Abstract
Introduction
Chronic kidney disease-associated pruritus (CKD-aP) affects up to 50% of dialysis patients and significantly impairs quality of life. Despite its prevalence and impact, CKD-aP remains under-recognized and undertreated in clinical practice.
Methods
A narrative review was conducted using PubMed, Scopus, and Google Scholar. Studies were selected based on clinical relevance, methodological rigor, and focus on validated patient-reported outcome measures (PROMs) and therapeutic trials, particularly involving gabapentinoids and κ-opioid receptor agonists. Key topics were reviewed jointly by nephrology and dermatology specialists, who collaborated to develop a synthesized management algorithm and treatment summary table through expert discussion.
Results
This interdisciplinary review provides an overview of CKD-aP pathophysiology (Figure 1) and outlines a diagnostic algorithm (Figure 2) incorporating symptom screening, exclusion of differential diagnoses, and PROM-based severity assessment. A stepwise treatment approach is presented (Figure 3), beginning with emollients, followed by gabapentinoids, and advancing to difelikefalin—the first FDA (United States), EMA (European Union) and HSA (Health Sciences Authority) of Singapore-approved treatment for moderate-to-severe CKD-aP. The review is designed as a user-friendly resource for clinicians and nurses, regardless of their specialty background.
Conclusion
CKD-aP is a complex and distressing condition requiring greater awareness and multidisciplinary care. While effective therapies like difelikefalin exist, their use is limited by cost and unfamiliarity. Future priorities should include improving access, comparing available treatments, exploring alternative drug delivery routes, and integrating quality-of-life assessments into routine care.
Introduction
Itch is a significant global health issue, affecting 39.8% of the global population regardless of the underlying cause. 1 Chronic kidney disease-associated pruritus (CKD-aP), previously known as uraemic pruritus, is a persistent and distressing symptom commonly experienced by patients with chronic kidney disease (CKD).2–4 Unlike dermatological causes of itch, CKD-aP typically lacks visible dermatosis.5–7 Approximately 20% of CKD patients experience this symptom, with prevalence up to nearly 50% in those undergoing dialysis. 8
CKD-aP profoundly impacts patients’ quality of life (QoL), which is often related to mortality and life expectancy. The Standardized Outcomes in Nephrology (SONG) initiative identified itch as a critical symptom in haemodialysis care. 9 CKD-related pruritus profoundly affects quality of life and healthcare utilization, leading to irritability, sleep disturbances, fatigue, anxiety, depression, and social withdrawal. 10 Moreover, it has been associated with increased hospitalizations due to infections and cardiovascular complications. Higher mortality rates also are observed in the Dialysis Outcomes and Practice Patterns Study (DOPPS) population, which was believed to be due to insomnia.11–13
Despite its burden, CKD-aP is underreported and under-treated, largely due to lack of awareness among patients, nurses, and physicians, as well as the effective, guideline-supported therapies. 14 This review provides an easily accessible and practical guide for healthcare providers to improve recognition, assessment, and management of CKD-aP in real-world clinical settings, regardless of their prior experience in nephrology or dermatology.
Methods
This narrative review compiles current literature on chronic kidney disease-associated pruritus (CKD-aP), to synthesize a comprehensive update on its pathophysiology, diagnostic approaches, and management strategies. Data were derived from randomized controlled trials (e.g., KALM-1, KALM-2), systematic reviews, real-world observational studies, and evidence-based clinical guidelines from both nephrology and dermatology perspectives. Emphasis was placed on high-quality studies, including meta-analyses and large cohort investigations, particularly those evaluating systemic treatments such as gabapentinoids and κ-opioid receptor agonists.
Relevant literature was identified through a comprehensive search of major databases, including PubMed, Scopus, and Google Scholar, using search terms such as “CKD-associated pruritus,” “uremic pruritus,” “difelikefalin,” “gabapentin,” “itch in dialysis,” and “pruritus management.” Articles were selected based on clinical relevance, methodological method, and applicability to routine clinical practice.
Validated assessment tools and evidence-based algorithms—such as the Dermatology Life Quality Index (DLQI) and the Worst Itch Numeric Rating Scale (WI-NRS)—were reviewed to support clinical utility. Key topics were reviewed jointly by nephrology and dermatology specialists, to develop a management algorithm and treatment summary table through expert discussion.
Summary of the authors’ recommended therapeutic agents for management of CKD-aP (Grade of recommendation/level of evidence is based on GRADE working group).
