toxic agent" (Cowper et al., 2001, p. 383), and with the help of investigators from the Centers for Disease Control (CDC), "a systematic investigation of the first cases of NFD in California suggested that no single medication or infectious agent was to blame" (Cowper, 2005, p.763). An NFD registry established at Yale University collects and organizes data about individuals with the disorder from around the world in an attempt to identify factors that may be the cause of this disease, as well as treatment successes and failures (www.icnfdr.org).

Clinical Manifestations

Characteristically, patients present with extensive thickening and hardening of the skin on their arms, legs and torso; the face is usually spared. Decreased joint mobility and flexion contractures develop quickly, making ambulation difficult. The skin lesions of NFD are typically symmetrical and are commonly distributed bilaterally between the ankles and mid-thighs, and between the wrists and mid-upper arms (Cowper, 2003); the lesions are described as papules or subcutaneous nodules that combine or fuse together to form erythematous to brawny hyperpigmented plaques with a peau d'orange (skin of an orange) appearance (Cowper et al., 2001); the plaques have a "distinctive irregular edge resembling amoeboid projections" (Mackay-Wiggan, Cohen, Hardy, Knobler, & Grossman, 2003, p.55); and patients often complain of pruritis and burning pain in the affected areas (Cowper, 2003). Histopathologically, NFD resembles scleromyxedema but is distinguished from it by the absence of paraproteniemia and the absence of pools of dermal mucin and plasma cell infiltrates (Daram, Cortese, & Bastani, 2005). Diagnosis of NFD is confirmed by specific features seen with skin biopsy, "namely thickened collagen bundles with surrounding clefts, mucin deposition and a proliferation of fibroblasts and elastic fibers" (Grobner, 2006, p. 1104).

NFD was thought to be a purely cutaneous disease affecting only the skin and underlying soft tissue until Ting, Stone, Madison, and Kurtz (2003) described a patient who died 11 months after developing NFD. Autopsy revealed fibrosis and calcification of the psoas muscle, renal tubules, testes, and diaphragm; "microscopically, most of the diaphragm was replaced by fibrous tissue with extensive vascular and extravascular calcium deposit" (Ting et al., p. 905). Subsequent reports by Leone et al. (2004) and Daram et al. (2005) established NFD as a systemic disease; its name was modified to Nephrogenic Systemic Fibrosis (NSF) to reflect an updated understanding of the disease process. Cowper, Bucala, and LeBoit (2006) note, "[NSF] is currently the preferred terminology, but, to keep this disorder safely tied to its historical moorings, we have come to refer to it as NFD/NSF" (p. 209). Both terms are used interchangeably throughout recent literature.

Contributing Factors

As more cases of NFD are reported, more information becomes available as to factors that may contribute to its development. Cowper (2003) categorized 100 available cases into subtypes based on recurrent patterns of NFD onset: 12% of patients had hypercoagulability and/or thromobotic episodes prior to developing NFD; 15% of patients had a non-transplant-related surgical procedure (usually vascular); 34% had kidney transplants; approximately 42% had dialysis fistula construction and/or central venous catheter placement; 2% had brain tumors; and a "significant number of patients with NFD have chronic hepatic disease" (p. 786), typically hepatitis B or hepatitis C-induced cirrhosis. Currently, there are about 200 identified cases in the NFD/NSF registry.

Additionally, Cowper and Bucala (2003) and Swartz, Crofford, Phan, Ike, and Su (2003) note the histologic similarities between NFD and wound healing and tissue remodeling; they propose that NFD "may be an aberrant and protracted tissue injury response" (Swartz et al., p.571) in the absence of overt tissue injury. Fazeli, Lio, and Liu (2004) hypothesize that a lack of treatment with an angiotensin-converting enzyme (ACE) inhibitor may partially explain the development of NFD, as ACE inhibitors "are known to be effective in protecting against fibrosis in different models of organ-induced damage" (p. 204). LeBoit (2003) notes that erythropoietin has potential fibrogenic properties, and suggest that decreasing the dose may improve NFD in some patients. Similarly, Swaminathan et al. (2006) found a correlation between high doses of erythropoietin and the development of NFD; data collected for 22 cases of NFD showed that 15 patients developed the disorder 1 month after initiating erythropoietin. They note "erythropoietin has been shown in vivo to trigger an exaggerated fibrin-induced wound-healing response that is histologically similar to nephrogenic fibrosing dermopathy" (p. 234). Of particular interest, Swaminathan et al. note that the use of erythropoietin increased greatly after the 1997 publication of the Dialysis Outcomes Quality Initiative (DOQI) guidelines for anemia management--the same year the first cases of NFD were seen.

