| Summary |
Uremic pruritus is one of the most common and bothersome symptoms in patients with end-stage renal disease. Most patients with uremic pruritus experience a prolonged, relapsing course and a significant deterioration in quality of life.
The pathophysiology of uremic pruritus is not completely understood. A complex interaction between skin biology and the nervous and immune systems has been implicated, involving several inflammatory mediators, neurotransmitters, and opioids.
The results of treatment for uremic pruritus are often unsatisfactory. Clinical trials have been mostly small-scale and have reported inconsistent results.
Recent evidence shows that gabapentinoids, nalfurafine, and diphelikephaline are effective in relieving uremic pruritus in hemodialysis patients.
This review provides an overview of the epidemiology and proposed mechanisms of uremic pruritus, then highlights the manifestations and clinical approach of uremic pruritus. The current evidence regarding treatment options is also described, including topical treatments, treatment of the underlying disease, phototherapy, and systemic treatments.
With a better understanding of uremic pruritus, more therapeutic options can be expected in the near future.
Uremic pruritus is one of the most common and distressing comorbid conditions in patients with end-stage renal disease (ESRD) and also occurs in patients with chronic kidney disease (CKD).
Uremic pruritus significantly affects multiple aspects of quality of life, including mood, sleep, and social relationships, and is often refractory to treatment. Furthermore, in patients with ESRD, higher pruritus intensity is associated with worse patient survival and more peritoneal dialysis (PD) technique failures.
In this review, we summarize the current knowledge on the epidemiology, pathophysiology, clinical presentation, clinical approach, and treatment of uremic pruritus.
Due to the various definitions of uremic pruritus used in the literature, we defined uremic pruritus as symptoms of chronic pruritus secondary to decreased renal function.
Articles reporting studies on pruritus secondary to ESRD or CKD were reviewed. For the pathophysiology and treatment of other pruritic diseases, we refer readers to other review articles.
| Epidemiology |
The prevalence of uremic pruritus varies by country, dialysis modality, dialysis unit, and study population.
Uremic pruritus affects 25% to 62% of patients receiving PD and 38% to 84% of patients receiving hemodialysis (HD).
In an international survey conducted between 1996 and 2015, the prevalence of bothersome uremic pruritus in HD patients gradually decreased from 28% to 18%. However, comparisons between HD patients and PD patients regarding the prevalence and severity of uremic pruritus remain inconsistent.
| Pathophysiology |
The pathophysiology of uremic pruritus has not been completely elucidated. Along the sensory pathway of itch , the proposed origins have been classified as follows:
1) pruritoceptive: induced by pruritogens in the skin, for example, allergic contact dermatitis;
2) neuropathic: resulting from a pathology in the afferent conduction pathway of the central and peripheral nervous system, for example, related to multiple sclerosis;
3) neurogenic: originating in the nervous system without neural damage, for example, opioid-induced pruritus;
4) psychogenic: due to psychiatric and psychosomatic causes without organic problems, for example, parasitophobia .
The mechanism of uremic pruritus may involve complex interactions from more than one proposed origin.
Skin moisture is lower in dialysis patients, and dry skin is very common in patients with uremic pruritus.
Dialysis patients with uremic pruritus showed lower levels of stratum corneum hydration than patients without pruritus, while some studies found no association between pruritus and skin hydration or transepidermal water loss. It is not clear whether there are more mast cells in the skin of patients with uremic pruritus.
Some studies have reported that the number of dermal mast cells in HD patients is significantly higher than that of healthy controls, while another report showed no relationship between the extent of pruritus, the number of mast cells in the skin, or the level of plasma histamine. in dialysis patients.
Divalent ions, calcium phosphate products, hyperparathyroidism, and uremic neuropathy have also been implicated in uremic pruritus.
The results of our previous study and those of others identified dialysis adequacy as an independent predictor of pruritus severity in HD patients, which suggested that the elimination of pruritogenic substances could influence pruritus severity.
Immune dysregulation plays a fundamental role in the pathophysiology of uremic pruritus. Compared with patients without pruritus, those with uremic pruritus show higher levels of C-reactive protein and several inflammatory mediators, such as histamine, interleukin (IL)-2, and IL-6.
