Long-Term Efficacy and Tolerability of an Emollient Containing Glycerol and Paraffin for Moderate-to-Severe Uremic Xerosis: A Randomized Phase 3 Study.

INTRODUCTION: There is an unmet need for effective topical therapies for patients with uremic xerosis and chronic kidney disease-associated pruritus (CKD-aP). The long-term efficacy and tolerability of an emollient containing glycerol 15% and paraffin 10% (V0034CR) was evaluated in a phase 3 study. METHODS: In this randomized, double-blind, two-parallel group, vehicle-controlled study, patients with moderate-to-severe uremic xerosis were randomized to once-daily application of V0034CR or vehicle control for 28 days (period I). This was followed by a treatment-free period of ≤ 21 days (period II), then all patients received open-label treatment with V0034CR for ≥ 84 days (period III). Outcomes included treatment response at the end of period I (El Gammal's xerosis severity score), instrumental measures of scaling (D-Squame technique), time to relapse during period II, rate of recurrence during period III, pruritus severity over time, patient acceptability, and adverse events (AEs). RESULTS: The intent-to-treat population comprised 235 patients randomized to V0034CR (n = 118) or vehicle control (n = 117) during period I. Treatment response at the end of period I was achieved by 71 patients (60.2%) in the V0034CR group versus 48 (41.0%) with vehicle control (p = 0.0041). This coincided with greater reductions in the total surface area of squames (p = 0.001 vs vehicle control). Xerosis relapsed progressively without treatment in period II; however, remission was durable under maintenance therapy in period III. Improvements in pruritus severity were comparable between V0034CR and vehicle control, suggesting that the antipruritic effect of V0034CR was mainly exerted by its oil-in-water emulsion base. V0034CR had high patient acceptability and was well tolerated; the most common treatment-related AEs were irritation or erythema (2.1%), exacerbated pruritus (1.3%), and vesicles at the application site (0.9%). CONCLUSION: These data support the use of V0034CR, with its hydrating and occlusive properties, for the long-term management of patients with moderate-to-severe uremic xerosis and CKD-aP. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01084148; EudraCT number 2006-002201-31.

People on dialysis often experience dry and itchy skin that is hard to treat. This study tested the effectiveness of a new moisturizing cream (called V0034CR) in people with dry skin caused by dialysis (also known as uremic xerosis). In this study, 235 people with moderate or severe uremic xerosis were randomly split into two groups. One group (118 people) was given V0034CR cream, which contains glycerol and paraffin as its "active" ingredients. The other group (117 people) was given a "control" cream, which contains the same ingredients as V0034CR cream but without glycerol and paraffin. Both groups applied their assigned cream to their skin once a day for 4 weeks. If a person's dry skin had improved after 4 weeks, then they could stop using the cream for up to 3 weeks, and then switch to V0034CR cream from week 7 until the end of the study (19 weeks). If a person's dry skin had not improved after 4 weeks, or if their dry skin returned after stopping the cream, then they could start using V0034CR cream early and for the rest of the study. The study found that using V0034CR cream improved the signs and symptoms of dry skin more than the control cream. Most people in the study said that V0034CR cream was effective and easy to use, and no serious side effects were reported. The results of this study suggest that V0034CR cream is an effective treatment for people with dry skin caused by dialysis.

The role of blood purification therapies in the treatment of chronic kidney disease-associated pruritus: a systematic review.

Chronic kidney disease-associated pruritus (CKD-aP) is a common complication in dialysis patients which is not fully addressed by pharmacological and dialytic therapy. The objective was to review the literature on the effects of extracorporeal blood purification modalities on CKD-aP. The population comprised patients aged ≥18 years on chronic dialysis. PubMed, Embase, and Medline were systematically searched until February 2024 for clinical studies comparing the effect of different dialysis modalities on pruritus intensity. Two reviewers extracted data independently. Risk of bias for randomized controlled trials (RCTs) was assessed using the Cochrane tool. Any extracorporeal blood purification therapy for the treatment of CKD-aP was included. Outcome was quantitative change in pruritus intensity on a validated itching scale. This review included eight RCTs examining five different dialysis modalities, three observational studies examining three dialysis modalities, and six prospective clinical trials assessing four dialysis modalities. These treatments included peritoneal dialysis, low-flux and high-flux dialysis, hemodiafiltration, expanded hemodialysis, hemadsorption, hemodiafiltration with endogenous reinfusion and dialysis with polymethylmethacrylate membrane. Risk of bias was high in most studies. The largest body of evidence was found for the efficacy of hemadsorption. Limitations of evidence included heterogeneity in diagnostic tools and treatment, risk of selection bias, small sample sizes and short follow-up durations that made it challenging to perform a robust systematic review and meta-analysis. Despite the high prevalence of pruritus among dialysis patients, current evidence for efficacy of standard dialytic treatment is weak. The only technique that appears to be effective is hemoadsorption alone or coupled with hemodialysis. More high-quality studies are needed to confirm the long-term benefits.

