INTRODUCTION — Pruritus (itch) is a common symptom among patients on maintenance dialysis that in many cases substantially impairs quality of life [1-3]. Less frequently, pruritus also occurs in patients with nondialysis chronic kidney disease (CKD). The pathophysiology is incompletely understood, and it is often difficult to eradicate although symptoms can usually be mitigated.
Although often referred to as "uremic pruritus," itch in this setting often occurs in adequately dialyzed patients or, in patients not on dialysis, in the absence of other symptoms associated with uremia. Thus, the preferred term is chronic kidney disease–associated pruritus (CKD-aP). CKD-aP 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 CKD-aP in adult patients with end-stage kidney disease has decreased with more effective dialysis [4]. Whereas the reported prevalence between 1980 and 1993 was 50 to 90 percent [5-7], subsequent surveys noted a lower rate (22 to 57 percent) [8-11]. In a report from a prospective cohort study (the Dialysis Outcomes and Practice Patterns Study [DOPPS]) that included more than 20,000 patients on hemodialysis, the prevalence of at least moderate pruritus was 37 percent, a rate that was relatively constant from 2009 to 2018 [12]. Seven percent of patients in this study reported that they were extremely bothered by pruritus.
Pruritus is underreported by patients and underappreciated by medical staff. For example, in reports of DOPPS participants who had severe pruritus, 18 percent received no treatment for pruritus, and 17 percent did not even report their itch symptoms to health care staff [10,13]. Over two-thirds of medical directors underestimated the prevalence of pruritus in their units [10,13].
The prevalence has not been as well studied in patients on peritoneal dialysis and in children. Historically, small series suggested that the prevalence is lower in children (approximately 9 percent) and similar between patients on hemodialysis and those on peritoneal dialysis [14-16]. However, two studies from Korea and Taiwan compared the prevalence of pruritus between patients on hemodialysis and those on peritoneal dialysis and showed conflicting results. The Korean study showed a higher rate of pruritus in patients on peritoneal dialysis compared with those on hemodialysis (68.2 versus 48.3 percent, respectively), whereas the Taiwanese cohort showed no significant difference between patients on hemodialysis and those on peritoneal dialysis [17,18].
CKD-aP in patients with nondialysis CKD is less common. In a report from a prospective cohort study that included over 5600 patients with stages 3, 4, and 5 nondialysis CKD, the prevalence of at least moderate pruritus was 24 percent, and of extreme pruritus was less than five percent [19]. The prevalence and severity of pruritus increased with CKD stage.
Risk factors and associations — No single cause underlying CKD-aP has been identified. Multiple factors have been associated in observational studies, and supportive therapies that are used to treat CKD-aP have targeted such factors. (See 'Management' below.)
The following factors have been identified in multiple studies:
●Inadequate dialysis [9,20,21]
●Hyperparathyroidism [22-24]
●Elevated serum calcium and/or phosphorus concentrations [9,24-26]
●Xerosis (dry skin caused by sweat gland atrophy) [27,28]
●Elevated serum magnesium and aluminum concentrations [29-31]
However, not all studies observed associations between elevated levels of parathyroid hormone or phosphorus and pruritus [13]. Other data suggest the following potential risk factors: 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 [10,25,32-34].
Risk appears to be independent of ethnicity, type of dialysis, and underlying kidney disease [4].
PATHOPHYSIOLOGY — The pathophysiology of CKD-aP is poorly understood. Hypotheses implicating immunologic and opioidergic systems have been proposed [35].
Immunohypothesis — The immunohypothesis proposes that CKD-aP is the result of systemic inflammation rather than a local skin disorder [36,37]. Immunomodulating therapies such as ultraviolet B (UVB) phototherapy, thalidomide, and calcineurin inhibitors have been shown to decrease CKD-aP in some studies [38-40].
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 among patients on hemodialysis with versus those without pruritus [37,41]. 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 [10,42].
Opioid hypothesis — The opioid hypothesis proposes that imbalances in the expression of mu and kappa opioid receptors cause pruritus [43,44]. Thus, pruritus is increased by mu-receptor activation and kappa-receptor blockade and decreased by kappa-receptor activation and mu-receptor blockade [45]. 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 patients on hemodialysis compared with healthy controls, and this ratio increased with severity of pruritus [46].
Other contributing factors — Mast cell release of histamine and other pruritogens and xerosis may all contribute to the pathogenesis of CKD-aP [43,47-49].
CLINICAL CHARACTERISTICS — CKD-aP most commonly affects the back but may also involve the arms, head, and abdomen [10,50]. 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 [51].
