Nephrogenic systemic fibrosis in advanced chronic kidney disease: A single hospital’s experience in Taiwan

ARTICLE

Auteur(s) : WenChieh Chen¹, Shen-Lin Huang¹, Ching-Shin Huang¹, Min-Chien Tsai¹, Han-Ming Lai³, Chun-Chung Lui⁴, Hock-Liew Eng⁵, Hsueh-Wen Chang⁶, Chih-Hsiung Lee², Feng-Rong Chuang²

¹Department of Dermatology,
²Division of Nephrology,
³Division of Rheumatology,
⁴Department of Radiology,
⁵Department of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine; Taiwan
⁶Department of Biological Sciences, National Sun Yat-Sen University, Taiwan

accepté le 25 Août 2008

Nephrogenic fibrosing dermopathy (NFD), first identified in 1997 and reported in 2000 [1], is an acquired, idiopathic disorder of unknown etiology, which occurs predominantly in patients with renal disease, displaying clinical features resembling scleroderma or eosinophilic fasciitis, and histopathological findings similar to scleromyxedema. NFD affects mostly middle-aged males and females in an equal proportion, without ethnic differences [2]. As the fibrosis of NFD can also involve internal organs such as the diaphragm, pleura and myocardium/pericardium, the nosology “nephrogenic systemic fibrosis” (NSF) is proposed to describe this generalized fibrosing process [3].

Studies on the true incidence of NFD/NSF are limited in Taiwanese patients with advanced chronic kidney disease [4]. There are approximately 120 cases of NSF reported in the English literature and over 215 cases recorded at the NFD/NSF Registry so far (http://www.icnfdr.org) [5, 6]. In 2000, eight of 265 (3%) kidney transplant recipients under dialysis at a hospital in California were found to develop NFD [1]. A recent study from India showed NFD in six of 2146 (0.28%) post-dialysis patients [7]. NFD have been found mostly in patients on haemodialysis (HD) for renal failure, with some cases on peritoneal dialysis (PD) and a few without dialysis [8]. Recently separate case series from Denmark and Austria have suggested an association between the development of NFD/NSF and exposure to gadolinium-containing radiocontrast medium during magnetic resonance imaging (MRI) or magnetic resonance angiography (MRA) [9-11].

The current study aimed to assess the incidence, risk factors, clinical characteristics, histopathology, and treatment of NFD/NSF in patients with advanced chronic kidney disease receiving MRI/MRA examinations at our hospital.

Material and methods

During this period of time, only one gadolinium-based contrast agent, gadodiamide, was administered to patients at our hospital. In general, MRI examinations were performed with gadodiamide at a dose of 0.1 mmol/kg, while the doses for MRA and abdominal MRI examinations were 0.2 mmol/kg. The incidence and odds ratio were calculated using 2 × 2 contingency tables.

The diagnosis of NFD/NSF was established by histopathological confirmation of the clinical manifestations in the form of skin induration, xerosis, roughness, infiltrated papules or infiltrated plaques, hyperpigmentation and rippled pigmentation [7].

Results

In table 2, dialysis type and the dose of gadodiamide exposure in relation to the development of NFD/NSF are shown and analyzed. Seven patients underwent two serial examinations of MRI/MRA with a total cumulative dose of 20 mL; four patients received a total cumulative dose of 30 mL, of them three patients had three and one patient had two serial examinations; one patient, who received a total cumulative dose of 50 mL in four serial examinations, developed NFD/NSF. The incidence of NFD/NSF among the dialysis patients exposed to gadodiamide was 1.23%. In a 2 × 2 contingency table analysis, the odds ratio was 1.71 (95% confidence interval, 0.07-42.63) for one NFD/NSF case among 98 gadodiamide-exposed cases vs. zero NFD/NSF cases among the 55 gadodiamide-unexposed patients. The odds ratio of NFD/NSF was 34.33 (95% CI 1.21-971.26) for double doses vs. single dose of gadodiamide administration, and 17.0 (95% CI 0.59-486.41) for greater than double doses vs. single dose of gadodiamide administration.