Difelikefalin and treatment of severe pruritus associated with chronic kidney disease - Real-life retrospective study in a dialysis center / Difélikéfaline et traitement du prurit modéré à sévère associé à la maladie rénale chronique - Étude rétrospective en vie réelle dans un centre de dialyse.

Introduction: Difelikefalin is to date the first and only specific treatment to be approved for the treatment of moderate-to-severe chronic kidney disease-associated pruritus (CKD-aP) in adult patients on hemodialysis. Patients and methods: This was a retrospective, single-center, real-life study in hemodialysis patients with CKD-aP treated with difelikefalin. The primary objective was to evaluate the evolution of the intensity of pruritus during treatment with difelikefalin using the Worst Itch Intensity-Numerical Rating Scale (WI-NRS). Adult patients were included if they had been on hemodialysis for at least 3 months and were suffering from moderate to severe CKD-aP (objectified by the WI-NRS score) for which difelikefalin had been prescribed. Results: 11 patients (7 men and 4 women; mean age, 63.8 years) with a mean (SD) weekly dialysis time of 13 h (2.4) were included. The mean hemodialysis duration was 5 (3.6) years and the mean pruritus duration was 4.3 (3.2) years. At inclusion, on-going treatments of CKD-aP were emollients in all patients and antihistamines in 9 patients. The mean WI-NRS score was 7.4 (1.1) at initiation of difelikefalin. At last assessment after a median follow-up of 9.0 months, the mean change of WI-NRS score was -5.1 (2.9) and 82% of patients had a decrease ≥ 3 points. Mild to moderate adverse reactions to difelikefalin were reported in 4 patients, all of whom recovered without sequelae. Conclusion: These results show that difelikefalin, prescribed according to its therapeutic indication, is effective in the treatment of CKD-aP under real-life conditions, outside the controlled conditions of a clinical trial.

Introduction: La difélikéfaline est à ce jour le premier et le seul traitement spécifique approuvé pour le traitement du prurit d'intensité modérée à sévère associé à la maladie rénale chronique (Pa-MRC) chez les patients adultes hémodialysés. Patients et méthodes: Il s'agit d'une étude rétrospective, monocentrique, en vie réelle, chez des patients hémodialysés souffrant de Pa-MRC et traités par difélikéfaline. L'objectif principal était d'évaluer l'évolution de l'intensité du prurit au cours du suivi à l'aide de l'échelle WI-NRS (Worst Itch Intensity-Numerical Rating Scale). Les patients adultes ont été inclus s'ils étaient hémodialysés depuis au moins trois mois et souffraient d'un Pa-MRC modéré à sévère (objectivé par le score WI-NRS) pour lequel la difélikéfaline avait été prescrite. Résultats: Onze patients (7 hommes et 4 femmes ; âge moyen : 63,8 ans) avec un temps de dialyse hebdomadaire moyen (SD) de 13 h (2,4) ont été inclus. La durée moyenne d'hémodialyse était de 5 ans (3,6) et la durée moyenne de prurit de 4,3 ans (3,2). À l'inclusion, les traitements du prurit en cours étaient des émollients pour tous les patients et des antihistaminiques pour 9 d'entre eux. Le score WI-NRS moyen était de 7,4 (1,1) au début du traitement par la difélikéfaline. À la dernière évaluation, après un suivi médian de 9 mois, la variation moyenne du score WI-NRS était de -5,1 (2,9) et 82 % des patients avaient une diminution ≥ 3 points. Des effets indésirables d'intensité légère à modérée liés à la difélikéfaline ont été rapportés chez 4 patients, tous rétablis sans séquelles. Conclusion: Ces résultats montrent que la difélikéfaline, prescrite conformément à son indication thérapeutique, est efficace en vie réelle dans le traitement du Pa-MRC, en dehors des conditions contrôlées d'un essai clinique.

Nomogram to Estimate the Risk of Chronic Kidney Disease-Associated Pruritus in Patients with End-Stage Renal Disease Undergoing Peritoneal Dialysis: Model Development and Validation Study.

