**2. Pathophysiology**

The pathophysiology for this condition is not well understood. Known risk factors that predispose patients to UP are male gender [19], although some studies showed a higher prevalence in females [22,28], high levels of blood urea nitrogen and elevated calcium, phosphorus and β2-microglobulin [22,29]. Other contributing factors include hypervitaminosis A [20], high aluminum levels [30], anemia, erythropoietin insufficiency, elevated ferritin, low transferrin, low albumin, peripheral neuropathy [31] and secondary hyperparathyroidism with elevated divalent ions such as calcium, phosphate and magnesium ions [22]. Xerosis, which is very frequent in uremic patients as a result of a decrease in sweat volume as well as atrophy of the sebaceous glands and dehydration of the stratum corneum, may indeed play a role in UP.

severe in 8- 40% of patients [10-12]. About half of UP patients suffer from continuous itch, while the others experience it only occasionally with episodes of exacerbation. UP affects quality of life because of serious discomfort, anxiety, depression and sleeping disorders, especially because it is usually worse at night [13]. Pruritus may increase in intensity during the summer months, possibly due to the rising skin temperature reducing the threshold for the perception of UP, as occurs in other types of pruritus [14]. For that reason, external heat, sweat and stress can aggravate UP, and cold or hot showers can alleviate the symptoms [15]. The skin may appear normal or display different types of lesions, mostly related to scratching

UP may be localized or generalized. Generalized itching is evident in about half of the patients [6]. Pruritus in dialysis patients is most commonly localized to the back, followed by the forearm with an arterio-venous fistula (perhaps due to frequent washing and traumatization of this region), abdomen, or head [16]. It has been reported that patient age, sex, underlying renal disease or dialysate solution used for hemodialysis (bicarbonate-based or acetate-based) have no influence on UP [6,10]. However, using less permeable and less biocompatible dialysis membranes show higher incidence of pruritus [6,10]. Moreover, patients with longer period of hemodialysis (> 3 months) may have high tendency to experience UP [13], possibly due to

Different scoring systems were used to quantify the severity of UP in clinical trials. The most commonly used include the visual analogue score (VAS) [17-19], a 4-point pruritus score [20] and a comprehensive validated questionnaire that was developed based on a short form of the McGill pain questionnaire [17,21]. This questionnaire was found to be reliable and provided valid data on the sensory, affective and overall intensity of UP and may provide a basis for

Clinical appearance of UP can be observed by secondary changes such as atrophy of adnexal structures, microangiopathy with necrosis of endothelial cells, changes of sebaceous glands, lesions or lichen complex chronicus, excoriations and prurigo nodularis [23]. Although hemodialysis and continuous ambulatory peritoneal dialysis (CAPD) seem to be associated with a similar incidence of UP [24,25], some have found its incidence with CAPD was 10% [4] to 14% [26] lower, possibly due to a more effective elimination of possible pruritogenic

Due to the effect of UP which can cause serious discomfort, severe anxiety or even depression andsleepingdisorders,itreallyaffectpatients'qualityoflife.Sincesleepingdisordersarerelated tochronic fatigue,ithas stronginfluenceonmentalandphysicalhealthofpatients [15].Recently, studies demonstrated an association between UP and an increased risk of mortality [7,19].

The pathophysiology for this condition is not well understood. Known risk factors that predispose patients to UP are male gender [19], although some studies showed a higher prevalence in females [22,28], high levels of blood urea nitrogen and elevated calcium, phosphorus and β2-microglobulin [22,29]. Other contributing factors include hypervitaminosis

the accumulation of undefined pruritogenic cytokines or other substances [10].

future cross-cultural studies of itching [17] and for other study-specific scales [22].

substances by the peritoneum than by artificial membranes [27].

**2. Pathophysiology**

20 Updates in Hemodialysis

(e.g., lichen simplex, prurigo nodularis or keratosis papules) [13].

It is hypothesized that UP is caused by the metabolic disequilibrium of CKD [32]. Some studies mentioned that it involves cutaneous nerve proliferation, pruritogenic cytokines or other chemicals, mast cell proliferation and secondary hyperparathyroidism. [5] Others propose that a poorly dialyzable substance is responsible for UP due to its systemic accumulation but that this resolves with renal transplantation [32]. UP has also been proposed to be a manifestation of multisystem dysfunction that is comorbid with renal failure. Proinflammatory mediators such as T-helper (Th)-1 cytokine and interleukin (IL)-2 may play a role in pruritus. Hypercal‐ cemia and hyperphosphatemia with secondary deposition of calcium phosphate crystals in the skin may also contribute to itch [32]. Some biochemical parameters have been reported to be associated with the development of UP including magnesium [33], intact-parathyroid hormone (iPTH) [34], phosphate [33] and calcium [35]. While uremia may cause pruritus, other etiologies of pruritus must also be ruled out. Patients must be evaluated for endocrine disorders, atopic dermatitis, infestations, psychiatric disorders (e.g., delusions parasitosis), contact dermatitis and allergic reactions to the dialysate [23].

In UP, the stimulation of free nerve endings or dermal itch receptors generate impulses via Cfibers to the spinal cord and further to thalamus and finally reach cerebrum [36]. It is believed that substanceP, whichis a type ofneurotransmitter,is a key to transmitthe sensationofitch[3].

The physical appearances of skin in patients with chronic renal failure are totally difference from healthy people. Microangiopathy, thickening of basement membrane, epidermal atrophy or atrophy of sebaceous glands are normally found in hemodialysis patient [37,38,39]. Due to the lower levels of fat and water content on stratum corneum of skin with chronic kidney diseases, pruritus is normally found [40]. Reduction of sweat is another factor related to UP since the amount of electrolytes, lactate, urea, protein, lipids and amino acid elimination are normally decreased [40]. There is a positive correlation between xerosis and pruritus [11,25], but no correlation between cutaneous water content or transepidermal water loss and pruritus has been found [41,42]. However, the stratum corneum layers on the skin of dialysis patients are significantly less hydration compared to healthy skin [43].

There are several reports indicated that serum levels of divalent ions such as magnesium, calcium, aluminum and phosphate are related to UP [3,10,40,44]. Magnesium can stimulate neuron or activate histamine releasing from mast cells [45] while calcium and phosphate can induce itch receptors and cause metastatic cutaneous calcification [10,30]. An elevated serum aluminum concentration in chronic hemodialysis patients with UP was also reported as a possible etiology [30].

Secondary hyperparathyroidism has been proposed as a possible cause of UP, and normally, end-stage renal disease (ESRD) patients develop secondary hyperparathyroidism [3,46]. However, UP is relieved after parathyroidectomy [46]. Although hyperparathyroidism in UP is frequently associated with pruritus [47], a positive correlation was not confirmed [3]. Intact 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 metabolites of parathyroid hormone is normally found in serum [6].

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

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

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 pruritogenic substances [6].

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 CD4+ 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 mechanisms, the certain pathophysiology of UP remains unknown.