In June 2006, the U.S. Food and Drug Administration (FDA) issued the first public health advisory against Gadolinium (Gd)-containing contrast agents used for magnetic resonance angiography (MRA) after 25 cases of NFD were reported within 3 months of receiving the contrast agent (USFDA, 2006). Twenty cases occurred in Denmark, and 5 cases occurred in Austria as presented by Grobner (2006), who reports that 5 of 9 patients with end stage renal disease (ESRD) developed NFD 2 to 4 weeks after receiving gadolinium for MRA. In comparing the two groups of patients, Grobner notes that "the only differences observed were that the mean time on dialysis was longer in affected patients and that they were acidotic at the time of using Gd" (p. 1107). Nowack and Wachtler (2006) describe a patient's complaints of burning sensations and reddening of the lower and upper extremities one day after undergoing an MRA using gadodiamide (a gadolinium-based MRI contrast agent). The patient was later diagnosed with NFD. Marckmann et al. (2006) reviewed all confirmed cases of NSF in their nephrology department with respect to clinical characteristics, gadodiamide exposure, and clinical course. They identified 13 patients with NSF, all of whom had been exposed to contrast-enhanced MRI with gadodiamide. Six of these patients had been exposed to gadodiamide previously without developing symptoms. It is important to note that NSF was not found in any patients who had not been exposed to gadodiamide. The FDA advisory explains that none of the five gadolinium-containing contrast agents approved for use with an MRI are approved for an MRA, and the dose of the contrast agent given during an MRA is often up to three times higher than the approved dose for an MRI.

By December 2006, the FDA had received reports of 90 patients with ESRD who had developed NFD/NSF after having an MRI or an MRA with Gd contrast, prompting the FDA to update its advisory notifying health care providers and patients with moderate to severe ESRD of a) the potential consequences of having an MRI or MRA; b) the need to contact a physician if symptoms develop; c) the urgency of immediate dialysis post-procedure; and d) the importance of reporting all possible cases of NSF/NFD to the FDA through the MedWatch program. The FDA is currently investigating the correlation between gadolinium-containing contrast agents in the renal population and the onset of NSF/NFD. It recommends that these agents be used only if absolutely necessary with prompt dialysis following the test in order to remove the circulating gadolinium-based contrast agent (USFDA, 2006).

While there is no consistently effective treatment for NFD, improvement and/or cessation of cutaneous symptoms have been seen with improved or restored renal function, due to either spontaneous recovery or renal transplantation (Cowper et al., 2001; LeBoit, 2003). Other treatment options being used, or under investigation, include oral and topical steroids, plasmapheresis, photopheresis, ultraviolet therapy, high dose intravenous Ig therapy, and physical therapy (Cowper, 2001-2007). Physical therapy has been found to improve range of motion and joint mobility.

Currently in our outpatient dialysis unit there are four individuals with the diagnosis of NFD. All of them experienced manifestations of the disease after exposure to the contrast agent gadolinium used for magnetic resonance. Three of these individuals had previous contrast-enhanced MRIs without developing symptoms.

Case 1

This 72-year-old Caucasian gentleman, with a history of renal cell carcinoma and subsequent bilateral nephrectomy, has been receiving hemodialysis since 2003. In May, 2005, he began to complain of bilateral hand pain with burning and itching.

Initially, he thought his symptoms were related to poor circulation, but the symptoms continued to increase and he developed tightness and swelling in his arms and legs, causing decreased joint mobility. The skin on the bottom of his feet became thick and swollen, making it difficult and painful to walk, and the skin over his left arm fistula became thick and hardened (see Figure 1) making it difficult to palpate his thrill and to insert the dialysis needles. He also developed brawny colored lesions on his arms from shoulder to wrist, and on both legs from ankles to groin.

[FIGURE 1 OMITTED]

Unfortunately, it was not until February, 2006 that a dermatologist diagnosed this gentleman with NFD as confirmed by punch biopsy of his left thigh. By this time, he had contractures in his hands (see Figure 2) and knees, making many activities of daily living, like buttoning his shirt, difficult to perform. It is interesting to note that this gentleman had received gadolinium-containing contrast agents with two previous MRIs from August 2004 until the MRI in April 2005, at which point he became symptomatic. He also had three other contrast-enhanced MRIs after the onset of symptoms just prior to his diagnosis in February 2006.

[FIGURE 2 OMITTED]

Once a very active man, his energy level has greatly decreased and he feels his quality of life has changed. Currently, he receives physical therapy and range of motion exercises to stretch his joints; he exercises in a heated pool; and he has deep massages and paraffin wax wraps to his hands several times a month to help loosen the tightness in his joints. He incurs the cost of most of these treatments himself as they are not covered by his insurance. He is aware that there is no cure for this disease but he tries to keep a positive attitude and do as much for himself as he can.