Abbreviation: Ca: calcium; CKD: chronic kidney disease; CKD-aP: chronic kidney disease associated pruritus; DOPPS: dialysis outcomes and practice patterns study; ESRD: end-stage renal disease; GRADE: grading of recommendations assessment, development and evaluation; HT3: 5-hydroxytryptamine type 3 receptor; IL-2: interleukin-2; Kt/V: clearance of urea times dialysis time (Kt) divided by the volume of urea distribution (V); MBD: mineral and bone disorder; PTH: parathyroid hormone; PO4: Phosphate; RNA: ribonucleic acid; Th1: T helper cells type 1; Th2: T helper cells type 2; TNF: tumor necrosis factor.
Results
Section 1: Pathophysiology of CKD-aP
The complex and multifactorial pathogenesis of CKD-aP is summarized in a simplified visual diagram, as illustrated in Figure 1. Pathophysiology of chronic kidney disease-associated pruritus (CKD-aP).
The accumulation of uraemic toxins is one of the earliest theories mentioned. Proposed pruritogenic toxins like aluminium, phosphorus, and vitamin A deposit in the skin, leading to local inflammation and pruritus. Hence inadequate dialysis clearance has been identified as the main contributor to pruritus intensity in haemodialysis (HD) patients, with poor removal of pruritogenic substances associated with increased itch severity.15,16
Another possible causative factor is peripheral neuropathy – where the damaged small nerve fibers are activated out of proportion, impairing autonomic regulation. This may enhance pruritic stimuli through central and peripheral mechanisms.17,18
Inflammatory dysregulation is another key factor. Elevated levels of IL-31, IL-4, and IL-13 activate pruritogenic pathways.17,18 This overlap with other chronic skin disorders such as atopic dermatitis. 19
Lastly, a recent and crucial discovery in the pathogenesis of CKD-aP involves dysfunction of the opioid receptor system, which has led to the development of targeted κ-opioid receptor agonists. Patients with CKD-aP exhibit an imbalance between mu-opioid receptors (MOR) and kappa-opioid receptors (KOR). KOR which has antipruritic effect are reduced, while MOR which is the antagonism of KOR are overstimulated. 20 These have founded the therapeutic rationale for selective KOR agonists such as difelikefalin and nalfurafine.5,21
Section 2: Initial assessment (e.g., WI-NRS, SADS, DLQI etc.)
CKD-aP often goes undiagnosed due to lack of awareness and diagnostic guidelines. We propose a three-step, simplified diagnostic algorithm as shown in Figure 2.22,23 (1) Screening can begin with a single, validated question: “Have you experienced itch recently?” This approach promotes early symptom recognition, as it is easily understood by patients and usable by healthcare personnel.1,24 It encourages multidisciplinary involvement in symptom monitoring as it can be readily adopted not only by busy physicians in polyclinics, nephrologist in ward round and dialysis nurses in dialysis centre. (2) Exclusion of other potential causes can be done by a thorough clinical history and physical examination. Conditions such as primary dermatological conditions (xerosis, atopic dermatitis), or secondary causes such as hepatic disorders, and neuropathic or psychogenic pruritus must be ruled out. Referral to dermatology is recommended when the diagnosis remains uncertain or treatment options need to be sought via multidisciplinary discussion. Additionally, laboratory investigations such as Kt/V or the urea reduction ratio should be performed to assess dialysis adequacy, along with serum phosphate, calcium, and parathyroid hormone levels, all of which may contribute to pruritus severity.
15
(3) Severity assessment of CKD-aP should incorporate validated patient-reported outcome measures (PROMs) to quantify both itch intensity and its impact on quality of life (QoL).17,25 Their main clinical utility is to facilitate the monitoring and treatment response.
26
(A) Unidimensional tools, such as Worst Itch Numerical Rating Scale (WI-NRS), Visual Analogue Scale (VAS), and Verbal Rating Scale (VRS), are commonly used in clinical practice due to their ease of administration and reliability.27 Among these, WI-NRS is particularly recommended, as it has been validated in major CKD-aP clinical trials such as KALM-1 and KALM-2.
28
This single-question assessment has shown strong correlation with health-related QoL domains and is feasible for routine use. It helps clinicians in individualizing the treatment decision, but with limitations such as subjectivity and reduced applicability in cognitively impaired individuals.
29
(B) Multidimensional PROMs—such as the Self-Assessed Disease Severity (SADS) scale, Dermatology Life Quality Index (DLQI), 5D-Itch Scale, Itch Severity Scale (ISS), and Skindex-10—provide broader insights into the psychological and social burden of pruritus. The DLQI is one of the most widely used instruments across dermatological conditions, evaluating the impact of itch across six domains of daily life.30,31 While it is easily understood by clinicians across specialties and has strong psychometric properties, it can be time-consuming to administer. Therefore, its use is more appropriate for research settings rather than routine clinical practice. An individualised CKD-aP diagnostic algorithm.