The patient identified with NFD/NSF was a 24-year-old woman with SLE since age 15. Due to a cerebrovascular event she underwent a MRI study with exposure to a single dose of 10 mL gadodiamide (0.5 mmol/mL, Omniscan^TM injection, Amersham Health As, Cork/Ireland) at dosage of 0.1 mmol/kg for three doses on January 21, February 7 and February 24, 2005, at which time renal function showed serum creatinine at 3.2 mg/dL, 2.5 mg/dL and 2.7 mg/dL, estimated GFR (eGFR) at 21.4 mL/min, 27.4 mL/min and 25.4 mL/min, respectively. Due to an unexplained abdominal pain, she underwent an abdominal MRI study containing an exposure to 20 mL of double doses of gadodiamide (0.2 mmol/kg) on November 7, 2005, with renal function of serum creatinine at 6.7 mg/dL and eGFR 10.2 mL/min. No supplementary hydration or HD was executed after four MRI examinations. Between February and November 2005, there were serial events of duodenal ulcer, hypertension, and pancreatitis. According to the patient, the skin changes developed from October 2005 and progressed rapidly, one month before a further MRA examination with administration of double doses of Omniscan^TM at 0.2 mmol/kg. The total cumulative dose of Omniscan^TM was about 50 mL (0.5 mmol/kg). With advanced lupus nephritis in uremic stage, she has been put on PD after Tenckcoff tube implantation since December 16, 2005.

The diagnosis of NFD/NSF was suggested in March 2006. Laboratory examination showed the following findings: hemoglobin 7.8 g/dL (normal range 12-16), hematocrit 34.7% (normal range 36-46), platelet 60,000, normal thyroid function, intact parathyroid hormone (iPTH) 20.2 pg/mL (normal range 10-65), ALT 26 U/L (normal range 0-40), fasting glucose 78 mg/dL (normal range 70-105), serum potassium 3.4 mEq/L (normal range 3.0-4.8), creatinine 7.8 mg/dL (normal range 0.4-1.4), ferritin 1160.9 ng/mL (normal range 10-291), erythrocyte sedimentation rate 65 MM/HR (normal range < 20), C reactive protein 13.1 mg/L (normal range < 5) and polyclonal hypergammaglobulinemia. Serology displayed anti-double strand DNA antibody 213.9 IU/mL (normal range < 35) and hypocomplementaemia with C3 70.9 (normal range, 90-180 mg/dL), in the absence of anti-Scl 70 antibody, anticardiolipin antibody, anti-beta 2-glycoprotein I antibody, cryoglubulinemia, cryofibrinogenmia, and antibodies against hepatitis B, hepatitis C or human immunodeficiency virus 1/2. Internal organ surveys revealed hypertrophic cardiomyopathy, enlarged kidneys (right 13.1 cm and left 12.8 cm), mild splenomegaly and moderate ascites (score 7-8), suspected of early cirrhosis.

On skin examination, there were several large erythematous to violaceous, pruritic, partially coalescent, infiltrative sclerotic plaques, in a somewhat geographic form with xerotic roughened surfaces, starting from the bilateral anterior thighs extending to lateroposterior aspects and downwards to the dorsal feet. The disease progressed to involve most of the bilateral lower extremities and part of the proximal upper limbs, with very mild flexion contracture (figure 1A and B). Histopathology revealed a moderately dense infiltrate of mononucleated lymphohistiocytes with abundant large, plump, epithelioid spindle cells with thick tracts of collagen bundles extending into the adipose layer (figure 2A and B). Many of the spindle cells had positive immunostaining with antibody CD68 (figure 2C) but negative with CD 34 (figure 2D). Mucin deposition was minimal.

The patient was then treated with oral pentoxifylline daily at 1,200 mg in divided doses, plus topical 0.05% clobetasol propionate ointment with sufficient emollient. At the 3-month follow-up, there was, subjectively as well as objectively, discernable improvement in the erythema, induration and xerosis of the sclerotic plaques (figure 1C and D). The skin condition seemed to stabilize without further deterioration but her renal function barely improved during treatment and further dialysis was required. Due to the dissatisfaction of the patient, the systemic treatment was then shifted to colchicine at 0.5 mg daily from the end of October 2006, resulting in a further improvement of skin fibrosis in five months.
Table 1 Characteristics of all advanced chronic kidney disease patients on hemodialysis (HD) and peritoneal dialysis (PD)

Discussion

Although miscellaneous factors have been suspected to be responsible for the development of NFD/NSD, none of these have been confirmed as acting as a predominant determinant, including hypercoagulability and deep venous thrombosis [18], vascular surgery, recent failure of a transplanted kidney [5, 19], sudden onset of kidney disease with severe anasarca, hepatitis C infection or liver transplantation [20, 21], high-dose erythropoietin [22], marked elevations of the erythrocyte sedimentation rate and/or C-reactive protein [5], elevated anticardiolipin antibodies [18], and the use of angiotensin-converting enzyme inhibitors [23].

