Real-world effectiveness and safety of difelikefalin for chronic kidney disease-associated pruritus: a systematic review.

Chronic kidney disease-associated pruritus (CKD-aP) affects 55% of hemodialysis patients and substantially impairs quality of life (QoL) and treatment adherence. Difelikefalin, a selective kappa-opioid receptor agonist, received regulatory approval following the KALM trials. However, the applicability of these findings to routine practice remains unclear. We systematically evaluated real-world evidence (RWE) on the effectiveness and safety of difelikefalin in patients with CKD-aP. Comprehensive searches of PubMed, Embase, CENTRAL, Scopus, Web of Science, and CINAHL were conducted on 15 December 2025. Inclusion criteria were RWE studies, including observational studies and trial extension analyses reporting the efficacy (WI-NRS and 5-D Itch scores), QoL (Skindex-10), or safety in patients with CKD-aP using difelikefalin. Exclusion criteria included RCTs without open-label extensions and pruritus due to alternative causes. Two reviewers independently screened studies and extracted data. The study was prospectively registered as CRD420251266218. Twelve studies (n = 3,524) met eligibility criteria. Across real-world settings, 35-92.9% of patients achieved a ≥ 3-point WI-NRS reduction, compared with 51% in pooled KALM-1/KALM-2 data. All studies assessing sleep-related QoL reported significant benefit. Overall AE incidence ranged from 0% to 64.4%, with 6.3-16% considered treatment-related. Common AEs included dizziness, diarrhea, nausea, hyperkalaemia, somnolence, and altered mental status. No treatment-related deaths or fatal serious adverse events were reported. RWE supports the effectiveness of difelikefalin in hemodialysis patients with CKD-aP. However, included studies are heterogeneous and at high risk of bias. Future research should investigate difelikefalin in peritoneal dialysis and earlier-stage CKD cohorts, alongside health economic evaluations and implementation studies.