Other characteristics include:
●Symptoms tend to be worse at night, resulting in sleep disruption [8-10,12,50,52,53]. The disruption of sleep is much worse in those with more severe pruritus, possibly resulting in marked fatigue and depression [10,12,13].
●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 [4].
●Some patients report exacerbation of pruritus during hemodialysis sessions, whereas pruritus appears to lessen during hemodialysis among others [26,50].
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 [6]. 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 [54].
Laboratory features may include serum blood urea nitrogen (BUN), parathyroid hormone (PTH), phosphate, calcium, and magnesium levels that are markedly elevated compared with patients without pruritus. Among 1773 adult patients on hemodialysis 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) [9].
DIAGNOSIS
Making the diagnosis — Our approach to diagnosing CKD-aP is based on the degree of kidney dysfunction:
●Patients with stage 5 CKD (including dialysis) – Since it is extremely common, we assume that pruritus presenting in patients with stage 5 CKD (whether on dialysis or not) is due to CKD-aP unless there is unequivocal and compelling evidence of another cause (eg, primary skin lesions including inflamed papules, patches, or plaques). 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 [53].
●Patients without stage 5 CKD – Because the prevalence of CKD-aP is less common in patients without stage 5 CKD, we diagnose CKD-aP in such patients only after evaluating and excluding other common etiologies of pruritus that occur in the general population. (See "Pruritus: Etiology and patient evaluation", section on 'Evaluation'.)
Differential diagnosis — A significant number of diseases can cause pruritus in patients with and without kidney disease. In general, alternatives to a diagnosis of CKD-aP should be considered among patients who have persistent pruritus that is refractory to common treatments such as topical emollients, topical analgesic agents, and oral antihistamines or gabapentinoids (ie, gabapentin or pregabalin). 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. (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", section on 'Signs and symptoms' and "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults", section on 'Pruritus'.)
MANAGEMENT — Treatment involves a stepwise approach that depends upon the severity of symptoms and the response to sequential therapies (algorithm 1). High-quality evidence on which to base recommendations for the treatment of CKD-aP 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 between 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 CKD-aP is the impressive placebo effect noted in many studies [55-57]. Finally, most studies examined patients on hemodialysis; data about treatment for patients on peritoneal dialysis and those with nondialysis CKD are sparse.
General measures in all patients — General measures for all patients with CKD-aP include the following:
●Optimal dialysis for patients with end-stage kidney disease since underdialysis is commonly associated with pruritus (see "Prescribing and assessing adequate hemodialysis" and 'Optimize dialysis' below)
●Optimal treatment of hyperparathyroidism and hyperphosphatemia (see 'Parathyroid, phosphate, and calcium' below)
●The regular use of emollients, particularly in patients with dry skin (see 'Skin emollients' below)
Optimize dialysis — For patients on dialysis, optimizing the dialysis dose and/or hemodialysis membrane may decrease pruritus. For patients with nondialysis CKD, we generally do not initiate chronic dialysis solely to treat pruritus; most patients with nondialysis CKD and pruritus can be treated medically, and the established risks associated with long-term dialysis typically outweigh the possible benefit of reduced itch. (See "Indications for initiation of dialysis in chronic kidney disease".)
●Dialysis dose – For patients on dialysis with Kt/V values that are less than generally accepted Kt/V targets for hemodialysis and peritoneal dialysis, we increase the dose of dialysis to meet those targets. We do this because of overall benefit conferred as well as for the potential beneficial effect on pruritus. (See "Prescribing and assessing adequate hemodialysis" and "Prescribing peritoneal dialysis".)
Increasing the dose of dialysis may improve pruritus [20,21,58]. A 12-month prospective study from 1995 included 59 patients on hemodialysis without significant disorders of bone metabolism who were stratified according to the degree of pruritus observed over three months [20]. 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) [20].
Importantly, the highest Kt/V values reported in this study from 1995 were still lower than the dose that is generally recommended today (ie, a target single-pool Kt/V of 1.4 per thrice weekly hemodialysis session with a minimum delivered single-pool Kt/V of 1.2).
Two additional observational studies 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 [59]. 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 [26]. 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.
●Biocompatible, high-flux hemodialysis membranes – Almost all patients on hemodialysis in the United States and other resource-abundant settings are dialyzed with biocompatible, high-flux membranes. However, for the rare patient who is being dialyzed with a bioincompatible and/or low-flux membrane, we switch to a biocompatible, high-flux membrane.
