American Journal of Kidney Diseases
Volume 46, Issue 4 , Pages 763-765, October 2005

Nephrogenic Systemic Fibrosis: The Nosological and Conceptual Evolution of Nephrogenic Fibrosing Dermopathy

Yale University, New Haven, Connecticut

published online 12 September 2005.

Article Outline

 

IN 1999, I HAD the tremendous good fortune to be invited to investigate a developing medical mystery. My academic mentor, Dr Philip Leboit, during a period of several years, had identified several patients with an as-yet undescribed skin disorder. A preliminary announcement and description was published,1 and a detailed examination of the clinical and histological characteristics of this disorder was published 1 year later.2 I was quite excited to be afforded the opportunity to name a new disease; after several alternatives were discussed and modified, Dr Leboit and I dubbed the newcomer “nephrogenic fibrosing dermopathy” (NFD).

At the time, NFD fairly well encapsulated what we knew of the disorder. The original details derived from the small sampling of patients in the initial study set remain essentially intact to this day. NFD was (and still is) a scleroderma-like disease of the skin that affects only patients with renal insufficiency. The clinical and histological findings are sufficiently unique to enable confident diagnosis in most cases.2

The dermopathy of NFD was “nephrogenic” in that renal dysfunction was (and still is) a prerequisite for all cases of NFD.3 The concept that renal function is tied to disease activity was reinforced by several additional observations: (1) a small number of patients with acute renal failure (of any cause) developed NFD within 2 to 4 weeks after the onset of renal dysfunction2, 4; (2) for the lucky few for whom renal failure could be restored, NFD generally improved and/or resolved without any skin-directed therapy2, 5, 6, 7; and (3) case reports and anecdotal evidence suggest that restoration of renal function by means of early transplantation improves and/or resolves NFD.5 To this day, all cases of NFD reported to the NFD Registry at Yale University8 have had some element of renal dysfunction at the time of disease onset.

In 1997 and 1998, as the first cases were uncovered in a renal transplantation center in southern California, the natural assumption was that transplantation (or the drugs administered after transplantation) might be to blame.9 As additional cases were identified (many in nontransplantation patients), attention shifted to dialysis. However, the findings could not be explained by any single dialysis regimen, and this explanation failed to incorporate the 10% of subsequent patients reported to the registry (and elsewhere) who had never been dialyzed at the time of NFD onset.2, 6, 7, 8, 10 A broader search for a common denominator resulted in the notion that—without exception—all patients with NFD have renal dysfunction.

The search for more common denominators was on. With help from the Centers for Disease Control and Prevention,11 a systematic investigation of the first cases of NFD in California suggested that no single medication or infectious agent was to blame. Epidemiological information from the registry indicates no sex or race predilection is present. Reports of isolated cases of NFD in Asia and Europe4, 12, 13, 14 indicate that this is not a phenomenon unique to the United States.

In 2003, several lines of evidence came together to lend strong support to the notion that NFD is a systemic illness. One observation was the identification of an immunologically unique cell in the biopsy material of many people with NFD: the circulating fibrocyte.15 The circulating fibrocyte is a relatively recently described bone marrow–derived leukocyte that is unique in its coexpression of leukocyte markers, markers of antigen presentation, and collagen I. This cell has been cultured in the laboratory, and its growth characteristics have been studied extensively. The circulating fibrocyte has been implicated in several disease processes and appears to be the major constituent in the cutaneous biopsy samples of most patients with NFD.16

A second line of evidence, developed in 2003, was the first reported autopsy of a patient with NFD.17 This, and several subsequent reports (including several cases investigated by the registry project, but not yet published), establish without question that NFD is a systemic disease.

In this issue of the American Journal of Kidney Diseases, Daram et al18 reinforce the concepts that have evolved during the past 8 years regarding NFD. Their work, along with the work of others, has argued successfully for an evolutionary step in the nomenclature of NFD. Approximately 1 year ago, on the basis of published reports and the volume of data available in the registry, the terminology of NFD was modified to reflect an updated understanding of the disease process: nephrogenic systemic fibrosis (NSF).

To many readers of this journal, NFD/NSF is a mysterious orphan disease that likely will never cross the office threshold. In the hopes of dispelling this notion, I share some observations drawn from my own experience. First, before 1997, this disorder did not exist. It is highly likely that a new agent or a technique (as yet unverified) is causing NFD/NSF.2, 3, 9 Until we identify this agent, more cases undoubtedly will develop. Second, this disease is devastating. I have encountered patients who, misunderstanding that dialysis might be causing their NFD/NSF, chose to voluntarily terminate dialysis therapy. Many patients progress from ambulation to wheel-chair dependency within a few weeks. Some patients experience intractable pain. Third, after clinicians have diagnosed NFD, they frequently find other cases—suggesting many cases are going unrecognized because of lack of familiarity.

NFD/NSF causes long-term morbidity and occasional mortality. Initial impressions suggest early and aggressive intervention is justified. Although several therapies have shown promise,3, 13 no therapy has been as effective as restoration of renal function. Many of these patients are already awaiting renal transplantation. For those who are eligible, it would be most judicious to proceed with transplantation as soon as it can be arranged. Because many patients with NFD/NSF harbor an underlying thrombotic tendency (as illustrated in the case report of Daram et al18 herein), a careful hypercoagulation workup should precede any surgery, and appropriate precautions should be taken to avoid thrombotic loss of the new renal graft.

For those who are unacceptable renal transplant candidates, additional therapeutic options have been described, but relatively few have been well documented. Perhaps the best-documented therapy to date is extracorporeal photopheresis. Extracorporeal photopheresis has proved beneficial in 3 patients in Europe.19 These patients, all of whom had been stricken with NFD for less than 1 year, showed measurable and sustained improvement. Unfortunately, extracorporeal photopheresis therapy was discontinued in 1 of these patients because of insurance issues. In the United States, insurance coverage for extracorporeal photopheresis also continues to be difficult to procure for patients with NFD, but occasional trials of therapy can be justified on the basis of its resemblance to systemic sclerosis.

