Recent Advances in the Treatment of Uremic Pruritus

Aaron J. Trachtenberg; David Collister; Claudio Rigatto

Disclosures

Curr Opin Nephrol Hypertens. 2020;29(5):465-470. 

In This Article

Treatment

Management of uremic pruritus involves a variety of nonpharmacological and pharmacological interventions, often applied in a stepwise manner. Emollients to address underlying xerosis contributing to disease severity are considered standard of care.[45] Oral and topical antihistamines are often employed, although the evidence is scant.[2,7] Additional treatment options, including many different categories of topical and systemic medications (for localized or generalized itching, respectively), ultraviolet light therapy, and adjustments in dialysis prescription have been reviewed by several groups.[5,7–9] Unfortunately, the randomized controlled trial (RCT) evidence supporting these treatments, with the exception of gabapentin, is weak and at high risk of bias, limiting conclusions.[7] In this section, we focus on treatments for which recent high-quality evidence is available (difelikafalin, gabapentin). Finally, we will summarize newer treatments in the development 'pipeline'.

KALM-1 Trial Introduces an Effective Agent for Uremic Pruritus in Hemodialysis

The KALM-1 trial[46] was a randomized, double-blind, placebo-controlled phase 3 trial comparing difelikefalin, a peripherally restricted selective κ-opioid receptor agonist to placebo in 378 adult hemodialysis patients across 56 sites in the United States. Patients were assigned 1:1 to receive intravenous difelikefalin at a dose of 0.5 μg/kg thrice weekly at dialysis, or a matched placebo. Difelikefalin activates peripheral-nerve κ-opioid receptors, inhibiting afferent activity signaling itch, and interacts with κ-receptors on immune system cells (monocytes and T lymphocytes) decreasing the release of proinflammatory and pruritogenic compounds. After 12 weeks, the proportion of patients with an improvement of least 3 points (considered a minimally clinically significant change) on the well-validated 24-h Worst Itching Intensity Numerical Rating Scale was significantly greater in the difelikefalin group than in the placebo group (49.1 versus 27.9%; RR, 1.65; 95% CI: 1.26–2.14; P < 0.001). This effect was consistent across all outcomes, including itch-related quality of life, and was of similar magnitude when stratified by baseline antipruritic medication use. In the difelikefalin group, there were no reports of euphoria, hallucinations, or other symptoms which could be associated with abuse and no evidence of withdrawal symptoms in the two weeks after discontinuation. The incidence of adverse events was similar in both groups [difelikefalin 68.8% (130 of 189 patients) versus placebo 62.2% (117 of 188 patients)]; the high prevalence in both groups likely reflects the generally high incidence of adverse events in the hemodialysis population. The most common adverse events in patients receiving difelikefalin were diarrhea, dizziness, and vomiting; these events were generally mild to moderate in severity and 'resolved without evident clinical consequence.' Adverse events led to discontinuation of treatment in 15 patients (7.9%) in the difelikefalin group and in nine patients (4.8%) in the placebo group. For patients on hemodialysis with uremic pruritus, the KALM-1 trial offers exciting evidence supporting a new and promising therapy; however, the cost and availability of this drug remains to be determined. An oral formulation of difelikefalin is currently being tested in nondialysis CKD patients with uremic pruritus (https://clinicaltrials.gov/ct2/show/NCT03617536)[47]

