Chronic kidney disease–associated pruritus (CKD-aP) is also known as uremic pruritus. Uremic pruritus is an intractable symptom in patients with end-stage kidney disease (ESKD) undergoing maintenance dialysis (Mettang and Kremer, 2015; Narita et al., 2022). Uremic pruritus is defined as ESKD people have itching that lasts for at least 3 months (Satti et al., 2019). It is a common, distressing, and underrecognized condition that affects more than 60% of patients undergoing hemodialysis, with 20%–40% of patients reporting moderate-to-severe pruritus (Aresi et al., 2019; Fishbane et al., 2020a). Persistent pruritus negatively affects physical and mental health. Uremic pruritus has also been associated with an increase in missed dialysis sessions, a higher risk of hospitalization, and an increase in mortality, particularly cardiovascular and infection-related mortality (Sukul et al., 2021).

The current management of uremic pruritus includes adequate dialysis, control of blood phosphorus, use of emollients, topical corticosteroids, immunosuppressants, antihistamines, gabapentin, pregabalin and Chinese medicine (Eusebio-Alpapara et al., 2020; Hercz et al., 2020). Despite the acknowledged importance of uremic pruritus to patients, with the exception of gabapentin, current evidence for its treatment is weak (Simonsen et al., 2017). However, it may have side effects. Natural or medicated topical treatments such as baby oil and moisturizers may cause burning or irritation in some patients (Lu et al., 2021). Topical corticosteroids or immunosuppressants may cause thin skin and decrease local resistance, thereby increasing the risk of infection. Tacrolimus is a calcineurin inhibitor and suppresses the production of IL-2 and has been demonstrated to be beneficial for uremic pruritus (Kuypers et al., 2004). However, topical tacrolimus carries a black-box warning of increased risk of skin cancer. Antihistamines are the most common clinical treatment for pruritus. Fifty-seven percent of doctors prescribed antihistamines as the first-line treatment for itch (Rayner et al., 2017). However, the use of antihistamines raises safety issues, especially in the elderly (Verduzco and Shirazian, 2020). The neuropathic/anticonvulsant agents Gabapentin and Pregabalin are the mostly widely studied systemic medications for the treatment of uremic pruritus. Their mechanism of action likely involves negative modulation of the alpha 2 delta subunit of voltage-gated calcium channels and/or inhibition of the release of calcitonin gene–related peptide (a mediator of itch) from primary afferent neurons. However, side effects such as somnolence and unsteadiness due to mononucleosis have been reported (Martin et al., 2020). Chinese medicine is also a means of uremic pruritus treatment, but at present there is little evidence of acupuncture therapy and Chinese herbal bath therapy (Lu et al., 2022).

Difelikefalin is a novel, selective kappa opioid receptor (KOR) agonist that does not readily enter the CNS owing to its hydrophilic D-amino acid peptidic structure (Viscusi et al., 2021). It exerts antipruritic effects by activating kappa opioid receptors in peripheral neurons and immune cells (Menzaghi et al., 2015). In phase 3 KALM-1and KALM-2 studies of intravenous (IV) difelikefalin in hemodialysis participants with moderate-to-severe pruritus, difelikefalin demonstrated significant reductions in itch intensity compared to placebo at week 12 (Fishbane et al., 2020b; Wooldridge et al., 2020). Some studies suggest that difelikefalin can effectively treat uremic pruritus with mild adverse reactions, but the evidence is limited. This study collected data from published randomized controlled trials for a systematic review and meta-analysis to explore the efficacy and safety of difelikefalin in the treatment of uremic pruritus and to provide evidence-based medical evidence for clinical treatment.

The pathogenesis of uremic pruritus has not been completely understood. Many theories have been proposed in numerous studies to explain it. Th1 cells, serum C-reactive protein (CRP), interleukin (IL)-6, and IL-2 levels have been found to be significantly raised in these patients, supporting the significance of inflammation in uremic pruritus (Agarwal et al., 2021). A theory of uremic pruritus pathogenesis implicated toxins in the skin and subcutaneous tissue. Proposed toxins included “uremic toxins,” vitamin A, aluminum, calcium, phosphorus, and magnesium (Verduzco and Shirazian, 2020). One study point that a metabolomic analysis of hemodialysis patients did not identify any solutes associated with pruritus. A role for uremic solutes in pruritus remains to be established (Bolanos et al., 2021). In a study with CKD stage 3–5 managed without dialysis, the authors found that those with moderate to severe pruritus had dry skin as compared to others (Sukul et al., 2019). Yosipovitch et al. (2007) however did not find an association. Szepietowski et al. (2004) have, at least partially, eliminated xerosis as causative of pruritus. Xerosis therefore is more likely to be an exacerbating rather than a causative factor (Makar et al., 2021). One hypothesis implicating an imbalance of opioid system had been proposed, and it emphasized that µ-opioid receptor activation and κ-opioid receptor blockade leading to pruritogenic nerve signaling and pruritogenic cytokines release (Zhang et al., 2023). The lower expression of κ-opioid receptor in uremic pruritus suggests that the peripheral opioid system plays an important role in uremic pruritus (Ko et al., 2023).

