INTRODUCTION — Pruritus is a common and bothersome symptom among patients with end-stage kidney disease (ESKD). The pathophysiology is incompletely understood, and it is often difficult to eradicate, although symptoms can usually be mitigated.
Uremic pruritus is discussed in this topic review. A general discussion of pruritus is presented separately. (See "Pruritus: Therapies for localized pruritus".)
EPIDEMIOLOGY
Prevalence — The reported prevalence of uremic pruritus in adult hemodialysis patients has varied over the years, and some studies suggest the prevalence may be decreasing with more effective dialysis [1]. Whereas the reported prevalence between 1980 and 1993 was 50 to 90 percent [2-4], subsequent surveys note a lower rate (22 to 57 percent) [5-8]. In a report from one of the largest trials (the Dialysis Outcomes and Practice Patterns Study [DOPPS]), the prevalence of moderate pruritus remained constant at 18 percent between the years 1996 to 2001 and 2012 to 2015 [7,9]. However, the percentage of patients who reported being very much or extremely bothered fell from 28 to 18 percent between these time intervals.
This study illustrates the lack of reporting of pruritus by patients and lack of awareness by medical staff. Of patients reporting being severely bothered by pruritus in 2012 to 2015, 18 percent used no treatment for pruritus, and 17 percent did not even report itching to health care staff. Sixty-nine percent of medical directors underestimated the prevalence of pruritus in their units [7,9].
The prevalence has not been as well studied in peritoneal dialysis patients and in children. Historically, small series suggested that the prevalence is lower in children (approximately 9 percent) and similar between hemodialysis and peritoneal dialysis patients [10-12]. However, two studies from Korea and Taiwan compared the prevalence of pruritus between hemodialysis and peritoneal dialysis patients and showed conflicting results. The Korean study showed a significantly higher rate of pruritus in peritoneal dialysis patients compared with hemodialysis patients (68.2 versus 48.3 percent, respectively), whereas the Taiwanese cohort showed no significant difference between hemodialysis and peritoneal dialysis patients [13,14].
Risk factors and associations — No single cause underlying uremic pruritus has been identified. Multiple factors have been associated in observational studies, and supportive therapies that are used to treat uremic pruritus have targeted such factors. (See 'Management' below.)
The following factors have been identified in multiple studies:
●Inadequate dialysis [6,15,16]
●Hyperparathyroidism [17,18]
●Elevated calcium x phosphorus product [6,19,20]
●Xerosis (dry skin caused by sweat gland atrophy) [21,22]
●Elevated serum magnesium and aluminum concentrations [23-25]
Less convincing associations have also been made to anemia, male sex, hypervitaminosis-A, increased beta-2 microglobulin levels, serotype human leukocyte antigen (HLA)-B35, and comorbidities including congestive heart failure, neurologic disease, and ascites [7,19,26-28].
Risk appears to be independent of ethnicity, type of dialysis, and underlying kidney disease [1].
PATHOPHYSIOLOGY — The pathophysiology of uremic pruritus is poorly understood. Hypotheses implicating immunologic and opioidergic systems have been proposed [29].
Immunohypothesis — The immunohypothesis proposes that uremic pruritus is the result of systemic inflammation rather than a local skin disorder [30,31]. Immunomodulating therapies such as ultraviolet B (UVB) phototherapy, thalidomide, and calcineurin inhibitors have been shown to decrease uremic pruritus in some studies [32-34].
A direct role for proinflammatory T cells and cytokines is suggested by studies that showed higher levels of proinflammatory T helper-1 (TH1) cells, C-reactive protein, interleukin-6, and interleukin-2 levels among hemodialysis patients with versus those without pruritus [31,35]. Other markers of inflammation including increased white blood cell count, low albumin, and high ferritin have also been associated with uremic pruritus in various studies [7,36].
Opioid hypothesis — The opioid hypothesis proposes that imbalances in the expression of mu and kappa opioid receptors cause pruritus [37,38]. Thus, pruritus is increased by mu-receptor activation and kappa-receptor blockade and decreased by kappa-receptor activation and mu-receptor blockade [39]. This hypothesis is supported by the observation that the ratio of the mu-receptor agonist (beta-endorphin) to the kappa-receptor agonist (dynorphin-A) is increased in hemodialysis patients compared with healthy controls, and this ratio increased with severity of pruritus [40].
