Moreover, no drugs have been approved by the U. Food and Drug Administration for this problem. Before considering the treatment of UP, an evaluation should be performed to define whether pruritus in a specific patient is caused by uremia which needs adequate dialysis or is related to dermatologic or systemic disease such as hyperparathyroidism, hyperphosphatemia and anemia that may require a different approach [ 2 ]. Once the etiology of pruritus has been established, several therapies can potentially be adopted.
Treatments can be classified as topical, physical or systemic applications. In order to control UP in dialysis patients, several factors need to be monitored such as improvement of nutritional status, monitoring of calcium and phosphorus levels, optimization of dialysis efficacy as well as use of biocompatible dialysis membranes [ 65 ].
Pruritus found in CKD may cause from other disorders such as liver diseases for instance; hepatitis , endocrine disorders for instance; Graves' disease, diabetes mellitus and hypothyroidism and skin disorders such as atopic dermatitis, psoriasis, contact dermatitis and urticaria. Pruritus found in these causes need specific treatments which may differ from standard treatment [ 53 ]. The prevalence of UP declines by using biocompatible dialysis membranes [ 66 ].
Hence, the first approach to improve UP is still to optimize the dialysis efficiency, use biocompatible dialysis membranes and improve the nutrition status of patients. One study demonstrates that in a series of 30 cases, a polymethylmethacrylate PMMA artificial kidney may be a useful adjuvant therapy in chronic hemodialysis patients with severe UP, as it may eliminate more serum cytokines by adsorption than other types of high-flux membranes [ 67 ].
However, drastic reduction in dialysate calcium concentration may possibly aggravate renal osteodystrophy. It is a common experience that pruritus is more frequent in underdialyzed patients and improves by increasing the efficacy of dialysis. Patients who experience pruritus together with hypercalcemia and hyperparathyroidism should be treated by parathyroidectomy [ 46 , 71 ]. However, there is no relation between parathyroid hormone and UP, parathyroidectomy should not be used as a routine procedure [ 2 ].
It was found that patients with hypocalcemia or serum calcium at the normal limit can still experience pruritus. It can be concluded that the relationship between serum calcium level and pruritus is hardly found [ 72 ].
The role of phototherapy in renal pruritus has been assessed by double-blind trials. Ultraviolet B UVB has been generally, although not uniformly, shown to be therapeutic. The mechanism of the antipruritic effect of UVB is not completely understood. Among the proposed mechanisms are inactivation of a circulating pruritogenic substance, formation of a photo-product that relieves pruritus, alteration of divalent ion content in the skin, suppression of histamine release as well as deactivation of circulating pruritogenic substances [ 16 ] and promotion of cutaneous nerve degeneration [ 73 , 74 ].
UVB phototherapy is well tolerated aside from occasional instances of sunburn [ 75 ]. The duration of the antipruritic effect of thrice-weekly, total body UVB phototherapy 8- 10 sessions in total is variable but can last for several months. In , Saltzer et al. The study also showed that there was no significant difference between remission rates or length of remission between the intensive, intermediate and prolonged treatment schedule [ 75 , 79 ].
Later, a study by Blachley et al. Further investigation has been performed using narrowband UVB phototherapy, as most of the data on UV radiation have been predominately derived from studies using broadband UVB [ 80 ].
The results showed the effectiveness of narrowband UVB, as 9 of 15 patients with UP were marked as responders; however, remission was not prolonged, as 4 of 6 responders who came back for a follow-up had a recurrence [ 80 , 81 ].
Narrowband UVB, which is generally accepted to be less carcinogenic than broadband UVB, should be a better alternative treatment in both efficacy and safety aspects. Modern medicine tries to explain the efficacy of acupuncture by describing its effects on the receptors of the nervous system, its action on the endogenous endorphin enkephalin and 5-hydroxytryptamine 5-HT , or that it can increase the number of leukocytes and strengthen the defensive mechanisms of the body [ 83 ].
Some studies show the benefit of acupuncture for UP. The fundamental information indicated that pruritus was transmitted by conductive C fibers, and acupuncture generates impulses that are carried by the smaller, myelinated, and rapidly conductive beta and delta fibers, all of which reach the spinal cord. There, opiate-like substances are released that block the slower C fiber impulses [ 84 ].
Using a transcutaneous electrical nerve stimulation TENS acupressure apparatus at those points also showed a benefit in reducing UP [ 86 ]. Duo also reported that an electric needle is effective at two similar points Quchi and Zusanli [ 87 ]. Che-yi et al. However, acupuncture does not change the level of biochemical parameters associated with the development of UP—including magnesium, iPTH, phosphate and calcium.
Hsu et al. The result implied that thermal therapy may have therapeutic benefits for UP. Stimulation of the sweat glands with a sauna has shown benefits, perhaps through augmented excretion of hypothetical pruritogen [ 89 ]. However, such treatment may cause major complications in fluid balance due to unquantifiable insensible water loss. Topical treatment with skin emollient contained high water to hydrate stratum corneum is considered as a primary therapy for UP in CKD patients.
