Uremic pruritus (UP) arises in end-stage renal disease (ESRD) and is not relieved by proper dialysis. While the pathogenesis of UP is not well understood, UP responds poorly to anti-histamines. We performed a case-control study to test if cutaneous protease-mediated, non-histamine itch is augmented in UP, and if UP is associated with altered epidermal and/or papillary dermal innervation. We recruited 12 hemodialysis subjects with ESRD-specific itch (cases) (Visual Analogue Scale (VAS)-average itch in the preceding week, 78/100), and 13 age- and sex-matched hemodialysis subjects without pruritus (controls) (VAS- average itch in the preceding week, 0/100; p<0.0001 cases vs. controls). Cowhage spicule-induced itch was induced in the back where all subjects exhibited itch, and the entire duration of itch was measured with the general Labeled Magnitude Scale. Subsequently, a punch biopsy was taken from this sensory-tested skin and multi-label immunohistochemistry was performed to measure epidermal and papillary dermal innervation. In cases vs. controls, cowhage-induced area under the curve (AUC) for itch was significantly larger (median, 25%–75%: 175.4, 101.0–252.2 vs. 42.4, 24.0–160; p=0.04) as was perceived peak itch intensity (53.6, 53.3–78.9 vs. 34.2, 20.9–55.6; p=0.02). Cases showed a significant reduction in papillary dermal nerve length (PDNL)/mm epidermis (2295, 1659–2970 vs. 2909, 2228–3523; p=0.003), resulting from the loss of papillary dermal (PD)-calcitonin gene related peptide (CGRP) (+) nerves (p<0.0001), with preservation of %PD-substance P (+) nerves (p=0.1) and intraepidermal nerve fiber density (p=0.1). VAS-average itch in the preceding week negatively correlated with PDNL/mm epidermis (correlation coefficient (CC)=-0.53, p=0.003) and %PD-CGRP (+) nerves (CC=-0.37, p=0.03). Cowhage-induced AUC-itch negatively correlated with %PD-CGRP nerves only in cases (CC=-0.40, p=0.02). Our data suggest augmented protease-dependent signaling contributes to UP and indicate a mechanism for how PD-CGRP (+) nerve loss contributes to UP and augmented cowhage-itch: loss of an afferent skin-derived itch-inhibition signal to the spinal cord dorsal horn. / 2016-10-02T00:00:00Z