Skin barrier: new therapeutic targets for chronic kidney disease-associated pruritus - a narrative review.

The current incidence of chronic kidney disease-associated pruritus (CKD-aP) in patients with end-stage renal disease (ESRD) is approximately 70%, especially in those receiving dialysis, which negatively affects their work and private lives. The CKD-aP pathogenesis remains unclear, but uremic toxin accumulation, histamine release, and opioid imbalance have been suggested to lead to CKD-aP. Current therapeutic approaches, such as opioid receptor modulators, antihistamines, and ultraviolet B irradiation, are associated with some limitations and adverse effects. The skin barrier is the first defense in preventing external injury to the body. Patients with chronic kidney disease often experience itch due to the damaged skin barrier and reduced secretion of sweat and secretion from sebaceous glands. Surprisingly, skin barrier-repairing agents repair the skin barrier and inhibit the release of inflammatory cytokines, maintain skin immunity, and ameliorate the micro-inflammatory status of afferent nerve fibers. Here, we summarize the epidemiology, pathogenesis, and treatment status of CKD-aP and explore the possibility of skin barrier repair in CKD-aP treatment.

Safety and effectiveness of HSK21542 for hemodialysis patients: a multiple ascending dose study.

Background: HSK21542, a novel selective peripherally-restricted κ-opioid receptor agonist has been proven to be a safe and effective analgesic and antipruritic drug in both in vitro and in vivo studies. We aimed to evaluate its safety, pharmacokinetics and efficacy in hemodialysis patients over a 1-week treatment period, and to establish the optimal dosage for a further 12-week stage 2 trial. Methods: In this multiple ascending dose study, hemodialysis patients were randomly assigned to receive HSK21542 (0.05-0.80 µg/kg), or a placebo three times within 2.5 h at the end of each dialysis session for 1 week. Safety evaluations included reports of treatment-emergent adverse events (TEAEs); pharmacokinetics and efficacy outcomes were also assessed. Results: Among the 44 screened patients, 41 were enrolled and completed the trial. The overall incidence of TEAEs was higher in the HSK21542 group compared to the placebo group, with an incidence of 75.0%, 50.0%, 75.0%, and 88.9% in the range of 0.05-0.80 µg/kg. All TEAEs were grade 1 or 2 in severity. HSK21542 exhibited linear pharmacokinetics characteristics within the dose range 0.05-0.80 µg/kg, without drug accumulation after multiple-doses. Compared to the placebo, a significant decrease of the weekly mean Worst Itching Intensity Numerical Rating Scale was found in the HSK21542-0.30 µg/kg group (p = 0.046), but without significant improvement in the Skindex-16 score. Conclusion: HSK21542 was well tolerated in the dose range 0.05-0.80 µg/kg in hemodialysis patients. HSK21542-0.3 µg/kg exhibited promising efficacy in patients with moderate to severe pruritus and warrants a further Stage 2 trial. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT04470154.

Management of Uremic Xerosis and Chronic Kidney Disease (CKD)-Associated Pruritus (CKD-ap) With Topical Preparations: A Systematic Review and Implications in the Indian Context.

Uremic xerosis and chronic kidney disease (CKD)-associated pruritus (CKD-ap) are the most commonly occurring dermatological problems faced by most of the CKD patients on hemodialysis which are not only annoying and draining to the patients but also have an intense effect on patients' quality of life. The PubMed, Scopus, Google Scholar, and Web of Science databases were searched for the literature with the following search terms: uremic xerosis OR CKD-ap OR uremic pruritus AND topical therapy OR topical ointment OR natural oil from the year 2002 -2022, and finally, 22 articles were chosen to write this review. Out of 22 studies, six used pharmacological preparations and remaining 16 studies used natural oils and components. All the articles were experimental studies (Pre/Quazi/RCT/True experimental) focusing on managing itch and xerosis associated with CKD and hemodialysis by topical application. The topical agents tried in various research studies are effective in managing itch and xerosis associated with CKD. They are safe, easy to use, and without allergic reactions. Natural oils like almond, chia seed, clove, glycerin, paraffin, and virgin coconut oil are readily available in home-care settings and can be used as a nurse-led intervention. Topical preparations for uremic xerosis and pruritus are effective, safe, and easy to apply on large body surface areas without systematic side effects. Natural oil-based topical preparations are cost-effective, safe, and easy to use.

Difelikefalin: A New κ-Opioid Receptor Agonist for the Treatment of Hemodialysis-Dependent Chronic Kidney Disease-Associated Pruritus.

OBJECTIVE: To review data for difelikefalin (Korsuva) intravenous solution for management of moderate-to-severe pruritus in hemodialysis (HD) patients. DATA SOURCES: Literature search of PubMed (January 1946-May 2022) and SCOPUS (January 1946-May 2022) was performed using the terms: Korsuva, CR845, and difelikefalin. Additional information sources include ClinicalTrials.gov, prescribing information, meeting posters, and references of identified articles. STUDY SELECTION AND DATA EXTRACTION: Clinical trials and articles evaluating difelikefalin for chronic kidney disease-associated pruritis (CKD-aP) in HD patients. DATA SYNTHESIS: Difelikefalin is a peripherally acting κ-opioid receptor agonist with antipruritic effects for HD patients with moderate-to-severe CKD-aP. A phase 3 study showed significant improvement of patient itch intensity and itch-related quality of life (QOL) when compared with placebo. More patients had decreased pruritus on the 24-hour Worst Itch Intensity Numerical Rating Scale with difelikefalin (49.1%) compared with placebo (27.9%, P < 0.001). A positive effect was seen with or without use of additional antipruritic agents. Common adverse events include diarrhea, dizziness, and vomiting; there were no signs of physical dependence or centrally acting opioid effects (euphoria, hallucinations). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Difelikefalin reduced itch intensity and improved QOL for patients with CKD-aP. Whether the benefit is continued long-term as well as how it compares with other effective agents is currently unknown. CONCLUSION: Difelikefalin is the only Food and Drug Administration-approved treatment for moderate-to-severe CKD-aP with additional research into its benefit in this and other types of pruritus ongoing.

