Official site of the Nephrogenic Systemic Fibrosis (NSF) Registry

The International Center for Nephrogenic Systemic Fibrosis Research (ICNSFR)

Last Updated October 25, 2009

The entire site has been substantially updated, so recent updates are NOT indicated in red, as is the usual practice for this site.

This site can be accessed at the following URL: http://www.icnsfr.org

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.

Updated Case Definition

A multidisciplinary team of clinicians and dermatopathologists highly experienced in nephrogenic systemic fibrosis has recently completed a clinicopathological definition of NSF. This definition relies upon a combination of clinical and pathological findings derived from the study of numerous patients, the relevant medical literature, and histological slides and data contained within the Yale NSF Registry to create a reproducible diagnostic and work-up scheme for putative cases of NSF. The definition is currently under peer review, and once published, will be reproduced in some form on this website for the use of clinicians and pathologists.

NSF…what is it?

Terminology:

Nephrogenic Systemic Fibrosis (NSF), formerly known as nephrogenic fibrosing dermopathy (NFD), is a condition that, to date, has occurred only in people with kidney disease. NSF is a systemic disorder with its most prominent and visible effects in the skin, hence its original designation as a dermopathy (dermopathy=disorder of skin). With the further clarification of hundreds of additional cases and the continued recognition that kidney disease seems to be a prerequisite for developing NSF (nephrogenic=starting with the kidney), NSF has been accepted as the terminology most reflective of the reality of the disorder.

Population Characteristics:

NSF affects 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 from North and South America, Europe, Asia and Australia. The majority of literature-reported cases have resided in the United States.

Some degree of kidney disease appears to be a common denominator in NSF. 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. No specific form of dialysis has been linked to NSF, although most patients with NSF do undergo dialysis procedures. Some patients who have never been dialyzed have developed NSF.

Theorized triggers:

MRI Contrast: Over the past several years, researchers have correlated the development of NSF with the increasing use of gadolinium-based MRI contrast agents in patients with kidney disease. Gadolinium, an element of the lanthanide series (atomic number 64) is the chief component of virtually all contrast agents administered for magnetic resonance imaging (MRI). While many MRI examinations do not require contrast enhancement, some studies, in particular those examining the blood vessels (angiography), benefit from the administration of one of these gadolinium-based contrast agents (GBCA).

Since gadolinium (Gd) is considered toxic, it is bound to other molecules (termed ligands) to exploit its superior imaging qualities while facilitating its safe transit through, and exit from, the body. GBCA are virtually entirely excreted via the kidneys. In patients with kidney disease, administered GBCA will require more time to exit the body. If there is no residual urine output, the only way such agents can exit the body is through diaysis procedures. While there are not many studies examining the excretion of GBCA via dialysis, there is no question that excretion is delayed (sometimes markedly so).

In patients with normal kidney function, GBCA are considered safe because the bond between the toxic Gd atom and its ligand molecule is extremely strong and because the GBCA molecule is flushed from the body so rapidly. There is a small risk that Gd atoms could dissociate (unbind) from their carrier ligands, but if this occurred, Gd (which acts much like calcium atoms in the body) would likely bind to readily-available phosphates and form insoluble molecules. In patients who receive large doses of GBCA and do not undergo rapid and effective dialysis, there is a risk that larger amounts of these gadolinium compounds could develop and remain in the body in a form that is not readily removable.

The recent focus on GBCA as a possible trigger for NSF derives from several observations:

1) GBCA were not widely used for angiography imaging in kidney patients prior to 1997. The earliest cases of NSF occurred in 1997.

2) Because of the long-recognized danger of contrast induced nephropathy (CIN) due to iodine-based contrast agents, GBCA were hailed as a way of avoiding CIN and thus preserving renal function (especially in those with diminished renal output). While the package inserts for these agents quite clearly indicated they were renally excreted--and users were warned that caution must be employed in those with reduced renal output--no specific warnings against their use were issued. During the 1997-2007 period no GBCA available in the USA was approved for MRA, although off-label use was widely adopted.

