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NDT Advance Access originally published online on November 23, 2006
Nephrology Dialysis Transplantation 2007 22(2):631-636; doi:10.1093/ndt/gfl600
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The case for ultraviolet light therapy in nephrogenic fibrosing dermopathy—report of two cases and review of the literature

Ihab M. Wahba1, Kevin White2, Mary Meyer1 and Eric L. Simpson3

1Division of Nephrology and Hypertension, 2Department of Pathology and 3Department of Dermatology, Oregon Health & Science University, Portland, OR 97239, USA

Correspondence and offprint requests to: Ihab Wahba, MD, Assistant Professor of Medicine, Division of Nephrology and Hypertension, Oregon Health & Science University, 3314 S.W. US Veterans Hospital Road, Portland, OR 97239, USA. Email: wahbai{at}ohsu.edu

Keywords: nephrogenic fibrosing dermopathy; photopheresis; PUVA; systemic lupus erythematosus



   Introduction
Top
 Introduction
Case reports
 Discussion
 Conclusion
 Acknowledgement
 References
 
Nephrogenic fibrosing dermopathy (NFD) is an emerging skin disease in patients with renal failure [1]. It is characterized by skin induration that affects the upper and lower extremities, and may progress to involve other areas of the body. Recent reports suggest that NFD may not be limited to the skin and could affect internal organs [2–5]. In all these patients, NFD appeared to be progressive and to affect vital organs including the heart and lungs. In one report, the patient apparently died from complications related to severe skin fibrosis involving the trunk and precluding dialysis catheter replacement [5]. Although there are no consistently effective therapies reported in the literature, ultraviolet light therapy in various forms, including photodynamic therapy and photopheresis has been recently reported to improve the disease [6–10]. Systemic lupus erythematosus was reported only recently to be a cause of renal failure in patients with NFD, and herein we extend this observation [11]. Ultraviolet light is known to exacerbate the cutaneous and perhaps even the systemic manifestations of lupus, which may deter clinicians from treating NFD with this form of therapy in lupus patients. Conversely, ultraviolet light therapy has been reported to improve lupus symptoms [12]. We report two patients with end-stage renal disease (ESRD) due to systemic lupus erythematosus who developed NFD and in whom ultraviolet light therapy, namely psoralen plus ultraviolet light A (PUVA) and extracorporeal photopheresis, resulted in significant improvement of NFD without exacerbation of their lupus symptoms. We then review the recent literature on NFD and summarize the published cases treated with the most successful therapies.



   Case reports
Top
 Introduction
 Case reports
Discussion
 Conclusion
 Acknowledgement
 References
 
Case 1
A 22-year-old Vietnamese woman received a deceased donor renal transplant in June 2001. She had ESRD due to systemic lupus erythematosus, and had been on haemodialysis since 1996. Her induction immunosuppression included steroids, thymoglobulin and azathioprine. Her medications included prednisone, tacrolimus, mycophenolate mofetil, trimethorpim/sulfamethoxazole, omeprazole, magnesium oxide, clonidine and aspirin. She had no anti-cardiolipin antibodies but a mildly elevated activated partial thromboplastin time (aPTT) and Russell Viper Venom time. Three weeks after transplantation, serum creatinine was 0.9 mg/dl and remained unchanged, and the rest of her laboratory data were unremarkable. Six weeks post transplantation, she developed mild leg oedema followed by erythematous papules that first appeared on the dorsum of both feet and then rapidly coalesced into plaques involving both legs and forearms. The plaques were indurated and sclerotic with a peau d’orange texture and an irregular border with some areas of clearing. The plaques on the legs rapidly progressed to involve the thighs, above the knees.

A biopsy from the anterior tibial skin revealed dense fibrosis involving the full thickness of the dermis and extending into subcutaneous fat septae, with mild lobular fat necrosis. There were increased numbers of small endothelial-lined vessels in the papillary dermis, some of which had slightly thick walls, while many of the fibroblasts had a thin and delicate curved appearance. The histology was typical of NFD (Figure 1). Potent topical steroids did not improve the patient's skin condition which continued to progress. PUVA therapy was initiated. The patient received 12 sessions. Her skin disease showed no further progression, her ‘amoeboid’ lesions regressed (Figure 2A and B) and the sclerotic plaques showed marked softening (Figure 2C). The skin improvement continued after PUVA discontinuation. She experienced no photosensitivity, discoid skin lesions or systemic symptoms during the course of her light therapy. In 2004, a repeat skin biopsy from the leg showed decreased cellularity and fibrosis compared with the first biopsy (Figure 3A and B), corresponding to the clinical improvement of NFD. As of 2006, her skin has remained softened without progression, but some skin laxity and post-inflammatory hyperpigmentation have developed.


