**4. Treatment for CKD-associated pruritus**

### **4.1. Modification of dialysis techniques**

The use of biocompatible dialysis membranes has been reported to reduce the prevalence of pruritus in HD patients [7]. However, it still remains uncertain whether alterations in dialysis therapy including changes in dialysis membrane can reduce pruritus [20, 21] or not [22]. Hiroshige et al. [23] analyzed data on 59 HD patients, who did not have disorders in calcium and phosphate metabolism, and found that more than 60% of them suffered from disabling pruritus possibly related to chronic uremia. Blood urea nitrogen [BUN] and plasma β2 microglobulin, both of which are biochemical factors that are associated with the prevalence of pruritus and dialysis efficacy, were investigated and calculated by urea kinetics. After 3 months without changing the dialysis prescriptions, 16 patients had significant reductions of the pruritic score ranging from 12.6 ±5.1 to 6.3 ±3.2 (P < 0.001). From this study, the authors concluded that higher dialysis efficacy with good nutritional state reduces the prevalence and degree of pruritus in HD patients.

Previously, Graf et al. [24] reported that lowering the dialysate magnesium concentration can restore nerve conduction velocity towards normal in patients receiving HD, and this could be the reason for the complete disappearance of pruritus in the study by Hiroshige et al [25]. In contrast, Carmichael et al. [25] failed to demonstrate a beneficial effect of reduction in mag‐ nesium on pruritus. In their trial, although they showed that a magnesium-free dialysis fluid corrected hypermagnesaemia, it failed to improve renal itch. In addition, the fall in serum magnesium concentration was associated with an increased concentration of parathyroid hormone, as previously noted, with the potential of producing renal osteodystrophy in the long term. It is therefore difficult to generalize the findings from the study by Hiroshige and colleagues.

The role of calcium in the dialysate was discussed by Kyriazi et al. [26], who showed that reduction in dialysis calcium concentrations from 1.75 to 1.0 mmol/L was associated with a 41.421 ± 8.47% (P < 0.05) relief from itching in 4 HD patients, indicating that at least in some uremic individuals, ionized calcium (iCa) has a pivotal role in the neuropathophysiology of CKD-associated pruritus. It has been postulated that calcium contributes to itching by influencing the degranulation of cutaneous mast cells, thus appearing to be a modifier rather than an initiator of CKD-associated pruritus.

Polymethylmethacrylate (PMMA) artificial kidney (AK) has been reported to adsorb more serum cytokines than other high-flux AK. In 30 patients with severe uremic pruritus out of 300 chronic patients in a single center who entered this prospective study, the dialyzers were changed to PMMA AK for 4 weeks. There were no significant differences in the laboratory assay results including predialysis serum BUN, creatinine (Cr), β2microglobulin, calcium, phosphate, calcium-phosphate product, intact parathyroid hormone (iPTH), ferritin, hema‐ tocrit, high-sensitivity C-reactive protein (hsCRP), interleukin (IL)-1β, IL-2, IL-6, IL-18, tumor necrosis factor (TNF)-α, and Kt/V. PMMA AK was effective in reducing the pruritus score from 23.46 ± 11.94 to 7.38 ± 6.42 (P < 0.001). The effect of uremic pruritus relief appeared after 1 week of PMMA AK use. In spite of this study, the mechanism for the beneficial effect of PMMA AK on uremic pruritus remains to be determined. However, it is proposed that PMMA AK may be a useful adjuvant therapy in chronic HD patients with severe uremic pruritus.

In line with this study, Kato et al. [27] carried out a prospective and crossover trial to investigate the effect of PMMA membrane on pruritus of HD patients with measurements of circulating levels of TNF-α and soluble TNF receptors (sTNFR-I, sTNFR-II) in 19 HD patients, who were complicated with prolonged severe pruritus for 6 months. However, there was no association between the degree of pruritus and circulating sTNFR-I and II values, although skin itching scale was significantly decreased following the use of PMMA membrane for 3 months. Combining with these finding together, it could be proposed that the PMMA dialyzer can improve renal itching.