Biocompatible dialysis membranes (such as those made with polymethylmethacrylate [PMMA]) may decrease pruritus [60-62]. In the largest study of 30 patients with CKD-aP, the mean pruritus score decreased four weeks after switching to a PMMA dialyzer [60]. Two smaller studies also demonstrated improvement with PMMA membranes [61,62].
Pruritus appears to be more common in patients dialyzed with low-flux dialyzers [59]. In a randomized, double-blind, placebo-controlled crossover study that included 116 patients on hemodialysis, 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 [63].
Parathyroid, phosphate, and calcium — We optimize treatment of CKD–mineral and bone disorder (CKD-MBD) in all patients with CKD-aP. The parathyroid hormone (PTH) and phosphate concentrations that should be maintained to prevent or treat CKD-aP are not known; we target the commonly accepted serum values that have been developed for the overall benefit of such patients, and we avoid treatment-associated elevations in serum calcium. Our treatment approaches to secondary hyperparathyroidism and hyperphosphatemia are detailed elsewhere. (See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease" and "Management of secondary hyperparathyroidism in adult patients on dialysis" and "Management of hyperphosphatemia in adults with chronic kidney disease".)
Limited data suggest that the treatment of hyperparathyroidism, hyperphosphatemia, and hypercalcemia reduces CKD-aP [22,23]. The best data are from a series of 37 patients on hemodialysis who underwent parathyroidectomy for bone pain, pruritus alone, or bone pain with pruritus [23]. The mean 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. 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, 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.
Although the effect of nonsurgical treatment of hyperparathyroidism, such as vitamin D derivatives and calcimimetics, on CKD-aP 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 patients on dialysis".)
Skin emollients — For most patients with CKD-aP, we suggest treatment with a topical emollient. We prefer emollients with a high water content. Because xerosis (dry skin) is common and often may be difficult to detect, we use emollient therapy even in patients without obvious xerosis. We generally treat with an emollient for at least two weeks to gauge efficacy before initiating other medical therapies; the exception is for adequately dialyzed patients who present with severe pruritus, in whom we do not delay additional treatment (see 'Sequential therapy for persistent pruritus' below). We typically continue treatment with emollients indefinitely, regardless of initial response, since inadequately treated xerosis may prevent or reduce the efficacy of other therapies.
Most trials reporting the efficacy of emollients have been small or uncontrolled [64,65]. However, a randomized, double-blind, intraindividual (left versus right comparison), multicenter trial 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 [66]. At seven days, more patients responded to the glycerol/paraffin emulsion than to the emulsion alone 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 [66].
There are no good comparative trials among various emollients for CKD-aP.
Sequential therapy for persistent pruritus — For patients with continued symptoms despite two weeks of the general measures above (see 'General measures in all patients' above), we treat with additional therapy. The exception is for adequately dialyzed patients who present with severe pruritus, in whom we start additional treatment without delay. The interventions below are trialed sequentially, stopping one before starting another. The process concludes when an effective intervention is identified (algorithm 1).
Topical analgesics — For patients with CKD-aP who have persistent symptoms despite use of a skin emollient or who present with severe pruritus despite adequate dialysis, we suggest a topical analgesic agent. Topical analgesics should be applied to localized areas of pruritus and should be stopped if an inadequate response is observed after approximately one week. Our preferred topical analgesic agent is pramoxine, which is available in over-the-counter preparations and is generally safe. In a randomized trial that included 28 patients on hemodialysis, twice daily application of pramoxine was associated with a greater reduction in pruritus compared with an emollient (61 versus 12 percent, respectively) [67].
We do not use topical nonsteroidal antiinflammatory drugs (NSAIDs) or capsaicin to treat CKD-aP. Topical NSAIDs have not been evaluated as a treatment for CKD-aP and carry a risk of adversely affecting residual kidney function. Capsaicin is a topical analgesic that has been reported to be effective for localized pruritus [68-70]. However, in many patients capsaicin causes an unpleasant (albeit temporary) localized burning/stinging sensation, and existing capsaicin trials have design flaws that hinder their interpretation [71].
Oral antihistamine trial — For patients with CKD-aP who do not respond to topical therapy, we suggest oral antihistamine therapy. We stop antihistamines if an inadequate response is observed after approximately one week. We use either hydroxyzine (25 mg orally once or twice daily) or diphenhydramine (25 mg orally three to four times daily). 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'.)
The beneficial effects of antihistamines in pruritus are believed to be mediated via both their sedating properties and ability to stabilize mast cell membranes [72]. There are no high-quality data demonstrating efficacy of antihistamines for CKD-aP; our use of these agents is based on their relative safety and tolerability, their low cost, and our clinical experience.