3) During this period, magnetic resonance angiography (MRA) also became widespread. MRA routinely employs 2-3x the usual dose of gadolinium based MRI contrast than does a standard MRI. MRA was commonly used in the pre-transplant setting to evaluate the renal vasculature.

4) Prior to warnings made by the FDA and European Medicines Agency regarding the association of GBCA with NSF, the incidence and recognition of NSF appeared to be rising. Following these announcements and widespread dissemination of the potential risk of NSF, the incidence of NSF appears to have dropped.

5) While many GBCA formulations exist in the world, only some of these have been associated with NSF, and only one has been associated with the vast majority of cases of NSF. Some have suggested that since this agent is slightly more likely to dissociate chemically, Gd dissociation (dechelation) might be the trigger of NSF at the cellular level. Some animal studies and cell culture studies seem to corroborate this hypothesis. Further study is ongoing.

Erythropoietin: Erythropoietin (Epo) is a hormone that controls red blood cell production. Many patients with kidney disease have anemia related to their kidney disease. Because of this, Epo is often administered to increase the output of red blood cells from the bone marrow. Because Epo gained widespread use among the renal population just as NSF emerged, some have suggested that Epo either triggers or facilitates the development of NSF. As Epo has so many applications beyond the treatment of anemia of chronic renal disease, and NSF is only seen among renal populations, Epo cannot be the sole trigger of NSF. In addition, the Yale NSF Registry has identified many persons with NSF who had never received Epo. Based on current data (especially very strong data implicating gadolinium based contrast agents) we cannot support Epo as a sole cause of NSF.

However, as Epo has the potential to affect the growth of other cells in the bone marrow, and as the cell responsible for producing much of the collagen deposition seen in NSF develops in the bone marrow, we find it an intriguing hypothesis that Epo could facilitate the development of NSF in some cases by increasing the number of circulating fibrocytes. At this time, this remains a hypothesis only.

Thrombosis/Endothelial Injury: Besides kidney disease, medical conditions that may be associated with NSF include hypercoagulation 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 there is an independent risk associated with endothelial damage or hypercoagulation remains an open question, although circulating fibrocyte migration from the blood is facilitated in both scenarios.

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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.

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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.

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Prognosis

As NSF is a rare, relatively recent diagnosis, the natural history of the disease is not fully 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.

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Suspected pathogenesis

As noted above, several triggers have been implicated in the development of NSF--chief among them, the use of GBCA in the setting of renal disease. Ultimately, these putative triggers lead to fibrosis that is mediated by a cell. 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 is a systemic disorder. Several reports have verified the presence of fibrosis in other organs in NSF. Observations of autopsy tissue from several decedants with NSF demonstrate reproducible and characteristic findings in the heart, lungs, sclerae, durae and kidneys of patients with NSF. The factors responsible for differentiation of CFs into terminal fibroblast-like cells are not clear, but are likely directly related to the underlying dysfunction of the kidneys.

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Links/Support

1. The Global Fibrosis Foundation: A new not-for-profit organization whose mission is to help educate patients, families and the medical community about Nephrogenic Systemic Fibrosis and other organ specific fibrosing processes; to support research into prevention and treatment; and to advocate on behalf of patients. The site is currently under development.
2. NSF 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 or the International Center for NSF Research.
3. Nephrogenic Systemic Fibrosis 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).

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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)
11. Business Week: The Spectre Haunting GE (October 15, 2009)

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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!

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The International Center for NSF Research (ICNSFR)

The ICNSFR 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. The Registry is the longest-running, most complete database of NSF related information at present. NSF cases reported to the Food and Drug Administration are not necessarily fully reported to the ICNSFR, and vice versa (due to privacy constraints in both institutions and differing missions). Ideally, all cases should be reported to both organizations as well as to the manufacturer of any gadolinium based contrast agent thought to be involved.

The goals of the ICNSFR 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

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The NSF Registry

Since NSF is a rare condition (with over 335 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.

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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 [ICNSFR Website]. 2001-2009. Available at http://www.icnsfr.org. Accessed mm/dd/yyyy.

Questions should be directed to the author at the email address below.

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Contact Information

e-mail (preferred): registermc@juno.com
telephone: (203) 785-3524
fax: (203) 737-4307

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.

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