#### **4.2. Topical treatments**

pruritus may be challenging because many patients with end-stage renal disease (ESRD) are suffering from other diseases, such as cardiovascular diseases, diabetes mellitus, chronic liver or hematological diseases, which may provoke itching either by itself or by medication given

A recent longitudinal study of CKD-associated pruritus in HD patients have clearly demon‐ strated that significant associations were found among itching intensity, severity, and healthrelated quality of life [HR-QOL] measures in domains such as mood, social relations, and sleep. In Japan, Narita et al. [16] recruited a total of 1773 patients on HD and evaluated the severity of pruritus with a visual analogue scale (VAS). Four hundred and fifty-three patients had severe pruritus with a VAS score of more than or equal to 7.0. Further, 70% of these patients complained of sleep disturbances. From these data, it is clear that patients who suffer from pruritus also have a lower HR-QOL including sleep disturbances which may lead to poor

The use of biocompatible dialysis membranes has been reported to reduce the prevalence of pruritus in HD patients [7]. However, it still remains uncertain whether alterations in dialysis therapy including changes in dialysis membrane can reduce pruritus [20, 21] or not [22]. Hiroshige et al. [23] analyzed data on 59 HD patients, who did not have disorders in calcium and phosphate metabolism, and found that more than 60% of them suffered from disabling pruritus possibly related to chronic uremia. Blood urea nitrogen [BUN] and plasma β2 microglobulin, both of which are biochemical factors that are associated with the prevalence of pruritus and dialysis efficacy, were investigated and calculated by urea kinetics. After 3 months without changing the dialysis prescriptions, 16 patients had significant reductions of the pruritic score ranging from 12.6 ±5.1 to 6.3 ±3.2 (P < 0.001). From this study, the authors concluded that higher dialysis efficacy with good nutritional state reduces the prevalence and

Previously, Graf et al. [24] reported that lowering the dialysate magnesium concentration can restore nerve conduction velocity towards normal in patients receiving HD, and this could be the reason for the complete disappearance of pruritus in the study by Hiroshige et al [25]. In contrast, Carmichael et al. [25] failed to demonstrate a beneficial effect of reduction in mag‐ nesium on pruritus. In their trial, although they showed that a magnesium-free dialysis fluid corrected hypermagnesaemia, it failed to improve renal itch. In addition, the fall in serum magnesium concentration was associated with an increased concentration of parathyroid hormone, as previously noted, with the potential of producing renal osteodystrophy in the

to treat these entities.

44 Updates in Hemodialysis

prognosis.

**3. Why is pruritus problematic?**

**4. Treatment for CKD-associated pruritus**

**4.1. Modification of dialysis techniques**

degree of pruritus in HD patients.

Emollients have been shown to be beneficial in patients with CKD-associated pruritus [28, 29, 30]. In general, emollients are proposed for use as first-line treatment. Among emollients, aqueous gels have been shown to reduce pruritus; previously, Okada and Matsumoto [31] demonstrated that emollients with high water content effectively reduced itch. In their report, 20 HD patients were divided into two groups; one group was treated with an aqueous gel containing 80% water (ADJUPEX Ensemble gel, ADJUPEX Co. Ltd. Tokyo, Japan) and another group did not receive any emollient treatment. The aqueous gel used in their study was composed by 80 g of water and 20 g of aloe vera extract, silk powder, naturally-derived vitamin E, squalane, and other naturally-derived ingredients. Moreover, the gel contained no synthetic and artificial substances. The emollient was applied twice daily for 2 weeks. VAS scores for itching at 2 weeks were significantly decreased compared with that at week 0. The results showed that an aqueous gel containing high water content effectively improves itching in HD patients with mild uremic pruritus. Besides, psychological discomfort also improved.

The effects of aromatherapy on mood and anxiety in HD patients had been reported by Itai et al. [32] that in HD patients, hiba oil is an effective, non-invasive treatment for depression and anxiety.

A cream with structured physiological lipids (DMS, Derma Membrane Structure) and endogenous cannabinoids was tested for 3 weeks in 21 subjects with pruritus [30]. A significant reduction in pruritus was noted during the test product application using both scales for itching intensity assessment (*P* < 0.0001). Pruritus was significantly decreased at the end of the 3-week treatment (*P* = 0.02) as compared to before treatment, and was completely eliminated in eight patients (38.1%). This is the first study to evaluate topical application of a preparation containing endocannabinoids in the treatment of uremic pruritus. Dvorak et al.[33] showed that treatment with cannabionoid receptor agonists produced reduction of histamine-induced itching and had vasodilation by these topical application.

