Supplementary Material for: The efficacy and safety of intravenous difelikefalin for the treatment of pruritus in patients undergoing hemodialysis: a systematic review and meta-analysis of randomized controlled trials

Introduction: Chronic kidney disease-associated pruritus (CKD-aP) is a common and distressing symptom in end-stage renal disease (ESRD) patients undergoing hemodialysis (HD), significantly impairing quality of life. This meta-analysis evaluates the efficacy and safety of difelikefalin for CKD-aP. Methods: We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and Scopus for randomized controlled trials (RCTs) on difelikefalin in HD patients up to November 19, 2024. Risk of bias was assessed using the Cochrane tool. Data were analyzed using Stata 15.1, with results expressed as risk ratios (RR) or mean differences (MD) with 95% confidence intervals (CI). Results: Five RCTs involving 937 HD patients were included. Difelikefalin significantly reduced weekly average WI-NRS score (MD: −0.41 [−0.51, −0.31]), 5-D Itch Scale (MD: −0.42 [−0.53, −0.31]), Skindex-10 (MD: −0.42 [−0.58, −0.26]), and Skindex-16 (MD: −0.16 [−0.23, −0.00]). It also increased the proportion achieving WI-NRS improvement ≥3 points (RR: 1.29), ≥4 points (RR: 1.45), and patient global impression of change (PGIC) response (RR: 1.44) (all p 0.05). Discussion: Difelikefalin is effective in reducing moderate-to-severe CKD-aP in HD patients, though it may increase non-serious adverse events. Limitations include limited evidence and short-term follow-up. Larger, multi-center RCTs are needed to confirm long-term safety and efficacy.