In 2006, Grobner from Austria first reported that five (age range 43-74 years) of their nine patients on HD developed skin changes of NFD within two to four weeks after administration of gadolinium-containing contrast agents during MRA examination [9]. Meanwhile Marckmann et al. from Denmark described 13 gadolinium-associated cases (age range 33-66 years) who noticed symptoms or signs of NFD 2-75 days after exposure to gadolinium during MRI examination [10]. As of late December 2006, the US Food and Drug Administration (FDA) MedWatch system had received 90 reports of NFD/NSF possibly related to gadolinium-containing contrast agents [24]. A further detailed description has been provided by different groups in USA; Broome et al. reported 12 patients (age range 26-64), eight with dialysis-dependent chronic renal insufficiency and four with acute hepatorenal syndrome, who developed skin fibrosis within 2-11 weeks after gadodiamide administration [15]. Sadowski reviewed 13 patients with NSF (age range 17-69 years), who had a history of exposure to gadolinium within 6 months of diagnosis, in combination with other risk factors such as chronic kidney disease (defined as GFR < 60 mL/min/1.73 m² for three months or more, irrespective of cause) and inflammatory burden [25, 26]. Khurana reported six patients (age range 23-71 years) with onset of symptoms consistent with NFD/NSF between 19 days and two months after gadodiamide exposure [27]. In a case control study, Cheng S et al. presented 25 confirmed cases (median age 50), of these 18 had a history of gadolinium exposure, with 14 patients being exposed to gadolinium within one year preceding disease diagnosis (not disease onset), while a longer incubation time between 16 and 68 months was found in four patients [23]. Discrepancy exists in the median onset age of skin disease, presence of metabolic acidosis, co-morbidities such as deep vein thrombosis, hypothyroidism, vascular surgery or dependent edema. The odds ratio for development of NFD/NSF after gadodiamide exposure was calculated to be between 22.3 and 32.5 [10, 15]. In our series, only one patient, under complex predisposing conditions including advanced kidney dysfunction, cerebrovascular event, and a high-dose gadodiamide exposure, developed NFD/NSF. The eGFR was between 10.2-27.4 mL/min (< 60 mL/min) at the time of diagnosis. The odds ratio for the development of NFD/NSF with gadodiamide exposure was ≤ 1.71.

Gadolinium-containing contrast agents have been approved for MRI use since 1988. They are excreted primarily via the kidneys and believed to be less nephrotoxic than iodinated contrast agents [28]. Although in most previous reports, development of NFD/NSD was mainly observed in patients on HD, PD might actually achieve a less effective clearance than HD, as 69% of total gadolinium-containing contrast was excreted after 22 days in patients on CAPD, while a similar percentage could be cleared after one HD session [29]. In Cheng’s report, there were more NFD/NSF cases who had actually received PD as their primary type of dialysis in the preceding 6 months, with the disease incidence rate (estimated for the four years in which cases were identified) being 4.6 cases per 100 PD-patients as compared to 0.61 cases per 100 HD-patients [24].

Using scanning electron microscopy conjugated with energy dispersive X-ray spectroscopy, two groups have lately demonstrated the presence of gadolinium particles within the diseased skin tissue of NFD/NSF patients [6, 30]. A tissue residence time of 4 to 11 months was observed, which is compatible with the reported intervals between exposure and disease onset in epidemiological studies [10]. Tissue retention of gadolinium within bone has been observed even in otherwise normal healthy patients [31]. It would be interesting to re-evaluate the presence of gadolinium in 2-5% of the previously reported NFD/NSF cases with coexistence of dystrophic calcification [32, 33], osseous metaplasia [34] or calciphylaxis in the skin [35], as free gadolinium can also form precipitates with anions such as phosphates and produce deposits with calcium phosphate, as demonstrated in rodents [36, 37].

Our case is among the few patients who develope NFD at an early age [15, 27], as compared to a median age of around 50 in most confirmed cases [10, 24]. The time span from gadolinium exposure to first signs of NFD/NSF varies from two days to as long as 68 months, with most cases appearing to have disease onset within three months. Absence of dialysis preceding skin alteration as seen in our case has also been observed in seven of the above collectives with a history of gadolinium exposure. It should be noted that before awareness of the causative role of gadolinium, only five cases with acute renal failure, but not on dialysis, were reported [8, 38]. Although a direct association between the dose of gadolinium and development of NFD/NSF remains to be determined, most of the affected patients had received a dose at 0.1-0.3 mmol/kg [10, 27], while the single standard dose recommended for MRI examination is 0.1 mmol/kg. Multiple exposures have also been noted in Cheng’s as well as in our own cases [24]. In addition to a single high-dose and multiple doses, the cumulative doses also appear to be an important risk factor [38,39].