Other contributing factors — Mast cell release of histamine and other pruritogens and xerosis may all contribute to the pathogenesis of uremic pruritus [37,41,42].
CLINICAL CHARACTERISTICS — Uremic pruritus most commonly affects the back but may also involve the arms, head, and abdomen [7,43]. Generalized pruritus is also noted in a significant number of patients. Some patients also experience pruritus for only a few minutes each day, whereas others have it nearly continuously [44].
Other characteristics include:
●Symptoms tend to be worse at night, resulting in sleep disruption [5-7,43,45,46]. The disruption of sleep is much worse in those with more severe pruritus, possibly resulting in marked fatigue and depression [7,9].
●Patients often report increased pruritus with heat (especially with excessive perspiration) and stress and decreased pruritus with physical activity, cooler temperatures, and with either hot or cold showers [1].
●Some patients report exacerbation of pruritus during hemodialysis sessions, whereas pruritus appears to lessen during hemodialysis among others [20,43].
Physical findings are limited unless there are superimposed dermatologic conditions from repetitive scratching such as excoriations, lichen simplex, pruritus nodularis, keratotic papules, and follicular hyperkeratosis [3]. Xerosis (dry skin), which is present in most patients with uremic pruritus, may not be apparent unless the skin is inspected closely when scaling and epidermal cracking may be visible [47].
Laboratory features may include serum blood urea nitrogen (BUN), parathyroid hormone (PTH), phosphate, calcium, and magnesium levels that are markedly elevated compared with dialysis patients without pruritus. Among 1773 adult hemodialysis patients who were stratified based upon the severity of pruritus, those with severe pruritus were more likely to have BUN >81 mg/dL (odds ratio [OR] 1.4), calcium >9.5 mg/dL (OR 1.4), or phosphate 6.6 mg/dL (OR 1.7) and less likely to have a PTH <200 pg/mL (OR 0.6) [6].
DIAGNOSIS — Since it is extremely common, we assume that pruritus presenting in dialysis patients is due to uremic pruritus unless there is unequivocal and compelling evidence of another cause. Characteristics suggestive of uremic pruritus include onset coincident with starting dialysis, persistence of symptoms, or markedly elevated calcium/phosphate, parathyroid hormone (PTH), and/or blood urea nitrogen (BUN) levels [46].
Differential diagnosis — A significant number of diseases can cause pruritus in patients with and without kidney disease. In general, a nonuremic cause of pruritus should be considered among dialysis patients with symptoms that are refractory to common treatments such as topical emollients and analgesic agents and oral antihistamines or gabapentin. This is discussed separately. (See "Pruritus: Etiology and patient evaluation".)
It is particularly important that the clinician consider the possibility of lymphoma, cholestasis (due to primary biliary cholangitis or viral hepatitis, for example), and hypersensitivity reactions as the cause of pruritus among dialysis patients. (See "Clinical manifestations, pathologic features, and diagnosis of peripheral T cell lymphoma, not otherwise specified", section on 'Clinical features' and "Pruritus associated with cholestasis" and "Pruritus: Etiology and patient evaluation", section on 'Dermatologic disorders' and "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis (primary biliary cirrhosis)", section on 'Signs and symptoms' and "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults", section on 'Pruritus'.)
MANAGEMENT — High-quality evidence on which to base recommendations for the treatment of uremic pruritus is limited. Most recommendations are based on anecdotal reports and small, uncontrolled clinical trials. Further complicating the interpretation of the studies that address management include the use of different scoring systems for the intensity of pruritus and a lack of head-to-head comparisons among different agents. In addition, many agents that have been studied may not be commercially available. Another complicating factor in interpreting the literature regarding therapies for uremic pruritus is the impressive placebo effect noted in some studies [48-50].
In a 2017 systematic review of treatment options for uremic pruritus, 39 different treatment options were evaluated in 44 trials. Most included trials were small with a high risk of bias; largest body of evidence was found for the effectiveness of gabapentin [51].
