Systemic Inflammatory Markers Correlate with Chronic Kidney Disease-Associated Pruritus and Response to Treatment.

Abstract

Chronic kidney disease-associated pruritus) 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 chronic kidney disease-associated pruritus. This was a retrospective analysis of data from 851 patients enrolled in 2 randomized phase 3 trials of difelikefalin, a selective kappa-opioid receptor agonist approved for treating moderate-to-severe chronic kidney disease-associated pruritus. Itch intensity was assessed using the patient-reported Worst Itching Intensity Numerical Rating Scale. Samples for marker measurement were collected at baseline (before 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, and TSLP) were significantly decreased from baseline in responders to difelikefalin treatment (defined as ≥30% Worst Itching Intensity Numerical Rating Scale score reduction) but not in nonresponders. Levels did not differ between placebo-treated responders and nonresponders. 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 chronic kidney disease-associated pruritus intensity is linked to systemic inflammation, potentially through a neuroimmune crosstalk mechanism. They also suggest that an anti-inflammatory mechanism of action provides a significant contribution to difelikefalin's efficacy.