Gadolinium – a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?

Abstract

Nephrogenic fibrosing dermopathy (NFD) is an acquired, idiopathic disorder that is observed in patients with renal disease. Most patients with NFD have undergone dialysis for renal failure [1,2]. It tends to affect mostly the middle-aged. An association of NFD with coagulation abnormalities, recent vascular surgery or intervention (e.g. shunt/fistula and angioplasty), and presence of antiphospholipid antibodies has been discussed by several authors thus far [1,3], but the origin of the disease is still unknown. A more widespread variant of this fibrosing skin disease with involvement of other organs (e.g. lungs, liver, muscles and the heart) is described as nephrogenic systemic fibrosis (NSF) by Leboit [4], Ting et al. [5] and Daram et al. [6]. NFD is characterized clinically by thickening, induration and hardening of the skin. Distinct nodules also can be seen. The (distal) extremities are the most common area of involvement, followed by the trunk, and the face is almost never involved [1]. The diagnosis of NFD is confirmed in a skin biopsy by specific histopathologic features, namely thickened collagen bundles with surrounding clefts, mucin deposition and a proliferation of fibroblasts and elastic fibers. Signs of inflammation are absent, which makes this disorder a distinct entity [1,7]. In this report, nine end stage renal disease patients undergoing magnetic resonance (MR) angiography are presented, in five of whom skin changes of nephrogenic fibrosing dermatopathy became apparent about 2–4 weeks after the administration of gadolinium (Gd)-containing contrast agent for MR. Patients with and without NFD were compared for possible risk factors to develop this skin disease. Gd is thought to be safe as a contrast agent in renal failure. This case series however, demonstrates that Gd–DTPA possibly plays a triggering role in the development of NFD under certain circumstances. Nine end stage renal disease patients of our dialysis unit underwent MR angiography using Gd–DTPA as contrast media over a period of approximately 2 years (mean age: 58±10.3 years; mean time on dialysis: 30.5±16.1 months). Among these patients, five were observed, all of whom developed thickening and induration of the skin, starting on the lower extremities and eventually spreading to the trunk and upper extremities (Table 1). Characteristics of affected patients Characteristics of affected patients The skin was shiny and hard to the touch and the patients suffered from concomitant pain in affected areas. Conjunctival erythaema and yellowish scleral plaques could also be observed in these patients. Histologic examination of the skin biopsies taken revealed the picture of NFD. A characteristic example is given in Figures 1 and 2A,B. Biopsy specimen of the skin of the right lower leg of patient 1. The thickened dermis demonstrates plumped collagen bundles with surrounding clefts, spindle cellproliferation. Interstitial mucin deposition is frequently present. Magnification of skin biopsy shown in figure 1. (A) Fibroblasts and plumped collagen bundles with surrounding clefts. (B) Increased interstitial mucin deposition. (Figures 1 and 2A,B: Haematoxylin and eosin stain). All affected patients underwent MR examination with the use of Gd–DTPA 2–4 weeks prior to development of the skin abnormalities. Until the development of the skin changes, their course was uneventful. The laboratory examination including antinuclear antibodies, antineutrophil cytoplasmatic antibodies, anti phospholipid antibodies, circulating immuncomplexes, anti glomerular basal membrane antibodies and complement factors C3, C4 were negative or showed normal findings. In one patient a pathological value regarding protein C and factor VIII was detected (Table 2). The mean time on dialysis of the five affected patients amounted to 36±16.5 months. Further characteristics of NFD – patients Further characteristics of NFD – patients Data of the four patients not affected by skin disease is given in Table 3. Their mean time on dialysis amounted to 23.75±12.5 months. No other differences were found with respect to age, sex, medication, underlying renal disease, dialysis modalities and comorbidities; only the mean time on dialysis seemed to be longer in affected patients. Characteristics of unaffected patients Characteristics of unaffected patients Strikingly, all affected patients had metabolic acidosis, while all unaffected patients showed normal findings regarding pH- value and actual bicarbonate at time of MR angiography. The mean age of the affected five patients was 57.2±10.7 years and their mean time on dialysis amounted to 36±16.5 months. The mean time of observation with the disease was 9.2±4.7 months. The mean age of the four patients without development of the skin changes was 59±9.7 years. Their mean time on dialysis amounted to 23.75±12.5 months. Comparing the two groups of patients, the mean time on dialysis was longer in affected patients. Age, sex, underlying renal