Treatment involves a stepwise approach that depends upon the severity of symptoms and the response to initial therapies.
Initial therapy — The initial therapy for all dialysis patients with uremic pruritus includes the following:
●Optimal dialysis since underdialysis is commonly associated with pruritus (see "Prescribing and assessing adequate hemodialysis" and 'Dialysis modification' below)
●Optimal treatment of hyperparathyroidism, hyperphosphatemia, and hypermagnesemia (see 'Parathyroid, calcium, and phosphate' below)
●The regular use of emollients and/or topical analgesics, such as pramoxine lotion (see 'Topical treatments' below)
Dialysis modification — Increasing the dose of dialysis may improve pruritus [15,16,52]. A 12-month prospective study from 1995 included 59 hemodialysis patients without significant disorders of bone metabolism who were stratified according to the degree of pruritus observed over three months [15]. In the first phase of the study, during which the dialysis dose was not changed, dialysis adequacy was inversely associated with the severity of pruritus; patients who never had pruritus (n = 16), those who had a reduction in pruritus over three months (n = 16), and those who had prolonged severe pruritus (n = 22) had mean Kt/V values of 1.31, 1.28, and 1.09, respectively.
In a second phase of this study, patients who had severe, prolonged pruritus were assigned to receive either increased dialysis (n = 9) or the same dialysis dose (n = 13) for an additional three months, with mean follow-up Kt/V values of 1.19 and 1.07, respectively. The percentage of patients who reported a decrease in pruritus was greater in patients assigned to receive more dialysis compared with those whose dialysis dose did not change (77 versus 8 percent, respectively) [15].
Importantly, the highest Kt/V values reported in this study from 1995 were still lower than the dose that is generally recommended today (which is a single-pool Kt/V for hemodialysis treatments of 1.4 to 1.6).
Two more recent observational studies have yielded conflicting results. In one five-year prospective study that included 111 patients, those with Kt/V <1.5 were more likely to have pruritus, and those with Kt/V >1.5 were less likely to have pruritus [53]. By contrast, in a study of a cohort of 105 patients, the mean Kt/V was 1.7 in those without pruritus and 1.82 in those with pruritus [20]. A posited explanation for this observation is that patients with the higher Kt/V had more prolonged contact with dialyzer membranes or silicone tubing, which caused pruritus. Alternatively, treatment times and Kt/V may have been higher among patients with lower residual kidney function or worse metabolic parameters, which could have accounted for the pruritus rather than the longer treatment time, per se.
We suggest using the generally accepted Kt/V targets for hemodialysis and peritoneal dialysis patients because of overall benefit conferred rather than a specific demonstrated effect on pruritus. (See "Prescribing and assessing adequate hemodialysis" and "Prescribing peritoneal dialysis".)
For patients who have severe pruritus despite achieving optimal Kt/V targets and who are highly motivated and able to comply, the dialysis dose may be increased further as a trial. We generally target a Kt/V of 1.5 to 1.7 for one to two months.
Conversely, for patients with a Kt/V >1.7, decreasing the Kt/V target to ≤1.7 may provide a benefit.
Switching to a biocompatible dialysis membrane (such as polymethylmethacrylate [PMMA]) may decrease pruritus in the rare patient who is being dialyzed with a bioincompatible membrane [54-56]. In the largest study of 30 patients with uremic pruritus, the mean pruritus score decreased four weeks after switching to a PMMA dialyzer [54]. Two smaller studies also demonstrated improvement with PMMA membranes [55,56]. Virtually all patients in the United States are already dialyzed against a biocompatible membrane, however. For patients who are already on a non-PMMA biocompatible membrane, switching to a PMMA membrane may be effective.
Patients who are dialyzed with a low-flux dialyzer may be switched to a high-flux dialyzer. In the cohort study cited above, pruritus was more common in patients dialyzed with low-flux dialyzers [53]. In a randomized, double-blind, placebo-controlled crossover study that included 116 hemodialysis patients, 12 weeks of dialysis with a high-flux dialyzer, but not a conventional flux dialyzer, was associated with a reduction in pruritus from a visual analog score of 6.22 to 2.23 [57]. (See "Clinical consequences of hemodialysis membrane biocompatibility".)
