The International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR)
Last Updated December 23, 2008
Please Note: All new updates are in a dark red type face to facilitate identifying changed information. You can now access this website through the new domain name http://www.icnfdr.org
By Shawn E. Cowper, MD
Associate Professor of Dermatology and Pathology
Yale University
Conference Announcement: Third Annual Scientific Symposium on NSF and MRI Contrast (Hold the date May 9, 2009)
Original Case Definition
Patients who have developed large areas of hardened skin with slightly raised plaques, papules, or confluent papules; with or without pigmentary alteration and/or with biopsies showing increased numbers of fibroblasts, alteration of the normal pattern of collagen bundles seen in the dermis, and often increased dermal deposits of mucin.
NSF…what is it?
Nephrogenic Systemic Fibrosis (NSF), also known as nephrogenic fibrosing dermopathy (NFD), is a condition that, so far, has occurred only in people with kidney disease. There is no convincing evidence that NSF is caused by a medication, a microorganism, or by dialysis. There have been no cases identified prior to early 1997. At this point it appears NSF is a systemic disorder with its most prominent and visible effects in the skin. For this reason, Nephrogenic Systemic Fibrosis has been suggested as an equivalent terminology in those previously diagnosed with NFD, and is preferred in that it more accurately reflects our current understanding of the disorder.
Neither the duration of kidney disease nor its underlying cause are related to the development of NSF. Some patients with NSF develop skin tightening in the earliest stages of kidney disease, and others may have had kidney disease for years. Specific triggers for the development of NSF are still being investigated. Recent reports have strongly correlated the development of NSF with exposure to gadolinium-containing MRI contrast agents. Further information from the US Food and Drug Administration regarding this observation can be found here: (http://www.fda.gov/cder/drug/advisory/gadolinium_agents.htm). The initial FDA advisory has been recently modified to the statement present at this site: (http://www.fda.gov/cder/drug/advisory/gadolinium_agents_20061222.htm) .
GE healthcare, one manufacturer of gadolinium-containing MRI contrast, has issued an informational announcement at: (http://www.amershamhealth-us.com/omniscan/safety/index.html). This announcement has been updated to include new information as of 12/2006 and is present at this site: (http://www.amershamhealth-us.com/omniscan/safety/safety%20update%202007.html)
NSF appears to affect males and females in approximately equal numbers. NSF has been confirmed in children and the elderly, but tends to affect the middle-aged most commonly. It has been identified in patients from a variety of ethnic backgrounds and from North America, Europe, and Asia.
Besides kidney disease, conditions that may be associated with NSF include coagulation abnormalities and deep venous thrombosis, recent surgery (particularly vascular surgery), recent failure of a transplanted kidney, and sudden onset kidney disease with severe swelling of the extremities. It is very common for the NSF patient to have undergone a vascular surgical procedure (such as revision of an AV fistula, or angioplasty of a blood vessel) or to have experienced a thrombotic episode (thrombotic loss of a transplant or deep venous thrombosis) approximately two weeks before the onset of the skin changes.
The associated conditions enumerated in the preceding paragraph frequently justify the use of gadolinium-enhanced MRI or MRA studies. Whether the recently announced association of NSF with gadolinium exposure is the common denominator of all NSF cases is still under investigation. A verifiable cause and effect relationship has not yet been established, but active efforts to prove or refute this relationship are underway. Two recent papers have verified the presence of gadolinium in the tissue of some patients with NSF, however, the study designs do not allow for determining whether the gadolinium caused the NSF (free article download #1)(free article download #2).
Top of the page
Symptoms and Signs
Patients with NSF describe swelling and tightening of the skin, usually limited to the extremities (images), but sometimes involving the trunk. The condition may develop over a period of days to several weeks. In many cases, the skin thickening inhibits the flexion and extension of joints, resulting in contractures. Severely affected patients may be unable to walk, or fully extend the joints of their arms, hands, legs, and feet. Complaints of muscle weakness are common. Approximately 5% of patients have a rapidly progressive (fulminant) course.
The skin changes may start as reddened or darkened patches, papules, or plaques. In time, the skin may feel “woody” and the surface may resemble the texture of the peel of an orange. Patients may experience burning, itching, or severe sharp pains in areas of involvement. Radiography may reveal calcifications of the soft tissue. Deep "bone pain" has been described in the hips and in the ribs.
The skin lesions are commonly symmetrical, with zones between the ankles and thighs most commonly involved, followed by involvement between the wrist and upper arms. Hand and foot swelling with blister-like lesions has also been reported. Some patients have reported yellow papules or plaques on or near the eyes. Rapid, new onset fluctuating hypertension of unknown cause has been described prior to the onset of the skin lesions.