Section 3: Stepwise management algorithm for CKD-associated pruritus (CKD-aP)
This section outlines a comprehensive, stepwise approach to the treatment of CKD-aP, integrating both non-pharmacological and pharmacological options, guided by symptom severity and patient-specific factors, as demonstrated in Figure 3. An individualised CKD-aP management algorithm.
A wide range of therapeutic interventions targeting multifactorial pathophysiology have been investigated for CKD-aP, while many treatments remain off-label. Current treatment follows a stepwise approach, starting with topical emollients and antihistamine for mild cases, followed by systemic agents such as gabapentinoids or κ-opioid receptor agonists (e.g., difelikefalin) for moderate-severe pruritic cases, and progressing to adjunctive options such as phototherapy, or acupuncture for treatment-resistant cases. Notably, CKD-aP may be partly reversible, as successful renal transplantation has been shown to significantly reduce its prevalence. 32 Authors have synthesized a summary table (Table 1) depicting the recommended therapeutic agents for management of CKD-aP according to grade of recommendation/level of evidence which is based on GRADE working group.
Step 1: Optimise dialysis and correct CKD-MBD abnormalities
Dialysis and CKD-MBD optimization
Initial management aims at identifying and addressing reversible contributors to pruritus. Optimising dialysis adequacy—typically targeting a Kt/V of ≥1.2–1.4—is essential, as inadequate clearance of middle molecules may exacerbate symptoms. Similarly, correction of mineral and bone disorder (CKD-MBD) through dietary measures, phosphate binders, vitamin D analogues, or calcimimetics should be ensured. Although this is considered foundational, the relationship between CKD-MBD parameters (such as serum phosphate, calcium, and parathyroid hormone) and pruritus severity remains inconsistent. For instance, Fishbane et al. found no significant correlation between serum phosphate levels and pruritus intensity in hemodialysis patients, and no definitive threshold values have been established. Nonetheless, addressing CKD-MBD abnormalities remains a prudent and necessary first step. 33
Step 2: First-line symptom relief – Emollients and antihistamines
Topical and oral agents are employed early to address xerosis and relieve mild symptoms.
Emollients
Topical emollients help relieve itching associated with xerosis, which is common in CKD patients due to impaired skin barrier function. Preparations containing urea, glycerol, or paraffin are preferred for their hydrating properties.2,14 Patients should be counselled to use a minimum of 200 g per week for adequate effect. 34
Topical alternatives
In cases of refractory xerosis or localized itch, topical agents such as capsaicin, pramoxine, or tacrolimus may be considered. These have shown benefit in reducing pruritus intensity in small studies and case series, particularly when conventional emollients are insufficient.4,35
Antihistamines
Oral antihistamines are generally ineffective for CKD-associated pruritus (CKD-aP), as histamine is not a primary mediator in its pathophysiology.3,36 The choice on first-generation (e.g., hydroxyzine, diphenhydramine) or 2nd generation (e.g., cetirizine, loratadine, fexofenadine) antihistamines may be considered in selected cases. Overall, their use requires caution, especially in elderly patients, due to the increased risk of cognitive impairment, daytime somnolence, reduced alertness, and falls.36,37 They are still commonly prescribed, as CKD-aP often overlaps with eczema.
Step 3: Moderate to severe pruritus – Gabapentinoids, difelikefalin
Patients with persistent symptoms require escalation to systemic therapies, including novel agents.
Gabapentinoids
Gabapentinoid dosing and titration in CKD-aP (by CKD stage).
Difelikefalin
Difelikefalin is a selective κ-opioid receptor (KOR) agonist that provides targeted relief of pruritus without the adverse effects typically associated with mu-opioid receptor (MOR) stimulation as shown in Figure 4. It is the first FDA (United States), EMA (European Union) and HSA (Health Sciences Authority) of Singapore-approved treatment for moderate-to-severe CKD-associated pruritus (CKD-aP).