Hemodiafiltration may improve pruritus. In a 12-week randomized controlled study including 51 patients, patients undergoing hemodiafiltration had improved pruritus as assessed by visual analog scores and lower beta-2 microglobulin, c-reactive protein (CRP), and interleukin (IL) 6 levels compared with the group undergoing high-flux hemodialysis [58]. Hemodiafiltration may be a promising option for patients with refractory pruritus.
Other changes in dialysate composition have not been shown to be effective [59].
Parathyroid, calcium, and phosphate — Limited data suggest that the treatment of hyperparathyroidism, hyperphosphatemia, and an elevated calcium x phosphate product reduces uremic pruritus [17,18]. The best data are from a series of 37 hemodialysis patients who underwent parathyroidectomy for bone pain, pruritus alone, or bone pain with pruritus [18]. The mean parathyroid hormone (PTH) level was 1473 pg/mL before surgery and 33 pg/mL postoperatively. Serum calcium and phosphate concentrations were 11.1 and 6.5 mg/dL preoperatively and 8.4 and 3.8 mg/dL postoperatively; the calcium x phosphate product decreased with surgery from 72 to 32 mg2/dL2. Pruritus quantitated by a visual analog scale decreased from 5.5 to 1.8, although a statistical correlation between pruritus and preoperative levels of calcium, phosphate, calcium-phosphate product, or PTH could not be demonstrated.
However, there are no data that suggest that parathyroidectomy is beneficial in the absence of markedly elevated PTH concentrations such as those present in the study cited above. The optimal PTH and phosphate concentrations that should be maintained in order to prevent or treat uremic pruritus are not known. We suggest targeting the commonly accepted phosphate and PTH concentrations that have been developed for the overall benefit of such patients. Goal phosphate and PTH values for dialysis and nondialysis chronic kidney disease (CKD) patients are discussed elsewhere. (See "Management of secondary hyperparathyroidism in adult dialysis patients".)
Although the effect of nonsurgical treatment of hyperparathyroidism, such as vitamin D derivatives and calcimimetics, on uremic pruritus has not been shown, such agents are standard therapy for secondary hyperparathyroidism and should be employed before parathyroidectomy is considered. Parathyroidectomy should be reserved for patients who have elevated PTH, hypercalcemia, or hyperphosphatemia that is refractory to medical therapy. (See "Refractory hyperparathyroidism and indications for parathyroidectomy in adult dialysis patients".)
Topical treatments — Effective topical treatments include emollients and analgesics.
Emollients and/or topical analgesic agents — Emollients are the preferred topical treatment of uremic pruritus, especially if xerosis (dry skin) is present on examination. Most trials that have been done to establish the efficacy of emollients have been small or uncontrolled, although one larger and controlled study has been published [60-62]:
●A randomized, double-blind, intraindividual (left versus right comparison), multicentric clinical study compared an oil and water emulsion containing glycerol (15 percent) and paraffin (10 percent) with emulsion alone among 99 patients with moderate to severe uremic xerosis [62]. At seven days, compared with the emulsion alone, more patients responded to the glycerol/paraffin emulsion with a reduction in pruritus (73 percent versus 44 percent, respectively).
Open-label use of the glycerol- and paraffin-containing emulsion on all xerotic areas for 49 days resulted in a substantial improvement of pruritus and quality of life of the patients at study end [62].
●In one uncontrolled trial of 21 patients, 16 reported significant relief, while 9 patients had complete resolution of uremic pruritus with regular emollient use [60].
●Twice-daily application of a high-water-content emollient decreased pruritus among 10 dialysis patients compared with control at two weeks [61].
There are no good comparative trials among various emollients for uremic pruritus. We suggest using a high-water-content emollient rather than other agents.
Topical analgesic agents, such as pramoxine, may relieve pruritus [63]. In one pharmaceutical company-sponsored randomized trial that included 28 hemodialysis patients, twice-daily application of pramoxine was associated with a greater reduction in pruritus compared with an emollient (61 versus 12 percent, respectively) [63]. Pramoxine was shown in this trial to be safe and convenient. Its use might be considered in patients who have persistent symptoms despite appropriate use of emollients.
