1 Department of Dermatology, Venereology and Allergology, University of Medicine, Wroclaw, Poland and 2 Department of Dermatology, New Jersey Medical School, New Jersey, USA
Correspondence and offprint requests to: Professor Jacek C. Szepietowski, MD, PhD, Department of Dermatology, Venereology and Allergology, University of Medicine, Ul. Chalubinskiego 1, 50-368 Wrocaw, Poland. Email. jszepiet{at}derm.am.wroc.pl
Keywords: emollients; haemodialysis; uraemic pruritus; uraemic xerosis
Introduction
Xerosis (rough and scaly skin) is a common chronic dermatological complication among patients undergoing maintenance renal dialysis (MRD) [13]. Although uraemic xerosis can also be observed in subjects with chronic renal failure before dialysis is needed, a significant increase in frequency of xerosis is observed when patients initiate dialysis. Furthermore, in the majority of cases, it typically disappears after renal transplantation. Interestingly, it is classically absent in acute renal failure, and is not correlated with the plasma urea level.
Uraemic xerosis was suggested to be an important factor influencing uraemic pruritus [1,3,4]. Based on large published series, xerosis of moderate to severe intensity leads to a 50100% increase in uraemic pruritus [3,5,6]. Moreover, some investigators postulated that the uraemic pruritus level is directly related to xerosis severity; the more intense the xerosis, the greater the amount of pruritus [3,6,7]. However, other studies did not find such a relationship when using objective measures of skin dryness [8,9]. Therefore, it seems that even if uraemic xerosis is not the primary cause of pruritus, it might be that in the presence of pruritus, uraemic xerosis will have a worsening effect by reducing the threshold for itch [4].
Frequency of uraemic xerosis
Up until now, uraemic xerosis has been poorly documented in the medical literature, although clearly recognized by practitioners. The reported frequency of xerosis among MRD patients ranged between 50 and 85% of the evaluated patients [3,5,7], whereas 3040% of patients reported this symptom before starting dialysis [5,10]. In a number of large series, including our own [3], the intensity of xerosis has been described as mild in 3040%, moderate in 3550% and severe in 1530% of the MRD patients [3,5]. Uraemic xerosis was found in a higher proportion in patients undergoing peritoneal dialysis than in those undergoing haemodialysis [5].
For the calculation of the prevalence of uraemic xerosis in the European Community, the most reliable sources have been used, resulting in an MRD prevalence of 5.21:10 000. The proportion of uraemic xerosis in the dialysis population has been evaluated in eight published clinical series, comprising a total of 565 MRD patients (Table 1) [3,5,712]. Among this population, 424 patients suffered from mild to severe xerosis, representing an overall proportion of 75% [95% confidence interval (CI) 71.478.6%] of MRD patients. By applying this proportion of patients with uraemic xerosis to the overall prevalence of MRD patients, an estimated prevalence of 3.91:10 000 (95% CI 3.724.10) can be deduced, resulting in an estimation of 148 000 patients (95% CI 140 500155 000) with uraemic xerosis in the European Community by the end of 2000. The progression rate of MRD in Europe was
4.0% per year between 1995 and 2000, whereas the annual growth of the population was
1%. Based on these progression rates (4% annual growth for MRD, 1% annual growth for the European population), a prevalence of 4.27:10 000 patients (95% CI 4.064.48) can be estimated, resulting in a number of patients with uraemic xerosis of
166 000 by the end of 2003.
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We do believe that uraemic xerosis may be regarded as a syndrome, gathering several characteristics according to topography and the presence of other related signs (e.g. turgor of the skin, pruritus). It is a chronic condition that does not tend to resolve spontaneously, although some limited seasonal variations still exist. Moreover, unlike common xeroses which prevail on the exterior surface of the lower limbs and commonly are of mild severity, it has a widespread distribution with marked involvement of the legs, back, chest and hands (Figures 1 and 2). Age is an aggravating factor. In some patients, uraemic xerosis is associated with poor wound healing [13]. Dry sky in uraemic xerosis is usually associated with signs (skin turgor, elastosis) indicating deeper alterations of the cutaneous structures underlying the epidermis (increased skin extensibility, dermal elastin fragmentation, atrophy of sweat glands and sebaceous glands), which could signify full-thickness skin dehydration [14].
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Psychological impact of uraemic xerosis
Uraemic xerosis may lead to discomfort and negative psychological implications. In a recent survey, the effect of uraemic xerosis of moderate to severe intensity on quality of life was investigated in a group of 99 MRD patients (P. Dupuy, personal communication). The mean DLQI score was significantly higher compared with the scores previously obtained in the normal population. The SF-12 scores were also significantly enhanced in both physical and mental components. Moreover, resolution of uraemic xerosis by treatment with moisturizing emollient was associated with a significant improvement in patient life quality. These data clearly emphasize that uraemic xerosis has a significant psychosocial impact that appears to be largely underestimated in clinical practice.