Figure 1
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  		Fig. 1. High power photomicrograph in Case 1 showing increased spindled fibrocytes and collagen bundles typical of nephrogenic fibrosing dermopathy. (Haematoxylin and eosin, 400x.)

 

Figure 2
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  		Fig. 2. (A) Indurated sclerotic plaques with an irregular ‘amoeboid’ border and a pebbly undulated skin surface on the extensor surface of the forearm prior to PUVA therapy in Case 1. (B) Disappearance of the ‘amoeboid edge’ and of the pebbly skin surface after PUVA therapy. (C) Softening of skin induration after PUVA therapy as indicated by an easily pinched skin on the forearm, whereas this was not possible before therapy.

 

Figure 3
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  		Fig. 3. (A) Full thickness skin biopsy from the anterior leg before PUVA treatment in Case 1 showing increased spindle cells and collagen extending to the subcutaneous fat. (B) Repeat biopsy from the leg after treatment showing reduction in spindle cells and fibrosis.

 
Case 2
A 70-year-old Vietnamese woman with ESRD due to lupus nephritis presented with lower extremity oedema, intense pain and pruritus in the arms, legs and feet. Her pruritus had failed to respond to anti-histamines and caused severe insomnia. She had been on dialysis for 6 years, had no documented anti-cardiolipin antibodies and had a normal aPTT. She had multiple vascular access procedures including the placement of a right arm brachio-cephalic arteriovenous fistula 4 months prior to presentation and placement of an indwelling dialysis catheter with subsequent angiography of her fistula 2 weeks prior to presentation. She also had had a gadolinium venogram 2 months prior to the onset of her symptoms. Her medications were erythropoietin, nifedipine, metoprolol, prednisone, nephrovite, pravastatin, calcium acetate, trazodone, levothyroxine, alprazolam and hydroxyzine. On examination, she had hyperpigmented, indurated and sclerotic plaques on the dorsal forearms and circumferentially on the legs extending up to the lower thighs (Figure 4). Serum protein electrophoresis was negative for a monoclonal spike.


Figure 4
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  		Fig. 4. Forearms with sclerotic plaques resulting in a diffuse ‘bound-down’ appearance in Case 2.

 
A skin biopsy from the left arm revealed changes diagnostic of NFD. The patient underwent one cycle of photopheresis (one treatment session for two consecutive days) every 2 weeks for 2 months with subsequent considerable improvement in her skin induration and pruritus. She has continued on one cycle of photopheresis per month with continued improvement and no disease progression. She has not developed photosensitivity or any subjective flares of her lupus while undergoing photopheresis.



   Discussion
Top
 Introduction
 Case reports
 Discussion
Conclusion
 Acknowledgement
 References
 
We report the successful treatment of NFD with phototherapy in two patients with systemic lupus erythematosus. Both patients had rapidly progressive disease prior to institution of phototherapy that remarkably improved after therapy. Table 1 summarizes the clinical features of NFD in both patients before and after phototherapy. Both PUVA and photopheresis were well tolerated and no flares of cutaneous or systemic lupus occurred during therapy. Renal function remained unchanged during and after phototherapy suggesting that the treatment was the most important variable associated with skin improvement. These two cases extend previous observations that several types of phototherapy (UVA1, photopheresis and photodynamic therapy) can be useful treatment modalities for NFD [6–10]. We were not able to identify any previous reports in the literature describing successful PUVA treatment for NFD and herein we report the first case.


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  		Table 1. Patient characteristics before and after treatment

 
Since the first publication by Cowper et al. [1], about 200 cases have been reported worldwide to the centres for disease control [13]. Acute renal failure, chronic renal failure and renal transplantation all predispose to NFD [14]. Other predisposing factors include history of vascular surgery, vascular access procedures (in 90% of cases), hypercoagulable states (particularly anti-cardiolipin antibodies) or thrombosis [14]. No drug exposure has been found to be associated with NFD to date. Recently, exposure to gadolinium contrast in the setting of systemic acidosis was reported to precede disease onset in some patients [15]. Case 2 in this report was exposed to gadolinium ~2 months before the onset of her symptoms, but had no documented acidosis. We could not document exposure to gadolinium in Case 1.