In order to avoid any allergic reaction, emollients without perfumes or other additives is preferable [ 43 , 90 ]. Because xerosis plays at least an adjuvant role in the development of UP, emollients are a mainstay in the treatment. It has been suggested by several researchers that the use of emollients with high water content should be the first-line treatment [ 91 , 92 ].
The benefit of using emollients to treat dry skin in patients with UP has been reported by Morton et al. The study by Balaskas et al. The addition of endocannabinoids to creams containing structured physiological lipids demonstrated good efficacy and tolerance in a clinical study [ 61 , 95 ].
Sericin, a biopolymer with a high molecular weight, is a water-soluble protein that is obtained from the silkworm Bombyx mori. Sericin also demonstrates many biological activities and has been widely studied for potential use in medicines and biomaterials [ 96 - ]. As previously mentioned, the immune-inflammatory hypothesis considers UP a dermatologic manifestation of chronic inflammation and treats the condition as a possible result of derangements in the immune system that are based on a pro-inflammatory pattern.
Based on this reasoning, sericin was investigated for relieving UP. The results showed that sericin reduces pruritus in patients with UP. The use of sericin cream significantly increased the level of skin hydration after 6 weeks of treatment compared to baseline and to the use of the cream base.
The use of sericin cream also significantly reduced the level of skin irritation and pigmentation after 6 weeks of treatment compared to baseline, while use of the cream base reduced skin pigmentation slightly but not significantly.
The overall score increased from The results of this study suggest that sericin cream may be a good choice for treating pruritus in hemodialysis patients.
Because sericin is obtained from natural sources that have high biocompatibility, it may cause fewer allergic reactions and lower resistances compared to other chemical substances. Capsaicin transmethyl-N-vanillylnonenamide , an extract from capsicum or common pepper plant, can be used as a main ingredient in cream for the treatment of painful disorders including postherpetic neuralgia, cluster headaches, diabetic neuropathy, osteoarthritis and phantom limb [ , ].
Capsaicin blocks pain and itching by depleting and preventing the re-accumulation of substance P from local type C sensory nerve terminals [ 89 , ]. After using 0. Although topical capsaicin might be useful for the treatment of localized disease, it is impractical for large areas or generalized pruritus. Tacrolimus is an immunomodulator targeting mainly at the T helper cells.
It blocks the differentiation of Th1-type lymphocytes, and therefore, suppresses the production of IL Due to these mechanisms, it was suggested that it might be beneficial in the treatment of UP.
An observational study of 3 cases of severe UP in patients on peritoneal dialysis indicated a short-term efficacy of 0. However, the use of this agent was not extended longer because of the potential carcinogenic effect of systemic tacrolimus [ ], which resulted in an FDA black-box warning that was issued in against the prolonged topical use of tacrolimus creams and ointments. Nevertheless, some studies failed to demonstrate any efficacy of the topical calcineurin inhibitor in patients with UP [ , ].
Endogenous opioids have been implicated in the genesis of the pruritus associated with cholestasis [ , ]. Only mild upper gastrointestinal tract symptoms were found to be the side effects [ ].
Opioid antagonists should therefore be considered for patients with severe and persistent UP [ 2 ]. Nalfurafine was administered intravenously postdialysis over weeks, and the results were encouraging, as improvements in the worst itching, itching intensity and sleep disturbances were noted in the nalfurafine group, with significant p values [ ].
In addition, the evaluation of adverse events demonstrated that nalfurafine was well tolerated. De Marchi et al. They found that erythropoietin improved UP and decreased plasma histamine concentrations. Further, they found that it can result in marked improvement of UP and that recurrence of pruritus occurred after discontinuation of erythropoietin [ ]. However, this effect was not related to the change in hemoglobin levels [ ].
Serotonin has been suggested as a possible mediator of cholestasis and UP. One study indicated that ondansetron, a selective inhibitor of serotonin type 3 receptors, at 4 mg twice a day for approximately 3 months can significantly reduce the severity of UP in peritoneal dialysis patients with moderate to severe pruritus [ ].
This treatment was well tolerated and showed no significant side effects. However, the study by Ashmore et al. Considering that neuropathic pain and pruritus share common pathogenic mechanisms, gabapentin, which is usually used to treat neuropathic pain, emerged as another possibility in the arsenal of treatment for severe UP resistant to other therapies [ 64 ].
Recent, limited data suggest that gabapentin is a promising drug in treating UP, given its efficacy and its safety [ 13 , 91 , ]. In a randomized, placebo-controlled, double-blind study, 25 patients were treated with gabapentin versus a placebo for 4 weeks; the treatment was then reversed, and the mean pruritus score dropped significantly.
No patient dropped out due to adverse events from gabapentin [ ]. Regarding its pharmacokinetics, gabapentin is eliminated primarily through the kidney, and it is removed by hemodialysis. It has a significantly longer half-life in patients on hemodialysis than in those with normal kidney function, and thus, these patients need lower doses at less frequent intervals [ 64 ].