Top of the page
Treatment options
While there is no consistently successful treatment for NSF, improving renal function (due to any modality) seems to slow or arrest NSF (and in many cases allows for gradual reversal of the process over time).
Critical assessment of the effects of any investigational therapy requires careful attention *and reporting* of the patient's renal function during therapy. Investigational therapies that show objective improvement in the setting of worsening or stable chronic renal failure should be targeted for further investigation. Therapies that show improvement of NSF while renal function is improving may or may not be contributing to the observed improvement. Given the recent association of NSF with gadolinium administration, any reports of investigational therapies should also clearly indicate whether gadolinium was administered during the therapeutic evaluation, and whether there was an identifiable clinical change in the patient's disease.
Treatments that have been tried and continue to be investigated include:
Oral steroids (prednisone): Has had some efficacy in doses of 1 mg/kg po qd. Patients with concurrent diabetes should be aware of the risks of hyperglycemia while taking this medication. All patients should be aware of the possibility of gastrointestinal ulceration while taking prednisone. In addition, osteoporosis is often accelerated while taking this medication, sometimes creating a rapid calcium-wasting state. It is not clear whether the prednisone is affecting the cutaneous disease, or the renal disease, but it does seem to work in a subset of patients.
Topical Dovonex (under occlusion): So far, responses have been anecdotal and largely subjective. Some patients report improvement in localized disease. The combination of occluded dovonex and clobetasol with vascular compression stockings has reportedly been of benefit.
Extracorporeal photopheresis (ECP): A recent article describes three patients in Europe who responded with softening of plaques after several courses of ECP. Each of these patients had no improvement in renal function during the treatment. All three of these patients had had NSF for less than one year. This report corroborates other anecdotal reports in the US that photopheresis is helpful in a subset of patients. Experience at Yale suggests that patients with longstanding NSF (arbitrarily set at one year) may not respond to this modality. This treatment is currently under investigation, although no formal trials are yet offered. Some insurance carriers are receptive to covering a trial of therapy, but in the event coverage cannot be secured, be advised that therapy is exceedingly expensive. Many patients and providers have reported that Medicare has provided coverage for ECP in recent cases.
Plasmapheresis: One study from Loma Linda University (ref 12) reported improvement in three patients with liver/kidney transplant. Two of these patients were noted to have concurrent improving renal function. It is unclear what contribution improving renal function may have had in the overall clinical improvement. Nevertheless, anecdotally, some persons have reported slight improvement following plasmapheresis. Several others have been reported who noted no improvement at all.
Cytoxan: Anecdotally, this medication has shown no improvement in a number of NSF patients.
Thalidomide: There are no formal reports on the success of this medication in NSF. However, some patients have reported subjective improvement. Long term tolerance of the drug may be an issue, however. There have been two reports among Registry patients of development of NSF in patients already taking thalidomide for other medical problems.
Ultraviolet therapy: I am aware of anecdotal use of PUVA, but have heard no reports of success. Article 38 discusses the use of UVA-1, evidently beneficial in the single case in this report. PUVA in combination with Soriatane and prednisone has been anecdotally helpful in two patients.
Physical therapy (PT): Some patients have reported that physical therapy, in particular, swimming, may be helpful in slowing the progression of joint contractures. There is no contraindication to PT, and the definite potential up-side suggests that PT should be pursued whenever possible. Deep massage has been reported to be of benefit.
Pentoxifylline (PXF): A recent report describes two NSF patients who received 1200 mg per day of oral pentoxifylline (ref 57). Both patients stabilized, and the one with less severe disease improved somewhat. The use of PXF is theoretically justified as it has known antifibrotic activity (thought to be at least partially related to TNF alpha antagonism). In addition, PXF is known to improve red blood cell flexibility, and therefore to improve circulation. As thrombosis seems to be an inciting event for many NSF patients, this mechanism could also be partially responsible for the improvements noted clinically. Many more patients will need to be treated to further evaluate the efficacy of this drug.
High Dose Intravenous Ig Therapy: Reference number 25 describes a patient who showed objective improvements with one cycle of therapy with this medication. Further improvement with additional cycles was not observed. No comment was made regarding the renal status of the patient while receiving this therapy. I have heard anecdotal information suggesting this therapy has been helpful in one other patient with NSF. Additional anecdotal data have been less promising.
Renal transplantation: Several patients have improved significantly with a return to normal kidney function (either as a result of transplantation or medical therapy). In other cases, kidney transplant has resulted in no obvious improvement of the lesions, even with a fully functioning, successfully transplanted organ. I am aware of no reason--at this time--that NSF patients should be excluded from receiving a renal transplant. There are many potential benefits to receiving a transplanted kidney, however, and further elaboration about this decision in the setting of NSF is discussed in reference 52. As many NSF patients have underlying hypercoagulable states, careful testing for coagulation disorders is recommended prior to transplantation to help reduce the incidence of unexpected and detrimental coagulopathies. Magnetic resononce angiography with gadolinium-containing agents should be avoided in NSF.