The topical analgesic agent, capsaicin, has been shown in various trials to be effective for localized pruritus [64-66]. However, all trials were subsequently criticized for design flaws (mostly lack of adequate blinding and crossover design) that hinder their interpretation [67]. In addition, capsaicin has been used primarily for well-circumscribed areas of pruritus; it may not be a practical solution for large areas or generalized pruritus [29]. We suggest not using capsaicin for uremic pruritus, unless all other therapies are ineffective.
Cromolyn sodium — Oral cromolyn sodium was reported to be helpful for two patients with uremic pruritus [68]. In a randomized, double-blind, placebo-controlled study that included 60 hemodialysis patients, twice-daily application of topical cromolyn sodium more effectively decreased pruritus compared with placebo. After four weeks, the pruritus score decreased from 2.5 to 0.3 in the cromolyn sodium-treated patients and from 2.7 to 1.3 in the control group [69].
Tacrolimus — We recommend not using topical tacrolimus for uremic pruritus. Although early reports suggested a possible benefit [34,70], a randomized, double-blind study showed no effect of 0.1% tacrolimus ointment among 12 hemodialysis patients compared with eight patients who received placebo [71]. In addition, a boxed warning has been issued against the prolonged use of topical tacrolimus because of an increased risk of skin malignancies demonstrated in animal studies [72].
Resistant pruritus — We define resistant pruritus as continued symptoms despite adequate dialysis, optimization of metabolic parameters, and the use of topical emollients and analgesics for approximately four weeks. Such patients may be treated with an oral antihistamine and, if that is ineffective after a one- to two-week trial, gabapentin or pregabalin.
Oral antihistamines — The beneficial effects of antihistamines in pruritus are believed to be mediated via both their sedating properties and ability to stabilize mast cell membranes [73]. We suggest the use of either hydroxyzine (25 mg orally three to four times daily) or diphenhydramine (25 mg orally three to four times daily) for patients who do not respond to other measures. Some patients, however, may find these agents overly sedating when taken during the day. For such patients, we suggest trying a less sedating agent, such as loratadine, during the day, with the continued use of the sedating antihistamines at night. (See "Pruritus: Therapies for generalized pruritus", section on 'Role of antihistamines'.)
Gabapentin and pregabalin — If oral antihistamines provide no relief of symptoms after a one-week trial, gabapentin or pregabalin may be prescribed. The preferred initiating dose of gabapentin is 100 mg after each dialysis session. The dose may be gradually increased to 300 mg daily. Doses greater than 300 mg daily are not recommended in dialysis patients. The preferred initiating dose of pregabalin is 25 mg daily. The dose may be gradually increased to 75 mg daily. Doses greater than 75 mg daily are not recommended in dialysis patients.
Gabapentin (a 3-aminobutyric acid analog anticonvulsant) and pregabalin (which binds to the alpha2-delta subunit of voltage-gated calcium channels within the central nervous system [CNS] and modulates calcium influx at nerve terminals) are used in a variety of neuropathic pain syndromes and have been effective for uremic pruritus [51,74-76].
●In a randomized, double-blind, placebo-controlled crossover study that included 25 hemodialysis patients, gabapentin (300 mg after each dialysis session), but not placebo, was associated with a significant reduction in pruritus from a visual analog score of 8.4 to 1.2 [74].
●Among 34 hemodialysis patients, gabapentin 400 mg twice weekly was associated with decreased pruritus compared with placebo (visual analog scores of 6.7 and 1.5, respectively) [75].
●A low dose of gabapentin (100 mg) after each dialysis decreased pruritus among five patients [76].
●In a randomized, double-blind, controlled study that included 52 patients, gabapentin (100 mg daily) and ketotifen (1 mg twice daily) both significantly reduced pruritus in 88.4 and 76.9 percent of patients, respectively. Adverse events were rare in both groups [77].
●In a randomized, double-blind, placebo-controlled study that included 54 patients, gabapentin (initial dose 100 mg after each hemodialysis session, titrated up to 300 mg, if necessary), but not placebo, was associated with a significant reduction in pruritus from a visual analog score of 7.63 to 1.81. Sixty-three percent of patients responded to the 100 mg dose [78].