Another naturally-derived agent that may be helpful in reducing pruritus is capsaicin, which is an alkaloid extracted from the common pepper plant and marketed as a topical analgesic. Capsaicin has a potential antipruritic property with desensitization of nociceptive nerve endings depletion of substance P and then might block the conductor of pruritus. Breneman et al. [34] carried out an open-label, uncontrolled trial and a double-blind, vehicle-controlled trial to evaluate the efficacy and safety of capsaicin 0.025% cream in the treatment of localized areas of pruritus in patients undergoing long term HD. They found marked relief of itching without serious treatment-related adverse reactions.

Further, Tarng et al. [35] reported that 19 HD patients with idiopathic, moderate (n = 5) to severe (n = 14) pruritus were examined in a double-blind, placebo-controlled, crossover study. The results showed that capsaicin was significantly more effective than placebo and a pro‐ longed antipruritic effect was observed 8 weeks post-treatment. Moreover, no serious side effects were noted during the study and there were no significant changes in serum concen‐ trations of albumin, calcium, phosphorus, alkaline phosphatase, or iPTH during the treatment with either capsaicin or placebo. According to their results, this study provides indirect evidence that in idiopathic pruritus in some patients on maintenance HD, substance P may be transmitted from the peripheral sensory neurons to the central nervous system because local application of capsaicin depletes the peripheral neurons of substance P and may block the conduction of pruritus. In another study, Weisshaar et al. [36] reported that 11 pruritic patients on HD and 10 controls were treated with capsaicin 0.05% liniment on the upper back three times daily for 5 days. They reported that topical capsaicin showed some antipruritic potency in HD patients, providing that topical capsaicin might be one of the choice for treatment for HD patients with pruritus.

In addition to the components described above, essential fatty acids and their derivatives are necessary for normal cutaneous function and are thus proposed as potential treatments of pruritus. Tamimi et al. [37] found that primrose oil rich in the essential fatty acid gammalinolenic acid (GLA) may be beneficial in alleviating pruritus. Chen et al. [38] found that GLA- rich cream was better than placebo-based cream for alleviating uremic pruritus, thus it is a useful adjuvant in the management of refractory uremic pruritus.

A new topically active antipruritic medication has been derived from the Amazonian medicine Sangre de Grado [39]. The reported antipruritic effect on itch induced by insect bite was convincing, based on its role as a potent inhibitor of sensory afferent nerves. Moreover, Sangre de Grado is an effective analgesic and anti-inflammatory agent when applied topically.

Further, naturally-derived agents, chemical formulations, such as Tacrolimus, have also been studied, however there have been no convincing data reported until the present time [40, 41]. Topical steroids were also prescribed to these patients, probably based on the assumption that drugs used for itch in other conditions may also work on uremic pruritus, however, the absence of controlled studies and potential serious side effects of these agents dampen the routine prescription of such drugs to HD patients.

### **4.3. Ultraviolet irradiation**

showed that an aqueous gel containing high water content effectively improves itching in HD

The effects of aromatherapy on mood and anxiety in HD patients had been reported by Itai et al. [32] that in HD patients, hiba oil is an effective, non-invasive treatment for depression and

A cream with structured physiological lipids (DMS, Derma Membrane Structure) and endogenous cannabinoids was tested for 3 weeks in 21 subjects with pruritus [30]. A significant reduction in pruritus was noted during the test product application using both scales for itching intensity assessment (*P* < 0.0001). Pruritus was significantly decreased at the end of the 3-week treatment (*P* = 0.02) as compared to before treatment, and was completely eliminated in eight patients (38.1%). This is the first study to evaluate topical application of a preparation containing endocannabinoids in the treatment of uremic pruritus. Dvorak et al.[33] showed that treatment with cannabionoid receptor agonists produced reduction of histamine-induced

Another naturally-derived agent that may be helpful in reducing pruritus is capsaicin, which is an alkaloid extracted from the common pepper plant and marketed as a topical analgesic. Capsaicin has a potential antipruritic property with desensitization of nociceptive nerve endings depletion of substance P and then might block the conductor of pruritus. Breneman et al. [34] carried out an open-label, uncontrolled trial and a double-blind, vehicle-controlled trial to evaluate the efficacy and safety of capsaicin 0.025% cream in the treatment of localized areas of pruritus in patients undergoing long term HD. They found marked relief of itching

