Nephrogenic Systemic Fibrosis

Nephrogenic Systemic Fibrosis

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Nephrogenic Systemic Fibrosis is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • NSF
  • gadolinium-associated nephrogenic systemic fibrosis
  • nephrogenic fibrosing dermopathy

Disorder Subdivisions

  • None

General Discussion

Nephrogenic systemic fibrosis (NSF) is a rare disorder that occurs in some individuals with reduced kidney function, who have been exposed to an intravenous contrast material that contains gadolinium. A contrast material is a dye that is sometimes used during magnetic resonance imaging (MRI). The term, fibrosis, refers to the thickening and scarring of connective tissue, most often the consequence of inflammation or injury. NSF is characterized by thickening and hardening (fibrosis) of the skin, subcutaneous tissues, and, sometimes, underlying skeletal muscle. The arms and legs are most often affected. In some cases, the skin on the trunk can also become involved. This proliferation of fibrotic tissue may become systemic, extending to other areas including the smooth, delicate membrane that surrounds the lungs (pleura), the sac surrounding the heart (pericardium), the thin sheet of muscle that aids respiration by moving up and down when breathing (diaphragm), and the outermost layer (dura mater) of the three membranes covering the brain and spinal cord.



NSF was thought to predominantly involve the skin and was originally referred to as nephrogenic fibrosing dermopathy. However, it is now known that it may involve several internal organs (systemic disorder), potentially leading to a progressive and severe disease course. NSF has not been reported in individuals with normal kidney function.



Since September of 2010, the U.S. Food and Drug Administration (FDA) has required that gadolinium-based contrast agents (GBCA) carry a warning on their labels about the risk of NSF when administered in certain individuals with kidney disease. In addition, the FDA also stated that three specific gadolinium-based contrast agents (Magnevist?, Omniscan?, and Optimark?) were contraindicated in individuals with severe chronic kidney disease or acute kidney injury. These three agents were the ones most often associated with NSF.

Symptoms

The symptoms of NSF may develop slowly over a few weeks to a few months after exposure to gadolinium-based contrast agents. The severity and progression of the disorder can vary from one person to another. The disorder can have a rapid, progressive course and can cause debilitating symptoms. In rare, rapidly-progressive cases, NSF can contribute to the development of severe, life-threatening complications.



The initial symptoms of NSF usually involve the skin, with a gradual tightening or thickening effect. Affected individuals may experience reddened (erythematous) or darkened patches or papules especially on the extremities. The areas between the ankles and the thighs and the wrists and the upper arms are most commonly affected. Swelling (edema) may also occur and the skin may be itchy (pruritic). In some cases, the skin may appear shiny. Skin abnormalities are usually symmetric, which means that the size, shape and location of the lesions are extremely similar on both sides of the body.



Over time, affected areas may eventually resemble the texture of an orange peel (peau d'orange). Skin hardening (induration) can become severe, causing chronic pain and loss of flexibility. The affected areas of skin can become hard to the touch. In general, the facial skin is not involved. In addition to the skin, underlying tissue may also be affected including the layer of connective tissue beneath the skin (subcutis), the tough band of fibrous tissue beneath the subcutis (fascia) and skeletal muscle.



In some cases, skin tightening and hardening may affect the range of motion and flexibility of the joints, causing contractures. A contracture is a condition in which a joint becomes permanently fixed in a bent (flexed) or straightened (extended) position, completely or partially restricting the movement of the affected joint. Severely affected individuals can lose the ability to walk or to fully extend the upper and lower limbs, potentially becoming wheelchair bound.



Complaints of muscle weakness are also common in individuals with NSF. Flesh-colored, reddish, or brownish papules (small, solid bumps arising from the skin) have been reported, and yellow scleral plaques (yellow areas in the whites [sclera] of the eyes) have also been observed.



Additional symptoms associated with NSF are highly variable depending upon the specific organ systems involved. NSF can potentially affect multiple organ systems and structures of the body including the lungs, hearts, esophagus and diaphragm. Involvement of the lungs or diaphragm can lead to a variety of breathing (respiratory) complications. Involvement of the heart can impair the ability of the heart to pump blood throughout the body.

Causes

The exact underlying cause of NSF is not fully understood. The disorder occurs in individuals with advanced kidney disease who have been exposed to gadolinium-based contrasts agents that are used in magnetic resonance imaging.



Gadolinium is a heavy metal with paramagnetic qualities that cause it to respond differently within a magnetic field. Because of this trait, gadolinium has been used for magnetic resonance imaging examinations. Gadolinium is considered toxic and, in order to be used in contrast dyes, is bound to other molecules to facilitate its passage through the body. Gadolinium contrast agents are ultimately excreted through the kidneys. Individuals with impaired kidney function cannot adequately and quickly eliminate GBCA from the body. Researchers believe this prolonged excretion may lead to a breakdown of the contrast chemical, with release of the Gadolinium atom (dechelation). This foreign material may then lead to a process resembling a chronic wound healing reaction, with abundant production of collagen.



