An update on pruritus associated with CKD

The prevalence of chronic kidney disease (CKD) and end-stage renal disease is increasing worldwide. Despite improvements in dialysis methods, including the development of novel biocompatible membranes and ultrapure dialysate, CKD-associated pruritus remains a common and significant public health issue. Not only does this distressing symptom profoundly impact on quality of life and sleep, recent evidence showed that pruritus also was associated with poor patient outcome. Nonetheless, nephrologists and other health care professionals often fail to recognize and adequately address the pruritus associated with CKD. The pathophysiological mechanism of CKD-associated pruritus is poorly defined, and, as a result, the development of specific therapies has proved to be a challenge. The purpose of this review is to highlight the importance of this neglected topic by providing an overview of recent epidemiological studies, outcomes data, proposed pathophysiological mechanisms, and emerging treatment options

Cutaneous effects of in utero and lactational exposure of C57BL/6J mice to 2,3,7,8-tetrachlorodibenzo-p-dioxin

To determine the cutaneous effects of in utero and lactational exposure to the AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), pregnant C57BL/6J mice were exposed by gavage to a vehicle or 5 _g TCDD/kg body weight at embryonic day 12 and epidermal barrier formation and function were studied in their offspring from postnatal day 1 (P1) through adulthood. TCDDexposed pups were born with acanthosis. This effect was AHR-dependent and subsided by P6 with no evidence of subsequent inflammatory dermatitis. The challenge of adult mice with MC903 showed similar inflammatory responses in control and treated animals, indicating no long-term immunosuppression to this chemical. Chloracne-like sebaceous gland hypoplasia and cyst formation were observed in TCDD-exposed P21 mice, with concomitant microbiome dysbiosis. These effects were reversed by P35. CYP1A1 and CYP1B1 expression in the skin was increased in the exposed mice until P21, then declined. Both CYP proteins co-localized with LRIG1-expressing progenitor cells at the infundibulum. CYP1B1 protein also co-localized with a second stem cell niche in the isthmus. These results indicate that this exposure to TCDD causes a chloracne-like effect without inflammation. Transient activation of the AhR, due to the shorter half-life of TCDD in mice, likely contributes to the reversibility of these effects

The Brain Processing of Scratching

Neuroimaging studies have examined the neural networks activated by pruritus but not its behavioral response, scratching. In this study, we examine the central sensory effects of scratching using blood oxygen level-dependent functional magnetic resonance imaging (fMRI) in 13 healthy human subjects. Subjects underwent functional imaging during scratching of the right lower leg. Scratching stimulus was started 60seconds after initiation of fMRI acquisition and was cycled between 30-second duration applications of scratching and 30-second duration applications of no stimuli. Our results show that repetitive scratching induces robust bilateral activation of the secondary somatosensory cortex, insular cortex, prefrontal cortex, inferior parietal lobe, and cerebellum. In addition, we show that the same stimulus results in robust deactivation of the anterior and posterior cingulate cortices. This study demonstrates brain areas (motor, sensory, and non-sensory) activated and deactivated by repetitive scratching. Future studies that investigate the central effects of scratching in chronic itch conditions will be of high clinical relevance

Voxel-based morphometry and arterial spin labeling fMRI reveal neuropathic and neuroplastic features of brain processing of itch in end-stage renal disease

Pruritus of end-stage renal disease (ESRD) is a multifactorial symptom of complex etiology not yet fully understood. In this study we have investigated the cerebral perfusion patterns at rest in ESRD patients on hemodialysis, compared with those in healthy volunteers. We have also studied the brain responses evoked by experimental itch induction in ESRD, after stimulating the two distinct histamine and cowhage itch pathways, and compared them with the responses evoked in healthy volunteers. To identify potential structural alterations in ESRD patients compared with a group of age-matched healthy volunteers, we calculated the density of gray matter for the entire brain using a voxel-based morphometric analysis. Our results indicated that gray matter density was significantly reduced in ESRD patients in the frontal, parietal, temporal, and occipital cortices, as well as in the S1, precuneus, and insula, whereas the brain stem, hippocampus, amygdala, midcingulate cortex, and nucleus accumbens displayed an increased gray matter density. Functionally, we found a significantly higher brain perfusion at baseline associated with ESRD pruritus in the anterior cingulate, insula, claustrum, hippocampus, and nucleus accumbens. The brain responses evoked by cowhage itch, which are mediated by protease-activated receptors (PAR2), displayed significant differences compared with responses in healthy individuals and were correlated with perceived itch intensity in a dual, complex manner. The inverse correlations in particular suggested that a negative feedback mechanism modulated itch intensity, when elicited in a preexistent chronic itch background