As with systemic sclerosis (and other primary fibrosing processes), the underlying trigger has not yet been identified. Although it is clear that NFD/NSF does not seem capable of developing in patients with normal renal function, why are only a select few stricken? I do not know the answer to this question, but a systematic investigation is underway that will begin to address some of the suspects that have been raised, including high-dose erythropoietin,9 selective serotonin reuptake inhibitors, and lack of treatment with angiotensin-converting enzyme inhibitors.20 However, logic suggests that a single agent probably is not to blame. I remain optimistic that the culprits will be found and that we will all learn something new about fibrosis and wound healing in the process.

Because the investigation of all aspects of NFD/NSF is still being pursued, all cases should be reported to the registry (http://www.icnfdr.org). The registry Web site is a regularly updated synopsis of the disease process and serves as the heart of the NFD/NSF research effort worldwide. Treatment experiences (both negative and positive) are especially helpful in the construction of future therapeutic trials.

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References 

  1. Cowper SE , Robin HS , Steinberg SM , Su LD , Gupta S , LeBoit PE . Scleromyxoedema-like cutaneous disease in renal-dialysis patients . Lancet . 2000;356:1000–1001
  2. Cowper SE , Su L , Robin H , Bhawan J , LeBoit PE . Nephrogenic fibrosing dermopathy . Am J Dermatopathol . 2001;23:383–393
  3. Cowper SE . Nephrogenic fibrosing dermopathy (The first six years) . Curr Opin Rheumatol . 2003;15:785–790
  4. Evenepoel P , Zeegers M , Segaert S , et al.   Nephrogenic fibrosing dermopathy (A novel disabling disorder in patients with renal failure) . Nephrol Dial Transplant . 2004;19:469–473
  5. Jan F , Segal JM , Dyer J , Leboit P , Siegfried E , Frieden IJ . Nephrogenic fibrosing dermopathy (Two pediatric cases) . J Pediatr . 2003;143:678–681
  6. Mackay-Wiggan JM , Cohen DJ , Hardy MA , Knobler EH , Grossman ME . Nephrogenic fibrosing dermopathy (scleromyxedema-like illness of renal disease) . J Am Acad Dermatol . 2003;48:55–60
  7. Swartz RD , Crofford LJ , Phan SH , Ike RW , Su LD . Nephrogenic fibrosing dermopathy (A novel cutaneous fibrosing disorder in patients with renal failure) . Am J Med . 2003;114:563–572
  8. Cowper SE: Nephrogenic Fibrosing Dermopathy [NFD/NSF Web site], 2001-2005. Available at: http://www.icnfdr.org. Accessed: July 28, 2005
  9. Leboit PE . What nephrogenic fibrosing dermopathy might be . Arch Dermatol . 2003;139:928–930
  10. Obermoser G , Emberger M , Wieser M , Zelger B . Nephrogenic fibrosing dermopathy in two patients with systemic lupus erythematosus . Lupus . 2004;13:609–612
  11. Centers for Disease Control and Prevention (CDC) (Fibrosing skin condition among patients with renal disease—United States and Europe, 1997-2002) . MMWR Morb Mortal Wkly Rep . 2002;51:25–26
  12. Dawn G , Holmes SC . Scleromyxoedema-like eruption following haemodialysis or nephrogenic fibrosing dermopathy? . Br J Dermatol . 2004;150:167–168 (letter)
  13. Lauchli S , Zortea-Caflisch C , Nestle FO , Burg G , Kempf W . Nephrogenic fibrosing dermopathy treated with extracorporeal photopheresis . Dermatology . 2004;208:278–280
  14. Tan AW , Tan SH , Lian TY , Ng SK . A case of nephrogenic fibrosing dermopathy . Ann Acad Med Singapore . 2004;33:527–529
  15. Cowper SE , Bucala R . Nephrogenic fibrosing dermopathy (Suspect identified, motive unclear) . Am J Dermatopathol . 2003;25:358; (letter)
  16. Quan TE , Cowper S , Wu SP , Bockenstedt LK , Bucala R . Circulating fibrocytes (Collagen-secreting cells of the peripheral blood) . Int J Biochem Cell Biol . 2004;36:598–606
  17. Ting WW , Stone MS , Madison KC , Kurtz K . Nephrogenic fibrosing dermopathy with systemic involvement . Arch Dermatol . 2003;139:903–906
  18. Daram SR , Cortese CM , Bastani B . Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis (Report of a new case with literature review) . Am J Kidney Dis . 2005;46:754–759
  19. Gilliet M , Cozzio A , Burg G , Nestle FO . Successful treatment of three cases of nephrogenic fibrosing dermopathy with extracorporeal photopheresis . Br J Dermatol . 2005;152:531–536
  20. Fazeli A , Lio PA , Liu V . Nephrogenic fibrosing dermopathy (Are ACE inhibitors the missing link?) . Arch Dermatol . 2004;140:1401; (letter)

PII: S0272-6386(05)01111-X

doi:10.1053/j.ajkd.2005.08.008

Refers to article:

  • Nephrogenic Fibrosing Dermopathy/Nephrogenic Systemic Fibrosis: Report of a New Case With Literature Review , 12 September 2005

    Sumanth R. Daram, Cherise M. Cortese, Bahar Bastani
    American Journal of Kidney Diseases October 2005 (Vol. 46, Issue 4, Pages 754-759)

American Journal of Kidney Diseases
Volume 46, Issue 4 , Pages 763-765, October 2005

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