Top of the page
Prognosis
As NSF is a rare, relatively recent diagnosis, the natural history of the disease is not well understood. Some patients report a gradual improvement in mobility and slight softening of the skin over time. Complete spontaneous healing in a patient with ongoing kidney disease has not yet been reported.
Several patients with NSF have died as a result of complications of their kidney disease or transplant surgery. One patient, who elected to discontinue dialysis, had widespread fibrosis involving the diaphragm, psoas muscles, proximal esophagus and intimal areas of vessels of the kidney and lungs.
As mentioned above, some patients with NSF (estimated at 5% or less) have an exceedingly rapid and fulminant disease course that may result in death. NSF, by itself, is not a cause of death, but may contribute to death by restricting effective ventilation, or by restricting mobility to the point of causing an accidental fall that may be further exacerbated by fractures and clotting complications.
Top of the page
Suspected pathogenesis
Recent investigations suggest the cell responsible for the fibrosis seen in NSF is a recently characterized cell involved in wound healing and tissue remodeling. This cell--a circulating fibrocyte (CF)--is distinct from a fibroblast in that it has a CD34/procollagen dual positive profile and is blood-borne. In NSF, CFs are thought to leave the circulation (possibly aberrantly, or as a result of passive diffusion in fluid overload states) and differentiate in the dermis into cells that functionally and histologically resemble normal dermal fibroblasts. Because of the presence of these circulating cells, NSF can be considered a systemic disorder. Several reports have verified the presence of fibrosis in other organs in NSF, but whether the fibrosis is more likely in these patients than in the general population has not been formally verified.
The factors responsible for differentiation of CFs into terminal fibroblast-like cells are not clear, but are likely directly related to the underlying function of the kidneys. Because of the close association of surgery and thrombosis in most cases of NSF, thrombosis and/or endothelial damage may be partially responsible for the initiation of a series of events that culminates in NSF.
Noting the common preceding events of vascular surgery and thrombosis (as well as brain tumors in a small number of NSF patients--ref 17), we have been actively investigating the possibility that radiographic contrast agents might be a trigger in some NSF patients. One common denominator in all of these recognized comorbidities is the frequent use of contrast agents for angiography (detecting clots, planning surgery, and evaluating the vascularity of brain neoplasms). We had noted that contrast agents had been used (and sometimes had been temporally related to disease onset) in several patients. We elaborated upon the possibility that peripherally deposited radiographic contrast might be a target for circulating fibrocytes in a recent publication (ref 62).
Interestingly, a group in Austria working along similar lines simultaneously published a report (ref 57) that the MRI angiographic contrast agent known as "Gadolinium" had been used in all NSF patients in their study group. Those patients who had renal disease and were also exposed to Gadolinium but did not develop NSF were not acidotic at the time of their studies (those who developed NSF were, in fact, acidotic). A comparison of medications revealed no single medication could account for the findings in all patients (including the use of angiotensin converting enzyme inhibitors).
Another recent and larger scale study from Denmark (ref 74) also associated the use of gadolinium-containing contrast agents with NSF onset, although the acidosis suspected as being a facilitator in the Austrian study (above) was not observed. At this time it is not clear whether systemic acidosis is an independent risk factor for NSF, or whether it is etiopathogenic in any sense.
Given these data, it would be most prudent to recommend that the use of gadolinium-containing contrast agents be excluded to the greatest extent possible in patients with renal disease until these observations can be confirmed and clarified. A formal announcement from the FDA is present at: (http://www.fda.gov/cder/drug/advisory/gadolinium_agents.htm).
Top of the page
Links/Support
1. NFD Support Group at Yahoo.com This site is a point of communication about the disease as well as an electronic forum to share ideas and possible treatment measures. It is not organized or run by Yale, however, I try to keep abreast of comments made and interject thoughts when I feel they are helpful to the understanding of the disorder.
2. NFD Support.com "Developed to help those diagnosed with Nephrogenic Fibrosing Dermopathy and their families."
3. Nephrogenic Fibrosing Dermopathy at Emedicine.com This site is also a freely available information source on NFD/NSF. Registration is free.
4. Photopheresis center locater This site is maintained by Therakos (maker of photopheresis kits). In the past, the site has only functioned with Internet Explorer.