The pathophysiology of NFD/NSF is still unclear. In the affected skin and muscle, a large number of CD68+/factor XIIIa+ dendritic cells and increased expression of TGFβ1 were found [40]. It is proposed that some specific circulating fibrocytes involved in wound repair and tissue remodeling may be aberrantly recruited to the skin and soft tissues of NFD/NSF patients [41]. On the other hand, the marked deposition of mucin (hyaluronic acid) in the dermis may be explained by the aberrant turnover of hyaluronic acid in renal failure, as the kidney fails to clear the intermediate-size fragments of hyaluronic acid, which are highly angiogenic, proinflammatory and fibrogenic [42]. Based on the detection of gadolinium in the diseased skin, the most widely accepted hypothesis currently is related to the dechelation of less stable gadolinium chelates, progressively releasing free Gd3+, which may subsequently lead to the attraction of CD34+, CD45+, pro-collagen+ circulating fibrocytes via the release of chemokines, thereby inducing systemic fibrosing disorders [43]. The scarcity of mucin deposition and CD34+ immunoreactivity in our histopathology may be due to the late biopsied skin examples [36]. It remains enigmatic why no such cases were identified prior to early 1997 and so far NFD/NSF has occurred only in people with kidney disease. As gadolinium has been used since 1988, it is also unknown why no such skin changes had ever been recognized in the interim. The hypothesis also needs to address the rarity of NFD/NSF among dialysis patients, predominance of HD over PD in the first described patients and the pathogenic role of gadolinium in inducing fibrosis with mucin formation, mainly in the skin.

Due to the rarity and chronicity of the disease, the responses to different therapeutic modalities reported so far are mostly anecdotal without consistent efficacy. In principle, the treatment rationale and concept resemble that of scleromyxedema or scleroderma. Positive results have been seen in extracorporeal photopheresis [16], plasmapheresis [20], UVA1 phototherapy [44], photodynamic therapy [45], high-dose intravenous immunoglobulin [46], thalidomide [47], while treatment with calcipotriene ointment (http://www.icnfdr.org), intralesional injection of triamcinolone, methotrexate or interferon-alpha, PUVA or Re-PUVA [48], systemic steroids [49], isotretinoin [18] or intravenous cyclophosphamide [14] usually exhibited incidental or unremarkable effects. The benefit of pentoxifylline was described by Grobner in two of his patients and is again supported by our experience. This may be explained by the suppressive effect of pentoxifylline on fibroblasts in the cell proliferation, in the production of collagen, glycosaminoglycans and fibronectin, as well as by its inhibitory effect on TGFβ1 [50, 51]. The advantage of systemic colchicine as observed in our patient has never been reported before. Of course, a spontaneous stabilization or improvement in our patient can not be totally ruled out.

In almost all cases of NFD/NSF, the disease course parallels the progress of the underlying renal dysfunction, although normalization of renal function does not guarantee a resolution of the skin disease [2]. Rare cases of partial-to-complete spontaneous resolution have been reported in the absence of specific therapy [52]. The presence of systemic involvement usually indicates a poor prognosis with a high mortality rate [5].

In conclusion, NFD/NSF is a novel relentless systemic disease with a preponderance of skin involvement. Patients with advanced chronic kidney disease and a history of exposure to gadolinium-containing contrast agent may represent a high-risk subgroup, more related to the PD as compared to the early reported cases mainly in association with HD. A substantial improvement or resolution of skin lesions appears problematic even with various empirical therapies. Clinicians should be aware of the onset of this disease in patients with chronic kidney disease with GFR < 60 mL/min/1.73 m² and/or in combination with pro-inflammatory conditions while being exposed to gadolinium-containing agents during MRI/MRA examination.

Acknowledgements

References

2 Cowper SE. Nephrogenic fibrosing dermopathy: the first 6 years. Curr Opin Rheumatol 2003; 15: 785-90.

3 Cowper SE. Nephrogenic systemic fibrosis: the nosological and conceptual evolution of nephrogenic fibrosing dermopathy. Am J Kidney Dis 2005; 46: 763-5.

4 Levey AS, Eckardt KU, Tsukamoto Y, et al. Definition and classification of chronic kidney disease: A position statement from kidney disease: improving global outcome (KDIGO). Kidney Int 2005; 67: 2089-100.

