Recent Advances in the Treatment of Uremic Pruritus

Aaron J. Trachtenberg; David Collister; Claudio Rigatto


Curr Opin Nephrol Hypertens. 2020;29(5):465-470. 

In This Article


The pathophysiology of uremic pruritus is complex and multifactorial. Two overarching mechanisms are implicated.[3–5,27] The immune hypothesis emphasizes the role of the chronic inflammatory state in CKD/ESKD, which, in conjunction with an altered ratio of proinflammatory Th1-helper cell to antiinflammatory Th2-helper cell, stimulates small unmyelinated C nerve fibers responsible for sensing itch. The opioid hypothesis emphasizes the role of increased μ-opioid receptor activity relative to κ-opioid receptor activity, which leads to pruritogenic nerve signaling and the release of pruritogenic cytokines.

Many additional predisposing/contributing factors have been reported. Xerosis (dry skin) resulting from the significantly decreased sweating and skin hydration associated with CKD is thought to be major contributor.[28–34] Dialysis adequacy, calcium/phosphate metabolism, hyperparathyroidism, histamine, tryptase, neuropathy, aluminum levels, vitamin excesses or deficiencies, anemia, hepatitis C infection, among other factors have also been implicated.[5,35–39] One recent review highlighted the contribution of dysbiosis (dysregulated intestinal microbiota), to uremic pruritus, and the potential of using activated charcoal or hemoperfusion in its treatment.[40]

Several recent studies support the role of the immune/inflammatory milieu in generating uremic pruritus. Keshari et al.[41] demonstrated that calcium phosphate injected directly into the skin of mice upregulated IL-6 levels in the skin and increased phosphorylation of extracellular signal-regulated kinases (ERKs) in the spinal cord, which was associated with scratching behavior. The cellular cascade and the scratching behavior were significantly attenuated in IL-6 knockout mice, suggesting a key role of this cytokine in pruritus. As a corollary, the authors also demonstrated increased IL-6 levels in the skin and blood of human patients with uremic pruritus.[41] Another recent study demonstrated increased serum levels of brain-derived nerve growth factor and neurotrophin-4, neurological mediators previously shown to be involved in itch signaling, in dialysis patients compared with controls. Levels of neurotrophin-4 were specifically elevated in patients with uremic pruritus and correlated with the severity of itch.[42] Relatedly, Momose et al.[43] demonstrated significant differences in the expression of several ion channels, namely Cav3.2, BKCa, anoctamin1, and TRPV1 in the skin and peripheral nerve endings of ESKD patients with and without pruritus. Finally, a 2018 pilot study demonstrated that serum metabolomics (metabolic profiling) can be used to identify a sensitive and specific array of phospholipids, uremic toxins, and steroids that differ in the blood of patients with severe versus mild uremic pruritus, raising the possibility of novel biomarkers for early identification or targets for intervention.[44]