Nephrogenic fibrosing dermopathy (NFD) is a newly recognized cutaneous fibrotic disorder occurring in individuals with end-stage renal disease (ESRD) (1, 2). With a few exceptions, the nearly 100 patients described to date were undergoing long-term hemodialysis or peritoneal dialysis and many had received kidney transplants. Although the etiologic factor(s) responsible for NFD is not known, renal insufficiency and dialysis appear to be intimately involved (for review, see ref. 3).
Initially, this fibrotic process was considered a form of scleromyxedema (1); however, subsequent studies indicated that the disease was unique (2). The histopathologic changes in affected skin included marked proliferation of spindle-shaped fibroblasts, the presence of numerous dendritic cells, and the accumulation of mucinous material and thick collagen bundles. Except for the severe cutaneous induration and thickening, no systemic involvement was described in the initial reports (1, 2). However, more recently, systemic features, including cardiomyopathy and pulmonary fibrosis (4), and fibrotic infiltration of the diaphragm, the psoas muscle, the kidney tubules, and the rete testes (5), have been documented.
We report here the clinical features of 9 new cases, the findings of histopathologic studies of skin, fascia, striated muscles, lungs, and heart, as well as the characterization of inflammatory cells and transforming growth factor β1 (TGFβ1) expression in affected skin, fascia, and striated muscles. Our studies indicate that the fibrotic process is not confined to the dermis, since severe fibrosis of the subcutaneous tissue and the fascia was universally present. Furthermore, some patients had fibrosis of the striated muscles, myocardium, lung parenchyma, and adventitia of lung arterioles. A marked accumulation of CD68+/factor XIIIa+ dendritic cells and an increased expression of TGFβ1 were observed in affected skin and muscle.
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- PATIENTS AND METHODS
A newly recognized disorder characterized by severe cutaneous fibrosis associated with ESRD and chronic dialysis has been recently described (1–3). The disorder has been named NFD. Although the initial reports and numerous subsequent descriptions (for review, see ref. 3) considered it to be a purely cutaneous disorder, our studies indicate that the fibrotic process affects the subcutaneous tissue, fascia, and other organs, including striated muscles, heart, and lungs, and therefore, it should be considered a systemic fibrosing process. It should be noted, however, that a shortcoming of the present study is that we did not perform a comparison of the extent or severity of the systemic fibrotic process in this cohort with a comparable group of patients with ESRD who did not have skin fibrosis. While the interstitial lung fibrosis was only moderate in the tissue samples we studied, a notable finding was adventitial and perivascular fibrosis in small and medium-sized arterioles of the lungs. Although less well recognized than the medial and intimal fibroproliferative lesions typically found in the pulmonary vasculature of patients with systemic sclerosis and pulmonary hypertension, adventitial fibrosis has also been described in these patients (6, 7). Adventitial and perivascular fibrosis in small myocardial vessels were also observed in the present study.
The systemic nature of this unique fibrotic process was further demonstrated by the substantial reduction in diffusion capacity for carbon monoxide in 5 of the 6 patients who had lung involvement, the presence of antinuclear autoantibodies in 4 patients, and the remarkable elevation of the erythrocyte sedimentation rate and/or serum C reactive protein levels in 6 patients. The occurrence of antinuclear antibodies is of substantial interest because it suggests that the fibrotic process per se may result in an autoimmune reaction, perhaps by the unmasking of hidden epitopes, the production of neoepitopes caused by protein modifications, such as protease cleavage or complex formation with a putative etiologic agent, or as described previously, as a result of apoptotic cell death (8). Alternatively, autoantibodies may have developed by a process of molecular mimicry, owing to structural similarities between the putative etiologic agent and endogenous proteins.
Although the etiology and pathogenesis of this severe fibrotic process remain elusive, our observations indicate that CD68+/factor XIIIa+ dendritic cells and TGFβ1 are intimately involved, since there was a remarkable increase in CD68+/factor XIII+ cells and in the expression of TGFβ1. It is possible that the prominent presence of dendritic cells may represent a response of the host in an attempt to eliminate a noxious putative etiologic agent. The high levels of TGFβ1 expression suggest that activation of the TGFβ1 pathway may be ultimately responsible for the remarkable tissue fibrosis. Since TGFβ is expressed in dendritic cells (9) and is involved in the regulation of the complex process of dendritic cell maturation (10, 11), it is possible that the causative agent(s) resulted in increased expression of this growth factor as part of the response of the dendritic cells to the noxious agent. The TGFβ produced by these cells is, in turn, responsible for both the fibrotic process and the expansion and enhancement or initiation of antigen-presenting functions of additional dendritic cells, establishing a vicious circle that results in their accumulation in affected tissues. If this possibility proves to be correct, therapeutic approaches aimed at removing TGFβ or counteracting its profibrotic effects may be an effective treatment for this currently incurable disease.
The term NFD has become accepted for this novel disorder; however, we believe that this term is a misnomer for two reasons. First, the term NFD implies that the kidneys cause the disease. If chronic renal disease is the cause of this disorder, it is difficult to explain why it is so rare and why it was not observed prior to 1997. Second, the disorder is not just a cutaneous disease, as implied by the term NFD. It is a systemic disease as well, with the fibrotic process affecting the muscles, myocardium, lungs, kidneys, and testes, and very likely other organs as well. Therefore, we suggest that the term dialysis-associated systemic fibrosis be used until a clearer understanding of the etiology and pathogenesis of the disease becomes apparent.
Whatever nomenclature is applied for this novel disorder, the study of its etiology and pathogenesis will undoubtedly provide valuable clues to the pathogenesis of systemic sclerosis, diffuse fasciitis, and other fibrotic diseases.