In addition to kidney disease and exposure to GBCAs, individuals with NSF may have a "proinflammatory" state, which refers to any condition that causes an inflammatory reaction in the body. In individuals who had developed NSF, this has included recent major surgery, infection, malignancy or the formation of blood clots (thrombosis). Many individuals with NSF have had recent vascular surgery or a thrombotic condition before the onset of the disorder. The exact relationship between these inflammatory conditions and risk for development of NSF is not known.



Researchers have also detected the presence of "circulating fibrocytes" (CFs) in the skin of individuals with NSF. CFs are circulating cells that respond to tissue damage by exiting the circulation and maturing into cells that produce fibrous tissue (collagen). They are normally participants in the wound healing process. Researchers believe that these cells are inappropriately summoned to the skin in great numbers, despite the lack of an obvious injury. Currently investigators suspect the dechelation event allows the CFs to home to the skin, where they produce the abundant collagen typical of NSF. The precise details of this process are not fully understood and require further study.

Affected Populations

NSF was first reported in the medical literature in 2000. The first case was noted in 1997. Researchers believe that the perceived safety and increased availability of gadolinium-based contrast dyes contributed to the rise of NSF since 1997.



NSF affects men and women in equal numbers. The exact incidence or prevalence of the disorder is not known, although cases have been identified all over the world, typically in developed countries. More than 375 cases have been identified by the NSF Registry. The disorder can affect children, adults or the elderly. It is most common in the middle-aged and no known ethnic or racial predilection exists. Confirmed cases of NSF have only occurred in individuals with kidney disease who have been exposed to gadolinium-based contrast agents.



Researchers believe that the increased awareness of the disorder and subsequent precaution or avoidance of using gadolinium-based contrast agents in individuals with decreased kidney function will lead to a decrease in the number of cases of NSF. Since identification of gadolinium as a potential trigger, European and American medical agencies have banned the use of certain GBCAs in individuals with renal disease. According to the International NSF Registry, there have been very few new cases of NSF since this ban went into effect.

Standard Therapies

Diagnosis

A set of diagnostic criteria for NSF have been recently developed. A diagnosis of NSF is usually made based upon a detailed patient history, a thorough clinical examination and identification of characteristic findings. Surgical removal and microscopic study of a small sample of affected skin tissue (skin biopsy) is required to verify the diagnosis. Additional tests may be performed to exclude several other disorders that can resemble NSF.



Treatment

There is no specific, consistently effective therapy available for individuals with NSF. Improvement in kidney function, either spontaneously after acute kidney injury or post-transplantation, appears to slow, or stop the progression of NSF. In some cases with improvement in kidney function, a gradual reversal of the disease process may occur over time.



A wide variety of different therapies have been tried in individuals with NSF with varying results. These therapies are detailed in the investigational therapies section below.



Because NSF can damage and restrict the joints, early physical therapy and medications for pain control may have a role in the treatment of affected individuals.



Individuals maintained on chronic hemodialysis and peritoneal dialysis have a significantly higher risk of developing NSF compared with individuals with advanced chronic kidney disease who have not yet started dialysis. Patients with acute kidney injury who have not been dialyzed within the 2 days preceding a GBCA injection may have a very high risk for NSF. Whether hemodialysis has value in preventing NSF post-exposure is unknown. Immediate hemodialysis within 2 hours of GBCA injection in patients on hemodialysis, peritoneal dialysis or those with severe acute kidney injury is recommended based on theoretical and observational data.

Investigational Therapies

Investigational therapies are treatment modalities that are not considered standard therapies for a particular disorder and have not been approved for the treatment of that disorder. Many times the benefits of these therapies have been noted anecdotally in only a few patients. In addition, in individuals with NSF, the follow-up time and techniques required to assess a therapy's effectiveness have not been determined.



A variety of different medications have been used to treat individuals with NSF including thalidomide, cytoxan, pentoxifylline, intravenous immunoglobulin, imatinib mesylate and oral steroids such as prednisone.



Two procedures that have been used to treat individuals with NSF include extracorporeal (outside the body) photopheresis and plasmapheresis. During photopheresis, the blood of an affected individual is withdrawn and treated with a drug that sensitizes the blood to ultraviolet light. The blood is then exposed to ultraviolet light and ultimately returned to the body.



Plasmapheresis is a procedure for removing unwanted substances (toxins, metabolic substances and plasma components) from the blood. Blood is removed from the patient and the solid blood cells are separated from the liquid plasma. The patient's plasma is then replaced with donor human plasma or albumin, which is retransfused, along with the patient's original blood cells. This therapy is still under investigation to analyze side effects and effectiveness.