Further, Tarng et al. [35] reported that 19 HD patients with idiopathic, moderate (n = 5) to severe (n = 14) pruritus were examined in a double-blind, placebo-controlled, crossover study. The results showed that capsaicin was significantly more effective than placebo and a pro‐ longed antipruritic effect was observed 8 weeks post-treatment. Moreover, no serious side effects were noted during the study and there were no significant changes in serum concen‐ trations of albumin, calcium, phosphorus, alkaline phosphatase, or iPTH during the treatment with either capsaicin or placebo. According to their results, this study provides indirect evidence that in idiopathic pruritus in some patients on maintenance HD, substance P may be transmitted from the peripheral sensory neurons to the central nervous system because local application of capsaicin depletes the peripheral neurons of substance P and may block the conduction of pruritus. In another study, Weisshaar et al. [36] reported that 11 pruritic patients on HD and 10 controls were treated with capsaicin 0.05% liniment on the upper back three times daily for 5 days. They reported that topical capsaicin showed some antipruritic potency in HD patients, providing that topical capsaicin might be one of the choice for treatment for

In addition to the components described above, essential fatty acids and their derivatives are necessary for normal cutaneous function and are thus proposed as potential treatments of pruritus. Tamimi et al. [37] found that primrose oil rich in the essential fatty acid gammalinolenic acid (GLA) may be beneficial in alleviating pruritus. Chen et al. [38] found that GLA-

patients with mild uremic pruritus. Besides, psychological discomfort also improved.

itching and had vasodilation by these topical application.

without serious treatment-related adverse reactions.

HD patients with pruritus.

anxiety.

46 Updates in Hemodialysis

Ultraviolet, especially narrowband UVB, has been proposed as a potential therapeutic agent for pruritus. Although exact mechanisms of UVB therapy in CKD-associated pruritus is unknown, some possible explanations have been proposed such as inactivation of circulating pruritogenic substances [42, 43], suppression of histamine release from cutaneous mast cells [44], and reduction of cutaneous nerve fibers [45, 46]. Blachley et al. [47] reported that 17 patients presenting with severe pruritus were treated thrice weekly with total body exposure to either UVA or UVB light. UVB light resulted in resolution of pruritus in all cases. The mechanism by which UVB improves pruritus is not clear, but it has been suggested that it may in part be due to its ability to reduce cytokine production by lymphocytes.

#### **4.4. Acupuncture**

Acupuncture can be defined as the stimulation of anatomical points on the body using a variety of techniques for therapeutic purposes.

Recently, Kim et al. [48] reported a systemic review of acupuncture for treating uremic pruritus in patients with ESRD. According to their analysis, all of the included subjects reported beneficial effects of acupuncture. Che-yi et al. [49] randomized 40 HD patients with uremic pruritus into two groups and reported that; in group 1 (n = 20), acupuncture was applied unilaterally at the Quchi (LI11) acupoint thrice weekly for 1 month, and in group 2 (controls, n = 20), acupuncture was applied at a non-acupoint 2 cm lateral to Quchi (LI11) thrice weekly for 1 month. In their findings, pruritus scores before and after acupuncture, and at the 3-month follow-up were 38.3±4.3, 17.3± 5.5, and 16.5± 4.9 in group 1, and 38.3± 4.3, 37.5± 3.2, and 37.1± 5 in group 2 (controls), respectively. From these findings, the authors concluded that acu‐ puncture at the Quchi (LI11) acupoint is an easy, safe, and effective method of relieving uremic pruritus.

In another study by Gao et al. [50], 68 cases were randomly divided by half into two groups, acupuncture or drug administration with chlor-trimenton and topical ointment for 2 weeks. While receiving HD treatment, the acupuncture group received treatment at Quchi (LI11) with lifting-thrusting reducing method, and Zusanli (ST36) with lifting-thrusting reinforcing method for 30 min. In patients who received acupuncture therapy, after one course of treat‐ ment, 24 of 34 cases (70.6%) had complete alleviation of pruritus, 9 cases (26.5%) had obvious alleviation of pruritus, and 1 case had no improvement.