NFD typically presents with oedema, pruritus and/or pain, followed by symmetric erythematous or hyperpigmented plaques involving the feet, legs, hands or forearms with an irregular or ‘amoeboid’ edge that advances proximally and results in a peau d’orange appearance. Eventually, joint contractures may occur, which can be debilitating [1,2,5,14]. More recently, several case reports of NFD affecting the limb muscles, diaphragm, pericardium, myocardium and the lungs were described, leading some investigators to change the nomenclature to ‘nephrogenic systemic fibrosis’ [2–5]. The differential diagnosis of NFD includes other sclerosing skin disorders including morphoea, scleroderma, scleromyxoedema, eosinophilic fasciitis, eosinophilia-myalgia syndrome and Spanish toxic-oil syndrome. Cutaneous histolopathological evaluation can differentiate between these clinically similar diseases [16].

The diagnosis of NFD relies on a skin biopsy. No laboratory tests are diagnostic. The distinctive histopathology consists of proliferating spindle-shaped cells (fibrocytes) associated with thickened collagen bundles in the dermis and subcutis (Figure 1). Immunohistochemical staining reveals the fibrocytes to be CD34+ and CD45RO+ dendritic cells thought to be circulating fibrocytes [1,5,17]. The histopathology of NFD closely resembles wound healing and repair, leading some investigators to postulate that NFD could be caused by translocation of circulating fibrocytes to the subcutaneous tissue [17]. This may explain the occurrence of the majority of cases following surgical vascular manipulations and procedures involving vascular access of dialysis patients [14]. In fact, NFD shortly followed renal transplantation in Case 1 and an angiographic procedure in Case 2. However, vascular procedures are common in patients with renal failure, so this association may be coincidental.

The natural course of NFD is likely to be progressive [1–5,14]. Anecdotally, some cases show no worsening or mild improvement in skin induration [13]. To our knowledge, there are no reported cases of significant improvement or complete regression of the skin disease unless renal function improves [13,14]. There are no consistently effective reported treatments for NFD [5,14]. Steroids, other immunosuppresives and thalidomide have not shown efficacy [14,16,18]. Plasmaphereis has been reported in one series to improve NFD, but two out of three patients had a concomitant improvement in renal function, therefore, it is unclear if improvement of NFD in these patients occurred because of improvement in renal function or because of the treatment itself [18]. Two other reports showed no benefit from plasmapheresis [19,20]. More convincingly, UVA1 therapy, photopheresis and photodynamic therapy were reported to be successful in patients with NFD and persistent renal failure [6–10]. Table 2 provides a summary of published cases to date in which the two most successfully used modes of therapy were reported, namely phototherapy and plasmapheresis. In case of photopheresis, the improvement in skin induration became noticeable after 2–4 cycles, similar to our patient.


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  		Table 2. Published cases of NFD treated with phototherapy and plasmapheresis

 
The mechanisms by which ultraviolet light therapy improves NFD are not clear. Both PUVA and photopheresis have shown efficacy in other sclerosing diseases such as morphoea and scleomyxoedema [12]. Significant reductions of proinflammatory cytokines released from peripheral blood mononuclear cells have been observed in patients undergoing PUVA therapy [21]. PUVA also exerts local immunomodulatory effects in the skin by reducing epidermal and dermal T-lymphocytes [22]. Photopheresis has a multitude of immunomodulatory effects including inducement of T-lymphocyte apoptosis and modulation of cytokine production to favour an anergic state [12,23]. Since T-cells have been shown to be necessary for fibrocyte maturation [24], lymphocyte apoptosis may be one mechanism by which phototherapy improves skin fibrosis in NFD. Therefore, PUVA and photopheresis may exert local or systemic effects on fibrocytes, monocytes or T-lymphocytes, resulting in reduced cytokine production (including transforming growth factor-ß1), reduced fibrocyte migration to the skin from the peripheral blood or reduced fibrocyte maturation and proliferation in the skin.