Top of the page
Health Report Timeline
1. GE Healthcare comments about their gadolinium containing product (June 6, 2006)
2. FDA reports on NSF and Gadolinium (June 8, 2006)
3. FDA reports on NSF and Gadolinium (December 21, 2006)
4. GE Healthcare comments about their gadolinium containing product (December 22, 2006)
5. Berlex Imaging comments about their gadolinium containing product (December 14, 2006)
6. MSNBC: FDA Warns Kidney Patients about new disease (December 22, 2006)
7. American Society of Healthcare Pharmacists article on NSF (December 26, 2006)
8. Medscape: Dialysis Recommended to Prevent NSF After Gadolinium-Based Imaging in Severe Renal Failure (January 15, 2007)
9. Docguide.com (January 25, 2007)
10. Medscape: Study Determines Risk for Nephrogenic Systemic Fibrosis in ESRD Patients Receiving Gadolinium (February 7, 2007)
Top of the page
Gifts of Support for NSF Research
Gifts of support are gratefully accepted, and are a special way to remember a friend or family member stricken with this disorder. Your cash donation is tax-deductible and forwarded immediately to the NSF research effort. Gifts should be addressed to Dr. Richard Edelson, Chairman of the Department of Dermatology at Yale University. A sample template letter is available here. Please feel free to modify it to suit your needs. Dr. Edelson's address, and instructions for completing the check, are present in the letter. [Please make the check payable to Yale University, not to Dr. Cowper!] If there are any questions, please contact our office. Thank you!
Top of the page
The International Center for NFD/NSF Research (ICNFDR)
The ICNFDR is a new appellation for a collaborating group of researchers based at Yale University who are involved with NSF research. The team consists of physicians and basic science researchers from several disciplines who have committed to working together in the search for the cause, treatment, and eventual eradication of NSF. The heart of the project is the NSF Registry (see below) a direct offshoot of the original CDC investigation that began in California several years ago. Until recently, the Centers for Disease Control have not been involved in NSF investigation for several years. However, the CDC has recently completed a site investigation, and when the data are released, new information will be posted. For now, continue to contact us as noted below. In addition, cases reported to the Food and Drug Administration are not necessarily fully reported to the ICNFDR, and vice versa (due to privacy constraints in both institutions and differing missions). Ideally, all cases should be reported to both organizations.
The goals of the ICNFDR are as follows:
1) Identification and diagnosis of individual cases of NSF (contacts via physicians and patients)
2) Informing the public and physicians about NSF (website, publication, lectures)
3) Researching the pathophysiology of NSF (lab studies, clinical studies, collaboration)
4) Clinical trials of promising therapies
In the next few months, this website will transition into the new ICNFDR website at Yale University. The official web address for the site is currently http://www.icnfdr.org . This new address is valid now, and will remain valid after the move to the Yale server.
Top of the page
The NSF Registry
Since NSF is a rare condition (with over 300 cases identified in the Registry so far) it is difficult to make generalizations about the disease. The Centers for Disease Control and Prevention (CDC) co-investigated cases of NFD/NSF with doctors from the University of California in San Francisco when the disorder was first identified. Since then, the investigative effort has moved to Yale University. Dr. Shawn Cowper is currently in charge of confirming and investigating cases of NSF.
The NSF Registry is a project that collects and organizes information about patients with NSF from all over the world. The goal of the project is to identify factors that may be related to or causative of NSF. In addition, information about treatment successes and failures will be collected in order to try to find effective therapies and design future medication/therapy trials. The summary of information you see on this website is the result of contributions of data to the NSF registry so far. The Registry is funded through several mechanisms (internally, through donations, and through grant monies provided by the General Clinical Research Center at Yale University).
In order to ensure that the data collected in the registry are accurate, it is important to first confirm the diagnosis. Several conditions resemble NSF, and these must be excluded from the data collection effort. If you suspect you or a loved one may have NSF, please have your physician contact Dr. Cowper as noted below.
If you have questions about NSF not answered by this information sheet, please forward them to Dr. Cowper at the e-mail address below. As you could imagine, the effort is quite complex and time consuming. Please be patient, your questions will be answered.
Top of the page
Citing this webpage
The information contained on this web page is copyrighted by Shawn E. Cowper, MD. The author grants permission to authors, educators, and physicians to use the information contained on this website if an appropriate citation is made. The format of the citation should be as follows:
Cowper SE. Nephrogenic Fibrosing Dermopathy [NFD/NSF Website]. 2001-2008. Available at http://www.icnfdr.org. Accessed mm/dd/yyyy.
Questions should be directed to the author at the email address below.
Top of the page
Contact Information
e-mail (preferred): registermc@juno.com
telephone: (203) 785-3524
fax: (203) 785-6869
Address to send microscope slides:
Carol Hribko
Yale Dermatopathology Service
PO Box 208059
15 York Street, LMP 5031
New Haven, CT. 06520-8059
Please do not send slides unless first instructed to do so by Dr. Cowper or Carol Hribko.
Top of the page