Case 2

On January 20, 2006, this 40-year-old Caucasian woman with ESRD secondary to Wegners granulomatosus, had an MRA to evaluate her for a superior vena cava thrombosis. She was started on intravenous heparin therapy and a repeat MRA was done 3 days later to reassess the treatment. She complained of weakness in her upper extremities several hours after having the second MRA, and later experienced pain in the back of her right leg and calf, and swelling and tightening of her right ankle, as though she had "masking tape on her legs." Due to her complaints, she was initially treated for a deep vein thrombosis (DVT), which was later ruled out. She developed erythematous lesions on her legs (see Figure 3)with a peau d'orange appearance. In March 2006, a punch biopsy of her right upper thigh showed findings consistent with NFD. She too has tightness in her hands and feet, but has not developed contractures of her joints. She continues to work and receives physical therapy and massage therapy to maintain joint mobility.

[FIGURE 3 OMITTED]

Case 3

This 55-year-old African American woman on peritoneal dialysis due to ESRD secondary to focal segmental glomerulosclerosis, had a cardiac MRI with Gd contrast in June 2006. She described immediate burning in her left elbow joint and left hip joint that was initially relieved by intravenous Toradol. The next day, she had burning pain in her right elbow and both knees, with a "cording" sensation of the muscles in her arms and legs.

Currently, her legs are tight, swollen, tender and warm to touch, and mildly erythematous with a peau d'orange appearance (see Figure 4). Although she continues to work full time as a nurse, she is having difficulty maintaining her usual level of activity because, despite the use of compression stockings, the pain and swelling in her legs becomes so severe by the end of her shift, that she has difficulty walking and performing her duties.

[FIGURE 4 OMITTED]

Case 4

At the time of writing, this person was in the intensive care unit suffering from what may be systemic complications of NFD. Abrupt symptom onset of swelling and firmness of the arms, legs, buttocks, and back began in January 2006, one month after having an MRI with Gd contrast. This person, who has a history of cancer, hepatitis, and multiple access failures due to clotting, was receiving hemodialysis through a left femoral venous catheter at the time of disease onset. During a previous hospitalization, the hardening and tightening of the skin made intravenous insertion impossible to obtain and physicians decided to use the client's dialysis central venous catheter as an access, which later clotted. Diagnosis of NFD was confirmed by punch biopsy of the thigh in April 2006.

At the time of publication, two of these patients have died. Patient 1 lost his battle to cancer in February 2007. Unfortunately, Patient 4 never made it out of the hospital and passed away almost 3 months after being admitted.

Conclusion

Nephrogenic fibrosing dermopathy or nephrogenic systemic fibrosis is a devastating disease that causes fibrosis of the skin and connective tissues. It seems to affect only those with some degree of renal dysfunction. Its cutaneous manifestations cause burning pain and joint contractures leading to impaired mobility. Its systemic effects can be severe and debilitating, leading to death. Although improved or restored renal function decreases the symptoms of the disease, for many people with chronic renal failure, this is not an option.

Currently, there is no known cause of NFD/NSF; however, recent reports have shown that the contrast agent gadolinium may be a trigger for this disease, and the FDA has issued an advisory limiting its use in individuals with renal failure. Not everyone with renal failure who has had gadolinium-enhanced MR/develops NFD; however, further investigation is ongoing to determine if gadolinium exposure is the common denominator of all NFD cases. It may be that it takes a while for the gadolinium to build up in the body and for symptoms to manifest itself with MRIs; however, given that an MRA uses a much higher dose, the manifestations may be more rapid. Unfortunately, since the disease is not well known, many institutions continue to use this agent with the renal population, potentially increasing the number of cases within the United States and worldwide.

There is presently no cure or a consistently effective treatment for NFD; therefore, prevention must be a top priority. Clients, physicians, and other members of the health care team must be educated about this disease; protocols should be developed for hemodialysis after an MR/or MRA; and the FDA recommendations for gadolinium use (especially with MRAs) should be followed.

Goal

Recognize nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis (NFD/NSF) in patients with chronic kidney disease (CKD).

Objectives

1. Identify the clinical manifestations of a patient presenting with NSF.

2. Discuss the FDA advisory concerning contrast enhanced MRI with gadodiamide in patients with CKD.

3. List the treatment options for NSF that are under investigation.

This offering for 1.4 contact hours is being provided by the American Nephrology Nurses' Association (ANNA).

ANNA is accredited as a provider of continuing nursing education (CNE) by the American Nurses Credentialing Center's Commission on Accreditation.

ANNA is a provider approved by the California Board of Registered Nursing, provider number CEP 00910. This CNE article may be applied to the required recertification contact hours in nephrology nursing.

Note: The authors reported no actual or potential conflict of interest in relation to this continuing nursing education article.

References

Cowper, S.E. (2003). Nephrogenic fibrosing dermopathy: The first six years. Current Opinion in Rheumatology, 15(6), 785-790.