Morphine has been reported to trigger itch, suggesting that the opioid system is involved in the mechanism of uremic pruritus. Furthermore, a selective peripherally restricted κ-opioid receptor agonist showed a significant antipruritic effect in a recent trial in HD patients.
| Clinical presentation |
Patients suffering from uremic pruritus often experience itching daily or almost daily. Pruritus can affect all areas of the body, affecting more than 25% of the body surface in more than half of patients with uremic pruritus.
The course is fluctuating and prolonged, usually lasting more than a year.
Patients with uremic pruritus often have pruritus in the absence of a primary skin rash. However, the vicious cycle of itching and scratching behaviors can lead to secondary skin changes, such as excoriations, prurigo nodularis, lichen simplex, or nonspecific eczema.
| Clinical approach |
The first step in controlling itching in patients with reduced kidney function is an accurate diagnosis. In addition to uremic pruritus, patients on dialysis and with CKD may present with several pruritic skin diseases, such as scabies, atopic dermatitis, and drug allergies.
A detailed medical history and skin examination are crucial for correct diagnosis. Causes other than uremic pruritus should be considered if an itchy skin condition occurred before the onset of kidney disease.
If pruritus is limited to localized areas or exacerbates over a short period, exposures or aggravating factors should be evaluated .
A careful review of the patient’s medication history can exclude drug-related pruritus or drug-related hypersensitivity reactions. If skin examination reveals primary skin eruptions, such as wheals, morbilliform eruptions, or bullae, other dermatologic diseases should be included in the differential diagnosis.
A skin biopsy is generally not necessary for the diagnosis of uremic pruritus. Laboratory and imaging studies may be considered for patients with manifestations suggesting other causes of itchy skin, such as hyperthyroidism or cutaneous T-cell lymphoma.
| Treatments |
Uremic pruritus is frequently refractory to multiple treatments. However, many studies on the treatment of uremic pruritus in recent years have shed light on this intractable disease.
| Topical treatments |
> Moisturizers
A high percentage of patients with uremic pruritus have dry skin. Maintaining adequate skin hydration is the cornerstone of antipruritic treatment.
In an uncontrolled study, 16 of 21 dialysis patients with uremic pruritus reported a reduction in pruritus severity after 1 week of regular emollient use.
> Steroids
Approximately 10% of physicians prescribe topical steroids as first-line treatment for uremic pruritus in patients with HD, but no trials have evaluated their efficacy.
As microinflammation plays an important role in the pathogenesis of uremic pruritus, topical steroids may provide antipruritic effects against uremic pruritus, especially in skin areas with secondary scratching-induced eczema or overt inflammation. However, because uremic pruritus typically affects a large percentage of the body surface area, use of potent topical steroids on large areas of skin may result in systemic absorption and adverse skin effects, such as skin atrophy and folliculitis.
Topical steroids should be prescribed with caution and patients should be educated on how to use them correctly.
> Capsaicin
Capsaicin, the active compound in chili peppers , depletes the neuropeptide substance P from sensory nerve terminals in the skin and blocks pain and itch conduction.
Topical capsaicin has been used to relieve pruritus, especially in neuropathic pruritus states, such as postherpetic pruritus, brachioradial pruritus, and notalgia paresthetica.
Two double-blind, randomized, crossover controlled trials (RCT) of HD patients showed that capsaicin 0.025% cream was significantly more effective in relieving uremic pruritus than placebo. Common side effects are local burning, stinging, and erythema at the application site.
> Calcineurin inhibitors
Topical calcineurin inhibitors, including tacrolimus and pimecrolimus, selectively inhibit calcineurin and therefore prevent the transcription of IL-2 and other cytokines in T cells.
Topical calcineurin inhibitors have been used in inflammatory skin disorders.
In an uncontrolled study of 25 dialysis patients, Kuypers et al. showed that tacrolimus ointment significantly reduced the severity of uremic pruritus after 6 weeks. However, in a 4-week double-blind RCT of 22 HD patients, Duque et al. showed that 0.1% tacrolimus ointment was no more effective than placebo in relieving uremic pruritus.
> Pramoxine
Pramoxine is a topical local anesthetic with a potential antipruritic effect that interferes with the transmission of impulses along sensory nerve fibers.
In a double-blind RCT of 28 HD patients, Young et al. reported that a lotion containing 1% pramoxine was more effective than the control lotion in reducing the intensity of uremic pruritus.