The recommended dose for hemodialysis patients is mg after each hemodialysis session, with somnolence, dizziness and fatigue being the most commonly reported side effects [ ]. Despite the fact that histamine might be implicated in the pathogenesis of UP and the demonstration of elevated histamine levels in patients with ESRD with pruritus [ 91 , ], classical antihistamines showed very limited efficacy in the treatment of UP [ 53 , 54 , 94 , ]. The response to the administration of antihistaminic agents is marginal, at best [ 9 ].
Mast cell stabilizers including ketotifen, mg per day for 8 weeks, [ 55 ] and cromolyn sodium [ 55 ], however, were demonstrated to be effective in case series. Abnormalities in the plasma composition of essential fatty acids may be related to the etiology of pruritus in patients undergoing hemodialysis. After administration of 6 grams of ethyl ester of either fish oil, olive oil or safflower oil in double-blind study of 25 hemodialysis patients, the results indicated that pruritus was significantly improved due to the altered plasma fatty acid profile and increased prostaglandin E 2 PGE 2 plasma concentration [ ].
Parenteral administration of lidocaine, a membrane-stabilizing antiarrhythmic agent, can relieve pruritus in double-blind study however, significant side effects such as hypotension and grand mal seizures were found [ ]. An oral dosage form of mexiletine, a longer half-life and less toxicity than lidocaine, was found to be ineffective for the treatment of UP [ ]. Low protein diet has been proposed for the treatment of UP due to the rational of less accumulation of renally excreted pruritogen [ ].
However, low protein diet may lead to malnutrition which can be dangerous in CKD patients and detoxification showed no benefit on pruritus [ 2 ]. With the rationale of adsorbing an unidentified pruritogen, oral activated charcoal at the dose of 6 grams per day has been used for uremic pruritus. A double-blind crossover trial and a single-blind study have yielded impressive results [ , ].
This preparation is effective, inexpensive, and has a favorable side effect profile. However, this treatment has not yet been accepted and utilized in clinical practice [ , ]. The success of cholestyramine in treating PU is inconsistent. When administered at a dose of 5 grams twice a day, the gastrointestinal side effects are normally found. Moreover, the risk of acidosis must also be taken into consideration, particularly in patients who are not on dialysis [ , ].
Patients on hemodialysis may develop pruritus when treated with porcine or bovine heparin. Pruritus is relieved promptly when another form of heparin is used, implying that these heparins act as allergens [ 9 ].
Paradoxically, administration of heparin at mg twice a day for weeks can improve UP in some dialysis patients [ ]. From the mechanism of action by inhibition of T-lymphocyte heparanase activity which is an important factor for T-cell migration to target tissues, low molecular weight heparin such as enoxaparin at low dose is effective in treating pruritus associated with lichen planus [ 2 , ].
A double-blind, placebo-controlled study that investigated the effect of 30 mg per day by mouth and 5 mg per day intravenously during dialysis, indicated relief of pruritus in most patients, and the effect lasted for 48 h with improvement persistent in long-term therapy 30 mg per day in most patients who responded to the initial treatment [ ]. Nicotinamide is the pyridinecarboxylic acid amide of niacin, a component of the vitamin B complex. Namazi et al. For those reasons, nicotinamide could be an effective treatment for UP.
However, clinical trials should be conducted to confirm its efficacy. It is considered to be an inflammatory systemic disease rather than a local skin disorder. Biomarkers of inflammation are increased in patients with UP, and an imbalance of the endogenous opioidergic system might be involved in the complex pathogenesis of the disease.
Given the complexity of its pathogenesis and the lack of clear evidence regarding the efficacy of more conservative therapies, the only definitive treatment is kidney transplantation.
Antihistamines, which are the most widely used antipruritic agents, are ineffective for the treatment of hemodialysis-related pruritus. Safe and effective modalities, and those that should probably be considered as first-line treatment, are topical emollients. Other physical therapies and medications should be further investigated due to the inconsistent trial results. Without definitive treatment of the underlying disease, therapy for hemodialysis-related pruritus is often palliative at best, aiming to minimize the severity of pruritus and to improve the quality of life.
The standard of care remains to optimize the dialysis dose and to use biocompatible membranes, as well as the treatment of mineral abnormalities and anemia. DermNet NZ does not provide an online consultation service. If you have any concerns with your skin or its treatment, see a dermatologist for advice.
Uraemic pruritus — codes and concepts open. Chronic kidney disease associated pruritus. Systemic disorder, Symptoms and findings. L29, N References Textbook of Dermatology. Jean L. Bolognia and Joseph L. Jorizzo, Ronald P Rapini. Second edition. Mosby Publications. Manenti L. Uraemic pruritus, clinical characteristics, pathophysiology and treatment. Drugs ; 69 3 Silverberg J. A successful case of dupilumab treatment for severe uremic pruritus. N Engl J Med. Gabapentin for uremic pruritus: a systematic review of randomized controlled trials.
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