Pathogenesis of uraemic xerosis
The cause of uraemic xerosis in MRD patients remains unclear. Multiple factors could contribute towards the rough and scaly skin appearance of MRD patients, including skin dehydration and reduced sebum and sweat excretion [21]. Uraemic xerosis appears to be the result of systemic and/or local factors. Typically, it associates three main events, varying with causal elements, such as cutaneous dehydration, altered barrier function and marked irritancy to external substances such as surfactants. Water depletion in the dermis, caused by a fluid shift during a single dialysis session, has been proposed as an explanation for uraemic xerosis. Skin perfusion has also been demonstrated to be impaired in MRD patients, which may contribute to the skin dehydration process [21]. Atrophy of sebaceous glands as well as the secretory and ductal portions of the eccrine sweat glands, resulting in lower levels of surface lipids of the skin and loss of integrity of the water content in the stratum corneum by skin barrier dysfunction, may also be important in the pathogenesis of uraemic xerosis [18]. Observations made among patients with atopic dermatitis could support the role of lipid abnormalities as a causal factor for uraemic xerosis. Sator et al. [22] clearly demonstrated that the dry skin of patients with atopic dermatitis is due not only to a decrease in skin moisture but also to a reduction of skin lipids. Moreover, the effectiveness of emollients in improving uraemic xerosis can also indirectly confirm the theory of lipid depletion in skin as a reason for xerosis in MRD patients [23].
Another possible explanation is an alteration in the metabolism of vitamin A, which is present in increased concentration in uraemic patients [24]. Xerotic skin of the hypervitaminosis A syndrome resembles the cutaneous lesions of xerotic patients subjected to dialysis. Other potential factors include thyroid underactivity and skin inflammation provoked by an increased number of cutaneous mast cells releasing histamine [25]. The possible explanation for skin dryness in MRD patients can also be disturbances of the pH in the stratum corneum. Elias et al. [26] indicated the pH level as one of the possible factors which regulate the cohesion/desquamation process in patients suffering from recessive X-linked ichtyosis. The increase of skin surface pH may activate different proteases, which mediate desquamation in the outer layer of the stratum corneum. It was shown that stratum corneum pH is elevated in MRD patients [9], which could lead to disturbance in activation of proteases and, as a consequence, to damage of the skin barrier in MRD patients. Although some data are currently available, further investigations on this phenomenon are needed.
Uraemic xerosis and uraemic pruritus
In dialysis subjects, the higher frequency of pruritus in severely xerotic areas leads one to consider the latter as an important factor. In a series of 72 MRD patients, pruritus of the legs was observed in only 16% of the cases without xerosis, and in 29% of the cases with moderate to severe xerosis. Thus, moderate to severe xerosis of the legs was overrepresented among the pruritic population, compared with the non pruritic population [6]. Moreover, pruritic patients in both the haemodialysis and peritoneal dialysis group had significantly reduced stratum corneum hydration compared with non-pruritic patients [6]. Similarly, in a large series of 189 MRD patients, pruritus was present in 39% of the cases with no xerosis, and in 77% of the cases with moderate to severe pruritus [5]. In our series of 130 patients, pruritus was experienced in significantly more patients with severe xerosis (34%) than in those without xerosis (21%) [3]. These findings suggest a direct clinical relationship between uraemic xerosis and uraemic pruritus.
Treatment of uraemic xerosis
In MRD patients, the skin appears rough, stiff, fragile and inelastic in large areas of the cutaneous surface, which, together with pruritus, facilitates the development of lichenification and in some prurigo nodularis [7]. Severe involvement of certain areas, such as the hands and feet, leads to greater discomfort and possible functional impairment. Because the cutaneous barrier function is reduced, the skin is more easily exposed to external insults by physical factors such as wind, cold, sun and reduced air humidity. As in some other severe xerotic conditions, a greater susceptibility to irritation caused by chemical irritants such as soaps and detergents may be observed. Therefore, patients should be advised to avoid frequent hand washing and bathing in order to limit cumulative soap-induced irritation [27]. Clothing should be of natural fabrics, such as cotton.
Because the pathogenesis of uraemic xerosis is unknown, no specific therapy has been tailored for it. Moisturizing emollients are used daily by many people to improve subjective and objective symptoms of common xeroses. When properly used, emollients reduce scaling and overall patient discomfort and improve quality of life. The beneficial effects of emollients on xerosis in MRD patients have also been clearly recognized by practitioners. Recently our group has observed a significant reduction of uraemic xerosis in haemodialysis patients after a 3 week application of a cream containing structured lamellar lipids and endocannabinoids: N-acetylethanolamine and N-palmitoylethanolamine. This was also clearly associated with a lowering of pruritus intensity (J. C. Szepietowski et al., unpublished data). Although the exact mechanism in which endocannabinoids could modify pruritus is not known, there are several possibilities. They have been demonstrated to down-modulate mast cell degranulation induced either by neurogenic (substance P) or immune-mediated stimuli, both in vitro and in vivo [28]. They also exert a potent inhibitory effect on cytokine (interleukins-4, -6 and -8) release from macrophages and peripheral blood mononuclear cells, and decrease the levels of tumour necrosis factor- (TNF-
) during inflammation [29]. Moreover, in the rat paw formalin-induced pain test, endocannabinoids were able to activate an analgesic response [30].
A reduction of uraemic pruritus was also documented after oil bath therapy [23]. It was postulated that emollient therapy acts on uraemic pruritus mainly by a direct effect on uraemic xerosis.
Conclusions
Uraemic xerosis may produce significant discomfort in some patients. In particular, it may provoke or exacerbate the bothersome symptom of pruritus, and be at least in part the cause of cutaneous complications including lichen simplex chronicus, prurigo nodularis and the secondary complication of impetigo [1]. Emollients should be used in MRD patients affected by xerosis with or without pruritus, either alone or in association with more specific anti-pruritic treatments.
Acknowledgments
The authors are grateful to Professor Dr Marian Klinger, the head of the Department of Nephrology and Transplantation Medicine in Wroclaw, Poland for his help in obtaining clinical pictures of the xerotic skin of patients on maintenance haemodialysis.
Conflict of interest statement. None declared.
References
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