> Gamma-linolenic acid
Gamma-linolenic acid is an essential fatty acid found in some plant seed oils that provides potential relief from itching through local anti-inflammatory or immunoregulatory effects.
In a double-blind crossover RCT of 17 dialysis patients, Chen et al. showed that cream containing 2.2% gamma-linolenic acid was more effective than control cream in relieving uremic pruritus.
> Cannabinoids
Cannabinoids are chemical compounds derived from cannabis and have therapeutic potential in several diseases, including chronic pruritus.
In an uncontrolled study of 23 HD patients, a topical cream containing endocannabinoids (N-acetylethanolamine and N-palmitoylethanolamine) completely eliminated pruritus in 38.1% of patients and significantly reduced xerosis after 3 weeks of treatment.
| Treatment of underlying disease |
> Optimization of dialysis dose and modality
Optimizing the dialysis dose and increasing the clearance of intermediate molecules could eliminate more pruritogenic substances and decrease the severity of pruritus; however, there is no standard dialysis goal or dialysis modality for pruritus symptoms.
In an intervention study of 22 HD patients with uremic pruritus, Hiroshige et al. reported that 78% of patients had a significant reduction in pruritus severity after increasing Kt/V (the assessment of dialysis dose) from 1.08 to 1.19, while only 8% of Patients who remained on the same dialysis dose had a reduction in pruritus severity.
In our 5-year cohort study of 111 HD patients, we found that a target Kt/V ≥ 1.5, which was slightly above the standard of ≥ 1.4, reduced the intensity of uremic pruritus.
In another 2-year cohort study of 85 PD patients, we found that a weekly total Kt/V of ≥1.88, which was higher than the standard of ≥1.7, was associated with lower intensity of uremic pruritus .
> Control of hyperparathyroidism
In a case series of 37 dialysis patients with uremic pruritus and hyperparathyroidism, Chou et al. found a significantly reduced pruritus intensity 1 week after parathyroidectomy.
In a 36-week open-label RCT of 82 HD patients with hyperparathyroidism, El-Shafey et al. reported better relief of pruritus severity in patients receiving cinacalcet, a calcium-sensing receptor that targets calcimimetics in parathyroid cells, compared with those receiving conventional therapy with vitamin D and phosphate binders.
Currently, parathyroidectomy or cinacalcet should only be considered based on the severity of hyperparathyroidism and not as a standard treatment for uremic pruritus.
> Kidney transplant
Successful kidney transplantation should be able to cure uremic pruritus, as a functional kidney graft alleviates the uremic state. However, a considerable number of kidney transplant recipients with good graft function still experience chronic pruritus.
> Phototherapy
Ultraviolet (UV) phototherapy is effective for several skin conditions and is better tolerated than many systemic treatments.
In a 4-week RCT of HD patients with intractable pruritus, broadband UVB phototherapy showed better antipruritic effects than UVA phototherapy. Despite concerns about photocarcinogenesis, UVB phototherapy has not been reported to increase the risk of nonmelanoma skin cancer and cutaneous melanoma in patients with uremic pruritus.
| Systemic treatments |
> Gabapentinoids
Gabapentinoids, including gabapentin and pregabalin, bind to voltage-gated calcium channels to decrease neurotransmitter release and are used for the treatment of postherpetic neuralgia, neuropathic pain, and fibromyalgia.
In a meta-analysis of five RCTs with 297 patients on HD, there was a significant benefit in favor of gabapentinoids compared to placebo in reducing the degree of uremic pruritus. Furthermore, a meta-analysis of five RCTs with 220 HD patients showed a better reduction in pruritus intensity in gabapentinoid users than in antihistamine users.
In a single-blind RCT of 90 HD patients, pregabalin was found to be more effective in reducing the severity of uremic pruritus than doxepin. In a crossover RCT of 50 HD patients, gabapentin and pregabalin showed similar antipruritic effects. Drowsiness and dizziness are common adverse effects of gabapentinoids, and dosage adjustment is necessary in patients with renal impairment.
> Opioid antagonists and agonists
Central μ-opioid receptors are involved in processing the sensation of itch, and activation of central κ-opioid receptors antagonizes the μ-opioid receptor-mediated process of itch development. Therefore, μ-opioid receptor antagonists and κ-opioid receptor agonists have been used in the treatment of pruritic skin diseases, such as nodular prurigo, cholestatic pruritus, and uremic pruritus.