●In two uncontrolled studies with a total of 28 hemodialysis patients with refractory pruritus, a low dose of pregabalin (25 mg/day) resulted in a significant decrease in pruritus in 24 patients. The remaining four patients were unable to tolerate the pregabalin [79,80].
●In a 12-week, randomized, double-blind, placebo-controlled study that included 179 hemodialysis patients, pregabalin (75 mg twice per week), but not ondansetron or placebo, was associated with a significant reduction in pruritus, from a visual analog score of 8.0 to 1.6 in the pregabalin group versus 8.0 to 5.8 in the other groups [81].
●In a four-week, randomized, single-blind, controlled study that included 72 patients, pregabalin (50 mg every other day) was associated with a greater reduction in pruritus compared with doxepin (10 mg daily), from a visual analog score of 7.5 to 2.1 in the pregabalin group versus 7.9 to 5.4 in the doxepin group [82].
●In a 14-week, randomized, prospective, crossover trial, 29 patients with pruritus were randomly assigned to gabapentin 300 mg after each hemodialysis session and pregabalin 75 mg daily. After six weeks of treatment and a two-week washout period, crossover was performed, and patients received the other drug for another six weeks. Gabapentin and pregabalin both improved pruritus significantly, and there was no difference between the study drugs in terms of efficacy [83].
If gabapentin does not work, pregabalin may be effective. In one study, 71 consecutive patients with refractory pruritus were treated with gabapentin or pregabalin [84]. Patients intolerant of gabapentin were offered pregabalin. Gabapentin relieved itching in 47 patients (66 percent). Of 21 patients who stopped gabapentin due to adverse effects, 16 started pregabalin. Pregabalin at a dose of 25 mg after hemodialysis to 50 mg daily relieved itching in 13 of the 16 patients (81 percent). In total, gabapentin or pregabalin relieved itching in 60 patients (85 percent) [84].
If gabapentin or pregabalin is used, the patient should be monitored closely for neurologic side effects such as dizziness and somnolence.
Sertraline — Antidepressants have been used for the treatment of pruritus in the general (ie, non-end-stage kidney disease [ESKD]) population (see "Pruritus: Therapies for generalized pruritus", section on 'Antidepressants'). The selective serotonin reuptake inhibitor (SSRI), sertraline, may be an effective treatment of uremic pruritus [85,86]. In one uncontrolled study, among 20 nondialysis CKD patients with severe pruritus refractory to antihistamines, 17 responded to sertraline after a mean duration of 5.1 weeks [86]. The mean effective daily dose was 35 mg.
In an eight-week randomized, double-blind, placebo-controlled study that included 50 patients, the group administered sertraline at 50 mg per day had a greater reduction in pruritus compared with placebo (visual analog score decreased from 9 to 1.8 in the sertraline group versus 8.8 to 3.2 in the placebo group). Of note, the benefit of sertraline only became manifest after four weeks [49].
Montelukast — Leukotrienes may play a role in inflammation-mediated uremic pruritus. Two studies have investigated montelukast, a leukotriene receptor antagonist.
●In a randomized, single-blind, placebo-controlled crossover study of 16 patients, 10 mg per day of montelukast resulted in greater improvement in pruritus symptoms compared with placebo (35 versus 7 percent reduction, respectively) [87].
●In a 30-day randomized, double-blind, controlled trial comparing 10 mg daily of montelukast and placebo, pruritus as assessed by a visual analog scale improved from 6.43 to 2.73 in the montelukast group versus a reduction from 6 to 5.47 in the placebo group [88].
No adverse symptoms were noted in the montelukast group.
Refractory pruritus — Most patients with uremic pruritus will at least partially respond to emollients, topical analgesics, oral antihistamines, or a gabapentinoid (ie, gabapentin or pregabalin). For patients who are refractory to these agents, we suggest difelikefalin. If difelikefalin is unavailable or ineffective, phototherapy is a potential alternative.