   Conclusion
Top
 Introduction
 Case reports
 Discussion
 Conclusion
Acknowledgement
 References
 
In conclusion, NFD is an emerging fibrosing skin disease with documented systemic manifestations in patients with renal failure. In this report, we extend prior observations that phototherapy either in the form of PUVA or extracorporeal photopheresis may be a safe and effective form of therapy for these patients even in the setting of lupus. The effect of phototherapy in NFD may be due to inhibition of T-lymphocyte interaction with fibrocytes in the circulation or locally in the skin. Further studies are needed to confirm these observations and to elucidate the mechanisms by which ultraviolet light therapy improves NFD.



   Acknowledgement
Top
 Introduction
 Case reports
 Discussion
 Conclusion
 Acknowledgement
References
 
The authors would like to thank Dr David Ellison for his invaluable advice during the preparation of this manuscript.

Conflict of interest statement. None declared.



   References
Top
 Introduction
 Case reports
 Discussion
 Conclusion
 Acknowledgement
 References
 

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  3. Levine JM, Taylor RA, Elman LB, et al. (2004) Involvement of skeletal muscle in dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy). Muscle Nerve 30:569–577.[CrossRef][Web of Science][Medline]
  4. Jimenez SA, Artlett CM, Sandofi N, et al. (2004) Dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy): study of inflammatory cells and transforming growth factor beta1 expression in affected skin. Arthritis Rheum 50:2660–2666.[CrossRef][Web of Science][Medline]
  5. Daram SR, Cortese CM, Bastani B. (2005) Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis: report of a new case with literature review. Am J Kidney Dis 46:754–759.[CrossRef][Web of Science][Medline]
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  11. Obermoser G, Emberger G, Wieser M, Zelger B. (2004) Nephrogenic fibrosing dermopathy in two patients with systemic lupus erythematosus. Lupus 13:609–612.[Abstract/Free Full Text]
  12. Russo GG and Mullen C. (2001) Cutaneous and non-cutaneous disorders treated with extracorporeal photopheresis. Int J Dermatol 40:89–100.[CrossRef][Web of Science][Medline]
  13. Cowper SE. Nephrogenic fibrosing dermopathy (NFD website 2001–6). Available at http://www.pathmax.com/dermweb Accessed on 4 August 2006.
  14. Cowper SE. (2003) Nephrogenic fibrosing dermopathy: the first 6 years. Curr Opin Rheumatol 15:785–790.[CrossRef][Web of Science][Medline]
  15. Grobner T. (2006) Gadolimium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic sclerosis. Nephrol Dial Transplant 21:1104–1108.[Free Full Text]
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  17. Ortonne N, Lipsker D, Chantrel F, Boehm N, Grosshans E, Cribier B. (2004) Presence of CD45RO+ CD34+ cells with collagen synthesis activity in nephrogenic fibrosing dermopathy: a new pathogenic hypothesis. Br J Dermatol 150:1050–1052.[CrossRef][Web of Science][Medline]
  18. Baron P, Cantos K, Hillebrand K, et al. (2003) Nephrogenic fibrosing dermopathy after liver transplantation successfully treated with plasmapheresis. Am J Dermatopathol 25:204–208.[CrossRef][Web of Science][Medline]
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  20. Hubbard V, Davenport A, Jarmulowicz M, Rustin M. (2003) Scleromyxoedema-like changes in four renal dialysis patients. Br J Dermatol 148:563–568.[CrossRef][Web of Science][Medline]
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  22. Vallat V, Guilleaudeau P, Battat L, et al. (1994) PUVA bath therapy strongly suppresses immunological and epidermal activation in psoriasis: a possible cellular basis for remittive therapy. J Exp Med 180:283–296.[Abstract/Free Full Text]
  23. Fimiani M, Di Renzo M, Rubegni P. (2004) Mechanism of action of extracorporeal photochemotherapy in chronic graft-versus-host disease. Br J Dermatol 150:1055–1060.[CrossRef][Web of Science][Medline]
  24. Abe R, Donnelly SC, Peng T, Bucala R, Metz CN. (2001) Peripheral blood fibrocytes: differentiation pathway and migration to wound sites. J Immunol 166:7556–7562.[Abstract/Free Full Text]
Received for publication: 13. 7.06
Accepted in revised form: 12. 9.06


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