Cowper, S.E. (2005). Nephrogenic systemic fibrosis: The nosological and conceptual evolution of nephrogenic fibrosing dermopathy. American Journal of Kidney Disease, 46(4), 763-765.

Cowper, S.E. (2001-2007). Nephrogenic Fibrosing Dermopathy [NFD/NSF Website]. Retrieved March 25, 2007 from http://www.icnfdr.org

Cowper, S.E. & Bucala, R. (2003). Nephrognic fibrosing dermopathy: Suspect identified, motive unclear [Letter]. American Journal of Dermopathology, 25(4), 358.

Cowper, S.E., Bucala, R.,& LeBoit, P.E. (2006). Editorial: Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis-setting the record straight. Seminars in Arthritis and Rheumatism, 35(4), 208-210.

Cowper, S.E., Robin, H.S., Steinberg, S.M., Su, L.D., Gupta, S., & LeBoit, P.E. (2000). Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. The Lancet, 356(9234), 1000-1001.

Cowper, S.E., Su, L.D., Bhawan, J., Robin, H.S., & LeBoit, P.E. (2001). Nephrogenic fibrosing dermopathy. The American Journal of Dermatopathology, 23(5), 383-393.

Daram, S.R., Cortese, C.M., & Bastani, B. (2005). Nephrogenic fibrosing dermopathy/ nephrogenic systemic fibrosis: Report of a new case with literature review. American Journal of Kidney Disease, 46(4), 754-759.

Fazeli, A., Lio, P.A., & Liu, V. (2004). Nephrogenic fibrosing dermopathy: Are ACE inhibitors the missing link? [Letter]. Archives of Dermatology, 140(11), 1401.

Grobner, T. (2006). Gadolinium-a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrology Dialysis Transplantation, 21, 1104-1106.

LeBoit, P.E. (2003). What nephrogenic fibrosing dermopathy might be. Archives of Dermatology, 139(7), 903-906.

Levine, J.M., Taylor, R.A., Elman, L.B., Bird, S.J., Lavi, E., Stolzenberg, E.D. et al. (2004). Involvement of skeletal muscle in dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy). Muscle & Nerve, 30, 569-577.

Mackay-Wiggan, J.M., Cohen, D.J., Hardy, M.A., & Grossman, M.E. (2003). Nephrogenic fibrosing dermopathy (scleromyxedema-like illness of renal disease). Journal of the American Academy of Dermatology, 48(1), 5.5-60.

Marckmann, P., Skov, L., Rossen, K., Dupont, A., Damholt, M.B., Heaf, J.G., & Thomsen, H.S. (2006). Nephrogenic systemic fibrosis: Suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. Journal of the American Society of Nephrology, 17, 2359-2362.

Nowack, R. & Wachtler, P. (2006). Scleroderma-like syndrome triggered by Gadolinium [Letter]. Nephrology Dialysis Transplantation Advance Access published July 19, 2006.

Swaminathan, S., Ahmed, I., McCarthy, J.T., Albright, R.C., Pittelkow, M.R., Caplice, N.M., et al. (2006). Nephrogenic fibrosing dermopathy and high-dose erythropoietin therapy. Annals of Internal Medicine, 145(3), 234-235.

Swartz, R.D., Crofford, L.J., Phan, S.H., Ike, R.W., & Su, L.D. (2003). Nephrogenic fibrosing dermopathy: a novel cutaneous fibrosing disorder in patients with renal failure. The American Journal of Medicine, 114(7), 563-572.

Ting, W.W., Stone, M.S., Madison, K.C., & Kurtz, K. (2003). Nephrogenic fibrosing dermopathy with systemic involvement. Archives of Dermatology, (139(7), 903-906.

U.S. Food and Drug Administration Public Health Advisory (December 22, 2006). Update on magnetic resonance imaging (MRI) contrast agents containing gadolinium and nephrogenic fibrosing dermopathy. Retrieved March 26, 2007 from http://www.fda. gov/cder/drug/advisory/gadolinium_agents_20061222.htm

Karen Hamilton-Persaud, BSN, RN, is Nurse Manager, Dialysis Program, Duke University Health System, Durham, NC. She is a member of ANNA's Cardinal Chapter. For more information on this article, contact the author at hamil045@mc.duke.edu.

Loretta D. Ezell, BSN, RN, CNN, is Clinical Operations Director, Dialysis Program, Duke University Health System, Durham, NC. She was the 2006-2007 President of ANNA's Cardinal Chapter.

Joyce G. Macklin, RN, CNN, is Charge Nurse, Duke University Health System, Durham, NC. She is a member of ANNA's Cardinal Chapter.
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Title Annotation:Continuing Nursing Education
Author:Hamilton-Persaud, Karen; Ezell, Loretta D.; Macklin, Joyce G.
Publication:Nephrology Nursing Journal
Geographic Code:1USA
Date:May 1, 2007
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