Difelikefalin — We suggest difelikefalin, a peripherally restricted selective kappa-opioid agonist, for patients on hemodialysis who have moderate to severe uremic pruritus that does not respond to other agents. Difelikefalin is administered intravenously (0.5 microgram/kg) three times a week at dialysis. We stop difelikefalin if no benefit is observed after 12 weeks of treatment. To avoid vascular access complications, we do not administer difelikefalin intravenously in settings other than dialysis.
Several randomized controlled trials using multiple quantitative measures of pruritus demonstrate modest efficacy of difelikefalin [50,89-91]. In a pooled analysis of two randomized controlled trials including 851 patients on maintenance hemodialysis with moderate to severe pruritus, more patients had improved itch intensity at 12 weeks (defined ≥3-point reduction from baseline in the weekly mean score on the 24-hour Worst Itching Intensity Numerical Rating Scale) with difelikefalin compared with placebo (51.1 versus 35.2 percent; p<0.001) [91]. In addition, difelikefalin resulted in greater improvement in itch-related quality of life, an effect that persisted in a 52-week open-label trial extension. Although difelikefalin resulted in clinically meaningful improvement compared with placebo in these trials, patients treated with placebo also experienced substantial reductions in itch symptoms.
In the pooled trials above, difelikefalin was generally well tolerated, with 6.8 percent in the difelikefalin arm withdrawing for adverse events compared with 4 percent with placebo [92]. The most frequent side effects with difelikefalin were diarrhea, dizziness, and nausea. In the first trial included in the pooled analysis, the difelikefalin group did not experience opioid-related adverse effects such as dysphoria, euphoria, hallucinations, or symptoms of withdrawal upon discontinuation of the drug [50]. Other data demonstrate that even higher doses of difelikefalin do not cause respiratory depression [93].
Long-term efficacy and safety data for difelikefalin are limited. Only a minority of patients in the pooled trials above completed the 52-week open-label trial extension. Furthermore, comparative efficacy data with other medications, such as gabapentin and pregabalin, are needed.
Another kappa-opioid agonist, nalfurafine, is approved for treating uremic pruritus in Japan. A randomized controlled trial conducted in the United States was terminated due to the inability to enroll sufficient patients [94].
Phototherapy — We reserve phototherapy for patients with persistent symptoms who cannot use other options. Ultraviolet B (UVB) irradiation may be effective in the treatment of uremic pruritus, as noted in small or uncontrolled studies [33,95-97]. As an example, in one study, 8 of 10 patients with refractory pruritus reported improvement in symptoms after UVB therapy [96]. The UVB dose was initiated at 200 to 400 mJ/cm2 and increased by 100 mJ/cm2 at each session to a maximum daily dose of 1500 mJ/cm2. Recurrence of symptoms following cessation of therapy may be a problem; in this study, four patients who responded initially had recurrence of symptoms.
The beneficial effects of UVB therapy are thought to be due to a decrease in proinflammatory cytokine levels and induction of mast cell apoptosis [98]. Specific UVB treatment protocols are discussed elsewhere. (See "UVB therapy (broadband and narrowband)".)
UVB therapy is associated with an increased risk of carcinogenesis and should not be used in patients who are on immunosuppressive therapy. The carcinogenic potential of UVB irradiation is an issue that should be discussed with all patients for whom such therapy is considered [29]. UVB therapy should not be used in patients with systemic lupus erythematosus, because of the known photosensitivity of such patients. (See "Overview of cutaneous lupus erythematosus".)
Therapies of limited use — Many other agents have been studied as therapies for uremic pruritus. However, we do not advocate routine use, because of insufficient data and/or side effects:
●Mixed opioid receptor agonists and antagonists – The mixed mu-antagonists/kappa-agonists nalbuphine and butorphanol and the opioid receptor antagonist naltrexone have been studied for the treatment of uremic pruritus:
•In 15 hemodialysis patients suffering from pruritus, an open-label, multiple escalating-dose study of the mixed mu-antagonist/kappa-agonist nalbuphine showed reduction in the mean visual analog score from 4 to 1.2 at 180 mg/day and 0.4 at 240 mg/day [99]. In an eight-week randomized, placebo-controlled trial, nalbuphine 120 mg twice a day, but not nalbuphine 60 mg twice a day, decreased pruritus as assessed by a numerical rating scale [48]. However, nalbuphine was poorly tolerated, with a high dropout rate (approximately 25 percent) in the active arms of the trial compared with placebo.
