Current (blue) and prospective (grey) uremic pruritus management strategies target various junctures of this mechanism, including receptors identified as itch modulators, which can be targeted by systemic pharmacological means (capsules; sharp-ended arrow = activation, flat-ended arrow = inhibition).Ca = calcium; GPCR = G protein-coupled receptor; NK-1 = neurokinin-1; KOR = -opioid receptor; MOR = -opioid receptors; TRP = transient receptor potential; GABA = gamma-aminobutyric acid. Dialysis optimization As it is likely that uremic toxins considerably contribute to the development of uremic pruritus, ensuring that patients are adequately dialyzed often leads to a modest improvement in symptoms. uremic pruritus, as well as the evidence (or lack thereof) supporting pharmacological and nonpharmacological treatments for uremic pruritus. The potential role of patient sex in the pathophysiology and management of uremic pruritus is also discussed. Key findings: The pathophysiology of uremic pruritus involves a complex interplay of uremic toxins, systemic inflammation, mast cell activation, and imbalance of opioid receptors. Classic treatment strategies for uremic pruritus include optimization of dialysis parameters, amelioration of CKD-related mineral and bone disease, topical emollients and analgesics, antihistamines, the anticonvulsant medications gabapentin and pregabalin, and ultraviolet light B (UV-B) phototherapy. Strong data to support many of these classical treatments for uremic pruritus are limited. Newly evolving treatment approaches for uremic pruritus include opioid receptor modulators, neurokinin-1 inhibitors, and cannabinoids. Further studies regarding their efficacy, pharmacodynamics, and safety in the CKD and ESKD population SOX18 are needed before these agents are accepted into widespread use. Additional nonpharmacological strategies aimed at treating uremic pruritus include psychotherapy, acupuncture, omega-3 fatty acids, and exercise. Finally, sex differences may exist regarding uremic pruritus, but studies directly addressing sex-specific mechanisms of uremic pruritus remain absent. Limitations: High-quality evidence in the management of uremic pruritus remains lacking. Most recommendations are based on expert opinion or studies involving small numbers of patients. In addition, our understanding of the pathophysiological mechanisms PF-06305591 behind uremic pruritus is incomplete and continues to evolve over time. Implications: Uremic pruritus is a common symptom which reduces quality of life in CKD and ESKD. The identification of novel targeted treatment approaches may ease the burden of uremic pruritus in the future. (Gabapentin, Pregabalin)Negatively modulate voltage-gated calcium channels and calcitonin geneCrelated peptide release34; possible modulation of -opioid receptors35Neurological side effects such as dizziness and somnolence reported36Opioid receptor modulators?-antagonist (Naltrexone, Naloxone)Inhibits -opioid receptor, a mediator of itchEffective in a subset of patients37 (Aprepitant, Serlopitant)Blocks substance P-mediated itch sensation in histamine-independent pruritus47Interactions of Aprepitant with other medications restrict use in some patients48,49 CKD = chronic kidney disease; MBD = mineral and bone disorder; ESKD = end-stage kidney disease; FDA = Federal Drug Agency; THC = tetrahydrocannabinol; CBD = cannabidiol; TRP = transient receptor potential. Open in a separate window Figure 1. Uremic pruritus pathophysiology and management strategies. Hemodialysis may lead to the development of uremic pruritus in a mechanism that involves mast cell activation, maladaptive dermal cell signaling and the induction of the itch sensation via various nociceptive receptors within the peripheral and central nervous systems. Current (blue) and prospective (grey) uremic pruritus management strategies target various junctures of this mechanism, including receptors identified as itch modulators, which can be targeted by systemic pharmacological means (capsules; sharp-ended arrow = activation, flat-ended arrow = inhibition).Ca = calcium; GPCR = G protein-coupled receptor; NK-1 = neurokinin-1; KOR = -opioid receptor; MOR = -opioid receptors; TRP = transient receptor potential; GABA = gamma-aminobutyric acid. Dialysis optimization As it is likely that uremic toxins considerably contribute to the development of uremic pruritus, ensuring that patients are adequately dialyzed often leads to a modest improvement in symptoms. For patients who have progressed to ESKD requiring dialysis, increasing the dose of hemo- or peritoneal dialysis may reduce itch.20-22 For instance, a prospective study among 111 patients on maintenance hemodialysis showed that achieving a Kt/V 1.5 was associated with a reduction in pruritus intensity compared with a Kt/V < 1.5.22 The use of high-flux versus low-flux dialyzers can further alleviate symptoms.23 Finally, the use of bioincompatible hemodialysis membranes may contribute to uremic pruritus PF-06305591 in PF-06305591 some patients. In these instances, transition to a biocompatible membrane (eg, polymethylmetacrylate) may reduce its severity.24 Optimization of CKD-MBD parameters Several small studies have suggested that an elevated calcium-phosphate product and secondary/tertiary hyperparathyroidism contribute.