The kappa opioid receptor (KOR) is a member of the G-protein-coupled receptor family and its natural endogenous ligand is dynorphin, which decreases synaptic transmission by inhibiting adenylate cyclase and voltage-gated calcium channels and activating voltage-gated potassium channels, resulting in decreased neuronal action potential production and neurotransmitter release (Beck et al., 2019; Zhou et al., 2022). KORs play a critical role in modulating dopamine, serotonin, and glutamate release in the central nervous system. KOR has been implicated in several psychiatric diseases, including schizophrenia, depression, bipolardisorder, and drug addiction (Clark and Abi-Dargham, 2019). Although activation of KOR can inhibit itching, the clinical utility of KOR agonists has been hindered by their dysphoric/psychotomimetic effects, which have been shown to be mediated by activation of central KORs and a downstream beta-arrestin signaling pathway. To avoid producing those adverse effects, novel KOR agonists have been developed through strategies involving G-protein-biased signaling and peripheral restriction. Difelikefalin is a peripheral kappa-opioid receptor agonist that acts primarily on peripheral neurons and cells of the immune system (Fotheringham et al., 2024). Activation of opioid receptors in peripheral neurons reduces afferent impulses to the central nervous system and reduces itching signals. Activating kappa opioid receptors on immune cells, decreases the release of pro-inflammatory chemicals such as IL-6, IL-2 and prostaglandins (Trachtenberg et al., 2020). Difelikefalin is not able to cross the blood-brain barrier due to its small hydrophilic peptide structure. Therefore, unlike many other opioid medications, it does not cause lethal central nervous system side effects such as respiratory depression (Viscusi et al., 2021). Difelikefalin has no action at the mu-opioid receptor, which is responsible for the euphoric effects of traditional opioid medications, so there is negligible abuse potential for this novel agent (Inan and Cowan, 2022). Following a successful phase 3 clinical trial, the FDA has approved the first selective KOR agonist in the US, difelikefalin, which is a peripherally restricted KOR agonist used for treatment-resistant pruritis in patients undergoing hemodialysis.

In recent years, numerous clinical trials have been conducted to evaluate the efficacy and safety of difelikefalin in hemodialysis patients with persistent pruritus. Our study included 4,118 subjects in 9 studies and explored the efficacy and safety of difelikefalin in the treatment of pruritus in hemodialysis patients. To our knowledge, only one relevant meta-analysis has been published, a total of 4 randomized controlled trials were included, it draws a conclusion that difelikefalin can improve itching symptoms in HD patients, it can also increase adverse reactions (Xue et al., 2024), Consistent with our conclusions. But our study had the largest number of included studies and the largest sample size. In this study, a meta-analysis was used to compare the efficacy and safety of difelikefalin and placebo in the treatment of uremic pruritus, providing evidence for clinical use. In the studies, several scales were used to assess the severity of itching, which allowed us to assess the effectiveness of difelikefalin and to compare the results of numerous studies with each other. By comparing the decrease of score of WI-NRS, 5-D itch scale total score and Skindex-10 scale score, difelikefalin can effectively improve the itching symptoms of patients with uremic pruritus. One systematic review shows that difelikefalin, due to its efficacy and good safety profile, can be regarded as the primary treatment for pruritus in patients with chronic kidney disease (Wala and Szepietowski, 2022). Narita I. et al. confirmed that intravenous difelikefalin reduced itching and improved quality of life in patients with moderate to severe pruritus who were undergoing maintenance hemodialysis (Narita et al., 2023). Although difelikefalin can increase adverse reactions, it was well tolerated in participants undergoing HD. Dizziness, Diarrhea, nausea, and headache, which are among the most common TEAEs with difelikefalin. Their incidence was slightly higher than in the placebo group, but not significantly. The risk of death was not statistically different between the two groups. Kraft L. et al. concluded that difelikefalin is effective in the treatment of uremic pruritus, and adverse events were mostly mild in their study population (primarily dizziness, diarrhea and headache) (Kraft et al., 2023). A single-dose, phase 1 study was conducted in healthy subjects and subjects on HD, difelikefalin appeared to have an acceptable safety and tolerability profile with no serious AEs reported. The most common TEAEs were dizziness, headache, paresthesia, and nausea. The majority of TEAEs were reported as mild and considered unrelated treatment (Stark et al., 2023). In a treatment atopic dermatitis’s study, 181 subjects (45.1%) reported 1 or more treatment emergent TEAEs, most were mild or moderate. The most reported TEAEs (>5% of subjects) were abdominal pain/discomfort, nausea, dry mouth, headache, dizziness, and hypertension (Guttman-Yassky et al., 2023).

Difelikefalin can effectively improve pruritus in patients with uremia. It can also increase adverse reactions; adverse events were mostly mild. The overall quality assessment of the included studies was satisfactory, but some of the included studies were biased by random assignment or blind method. Due to the small sample size of inclusion, further evidence is needed. Indeed, there is no long-term efficacy and safety of difelikefalin. Large, multicenter, high-quality RCTS will be required to provide a basis for clinical drug use.