SYSTEMIC INFLAMMATORY MARKERS CORRELATE WITH CHRONIC KIDNEY DISEASE-ASSOCIATED PRURITUS AND RESPONSE TO TREATMENT.

Chronic kidney disease-associated pruritus (CKD-aP) is a distressing condition with a poorly understood pathogenesis. We investigated the relationship between itch intensity and serum levels of 20 pruritic and inflammatory markers in patients with moderate-to-severe CKD-aP. This was a retrospective analysis of data from 851 patients enrolled in two randomized phase 3 trials of difelikefalin, a selective kappa-opioid receptor agonist approved for treating moderate-to-severe CKD-aP. Itch intensity was assessed using the patient-reported Worst Itching Intensity Numerical Rating Scale (WI-NRS). Samples for marker measurement were collected at baseline (pre-treatment) and at Week 12. Multiple regression analysis revealed that baseline itch intensity correlated with a group of chemokines and other markers (CCL2, CCL17, CCL22, CCL27, CXCL10, CXCL11, IFNγ, IL-2, IL-31, NGF). At Week 12, levels of 10 markers (CCL2, CCL22, CXCL2, CXCL10, IFNγ, IL 2RA, IL-31, NGF, TNFα, TSLP) were significantly decreased from baseline in responders to difelikefalin treatment (defined as ≥30% WI-NRS score reduction), but not in non-responders. Levels did not differ between placebo-treated responders and non-responders. The difelikefalin-associated reductions in the 10-marker group levels examined together also revealed a significant difference between the entire difelikefalin- and placebo-treated populations. These findings indicate that CKD-aP intensity is linked to systemic inflammation, potentially via a neuroimmune crosstalk mechanism. They also suggest an anti-inflammatory mechanism of action provides a significant contribution to difelikefalin's efficacy.