5 Mendoza FA, Artlett CM, Sandorfi N, et al. Description of 12 cases of nephrogenic fibrosing dermopathy and review of the literature. Semin Arthritis Rheum 2006; 35: 238-49.

6 High WA, Ayers RA, Chandler J, et al. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 2007; 56: 21-6.

7 Panda S, Bandyopadhyay D, Tarafder A. Nephrogenic fibrosing dermopathy: a series in a non-Western population. J Am Acad Dermatol 2006; 54: 155-9.

8 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: 469-73.

9 Grobner T. Gadolinium - a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006; 21: 1104-8.

10 Marckmann P, Skov L, Rossen K, et al. Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 2006; 17: 2359-62.

11 Grobner T, Prischl FC. Gadolinium and nephrogenic systemic fibrosis. Kidney Int 2007; 72: 260-4.

12 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: 25-6.

13 Obermoser G, Emberger M, Wieser M, et al. Nephrogenic fibrosing dermopathy in two patients with systemic lupus erythematosus. Lupus 2004; 13: 609-12.

14 Tan AW, Tan SH, Lian TY, et al. A case of nephrogenic fibrosing dermopathy. Ann Acad Med Singapore 2004; 33: 527-9.

15 Broome DR, Girguis MS, Baron PW, et al. Gadodiamide-associated nephrogenic systemic fibrosis: why radiologists should be concerned. AJR Am J Roentgenol 2007; 188: 586-92.

16 Gilliet M, Cozzio A, Burg G, et al. Successful treatment of three cases of nephrogenic fibrosing dermopathy with extracorporeal photopheresis. Br J Dermatol 2005; 152: 531-6.

17 Ribeiro FM, Leite MA, Velarde GC, et al. Activity of systemic lupus erythematosus in end-stage renal disease patients: study in a Brazilian cohort. Am J Nephrol 2005; 25: 596-603.

18 Mackay-Wiggan JM, Cohen DJ, Hardy MA, et al. Nephrogenic fibrosing dermopathy (scleromyxedema-like illness of renal disease). J Am Acad Dermatol 2003; 48: 55-60.

19 Shelekhova KV, Kazakov DV, Michal M. Nephrogenic fibrosing dermopathy. Arkh Patol 2006; 68: 42-3.

20 Baron PW, Cantos K, Hillebrand DJ, et al. Nephrogenic fibrosing dermopathy after liver transplantation successfully treated with plasmapheresis. Am J Dermatopathol 2003; 25: 204-9.

21 Maloo M, Abt P, Kashyap R, et al. Nephrogenic systemic fibrosis among liver transplant recipients: a single institution experience and topic update. Am J Transplant 2006; 6: 2212-7.

22 Swaminathan S, Ahmed I, McCarthy JT, et al. Nephrogenic fibrosing dermopathy and high-dose erythropoietin therapy. Ann Intern Med 2006; 145: 234-5.

23 Fazeli A, Lio PA, Liu V. Nephrogenic fibrosing dermopathy: are ACE inhibitors the missing link? Arch Dermatol 2004; 140: 1401.

24 Centers for Disease Control and Prevention (CDC). Nephrogenic fibrosing dermopathy associated with exposure to gadolinium-containing contrast agents--St. Louis, Missouri, 2002-2006. MMWR Morb Mortal Wkly Rep 2007; 56: 137-41.

25 Sadowski EA, Bennett LK, Chan MR, et al. Nephrogenic systemic fibrosis: risk factors and incidence estimation. Radiology 2007; 243: 148-57.

26 Levey AS, Eckardt KU, Tsukamoto Y, et al. Definition and classification of chronic kidney disease: A position statement from kidney disease: improving global outcome (KDIGO). Kidney Int 2005; 67: 2089-100.

27 Khurana A, Runge VM, Narayanan M, et al. Nephrogenic systemic fibrosis: a review of 6 cases temporally related to gadodiamide injection (omniscan). Invest Radiol 2007; 42: 139-45.

28 Runge VM. Safety of approved MR contrast media for intravenous injection. J Magn Reson Imaging 2000; 12: 205-13.

29 Joffe P, Thomsen HS, Meusel M. Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Acad Radiol 1998; 5: 491-502.

30 Boyd AS, Zic JA, Abraham JL. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol 2007; 56: 27-30.

31 White GW, Gibby WA, Tweedle MF. Comparison of Gd (DTPA-BMA) (Omniscan) versus Gd (HP-DO3A) (ProHance) relative to gadolinium retention in human bone tissue by inductively coupled plasma mass spectroscopy. Invest Radiol 2006; 41: 272-8.