INTRODUCTION: Chronic kidney disease-associated pruritus (CKD-aP) frequently occurs in patients with end-stage renal disease (ESRD) undergoing peritoneal dialysis (PD) and presents a therapeutic challenge to physicians owing to the diversity of its pathogenesis. Herein, we developed and validated a nomogram model for individualized risk estimation of CKD-aP and investigated the possible causes of CKD-aP in PD patients. METHODS: We retrospectively screened patients with CKD-aP who underwent PD between 2021 and 2023 at the First Affiliated Hospital of Xi'an Jiaotong University Peritoneal Dialysis Center. Nomograms for each outcome were computed from multivariate logistic regression models with the least absolute shrinkage and selection operator regression and univariate logistic regression for variable selection. The discriminative ability was estimated by Harrell's C-index, and the accuracy was assessed graphically with a calibration curve plot. Models were validated internally using bootstrapping and externally by calculating their performance on a validation cohort. Decision curve analysis was used to assess the model's clinical usefulness. RESULTS: In all, a total of 487 patients were entered in the analysis, including 325 in the development cohort and 162 in the validation cohort. The final nomogram incorporated five variables: age, interleukin-6, hemoglobin, residual urine volume, and renal Kt/V. The C-index of the model was 0.733 (95% CI: 0.679-0.787), and the calibration curve was a straight line with a slope close to 1. Both internal and external validations confirmed the model's good performance, with C-index of 0.725 (95% CI: 0.662-0.774) and 0.706 (95% CI: 0.623-0.789), respectively. Decision curve analysis showed that the nomogram had good clinical benefits. CONCLUSION: Our study proposes a nomogram model for CKD-aP risk assessment in ESRD patients with PD. This nomogram might help in clinical decision-making and evidence-based selection of therapy.

Pathways for Diagnosing and Treating CKD-Associated Pruritus: A Narrative Review.

Purpose of Review: Chronic kidney disease (CKD)-associated pruritus is a common, persistent, and distressing itch experienced by patients across the CKD spectrum. Although the disorder is associated with adverse outcomes and poor health-related quality of life, it remains underdiagnosed and undertreated. The purpose of this narrative review is to offer health care providers guidance on how to effectively identify, assess, and treat patients with CKD-associated pruritus, with the goal of reducing symptom burden and improving patient-important outcomes, such as quality of life (QoL). Sources of Information: A panel of nephrologists and researchers from across Canada and the United States was assembled to develop this narrative review based on the best available data, current treatment guidelines, and their clinical experiences. Methods: A panel of nephrologists who actively care for patients with pruritus receiving dialysis from across Canada was assembled. Two researchers from the United States were also included based on their expertise in the diagnosis and management of CKD-associated pruritus. Throughout Spring 2023, the panel met to discuss key topics in the identification, assessment, and management of CKD-associated pruritus. Panel members subsequently developed summaries of the pertinent information based on the best available data, current treatment guidelines, and added information on their own clinical experiences. In all cases, approval of the article was sought and achieved through discussion. Key Findings: This narrative review provides pragmatic guidance addressing: (1) methods for screening CKD-associated pruritus, (2) assessing severity, (3) management of CKD-associated pruritus, and (4) suggested areas for future research. The panel developed a 3-pillar framework for proactive assessment and severity scoring in CKD-aP: systematic screening for CKD-associated pruritus (pillar 1), assessment of pruritus intensity (pillar 2), and understanding the impact of CKD-associated pruritus on the patient's QoL (pillar 3). Management of CKD-associated pruritus can include ensuring optimization of dialysis adequacy, achieving mineral metabolism targets (ie, calcium, phosphate, and parathyroid hormone). However, treatment of CKD-associated pruritus usually requires additional interventions. Patients, regardless of CKD-associated pruritus severity, should be counseled on adequate skin hydration and other non-pharmacological strategies to reduce pruritus. Antihistamines should be avoided in favor of evidence-based treatments, such as difelikefalin and gabapentin. Limitations: A formal systematic review (SR) of the literature was not undertaken, although published SRs were reviewed. The possibility for bias based on the experts' own clinical experiences may have occurred. Key takeaways are based on the current available evidence, of which head-to-head clinical trials are lacking. Funding: This work was funded by an arm's length grant from Otsuka Canada Pharmaceutical Inc. (the importer and distributer of difelikefalin in Canada). LiV Medical Education Agency Inc. provided logistical and editorial support.