Gabapentin Erging as an Evidence-based Treatment for Uremic Pruritus

Gabapentin and pregabalin are anticonvulsants structurally related to γ-aminobutyric acid, which are thought to act on voltage-dependent calcium-ion channels altering nerve impulses crucial in the generation of pruritus.[47] In our previous systematic review, we identified these agents as having the strongest evidence of efficacy in uremic pruritus, although there was still a paucity of high-quality data because of inadequate random sequence generation, allocation concealment, and blinding.[7] More recently, Eusebio-Alpapara et al.[47] performed systematic review and metaanalysis focusing on gabapentin in the treatment of uremic pruritus. They identified seven small (n ≤ 60) randomized trials of varying quality, all of which supported gabapentin as a useful treatment for uremic pruritus. The effect was most convincing when placebo was the comparator, and pregabalin appeared to offer similar reduction in symptoms.[48] The metaanalysis included four studies (combined n = 171) that reported the primary outcome of interest, namely a 50% or greater reduction in pruritus scores. Two trials were placebo controlled and two used an active antihistamine comparator. The analysis compared the incidence of treatment failure, defined as not achieving a 50% reduction in symptoms. Gabapentin was associated with a significantly lower risk of failure, with negligible heterogeneity (RR = 0.18, 95% CI: 0.09, 0.33; P < 0.000001, I2 = 4%), and in three of the four studies the number needed to treat was less than 2. Gabapentin was also associated with a higher incidence of adverse drug events but due to a lack of statistical power the results were not statistically significant (RR = 1.3, 95% CI: 0.81, 2.11; P = 0.28, I2 = 37%). Both of the systematic reviews found drowsiness, dizziness, and somnolence to be common side-effects of gabapentin. This may be a more significant issue than previously thought: recent data from the US Renal Data System suggest gabapentin and pregabalin are associated a 50% or higher increase risk of hospitalization or emergency room visits related to altered mental status, falls, or fractures, even at low starting doses of 100 and 25 mg, respectively.[48] In our opinion, the current literature supports the use of gabapentin as a first-line agent in treating uremic pruritus, but patients must be informed of the significant adverse risks and monitored carefully for adverse events.

Novel Therapies

As more is learned about the pathophysiology of uremic pruritus, particularly the role of immune dysregulation, novel targeted therapies are starting to be considered. Dupilumab, a fully human monoclonal IL-4 receptor antibody used in atopic dermatitis and asthma has been shown to successfully treat a handful of patients with recalcitrant uremic pruritus and other causes of chronic pruritus in a recent case report and case series.[49,50] Notably, the treatment was well tolerated, and several of the responders appeared to achieve cure of their uremic pruritus after 4–6 months of treatment. These results will have to be replicated in controlled trials before firm recommendations regarding dupilumab can be made. Kim et al.[51] have published the study protocol for the SNUG trial, a multicenter, randomized, double-blind, placebo-controlled clinical trial examining the antipruritic effects and safety profile of PG102P in hemodialysis patients.[52] PG102P, which is prepared from the 'hardy kiwifruity' Actinidia arguta, is an orally active immune-modulating compound that works through T-helper 1/2 pathways and has shown promise in animal models of atopic dermatitis and other allergic conditions. It has been shown to be safe in patients with atopic dermatitis and is relatively inexpensive.[51] In a mouse model, Cutibacterium acnes and metabolites of its glucose fermentation process have been shown to disrupt the IL-6/ERK pathway of pruritus described above and reduce scratching behavior, raising the possibility of a postbiotic topical treatment for patients with uremic pruritus.[41] Sensory neurons expressing neuropeptide natriuretic polypeptide b and its receptor natriuretic peptide receptor 1 (NPR1) are implicated in acute and chronic itch of all causes. A recent study showing that a novel NPR1 antagonist JS-11 reduces itch signaling in vitro and mouse itching behavior in vivo[52] may lead to novel uremic pruritus treatments, although several steps of translational research are yet required.[53] There has also been a small pilot RCT of omega-3 supplementation showing promising results in peritoneal dialysis patients with uremic pruritus, a patient group that is often understudied.[54] Finally, cannabinoids are potentially interesting therapeutic adjuncts for patients with chronic pruritus of many causes (e.g., chronic pruritus, atopic dermatitis). Cannabinoid receptors, CB1 and CB2, are present in the skin, and appear to mediate antiinflammatory/antiproliferative effects.[55–57] Rigorously controlled trials of cannabis products for treatment of uremic pruritus are warranted.[58]

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