32 Taylor EN, Henderson JM, Rennke HG, et al. Traumatic calcinosis cutis in a dialysis patient. Am J Kidney Dis 2004; 44: e18-e21.

33 Hershko K, Hull C, Ettefagh L, et al. A variant of nephrogenic fibrosing dermopathy with osteoclast-like giant cells: a syndrome of dysregulated matrix remodeling? J Cutan Pathol 2004; 31: 262-5.

34 Ruiz-Genao DP, Pascual-Lopez MP, Fraga S, et al. Osseous metaplasia in the setting of nephrogenic fibrosing dermopathy. J Cutan Pathol 2005; 32: 172-5.

35 Edsall LC, English 3rd JC, Teague MW, et al. Calciphylaxis and metastatic calcification associated with nephrogenic fibrosing dermopathy. J Cutan Pathol 2004; 31: 247-53.

36 Ortonne N, Lipsker D, Chantrel F, et al. Presence of CD45RO+ CD34+ cells with collagen synthesis activity in nephrogenic fibrosing dermopathy: a new pathogenic hypothesis. Br J Dermatol 2004; 150: 1050-2.

37 Spencer AJ, Wilson SA, Batchelor J, et al. Gadolinium chloride toxicity in the rat. Toxicol Pathol 1997; 25: 245-55.

38 Gibson SE, Farver CF, Prayson RA. Multiorgan involvement in nephrogenic fibrosing dermopathy: an autopsy case and review of the literature. Arch Pathol Lab Med 2006; 130: 209-12.

39 Ng YY, Lee RC, Shen SH. Gadolinium-associated nephrogenic systemic fibrosis: double dose, not single dose. Am J Radiol 2007; 188: W582.

40 Jimenez SA, Artlett CM, Sandorfi N, et al. Dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy): study of inflammatory cells and transforming growth factor beta1 expression in affected skin. Arthritis Rheum 2004; 50: 2660-6.

41 DeHoratius DM. Cowper SE, 2006 Nephrogenic systemic fibrosis: an emerging threat among renal patients. Semin Dial 2006; 19: 191-4.

42 Neudecker BA, Stern R, Mark LA, et al. Scleromyxedema-like lesions of patients in renal failure contain hyaluronan: a possible pathophysiological mechanism. J Cutan Pathol 2005; 32: 612-5.

43 Idée JM, Port M, Medina C, et al. Possible involvement of gadolinium chelates in the pathophysiology of nephrogenic systemic fibrosis: a critical review. Toxicology 2008; 248: 77-88.

44 Kafi R, Fisher GJ, Quan T, et al. UV-A1 phototherapy improves nephrogenic fibrosing dermopathy. Arch Dermatol 2004; 140: 1322-4.

45 Schmook T, Budde K, Ulrich C, et al. Successful treatment of nephrogenic fibrosing dermopathy in a kidney transplant recipient with photodynamic therapy. Nephrol Dial Transplant 2005; 20: 220-2.

46 Chung HJ, Chung KY. Nephrogenic fibrosing dermopathy: response to high-dose intravenous immunoglobulin. Br JDermatol 2004; 150: 596-7.

47 Weiss AS, Lucia MS, Teitelbaum I. A case of nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis. Nat Clin Pract Nephrol 2007; 3: 111-5.

48 Läuchli S, Zortea-Caflisch C, Nestle FO, et al. Nephrogenic fibrosing dermopathy treated with extracorporeal photopheresis. Dermatology 2004; 208: 278-80.

49 Perazella MA, Ishibe S, Perazella MA, et al. Nephrogenic fibrosing dermopathy: an unusual skin condition associated with kidney disease. Semin Dial 2003; 16: 276-80.

50 Berman B, Duncan MR. Pentoxifylline inhibits the proliferation of human fibroblasts derived from keloid, scleroderma and morphoea skin and their production of collagen, glycosaminoglycans and fibronectin. Br J Dermatol 1990; 123: 339-46.

51 Lin SL, Chen RH, Chen YM, et al. Pentoxifylline attenuates tubulointerstitial fibrosis by blocking Smad3/4-activated transcription and profibrogenic effects of connective tissue growth factor. J Am Soc Nephrol 2005; 16: 2702-13.

52 Scheinfeld N. Nephrogenic fibrosing dermopathy: a comprehensive review for the dermatologist. Am J Clin Dermatol 2006; 7: 237-47.