Motif de la revue: Le prurit associé à l'insuffisance rénale chronique (IRC) est une démangeaison cutanée fréquente, persistante et invalidante que les patients de tout le specter de l'IRC peuvent ressentir. Bien que le prurit soit associé à des effets indésirables et à une mauvaise qualité de vie liée à la santé, il demeure sous-diagnostiqué et sous-traité. L'objectif de cette revue narrative est d'offrir des conseils aux professionnels de la santé sur la façon d'identifier, d'évaluer et de traiter efficacement les patients atteints de prurit associé à l'IRC; ceci dans le but de réduire la charge des symptômes et d'améliorer les résultats importants pour les patients, notamment leur qualité de vie (QdV). Sources de l'information: Un comité de néphrologues et de chercheurs de partout au Canada et des États-Unis a été constitué pour élaborer la présente revue narrative à partir des meilleures données disponibles, des lignes directrices actuelles pour le traitement et de leurs expériences cliniques. Méthodologie: Un groupe de néphrologues canadiens qui s'occupent activement de patients dialysés souffrant de prurit a été constitué. Deux chercheurs des États-Unis ont été inclus au groupe en raison de leur expertise dans le diagnostic et la prise en charge du prurit associé à l'IRC. Le comité s'est réuni tout au long du printemps 2023 pour discuter de sujets clés en lien avec l'identification, l'évaluation et la prise en charge du prurit associé à l'IRC. Les membres du comité ont par la suite rédigé des résumés des informations pertinentes en se basant sur les meilleures données disponibles et les lignes directrices actuelles pour le traitement, auxquels ils ont ajouté des informations issues de leurs propres expériences cliniques. Dans tous les cas, l'approbation du manuscrit a été sollicitée et obtenue par discussion. Principaux résultats: Cette revue narrative offre des conseils pragmatiques sur les points suivants: (1) les méthodes de dépistage du prurit associé à l'IRC; (2) l'évaluation de sa gravité; (3) sa prise en charge; et (4) les domaines suggérés pour de futures recherches. Le comité a développé un cadre à trois piliers pour l'évaluation proactive du prurit associé à l'IRC et l'établissement d'un score de gravité: le dépistage systématique du prurit associé à l'IRC (pilier 1), l'évaluation de son intensité (pilier 2) et la compréhension de son impact sur la QdV du patient (pilier 3). La prise en charge du prurit associé à l'IRC peut inclure l'optimisation de l'adéquation de la dialyse et l'atteinte des cibles du métabolisme minéral (c.-à-d. calcium, phosphate et hormone parathyroïdienne). Cependant, son traitement nécessite habituellement des interventions supplémentaires. Les patients, quelle que soit la gravité du prurit associé à l'IRC, devraient être avisés d'hydrater adéquatement leur peau et informés des autres stratégies non pharmacologiques afin de réduire le prurit. On devrait éviter les antihistaminiques et les remplacer par des traitements fondés sur des données probantes comme la difélikéfaline et la gabapentine. Limites: Aucune revue systématique de la littérature n'a été formellement entreprise, bien que les revues systématiques publiées aient été examinées. La possibilité d'un biais fondé sur les expériences cliniques des experts est envisageable. Les principales conclusions de cette étude sont fondées sur les données probantes actuellement disponibles, pour lesquelles il n'existe pas d'essais cliniques comparatifs. Financement: Ces travaux ont été financés par une subvention indépendante d'Otsuka Canada Pharmaceutical Inc. (l'importateur et distributeur de la difélikéfaline au Canada). Un soutien logistique et éditorial a été fourni par liV Medical Education Agency Inc.

Difelikefalin in Black/African American Hemodialysis Patients with Moderate-to-Severe Pruritus: Post hoc Analysis of KALM-1 and KALM-2.