•A beneficial effect of intranasal butorphanol, a kappa-opioid receptor agonist and mu-receptor antagonist, was demonstrated in a limited, five-patient case series [100].
•Although a few short-term studies suggested that naltrexone was effective for uremic pruritus [101-104], no benefit was demonstrated in a randomized, double-blind, placebo-controlled crossover study [8].
●Other – Various other therapies have been studied, including omega-6 fatty acid [105], omega-3 fatty acid [106,107], turmeric [108], zinc [109], activated charcoal [110,111], selective inhibitors 5-hydroxytryptamine receptors [112], oral cromolyn sodium [68,113], cholestyramine [114], nicergoline [115], thalidomide [32], ketotifen [116], dupilumab [117,118], and topical agents such as gamma linolenic acid [119], sericin cream [120], endocannabinoids [121], and topical vitamin D [122].
IMPACT OF TRANSPLANTATION — Kidney transplantation is definitive therapy for uremic pruritus. As an example, one retrospective study reported that generalized pruritus completely disappeared following successful transplantation [123]. For patients who are undecided about whether to undergo a kidney transplant, persistent pruritus may provide incentive.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pruritus" and "Society guideline links: Dialysis".)
SUMMARY AND RECOMMENDATIONS
●Overview – Pruritus is common among patients with end-stage kidney disease (ESKD). The etiology is not known. Pruritus has been associated with inadequate dialysis and abnormal bone and mineral metabolism as well as xerosis (dry skin caused by sweat gland atrophy). (See 'Introduction' above and 'Risk factors and associations' above.)
●Initial therapy – Treatment involves a stepwise approach that depends upon the severity of symptoms and the response to initial therapies. Our suggested treatment approach is as follows:
•All patients with uremic pruritus should be optimally dialyzed using the generally accepted Kt/V targets. For patients who have severe pruritus despite achieving optimal Kt/V targets and who are highly motivated and able to comply, we suggest increasing the dialysis dose as a trial (Grade 2C). (See "Prescribing peritoneal dialysis" and "Prescribing and assessing adequate hemodialysis".)
•All patients with uremic pruritus should be treated for hyperparathyroidism, hyperphosphatemia, and hypermagnesemia to generally accepted target values.
•For all patients with uremic pruritus, we recommend treatment with emollients and/or topical analgesics, especially if xerosis or dry skin is present. (Grade 1B). (See 'Emollients and/or topical analgesic agents' above.)
●Resistant pruritus – Oral antihistamines, gabapentin, and pregabalin may be effective for the treatment of pruritus that is resistant to topical therapies.
•For patients with resistant pruritus despite the use of topical emollients and/or topical analgesics, we suggest an oral antihistamine (Grade 2C). Either hydroxyzine or diphenhydramine may be used. Patients who find these agents overly sedating may try a less sedating agent (such as loratadine) during the day, with the continued use of the sedating antihistamines at night. (See 'Resistant pruritus' above.)
•For patients who have resistant pruritus despite oral antihistamines and other therapies, we suggest gabapentin or pregabalin rather than other oral therapies (Grade 2B). We generally try gabapentin first since it is less expensive. If gabapentin is used, the patient should be closely monitored for signs of neurotoxicity. If gabapentin does not work, pregabalin may be effective. (See 'Resistant pruritus' above.)
●Refractory pruritus – For patients on hemodialysis who have moderate to severe uremic pruritus that does not respond to other agents, we suggest difelikefalin (Grade 2C). Ultraviolet B (UVB) phototherapy is an alternative for people who do not have access to or do not respond to difelikefalin. (See 'Difelikefalin' above.)
●Impact of transplantation – Uremic pruritus resolves following kidney transplantation. For transplant candidates who are undecided, persistent pruritus may provide additional incentive to undergo transplantation. (See 'Impact of transplantation' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Theodore Tzeremas, MD, who contributed to earlier versions of this topic review.
