**3. Treatment**

parathyroid hormone is not related to UP while mid-region parathyroid hormone (m-PTH) shows some correlation [6]. In patients with UP, the large amounts of inactive carboxy-terminal

Mast cell accumulation and degranulation may play a role in UP [10,48,49]. Parathyroid hormone is known to stimulate mast cell production and accumulation in various organs [49]. Some studies have shown an increased number of cutaneous mast cells in uremic patients compared with healthy subjects [10,38], but very few reports show the correlation between mast cells and pruritus [47,50]. Very numerous, degranulated mast cells with diffusely distribution within dermis are normally found in patients with UP while mast cells in healthy

Mediators of inflammation may also be important. Histamine, a well-known mediator of pruritus in dermatologic disease, is elevated in the plasma of patients with ESRD as a result of histamine retention in renal insufficiency [52]. Histamine is released from mast cells in response to substance P and is thought to be implicated in UP. The number of mast cells is increased in patients with CKD, and increased plasma levels of tryptase and histamine have been reported in patients with severe UP [53]. In addition, prostaglandins are thought to modulate pruritus by lowering the threshold for histamine-induced pruritus [54]. There is a correlation between plasma histamine levels and pruritus [52,55]. It is found that histamine levels in patients with UP is significant higher compared to nonpruritic subjects [52,55] but specific differences in plasma histamine levels in subjects with and without UP cannot be found [26,56]. Since antihistamine has been widely used but ineffective for the treatment of UP,

It is possible that there are unknown pruritogenic cytokines produced by activated cells in some itching dermatoses [36]. Nitric oxide was also postulated to have a possible role in the development of UP [58], as it can be synthesized from cells under inflammatory stimulants including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and IL-1β, and it has cytotoxic effects that can be involved in inflammatory dermatoses. During hemodialysis, several cytokines, including IL-1, are released following contact between plasma and the dialysis membrane [59]. IL-1 has been postulated to induce the release of inflammatory and potentially

The two newest hypotheses that were proposed to explain the underlying pathophysiological mechanisms of UP are the immune hypothesis and the opioid hypothesis [22]. The immune hypothesis considers UP to be an inflammatory systemic disease [21] with over-activation of

TH1 lymphocytes and overproduction of IL-2, IFN-γ and TNF-α. IL-2 is released during hemodialysis secondary to the contact of blood and dialysis membranes [60], and it is known to be pruritogenic when injected into the skin. The increased serum levels of inflammatory biomarkers such as C-reactive protein and IL-6 confirms the inflammatory nature of the disease [61]. For the opioid hypothesis, it is well known that opioids play a role in modulating the sensation of pruritus both centrally and peripherally. Endogenous opioids are known to play a role in cholestatic prutitus [22], but it was also postulated that they have a role in UP secondary to the overexpression of opioid µ-receptors in dermal cells and lymphocytes, and concomitant down-regulation of opioid κ-receptors caused by the increase in serum βendorphin to endorphin A ratio that is observed in patients with CKD [62]. Despite all these

metabolites of parathyroid hormone is normally found in serum [6].

subjects are mainly localized and intact in the upper dermis [10,51].

histamine should not have a significant role for this symptom [57].

mechanisms, the certain pathophysiology of UP remains unknown.

pruritogenic substances [6].

22 Updates in Hemodialysis

CD4+

Despite high prevalence and life-altering comorbidities, UP remains poorly characterized and lacks effective treatment [63]. Because the pathophysiological mechanisms of UP are poorly understood, the treatments have largely been empirical, and no treatment has been shown to have sufficient efficacy and safety [64]. Moreover, no drugs have been approved by the U.S. Food and Drug Administration for this problem. Before considering the treatment of UP, an evaluation should be performed to define whether pruritus in a specific patient is caused by uremia (which needs adequate dialysis) or is related to dermatologic or systemic disease such as hyperparathyroidism, hyperphosphatemia and anemia that may require a different approach [2]. Once the etiology of pruritus has been established, several therapies can potentially be adopted. Treatments can be classified as topical, physical or systemic applications.

In order to control UP in dialysis patients, several factors need to be monitored such as improvement of nutritional status, monitoring of calcium and phosphorus levels, optimization of dialysis efficacy as well as use of biocompatible dialysis membranes [65]. Pruritus found in CKD may cause from other disorders such as liver diseases (for instance; hepatitis), endocrine disorders (for instance; Graves' disease, diabetes mellitus and hypothyroidism) and skin disorders (such as atopic dermatitis, psoriasis, contact dermatitis and urticaria). Pruritus found in these causes need specific treatments which may differ from standard treatment [53]. A stepup therapeutic approach for UP in patients with CKD is presented in Figure 1.

a Use of evening primrose oil rich in essential fatty acids (γ-linolenic acid), bath oil that contains polidocanol and cream that contains natural lipids and endocannabinoids can be attempted if simple emollients fail.

**Figure 1.** Step-up therapeutic approach for UP in a patients with CKD.

b For intractable UP that does not respond to nalfurafine (5 µg intravenously thrice weekly for 4 weeks), treatment with short courses of topical tacrolimus ointment (0.1% for 2-6 weeks) or oral thalidomide (100 mg daily for 2-4 weeks) can be attempted.

<sup>\*</sup>Reprint with permission from publisher (Kuypers, DRJ., Skin problems in chronic kidney disease. *Nat. Clin. Pract. Nephrol.* (2009).