INTRODUCTION: Black and African American (AA) people are over-represented in the kidney failure population; therefore, the safety and efficacy of difelikefalin in Black/AA patients was evaluated. METHODS: This was a post hoc, pooled exploratory subgroup analysis of the Phase 3 KALM-1 and -2 studies. Patients undergoing hemodialysis (HD) who had moderate-to-severe chronic kidney disease-associated pruritus (CKD-aP) at enrollment were stratified into self-reported Black/AA or White subgroups. Patients were randomized (1:1) to receive intravenous (IV) difelikefalin 0.5 µg/kg or placebo for 12 weeks. Difelikefalin efficacy was assessed with validated patient-reported outcome questionnaires: 24-h Worst Itch Numerical Rating Scale (WI-NRS), 5-D itch, and Skindex­10. RESULTS: There were 249 (29.3%) patients from the KALM studies that self-identified as Black/AA (n = 135 difelikefalin; n = 114 placebo). Clinically meaningful (≥3-point) reduction in WI-NRS score was achieved by 47.9% of Black/AA patients with difelikefalin versus 24.6% with placebo (p < 0.001). More Black/AA patients achieved a ≥5-point 5-D itch total improvement (54.9% vs. 35.7%; p = 0.013) and a ≥15-point Skindex-10 score improvement with difelikefalin versus placebo (49.0% vs. 28.9%; p = 0.006) compared with White patients. Incidence of treatment-emergent adverse events (TEAEs) was higher for Black/AA patients (difelikefalin: 78.5%; placebo: 70.8%) versus White patients (difelikefalin: 64.8%; placebo: 61.8%). CONCLUSION: In this post hoc analysis, difelikefalin was efficacious in the Black/AA population and had an acceptable safety profile.

Practical Use of Patient-Reported Outcome Measures in Chronic Kidney Disease-Associated Pruritus.

Regulatory and clinical stakeholders are increasingly advocating for the use of patient-reported outcome (PRO) measures; however, the use of PROs is still not widespread. Patient reports are often the best ways to diagnose and monitor the effect of treatment on symptoms when the symptoms are subjective, as with pruritus. While many PRO tools are available to assess the severity of pruritus and its impact on quality of life (e.g., sleep), these are not used in a consistent manner and their results may not translate into clinical action. In this article, we present an introduction to PROs and their use in the assessment of chronic kidney disease-associated pruritus, as well as a practical guide to some of the PRO tools currently available, to empower all members of the nephrology patient care team to use these tools appropriately for the benefit of the patient.

Diagnosis and management of pruritus associated with chronic kidney disease in hemodialyzed patients / Diagnostic et prise en charge du prurit associé à la maladie rénale chronique chez les patients hémodialysés

Chronic kidney disease-associated pruritus (CKD-aP) is a disabling symptom which is frequent and often underestimated. Pa-MRC has a negative impact on quality of life, and is frequently accompanied by sleep disorders and depression. The approval of difelikefalin ­ a kappa opioid receptor agonist ­ in this indication requires updated recommendations. As a first step, secondary causes of pruritus without skin lesions must be ruled out, and general measures taken (emollients, psychological support, optimization of dialysis, normalization of serum calcium, phosphate and PTH in the range proposed by the KGIDO guidelines, treatment of iron deficiency). A therapeutic test with a non-sedating oral antihistamine may be proposed. If this test is negative, Pa-MRC must be strongly suspected, and its intensity (WI-NRS scale) and impact on quality of life assessed. In the case of mild Pa-MRC (WI-NRS ≤ 3), only general measures are implemented. If Pa-MRC is moderate to severe (WI-NRS ≥ 4), specific treatment with difelikefaline can be initiated for 6 months in addition to general measures. At 3 months, if the response is complete (WI-NRS score ≤ 1) or partial (decline ≥ 3 points), treatment is continued. At 6 months, if the response is complete, treatment may be discontinued with the patient's agreement; treatment is maintained if the response is partial. At 3 or 6 months, if response is insufficient (decline < 3 points) and/or in the event of intolerance, treatment is discontinued and an alternative treatment (e.g., gabapentinoids, UVB) may be considered after dermatological consultation.

Le prurit associé à la maladie rénale chronique (Pa-MRC) est un symptôme invalidant qui est fréquent et souvent sous-estimé. Le Pa-MRC a des conséquences négatives sur la qualité de vie et s'accompagne fréquemment de troubles du sommeil et de dépression. L'approbation de la difélikéfaline ­ agoniste des récepteurs opioïdes kappa ­ dans cette indication nécessite l'actualisation des recommandations. Les causes secondaires de prurit sans lésions cutanées doivent être exclues et des mesures générales doivent être prises (émollients, aide psychologique, optimisation de la dialyse, équilibre phosphocalcique avec parathormone [PTH] dans la cible KDIGO [Kidney Disease: Improving Global Outcomes], traitement de la carence martiale). Une épreuve thérapeutique avec un antihistaminique oral non sédatif peut être proposée. En cas de test négatif, il faut fortement suspecter un Pa-MRC et évaluer son intensité (échelle WI-NRS [Worst Itch Numeric Rating Scale]) et son impact sur la qualité de vie. En cas de Pa-MRC léger (WI-NRS ≤ 3), seules les mesures générales sont mises en œuvre. Si le Pa-MRC est modéré à sévère (WI-NRS ≥ 4), un traitement spécifique par difélikéfaline peut être instauré pour 6 mois en plus des mesures générales. À 3 mois, si la réponse est complète (score WI-NRS ≤ 1) ou partielle (baisse ≥ 3 points), le traitement est poursuivi. À 6 mois, si la réponse est complète, l'arrêt du traitement peut être envisagé avec l'accord du patient ; il est maintenu en cas de réponse partielle. À 3 ou 6 mois, en cas de réponse insuffisante (baisse < 3 points) et/ou d'intolérance, le traitement est interrompu et un autre traitement (par exemple, gabapentinoïdes, ultraviolet de type B [UVB]) peut être envisagé après avis dermatologique.