Sakurada et al. [51] reported that almost one-third of HD patients had undergone acupuncture or had a desire to try acupuncture treatment to manage common complications. Similar findings were also reported by Shapiro et al. [52] in an observational study. Further, electroacupuncture was performed on 7 HD patients with pruritus. Surprisingly, complete relief after one session of acupuncture treatment was reported in 6 patients and effects lasted up to one year.

Our group recently demonstrated a marked improvement of symptoms related with pruritus. Acupuncture was administered in 12 HD patients 1 to 3 times a week for one year. With improvement of these symptoms, QOL as evaluated by short form 36 (SF-36) health survey showed a marked increase in physical activity and sleep quality (personal communication). Interestingly, the BUN levels were significantly decreased, and those of hemoglobin increased although it did not reach statistical significance (Figs. 1-3).

**Figure 1.** Changes in pruritus and general symptoms related with hemodialysis therapy by acupuncture 1 to 3 times a week for one year. Acupuncutre 1 to 3 times a week for one year produced a marked improvement in pruritus and general symptoms in patients with hemodialysis. \* indicates P<0.05.

**Figure 2.** Changes in energy level and sleep of patients with hemodialysis by acupuncture 1 to 3 times a week for one year as evaluated by SF36. Acupuncutre 1 to 3 times a week for one year produced a marked improvement in energy level and sleep in patients with hemodialysis. **Figure 2.** Changes in energy level and sleep of patients with hemodialysis by acupuncture 1 to 3 times a week for one year as evaluated by SF-36. Acupuncutre 1 to 3 times a week for one year produced a marked improvement in energy level and sleep in patients with hemodialysis.

**Hemoglobin**

puncutre 1 to 3 times a week for one year produced a marked improvement in blood urea nitrogen and hemoglobin levels in patients with hemodialysis. Our group recently demonstrated a marked improvement of symptoms related with pruritus. **Figure 3.** Changes in blood urea nitrogen and hemoglobin levels by acupuncture 1 to 3 times a week for one year. Acu‐ puncutre 1 to 3 times a week for one year produced a marked improvement in blood urea nitrogen and hemoglobin levels in patients with hemodialysis.

Acupuncture was administered in 12 HD patients 1 to 3 times a week for one year. With

#### improvement of these symptoms, QOL as evaluated by short form 36 (SF36) health survey **4.5. Rubdown with Japanese dry towels**

+HPRGLDO\VLV

While receiving HD treatment, the acupuncture group received treatment at Quchi (LI11) with lifting-thrusting reducing method, and Zusanli (ST36) with lifting-thrusting reinforcing method for 30 min. In patients who received acupuncture therapy, after one course of treat‐ ment, 24 of 34 cases (70.6%) had complete alleviation of pruritus, 9 cases (26.5%) had obvious

Sakurada et al. [51] reported that almost one-third of HD patients had undergone acupuncture or had a desire to try acupuncture treatment to manage common complications. Similar findings were also reported by Shapiro et al. [52] in an observational study. Further, electroacupuncture was performed on 7 HD patients with pruritus. Surprisingly, complete relief after one session of acupuncture treatment was reported in 6 patients and effects lasted up to one

Our group recently demonstrated a marked improvement of symptoms related with pruritus. Acupuncture was administered in 12 HD patients 1 to 3 times a week for one year. With improvement of these symptoms, QOL as evaluated by short form 36 (SF-36) health survey showed a marked increase in physical activity and sleep quality (personal communication). Interestingly, the BUN levels were significantly decreased, and those of hemoglobin increased

**Figure 1.** Changes in pruritus and general symptoms related with hemodialysis therapy by acupuncture 1 to 3 times a week for one year. Acupuncutre 1 to 3 times a week for one year produced a marked improvement in pruritus and

alleviation of pruritus, and 1 case had no improvement.

although it did not reach statistical significance (Figs. 1-3).

general symptoms in patients with hemodialysis. \* indicates P<0.05.

year.