Double-blind RCTs on the antipruritic effect of naltrexone, a μ-opioid receptor antagonist, showed conflicting results in dialysis patients. In a crossover RCT of 15 HD patients, Peer et al. showed that the use of naltrexone 50 mg daily for 1 week significantly improved uremic pruritus compared with placebo.
> Antihistamines, mast cell stabilizers and leukotriene receptor antagonists
Oral antihistamines are the most frequently prescribed drugs for uremic pruritus, but few trials have evaluated their effectiveness on uremic pruritus.
In an uncontrolled study of five HD patients with severe uremic pruritus, all patients had a significant reduction in pruritus intensity after receiving ketotifen for 8 weeks.
In an 8-week double-blind RCT of 62 HD patients with pruritus,cromolin sodium showed a greater reduction in pruritus severity than placebo.
In a double-blind RCT of 80 HD patients with chronic pruritus, the reduction in pruritus severity was greater in patients who received montelukast for 30 days than in those who received placebo.
> Oral activated charcoal
Activated charcoal is used as a non-selective intestinal adsorbent for certain types of poisons. An early double-blind crossover RCT of 11 patients showed that 6 g of oral activated charcoal taken daily for 8 weeks was more effective in relieving pruritus and resolving scratch-induced skin lesions than placebo dextrose.
AST-120, an oral activated charcoal adsorbent used to treat uremic symptoms and postpone the initiation of dialysis, has been reported to relieve pruritus in HD patients with generalized pruritus. Gastrointestinal symptoms, such as constipation, nausea, and bloating, are side effects of oral activated charcoal.
> Cholestyramine
Cholestyramine is a nonabsorbable resin used for the treatment of hyperlipidemia and pruritus in patients with chronic liver disease and biliary obstruction.
In an early double-blind RCT of 10 HD patients, Silverberg et al. demonstrated that uremic pruritus improved significantly in four of five patients using cholestyramine 5 g twice daily compared with improvement in only one of five patients in the placebo group.
> Organic products
Serum IL-31 is positively associated with pruritus and may play a critical role in uremic pruritus.
Nemolizumab, an antibody against IL-31 receptor A, has been shown to reduce the severity of pruritus in patients with atopic dermatitis. However, a double-blind phase II RCT comparing nemolizumab with placebo showed no significant difference in pruritus intensity among HD patients with uremic pruritus.
Dupilumab, a human monoclonal antibody that blocks IL-4 and IL-13, has been approved for the treatment of moderate to severe atopic dermatitis. In a case report and case series, dupilumab significantly reduced uremic pruritus in patients with CKD and dialysis.
> Thalidomide
Thalidomide has been shown to have sedative, immunomodulatory and antiangiogenic properties.
In a double-blind crossover RCT of 29 HD patients with refractory uremic pruritus, Silva et al. demonstrated the antipruritic efficacy of thalidomide, as 55.6% of thalidomide users had reduced pruritus intensity compared to 13.3% of placebo users.
However, the benefits and risks should be carefully evaluated before initiating thalidomide therapy due to its potential side effects, including teratogenicity, peripheral neuropathy, constipation, and sedation.
> Sertraline
Sertraline, a selective serotonin reuptake inhibitor, is used for the treatment of major depressive disorder, panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder.
In a retrospective cohort study of 17 patients with pruritus related to late stages of CKD, patients reduced the severity of pruritus after using sertraline for a median duration of 5.1 weeks.
In a double-blind RCT comparing sertraline with placebo in HD patients with uremic pruritus, both groups showed a reduction in pruritus intensity. Common adverse reactions of sertraline include nausea, tremors, and drowsiness.
| Conclusions |
Correct evaluation and diagnosis, optimization of metabolic profiles and dialysis regimens, proper skin care and protection, selection of appropriate topical and oral medications, and monitoring of medication side effects are important. in the treatment of uremic pruritus.
Recent evidence shows that gabapentinoids, nalfurafine, and diphelikephaline are effective in relieving uremic pruritus in patients with HD.
Topical steroids, topical capsaicin, phototherapy, antihistamines, mast cell stabilizers, leukotriene receptor antagonists, activated charcoal, and optimization of dialysis dose and modality may also be therapeutic options, although they are needed. more test results.
With a better understanding of the pathophysiology of pruritus and updated clinical trials, more treatment options for uremic pruritus can be expected.