Difelikefalin improves itch-related sleep disruption in patients undergoing haemodialysis.

BACKGROUND: Poor sleep quality is associated with increased mortality and lower quality of life in patients with chronic kidney disease-associated pruritus (CKD-aP). Difelikefalin reduces itch in patients with CKD-aP undergoing haemodialysis. This post hoc analysis of Phase 3 studies (3105 and the pooled dataset from KALM-1 and KALM-2) evaluated whether itch reduction in CKD-aP improved sleep quality. METHODS: Itch intensity was assessed in patients undergoing haemodialysis, who had moderate-to-severe CKD-aP treated with intravenous difelikefalin (0.5 µg/kg, three times weekly) (N = 222, Study 3105; N = 426, KALM-1/-2) or placebo (N = 425, KALM-1/-2) for 12 weeks, using the Worst Itch Intensity Numerical Rating Scale (WI-NRS). Sleep quality was assessed using the sleep disability question of the 5-D itch scale (5­D SDQ) in all studies and, in Study 3105, with the Sleep Quality Numeric Rating Scale (SQ-NRS). RESULTS: Greater improvements in sleep quality were observed in patients with ≥ 3-point, versus < 3-point WI-NRS improvement using SQ-NRS in Study 3105 (mean [95% confidence interval]: -5.2 [-5.6, -4.8] vs -1.5 [-2.0, -1.0]) and 5-D SDQ in KALM-1/-2 (-1.8 [-2.1, -1.6] vs -0.8 [-1.1, -0.4]). SQ-NRS and WI-NRS scores correlated strongly at baseline and Week 12 in Study 3105 (Spearman correlation coefficient: 0.77 and 0.84, respectively). Correlations were also observed between 5-D SDQ and WI-NRS scores in Study 3105 and KALM­1/­2. CONCLUSIONS: In patients undergoing haemodialysis with moderate-to-severe CKD-aP, itch reduction with intravenous difelikefalin was associated with improved sleep quality. As disturbed sleep may contribute to mortality and morbidity in CKD-aP, difelikefalin may help to address a major clinical burden by improving sleep quality, secondary to itch relief.

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.

Chronic kidney disease-associated pruritus (CKD-aP) is associated with worse quality of life and increased healthcare utilization among dialysis patients.

PURPOSE: Chronic pruritus significantly impairs hemodialysis patients' health status and quality of life (QOL) and it is associated with higher mortality rate, more frequent hospitalizations, poorer dialysis and medication adherence, and deteriorated mental status. However, pruritus is still underestimated, underdiagnosed, and undertreated in the real-life clinical scenario. We investigated prevalence, clinical characteristics, clinical correlates, severity as well as physical and psychological burden of chronic pruritus among adult hemodialysis patients in a large international real-world cohort. METHODS: We conducted a retrospective cross-sectional study of patients registered in 152 Fresenius Medical Care (FMC) NephroCare clinics located in Italy, France, Ireland, United Kingdom, and Spain. Demographic and medical data were retrieved from the EuCliD® (European Clinical) database, while information on pruritus and QoL were abstracted from KDQOL™-36 and 5-D Itch questionnaire scores. RESULTS: A total of 6221 patients were included, of which 1238 were from France, 163 Ireland, 1469 Italy, 2633 Spain, and 718 UK. The prevalence of mild-to-severe pruritus was 47.9% (n = 2977 patients). Increased pruritus severity was associated with increased use of antidepressants, antihistamines, and gabapentin. Patients with severe pruritus more likely suffered from diabetes, more frequently missed dialysis sessions, and underwent more hospitalizations due to infections. Both mental and physical QOL scores were progressively lower as the severity of pruritus increased; this association was robust to adjustment for potential confounders. CONCLUSION: This international real-world analysis confirms that chronic pruritus is a highly prevalent condition among dialysis patients and highlights its considerable burden on several dimensions of patients' life.