48 Updates in Hemodialysis

Our group examined the effects of "rubdown with Japanese dry towels" on CKD-associated pruritus. This method is a traditional Japanese alternative medical treatment to strengthen the barrier function of the skin. Briefly, subjects were naked or wore minimal clothing to maximally expose the skin of their body. Then, the subjects prepared three sets of Japanese dry towels made with cotton. These towels were cleansed with water and then dried under sunlight. After drying, the subjects gently rubbed their whole body with these towels, and if possible, this procedure was carried out in direct sunlight. The results are shown in Fig.4. The mechanism by which this traditional Japanese alternative medical procedure aids in symptom relief may be because skin-rubbing produces secretion of corticosteroid hormone through stimulation of the thalamus [53]. Further, skin-rubbing eliminates the bacterial flora on the surface of the skin [54]. In combination with ultraviolet rays, skin-rubbing may prevent intrusion of c-fiber from the dermis into the epidermis which is one of the causes of itch [55, 56]

**Figure 4.** Effect of rubdown with Japanese dry towels on change in visual analog scale for itching. Manipulation by rubdown with Japanese dry towels produced a marked reduction in pruritus using the visual analog scale. \*\* indicates P<0.01.

#### **4.6. Opioid antagonists**

The use of opioid antagonists in uremic pruritus was first brought to our attention by Andersen et al. [57] when they published a case report about a terminally ill uremic patient successfully treated by naloxone for persistent itching. However, few studies were published, and these had conflicting findings. While Peer et al. [58] showed in a small placebo-controlled clinical trial that naltrexone, which is a µ-receptor antagonist, is effective, Pauli-Magnus et al. [40] failed to demonstrate any efficacy of naltrexone in the treatment of uremic pruritus. Later, Legroux-Crespel et al. [59] conducted a comparative study between naltrexone and loratadine, and concluded that naltrexone is not effective and not well-tolerated because of frequent side effects, except in a small subset of patients. More recently, another perspective was elaborated regarding the use of a қ-agonist, for қ -receptor stimulation inhibits µ-receptor effects both peripherally and centrally, and hence might inhibit itching induced by substance P. In line with this concept, Wikstrom et al. [60] conducted two multicenter, randomized, double-blind, placebo-controlled studies that enrolled 144 patients with uremic pruritus to receive postdialysis intravenous treatment with either nalfurafine, a novel қ -receptor agonist, or placebo for 2 to 4 weeks. Statistically significant reductions in itching, itching intensity, excoriations, and sleep disturbances were noted in the nalfurafine group as compared to the placebo group.

In light of all these findings, Toray Industries, Inc., Japan, recently developed nalfurafine, with refined opioid receptor affinity and selectivity, as an agent for relief of pruritus [61, 62]. In studies using animal models, nalfurafine exerted antipruritic activity not only for antihista‐ mine-sensitive itch, but also for antihistamine-resistant itch [63, 64].

Kumagai et al. [65] carried out a prospective, randomized, double-blind comparative study for 2 weeks to compare the antipruritic effect of oral nalfurafine (2.5 and 5.0 µg) with a placebo in 337 patients. The mean pruritus value as assessed by VAS was 75.2 mm during the preobservation period, which decreased significantly to 50.9 in weeks 2. The mean decrease in VAS from baseline was significantly larger in the 2 µg (n=112, P = 0.0001) and 5 µg (n=114, P = 0.0002) nalfurafine groups than in the placebo group (n=111). However, adverse drug reactions (ADRs) occurred in 103 patients, and the incidence was 25.0% in the 2.5 µg group, 35.1% in the 5 µg group, and 16.2% in the placebo group. The most common ADR was insomnia, observed in 24 of the 226 nalfurafine patients (22.3%). It is interesting to note that the group that received placebo also had a similar decrease in itching. It is well known that placebo-induced expectancies have been shown to decrease pain in a manner reversible by opioid antagonists. This phenomenon is corroborated by the findings of Wager et al. [66], who demonstrated using functional magnetic resonance image that placebo analgesia was related to decreased brain activity in pain-sensitive brain regions, including the thalamus, insula, and anterior cingulate cortex.

Further, Kumagai et al. [67] carried out an open-label study examining the effects and ADRs of 52-week oral administration of nalfurafine hydrochloride in 211 HD patients with treatmentresistant itch. They found that the mean pruritus values as assessed by the VAS was 75.2 mm during the pre-observation period, which decreased significantly to 50.9 and 30.9 mm in weeks 52, indicating a long-lasting efficacy. ADRs occurred in 103 patients. Frequent ADRs were insomnia (19.4%), constipation (7.1%)**,** and increased blood prolactin (3.3%).