A pramoxine-based anti-itch lotion is more effective than a control lotion for the treatment of uremic pruritus in adult hemodialysis patients

Objective: The objective of this study was to evaluate the efficacy of a commercially available anti-itch lotion containing 1% pramoxine hydrochloride versus control lotion in the treatment of uremic pruritus in adult hemodialysis patients. Methods: This was a randomized, double-blind, controlled comparative trial set in a community hemodialysis center. The study population comprised 28 individuals (mean age 53.5) with moderate to severe uremic pruritus who had been receiving hemodialysis for at least 3 months. All participants were recruited from one community hemodialysis center. Topical anti-itch lotion containing 1% pramoxine was applied twice daily to all affected areas of pruritus for 4 weeks. The main outcome measure was a reduction in itch intensity. Secondary outcomes included increases in the investigator's global assessment and improvement in skin hydration. Results: There was a 61% decrease in itch intensity in the treatment group, whereas a 12% reduction in itch intensity was observed in the control group. The rate of decline in itching was also greater in the treatment arm versus the control arm. No significant differences were displayed in other studied disease-related variables. Conclusion: Our study shows that individuals using pramoxine 1% lotion experienced a reduction in pruritus to a greater degree than those using the control lotion. This safe, convenient and effective topical lotion may potentially benefit the large number of patients affected by pruritus associated with end-stage renal disease

Skin barrier structure and function and their relationship to pruritus in end-stage renal disease

Background. The relationship between dry skin and uraemic pruritus remains controversial. In addition, there is a lack of published data describing the structure and function of the stratum corneum (SC) in end-stage renal disease (ESRD). The purpose of the present study was to assess the function and structure of the skin barrier in patients with ESRD and to correlate any abnormalities with uraemic pruritus. Methods. Thirty-eight subjects participated in the study; 20 with ESRD and 18 healthy controls. Subjects underwent evaluation of SC integrity and permeability barrier recovery, SC surface pH, pruritus and dry skin. The content of glycerol, an important endogenous humectant, was assessed in D-squame tape strips from seven patients with ESRD. Skin biopsies from six of these patients were examined by electron microscopy using ruthenium tetroxide (Ru04)-post-fixation. Results. Although SC integrity was impaired in ESRD patients (P = 0.001), there were no significant differences in permeability barrier recovery rates between ESRD subjects and controls. However, there was a high significant negative correlation between SC glycerol content and dry skin in the arms of ESRD subjects (r = −0.866, P = 0.01). Yet, there was no consistent correlation between pruritus and either dry skin, SC integrity, glycerol content or surface pH. Electron microscopy revealed no significant ultra-structural abnormalities, with particular reference to the lipid bi-layer. Conclusions. SC integrity, but not permeability barrier recovery, is impaired in dialysis patients. Although dry skin in ESRD is associated with reduced SC glycerol levels, the ultra-structure appears to be unaffected

17,20S(OH)2pD Can Prevent the Development of Skin Fibrosis in the Bleomycin-Induced Scleroderma Mouse Model

Systemic sclerosis (SSc; scleroderma) is a chronic fibrotic disease involving TGF-β1. Low serum vitamin D (vit D) correlates with the degree of fibrosis and expression of TGF-β1. This study was designed to determine whether the noncalcemic vit D analog, 17,20S(OH)2pD, suppresses fibrosis and mediators of the TGF-β1 pathway in the bleomycin (BLM) model of fibrosis. Fibrosis was induced into the skin of female C57BL/6 mice by repeated injections of BLM (50 μg/100 μL) subcutaneously. Mice received daily oral gavage with either vehicle (propylene glycol) or 17,20S(OH)2pD using 5, 15, or 30 μg/kg for 21 days. The injected skin was biopsied; analyzed histologically; examined for total collagen by Sircol; and examined for mRNA expression of MMP-13, BMP-7, MCP-1, Gli1, and Gli2 by TR-PCR. Spleen was analyzed for lymphocytes using flow cytometry. Serum was analyzed for cytokines using a multiplexed ELISA. Results showed that all three doses of 17,20S(OH)2pD suppressed net total collagen production, dermal thickness, and total collagen content in the BLM fibrosis model. 17,20S(OH)2pD also increased MMP-13 expression, decreased MCP-1 and Gli-2 expression in vivo, and suppressed serum levels of IL-13, TNF-α, IL-6, IL-10, IL-17, and IL-12p70. In summary, 17,20S(OH)2pD modulates the mediators of fibrosis in vivo and suppresses total collagen production and dermal thickness. This antifibrotic property of 17,20S(OH)2pD offers new therapeutic approaches for fibrotic disorders