Difelikefalin for the treatment of moderate-to-severe pruritus associated with chronic kidney disease on hemodialysis.

INTRODUCTION: Chronic kidney disease-associated pruritus (CKD-aP) is often experienced by patients with CKD receiving dialysis. Approximately 40% of hemodialysis patients are 'moderately' to 'extremely bothered' by itching, associated with reduced quality of life, poor sleep quality, and depression as well as worse clinical outcomes, including increased medication use, infections, hospitalizations, and mortality. AREAS COVERED: This review covers the pathophysiology and treatment landscape of CKD-aP, and the development, clinical efficacy, and safety profile of difelikefalin. We summarize the existing evidence, and discuss both the position of difelikefalin in the treatment pathway and potential future developments. EXPERT OPINION: Difelikefalin is a kappa opioid receptor agonist, with a primary mode of action that is outside of the central nervous system and provides an improved safety profile compared with other opioid agonists, with limited potential for abuse and dependency. Difelikefalin has demonstrated efficacy, tolerability, and safety profile in several large-scale clinical trials in more than 1,400 hemodialysis patients with CKD-aP treated for up to 64 weeks. Difelikefalin is the only approved treatment for CKD-aP in the U.S.A and Europe; other treatments are used off-label, have limited proof of efficacy in large-scale clinical trials in this patient population, and may present an increased risk of toxicity in patients with CKD.

A phase 2 study of oral difelikefalin in subjects with chronic kidney disease and moderate-to-severe pruritus.

INTRODUCTION/BACKGROUND: Chronic pruritus is burdensome for patients with chronic kidney disease (CKD). OBJECTIVE: We evaluated difelikefalin efficacy and safety in reducing itch in subjects with non-dialysis-dependent CKD and those undergoing hemodialysis (HD). METHODS: This phase 2, double-blind, randomized, placebo-controlled, dose-finding study enrolled non-dialysis-dependent CKD (stage 3-5) and HD subjects with moderate-to-severe pruritus. Subjects were equally randomized to oral difelikefalin (0.25, 0.5, or 1.0 mg) or placebo once daily for 12 weeks. The primary end point was the change in the weekly mean Worst Itching Intensity Numeric Rating Scale (WI-NRS) score at week 12. RESULTS: Two hundred sixty-nine subjects were randomized (mean [SD] baseline WI-NRS: 7.1 [1.2]). Difelikefalin 1.0 mg significantly reduced weekly mean WI-NRS scores versus placebo at week 12 (P = .018), with numerical reductions observed with difelikefalin 0.25 and 0.5 mg. At week 12, 38.6% of subjects receiving difelikefalin 1.0 mg achieved a complete response (WI-NRS 0-1) versus 14.4% receiving placebo. Difelikefalin resulted in ∼20% improvement in itch-related quality-of-life measures. The most common treatment-emergent adverse events were dizziness, fall, constipation, diarrhea, gastroesophageal reflux disease, fatigue, hyperkalemia, hypertension, and urinary tract infection. LIMITATIONS: Study duration was 12 weeks. CONCLUSIONS: Oral difelikefalin significantly reduced itch intensity in stage 3-5 CKD subjects with moderate-to-severe pruritus, supporting continued development for this condition.

Endogenous Opioid Imbalance as a Potential Factor Involved in the Pathogenesis of Chronic Kidney Disease-Associated Pruritus in Dialysis Patients.

Chronic pruritus is one of the most common symptoms of dermatological diseases. It may occur in the course of other disorders, such as kidney disease. Chronic kidney disease-associated pruritus (CKD-aP) most often affects people with end-stage renal disease. The etiology of this condition is still not fully understood, but researchers are currently focusing on a thorough analysis of the association between disturbed opioid balance and increased neuronal signaling leading to pruritus. The aim of this study is to assess the concentration of endogenous opioids in dialysis patients with and without pruritus and in the control group, and to determine the correlation between the concentration of these substances and the occurrence and severity of itching. The study involved 126 dialysis patients and 50 healthy controls. Patients were divided into groups with pruritus (n = 62) and without pruritus (n = 64). The severity of pruritus was assessed using the NRS scale. The concentration of endogenous opioids was determined using the ELISA. The concentration of met-enkephalin was higher in the group of patients with pruritus compared to the control group. Moreover, significantly lower levels of ß-endorphin and dynorphin A were observed in the group of dialysis patients compared to the control group. In addition, a statistically significant difference was seen between the ß-endorphin concentration in the group of dialysis patients with pruritus compared to the group without pruritus. The ratio of ß-endorphin/dynorphin A concentrations was significantly lower in the group of patients with pruritus compared to patients without pruritus and the control group. No correlations were found between serum level of studied opioids and the severity of pruritus. The concentrations of the studied opioids did not correlate with the severity of pruritus. Observed opioid imbalance may affect the occurrence of CKD-aP in dialysis patients, but a thorough understanding of the mechanism of action of these substances in the sensation of pruritus is necessary to assess the possibility of finding a new therapeutic target.

