The neuroimmune architecture of uremic pruritus: mechanisms and therapeutic targeting

Chronic kidney disease-associated pruritus (CKD-aP) remains a prevalent and burdensome symptom whose management is often empirical and only partially effective. Its pathophysiology appears to arise from interacting systemic, cutaneous, neural, and central mechanisms rather than from a single dominant pathway. In this review, we synthesize the evidence for a broader neuroimmune framework encompassing retained uremic solutes, microinflammation, xerosis and barrier dysfunction, immune dysregulation, neuropathic sensitization, opioid imbalance, and neuropeptide signaling. On this basis, we propose a four-node organizing model-Peripheral Neuroimmune Synapse (Node I), Neural Transmission and Hyperexcitability (Node II), Central Opioid Modulation (Node III), and Substance P/NK-1 Amplification (Node IV)-to translate mechanistic complexity into clinically intelligible domains. This model is intended as a pragmatic and hypothesis-generating framework, not as a validated endotyping system. Framed this way, it may help contextualize the observed benefits of therapies such as gabapentinoids and difelikefalin, clarify the limited performance of traditional antihistamine-based strategies, and support a more structured approach to bedside phenotyping and future enrichment-based trials. Prospective validation remains necessary before mechanism-guided therapeutic matching can be recommended as routine clinical practice.