Some individuals with NSF who have undergone a kidney transplant have exhibited a significant improvement in the symptoms of NSF, although this response is not universal. Consequently, some researchers have advocated a kidney transplant for affected individuals who are eligible. In general, the earlier this transplant can be accomplished the better, as excess collagen production is ongoing and difficult to reverse once established. Many of these patients are already on kidney transplant waiting lists. NSF should not be used as an excuse to exclude a patient from receiving a transplanted kidney.



The above mentioned therapies require further research and in-depth clinical studies to determine their long-term safety and effectiveness as treatments for individuals with NSF.



Prevention of NSF is the key to eradicating this disease. The FDA currently requires screening for kidney function in individuals at risk for having kidney disease before the administration of a GBCA. In addition, using alternative imaging modalities that do not utilize GBCAs should be used whenever possible in the renal population. If after assessment of risks and benefits a GBCA administration is unavoidable in this setting, the use of low-risk GBCAs has been advocated.



Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com



Contacts for additional information about nephrogenic systemic fibrosis:



Shawn Cowper, MD

The International Center for Nephrogenic Systemic Fibrosis Research (ICNSFR)

http://www.icnsfr.org

Associate Professor of Dermatology and Pathology

Yale University

PO Box 208059

LMP 5031, 15 York Street

New Haven, CT. 06520-8059

Phone: 203-785-4094

Telefax: 203-737-4307

Assistant: Carol Hribko (203-7850-3524)





Ali K. Abu-Alfa, M.D., F.A.S.N,

Professor of Medicine

Head, Division of Nephrology and Hypertension

American University of Beirut

Beirut, Lebanon

Tel: 1-203-654-9779 (voicemail, USA)

Tel: 011-961-71-423483

Email: abualfa@aub.edu.lb

References

JOURNAL ARTICLES

Abu-Alfa, AK. Nephrogenic Systemic Fibrosis and Gadolinium-Based Contrast Agents. Adv Chronic Kidney Dis. 2011 May;18(3):188-98



Cuffy MC, Singh M, Formica R, et al. Renal transplantation for nephrogenic systemic fibrosis: a case report and review of the literature. Nephrol Dial Transplant. 2011 Mar;26(3):1099-101.



Cheong BYC, Muthupillai R. Nephrogenic systemic fibrosis: A concise review for cardiologists. Tx Heart Inst J. 2010;37:508-515.



Schlaudecker J, Bernheisel CR. Gadolinium-associated nephrogenic systemic fibrosis. Am Fam Physician. 2009;80:711-714.



Cowper SE. Nephrogenic systemic fibrosis: an overview. J Am Coll Radiol. 2008;5:23-28.



Broome DR, Girguis MS, Baron PW, et al. Gadodiamide-associated nephrogenic systemic fibrosis: why radiologists should be concerned. AJR. 2007;188:586-592.



Richmond H, Zwerner J, Kim Y, Fiorentino D. Nephrogenic systemic fibrosis: relationship to gadolinium and response to photopheresis. Arch Dermatol. 2007;143:1025-1030.



Cowper SE. Nephrogenic systemic fibrosis: an overview. J Am Coll Radiol. 2008;5:23-28.



Cowper SE, Boyer PJ. Nephrogenic systemic fibrosis: an update. Curr Rhematol Rep. 2006;8:151-157.



Cowper SE, Su LD, Bhawan J, Robin HS, LeBoit PE. Nephrogenic fibrosing dermopathy. Am J Dermatopathol. 2001 Oct;23(5):383-93.



Cowper SE, Robin HS, Steinberg SM, et al. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet. 2000;356:1000-1001.



FROM THE INTERNET

Cowper SE. Nephrogenic Fibrosing Dermopathy [ICNSFR Website]. 2001-2010. Available at: http://www.icnsfr.org. Accessed on: 12/18/2010



Scheinfeld NS, Cowper S. Nephrogenic Systemic Fibrosis. Emedicine Journal, Sep. 13, 2010. Available at: http://emedicine.medscape.com/article/1097889-overview. Accessed December 28, 2010.



FDA Drug Safety Communication: New warnings for using gadolinium-based contrast agents in patients with kidney dysfunction. U.S. Food and Drug Administration

Available at: http://www.fda.gov/Drugs/DrugSafety/ucm223966.htm. Accessed December 28, 2010

Resources

National Kidney Foundation

30 East 33rd Street

New York, NY 10016

Tel: (212)889-2210

Fax: (212)689-9261

Tel: (800)622-9010

Email: info@kidney.org

Internet: http://www.kidney.org



NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (deleted)

9000 Rockville Pike

Bethesda, MD 20892

Tel: (301)496-8188

Fax: (301)718-6366

Tel: (877)226-4267

TDD: (301)565-2966

Email: NAMSIC@mail.nih.gov

Internet: http://www.nih.gov/niams/



Global Fibrosis Foundation

5036 Dr. Phillips Boulevard

Suite 244

Orlando, FL 32819

Tel: (407)909-0753

Fax: (407)909-0153

Tel: (800)872-6874

Email: globalfibrosis@gmail.com

Internet: http://www.globalfibrosis.com



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

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