Gabapentin and pregabalin — For patients with CKD-aP who do not respond to oral antihistamines, we suggest gabapentin or pregabalin. We stop these agents if an inadequate response is observed after four to six weeks. The preferred initial dose of gabapentin is 100 mg after each dialysis session. The dose may be gradually increased to 300 mg daily, based on response. Pregabalin is initiated at 25 mg daily, and the dose may be gradually increased to 75 mg daily. Gabapentin doses greater than 300 mg daily and pregabalin doses of greater than 75 mg daily are not recommended in patients with stage 5 CKD, whether on dialysis or not. Patients taking gabapentin or pregabalin should be monitored closely for neurologic side effects such as dizziness and somnolence.
Gabapentinoids are used in a variety of neuropathic pain syndromes and have demonstrated efficacy for the treatment of CKD-aP in a number of relatively small trials [73-82]. In a meta-analysis of randomized controlled trials that included five studies and 297 patients with CKD-aP, treatment with gabapentin or pregabalin reduced pruritus by approximately five points on a continuous 10-point visual scale [83].
Refractory pruritus — Most patients with CKD-aP will at least partially respond to emollients, topical analgesics, oral antihistamines, or a gabapentinoid. For patients on hemodialysis who are refractory to these agents, we use difelikefalin. Other options for refractory CKD-aP include dialysis modification, selective serotonin reuptake inhibitors, and phototherapy.
Difelikefalin for patients on hemodialysis — For patients on hemodialysis who have moderate to severe CKD-aP that does not respond to other agents, we suggest difelikefalin. Difelikefalin is a peripherally restricted selective kappa-opioid agonist that is administered intravenously (0.5 microgram/kg) three times a week at dialysis. We stop difelikefalin if an inadequate response 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 [57,84-87]. 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) [86]. 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 [88]. The most frequent side effects with difelikefalin were diarrhea, dizziness, and nausea. Somnolence was more common in patients receiving difelikefalin compared with placebo (4.2 percent versus 2.4 percent), especially in patients aged 65 years or older (7 percent versus 3 percent). 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 [57]. Other data demonstrate that even higher doses of difelikefalin do not cause respiratory depression [89].
Several concerns surround the use of difelikefalin. First, 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. Second, comparative efficacy data with other medications, such as gabapentin and pregabalin, are needed. Finally, the cost of difelikefalin may complicate accessibility and long-term use [90].
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 [91].
Other therapies — If difelikefalin is unavailable or ineffective, or if a patient is on peritoneal dialysis, we offer a trial of intensified dialysis. For patients on hemodialysis, switching to hemodiafiltration may be an option in certain settings. Potential alternatives to difelikefalin also include selective serotonin reuptake inhibitors and phototherapy.
●Dialysis modification
•Intensify dialysis – For patients on hemodialysis or peritoneal dialysis who have severe pruritus despite achieving optimal Kt/V targets and who are highly motivated, the dialysis dose may be increased further as a trial. For patients on thrice weekly hemodialysis who choose intensified dialysis, we generally target a single-pool Kt/V of 1.5 to 1.7 per hemodialysis session. For patients on peritoneal dialysis who choose intensified dialysis, we generally target a total (ie, residual kidney plus peritoneal) Kt/V of 1.9 to 2.1 per week. If an inadequate response is observed after six to eight weeks, we resume the regular dialysis regimen.
•Hemodiafiltration for patients on hemodialysis – Hemodiafiltration is generally not available in the United States. However, if available, switching a patient from hemodialysis to 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, and interleukin 6 levels compared with the group undergoing high-flux hemodialysis [92].
●Sertraline – A trial of the selective serotonin reuptake inhibitor (SSRI) sertraline is reasonable in patients with refractory pruritus [56,93-95]. Sertraline should be stopped if an inadequate response is observed after four to six weeks. Antidepressants have been used for the treatment of pruritus in the general (ie, non-CKD) population (see "Pruritus: Therapies for generalized pruritus", section on 'Antidepressants').
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 [94]. The mean effective daily dose was 35 mg. In a subsequent eight-week randomized, double-blind, placebo-controlled study that included 50 patients on dialysis, 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). The benefit of sertraline was noted only after four weeks of treatment [56].