Obstacles to Early Diagnosis and Treatment of Pruritus in Patients with Chronic Kidney Disease: Current Perspectives.

Chronic kidney disease-associated pruritus (CKD-aP) is a common condition amongst patients with advanced chronic kidney disease (CKD). Several studies have confirmed that more than four out of ten early-stage CKD patients suffer from this condition, while its prevalence among CKD patients on dialysis reaches up to seven out of ten. It is noted to be associated with other disabling symptoms and serious outcomes. It has significant impact on sleep, mood, daily activities, and quality of life of CKD patients, and increased mortality risk of patients on hemodialysis. The Dialysis Outcomes and Practice Patterns Study found 17% higher mortality among patients with moderate to extreme pruritus compared with patients with no or mild pruritus. Despite its high prevalence, ill-effect, and suffering associated with it, CKD-aP remains surprisingly under-reported on the patient's part and under-recognized by the healthcare team. Even upon being noticed, it remains unattended and poorly treated. Its etiopathogenesis is complex and not fully understood. Many treatment options are available but good quality evidence about most of those is absent, and to date, only two medications are approved for use in this condition. While a validated guideline is very much required for the benefit of the patients and caretakers, further research on several aspects of this issue is required.

Pruritus-reducing effects of omega-3 fatty acids in hemodialysis patients: A cross-over randomized clinical trial.

INTRODUCTION: Chronic kidney disease-associated pruritus is a common complication in patients with end-stage renal disease. In this study, we have explored the outcome of omega-3 supplementary intake for the treatment of this symptom. METHODS: This double-blinded, randomized, crossover study was conducted in two dialysis centers in which 40 hemodialysis patients suffering from pruritus were randomly assigned into two groups (Group A and Group B). Patients in Group A consumed omega-3 capsules for 4 weeks and after a washout period (6 weeks), they took placebo for another 4 weeks. The same was performed in Group B but in the reverse order. Pruritus score was determined at the baseline, Week 4, 10, and 14. Serum levels of prostaglandin E2 were also recorded at the baseline and Week 4. RESULTS: There was a statistically significant reduction of pruritus score in patients who took the omega-3 fatty acid supplement. The mean pruritus score decreased significantly in both first (-3.41 ± 2.62, p < 0.001) and second (-1.00 ± 1.84, p = 0.04) treatment period after omega-3 treatment; but no significant mean pruritus score difference in placebo group after both intervention periods was observed. The decrease in prostaglandin E2 amount was not statistically significant in the intervention (omega-3) group compared to the placebo group (p = 0.204). DISCUSSION: Our observations indicate that omega-3 fatty acids (3 grams per day) have decreasing effects on pruritus. Also, reduction in prostaglandin E2 levels in the omega-3 group did not differ from the changes in the placebo group.

Clinical management of chronic kidney disease-associated pruritus: current treatment options and future approaches.

Chronic kidney disease (CKD)-associated pruritus (CKD-aP) is an underdiagnosed yet severely distressing condition that impacts 60% of patients on dialysis and many nondialysis patients with Stages 3-5 CKD. However, despite its high prevalence, there are currently limited treatment options available for these patients and a lack of treatment guidelines for clinicians. In this manuscript, we reviewed the available literature in order to evaluate the current management and treatment options for CKD-aP, including dialysis management, topical treatments, gabapentinoids, opioids and alternative medicine. We also review the available data on CKD-aP treatments in development and propose new guidelines for managing patients with CKD-aP.

Randomized Controlled Trial of Difelikefalin for Chronic Pruritus in Hemodialysis Patients.

INTRODUCTION: There is an unmet medical need for pruritus associated with chronic kidney disease, a distressing complication characterized by generalized and persistent itch affecting 20% to 40% of patients undergoing hemodialysis. Here we report the results of a phase 2 trial evaluating the efficacy and safety of a novel peripherally restricted kappa opioid receptor agonist, difelikefalin, in adult patients undergoing hemodialysis with pruritus. METHODS: In this study, 174 hemodialysis patients with moderate-to-severe pruritus were randomly assigned to receive difelikefalin (0.5, 1.0, or 1.5 µg/kg) or placebo intravenously thrice weekly after each hemodialysis session for 8 weeks in a double-blind, controlled trial. The primary endpoint was the change from baseline at week 8 in the weekly mean of the 24-hour Worst Itching Intensity Numerical Rating Scale score. The secondary efficacy endpoint was the change in itch-related quality of life measured by the Skindex-10 questionnaire. Other endpoints included safety, sleep quality, and additional measures including the 5-D itch scale. RESULTS: A significant reduction from baseline in itch intensity scores at week 8 favored all difelikefalin doses combined versus placebo (P = 0.002). Difelikefalin also showed improvement over placebo in Skindex-10, 5-D itch, and sleep disturbance scores (P ≤ 0.005). Overall, 78% of patients receiving difelikefalin reported treatment-emergent adverse events versus 42% of patients given placebo, with diarrhea, dizziness, nausea, somnolence, and fall being the most frequent (≥5%). CONCLUSION: In this trial, difelikefalin effectively reduced itching intensity and improved sleep and itch-related quality of life.