Serum Level of Protein-Bound Uraemic Toxins in Haemodialysis Patients with Chronic Kidney Disease-Associated Pruritus: Myths and Facts.

Recent studies place great importance on Protein-Bound Uraemic Toxins (PBUT) in the context of etiopathogenesis of chronic kidney disease-associated pruritus (CKD-aP). This study aimed to investigate the possible contribution of free and total Indoxyl Sulfate (IS) and p-Cresol Sulfate (PCS) to the cause of CKD-aP. Group A included 64 patients on maintenance haemodialysis (HD) with CKD-aP. Group B included 62 patients on maintenance HD that did not report CKD-aP, and group C included 50 healthy controls. Pruritus severity was assessed using a Numerical Rating Scale (NRS). Moreover, other tools like UP-Dial, ItchyQoL, and the 4-Item Itch Questionnaire evaluating CKD-aP were completed by the patients. The serum levels of free and total IS and PCS concentrations were measured using the Ultra Performance Liquid Chromatography System. No significant difference in the serum level of free and total IS, or PCS, was observed between the patients who reported CKD-aP and those without pruritus. Moreover, there was no correlation between serum IS or PCS levels and the severity of the itch. Our study does not support earlier findings about higher levels of IS and PCS in patients reporting CKD-aP. Further studies will be needed to investigate these discrepancies as well as to understand the cause of CKD-aP.

Randomized controlled trial of nalfurafine for refractory pruritus in hemodialysis patients.

Background: Chronic kidney disease-associated pruritus (CKD-aP) is very common and sometimes refractory to treatment in hemodialysis patients. In a trial conducted in Japan, nalfurafine, effectively reduced itching of treatment-resistant CKD-aP. Our present bridging study aimed to evaluate the efficacy and safety of nalfurafine in Chinese cohort with refractory CKD-aP.Methods: In this phase III, multicenter bridging study conducted at 22 sites in China, 141 Chinese cases with refractory CKD-aP were randomly (2:2:1) assigned to receive 5 µg, 2.5 µg of nalfurafine or a placebo orally for 14 days in a double-blind manner. The primary end point was the mean decrease in the mean visual analogue scale (VAS) from baseline.Results: A total of 141 patients were included. The primary endpoint analysis based on full analysis set (FAS), the difference of mean VAS decrease between 5 µg nalfurafine and placebo group was 11.37 mm (p = .041); the difference of mean VAS decrease between 2.5 µg and placebo group was 8.81 mm, but not statistically significantly different. Both differences were greater than 4.13 mm, which met its predefined success criterion of at least 50% efficacy of the key Japanese clinical trial. The per protocol set (PPS) analysis got similar results. The incidence of adverse drug reactions (ADRs) was 49.1% in 5µg, 38.6% in 2.5 µg and 33.3% in placebo group. The most common ADR was insomnia, seen in 21 of the 114 nalfurafine patients.Conclusions: Oral nalfurafine effectively reduced itching with few significant ADRs in Chinese hemodialysis patients with refractory pruritus.

Alleviating symptoms in patients undergoing long-term hemodialysis: a focus on chronic kidney disease-associated pruritus.

Since the breakthrough of kidney replacement therapy, increases in life expectancy for patients with end-stage kidney disease have been limited. However, patients have become increasingly vocal that, although mortality and life expectancy matter to them, the quality of their life, and particularly the relief of symptoms associated with their treatment, are in many cases more important. The majority of dialysis-associated symptoms and adverse effects do not currently have any approved treatments in this patient population, with the few treatments that are available used off-label, frequently without proven efficacy, yet still potentially adding further adverse effects to patients' current symptom burden. This article will illustrate how understanding the pathophysiology of a single, particularly burdensome symptom of dialysis (chronic kidney disease-associated pruritus) resulted in the design, development and regulatory approval of a treatment for that symptom. The pathway described here can be applied to other symptoms associated with dialysis, meaning that if we cannot add years to patients' lives, we can at least add life to their remaining years.

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.