●Phototherapy – We generally reserve phototherapy for patients with persistent symptoms who have not responded to or tolerated other options. Ultraviolet B (UVB) irradiation may be effective in the treatment of CKD-aP, as noted in small or uncontrolled studies [39,96-99]. As an example, in one study, 8 of 10 patients with refractory pruritus reported improvement in symptoms after UVB therapy [97]. 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 [100]. Specific UVB treatment protocols are discussed elsewhere. (See "UVB phototherapy (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 [35]. 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 CKD-aP. However, we do not advocate their use because of insufficient data and/or side effects. If clinicians use these therapies, they should prioritize agents with a minimal side effect profile and should stop treatment after inadequate response.
●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 CKD-aP:
•In 15 patients on hemodialysis 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 [101]. 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 [55]. 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 [102].
•Although a few short-term studies suggested that naltrexone was effective for CKD-aP [103-106], no benefit was demonstrated in a randomized, double-blind, placebo-controlled crossover study [11].
●Other – Various other therapies have been studied, including omega-6 fatty acid [107], omega-3 fatty acid [108,109], turmeric [110], zinc [111], acupuncture [112], activated charcoal [113,114], selective inhibitors 5-hydroxytryptamine receptors [115], oral cromolyn sodium [116,117], cholestyramine [118], nicergoline [119], thalidomide [38], ketotifen [49], dupilumab [120,121], montelukast [122,123], and topical agents such as gamma linolenic acid [124], sericin cream [125], endocannabinoids [126], topical vitamin D [127], cromolyn sodium [128], and topical tacrolimus [40,129-131].
IMPACT OF TRANSPLANTATION — Kidney transplantation is definitive therapy for CKD-aP. As an example, one retrospective study reported that generalized pruritus completely disappeared following successful transplantation [132]. 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 stage 5 chronic kidney disease (CKD). The etiology is not known. CKD-associated pruritus (CKD-aP) 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.)
●Diagnosis – Our approach to diagnosing CKD-aP is based on the degree of kidney dysfunction. (See 'Diagnosis' above.)
●Management – Treatment involves a stepwise approach that depends upon the severity of symptoms and the response to sequential therapies (algorithm 1). (See 'Management' above.)
•General measures in all patients – General measures for all patients with CKD-aP include the following (see 'General measures in all patients' above):
-For patients on dialysis with Kt/V values that are less than generally accepted Kt/V targets for hemodialysis and peritoneal dialysis, we increase the dose of dialysis to meet those targets.
-We optimize treatment of CKD-mineral and bone disorder (CKD-MBD).
-For most patients with CKD-aP, we suggest treatment with a topical emollient (Grade 2C). We typically continue treatment with emollients indefinitely, regardless of initial response, since inadequately treated xerosis may prevent or reduce the efficacy of other therapies.
•Sequential therapy for persistent pruritus – For patients with continued symptoms despite two weeks of the general measures above, we treat with additional therapy. The exception is for adequately dialyzed patients who present with severe pruritus, in whom we start additional treatment without delay. The interventions below are trialed sequentially, stopping each one before starting another. The process concludes when an effective intervention is identified. (See 'Sequential therapy for persistent pruritus' above.)
-For patients with CKD-aP who have persistent symptoms despite use of a skin emollient, or who present with severe pruritus despite adequate dialysis, we suggest a topical analgesic agent rather than oral agents (Grade 2C). We stop this agent if an inadequate response is observed after approximately one week. (See 'Topical analgesics' above.)
-For patients with CKD-aP who do not respond to topical therapy, we suggest oral antihistamine therapy (Grade 2C). We stop antihistamines if an inadequate response is observed after approximately one week. (See 'Oral antihistamine trial' above.)
-For patients with CKD-aP who do not respond to oral antihistamines, we suggest gabapentin or pregabalin (Grade 2B). We stop these agents if an inadequate response is observed after four to six weeks. (See 'Gabapentin and pregabalin' above.)
•Refractory pruritus – For patients on hemodialysis who have moderate to severe CKD-aP that does not respond to other agents, we suggest difelikefalin (Grade 2C). We stop difelikefalin if an inadequate response is observed after 12 weeks of treatment. Other options for refractory CKD-aP include dialysis intensification, selective serotonin reuptake inhibitors (SSRIs), and phototherapy. (See 'Difelikefalin for patients on hemodialysis' above and 'Other therapies' above.)
●Impact of transplantation – CKD-aP 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
We are saddened by the death of Sidney Kobrin, MD, who passed away in October 2023. UpToDate wishes to acknowledge Dr. Kobrin's many valuable contributions, including his past work as an author for this topic.
The UpToDate editorial staff acknowledges Theodore Tzeremas, MD, who contributed to earlier versions of this topic review.
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