41
Its efficacy and safety were demonstrated in two pivotal phase 3 randomized controlled trials—KALM-1 and KALM-2. In KALM-1, 51.9% of hemodialysis patients treated with difelikefalin achieved a clinically meaningful reduction of ≥3 points on the Worst Itch Numerical Rating Scale (WI-NRS), compared to 30.9% in the placebo group. These results were consistent with findings from KALM-2, further validating the therapeutic benefit. Patients also reported significant improvements in itch-related quality of life, including better sleep, emotional well-being, and social engagement, as assessed by instruments such as the 5-D Itch Scale and Skindex-10.41–43 Difelikefalin was generally well-tolerated, with common adverse events including diarrhea, dizziness, somnolence, and mental status changes, most of which were mild to moderate in severity. There is data supporting tolerability for up to 64 weeks also.5,41 These findings support difelikefalin’s role as a safe and effective treatment option for hemodialysis patients suffering from moderate-to-severe CKD-aP. This treatment can only be prescribed by a dermatologist/nephrologist and administered during haemodialysis. Mechanism of action of difelikefalin.
Nalfurafine
Nalfurafine is a centrally acting selective κ-opioid receptor agonist approved in Japan in 2009 for the treatment of CKD-aP. Phase 3 RCTs in Japanese dialysis patients demonstrated significant reductions in itch severity with 2.5–5 µg/day nalfurafine compared to placebo. 44 However, its availability remains limited (only Japan and Korea), and its use is associated with central nervous system side effects, including insomnia and hallucinations at higher doses. Thus, while it offers a convenient oral option, its use remains limited to this specific hemodialysis patient group and geographic region.
Step 4: Refractory cases – Phototherapy and specialist involvement
Phototherapy
Narrowband ultraviolet B (NB-UVB) therapy has shown efficacy in reducing pruritus severity by modulating immune pathways and lowering pro-inflammatory cytokine levels.31,32 However, its use may be limited by accessibility, cost, and concerns over long-term skin cancer risk, especially in immunosuppressed patients. This treatment can only be prescribed by a dermatologist. Patients must also be physically able to tolerate short-duration sessions (1–3 times per week).
Other non-pharmacological options
Acupuncture, transcutaneous electrical nerve stimulation (TENS), and omega-3 fatty acid supplementation—may be considered in refractory cases. Although some patients report benefit, the supporting evidence remains limited and further research is needed.4,11
Other pharmacologic adjuncts
Serotonin (5-HT3) antagonist (ondansetron)
Serotonin (5-HT3) receptor antagonists such as ondansetron have been studied for their antipruritic effects due to serotonin’s role in pruritus signaling. While small studies have shown modest improvement in CKD-aP symptoms, the evidence remains limited and inconsistent. 45 Given their favorable safety profile, serotonin antagonists may be considered in select cases, although they are not routinely recommended.
Selective serotonin reuptake inhibitors (SSRIs)
SSRIs, including paroxetine and sertraline, have been explored for pruritus management due to their modulatory effects on central neurotransmitters involved in itch perception. Some reports suggest a benefit, 46 particularly in patients with concurrent depression or anxiety, but clinical trial data are sparse. SSRIs may be useful as adjuncts in CKD-aP cases with a strong psychogenic component, rather than as primary therapy.
Naltrexone/Naloxone
Both are mu-opioid receptor antagonists that have been investigated for pruritus management based on the theory that mu-receptor overstimulation contributes to itch. Some small studies have reported symptomatic improvement in CKD-aP, but the results are inconsistent. A randomized crossover study (n = 23) showed no statistically significant benefit compared to placebo; moreover, side effects were common. 47 They are not widely used due to the limited efficacy and potential side effects, including nausea and hepatotoxicity.
Nalbuphine
Nalbuphine is a mixed mu-opioid receptor antagonist and κ-opioid receptor agonist, offering a dual mechanism that may alleviate pruritus. Early phase clinical studies in dialysis patients have shown promising results in itch reduction with an acceptable safety profile. 48 However, more robust, large-scale trials are needed to confirm its role in CKD-aP management.
Discussion
Chronic kidney disease-associated pruritus (CKD-aP) is a prevalent and distressing symptom, especially among patients undergoing maintenance on dialysis. It significantly impairs health-related quality of life and has been associated with poor sleep, depression, and increased mortality. An effective approach to CKD-aP management requires a multidisciplinary strategy that includes nephrologists, dermatologists, dialysis nurses, and active patient involvement.
Traditionally, the management of CKD-aP has centred on nephrology-led strategies, particularly the optimisation of dialysis adequacy and correction of biochemical derangements. While these remain foundational, they are frequently inadequate to address moderate-to-severe or refractory pruritus. Dermatologists can provide critical expertise in the evaluation and management of chronic itch, offering therapies such as topical corticosteroids, emollients, and phototherapy, which complement nephrologist-led treatment approaches.
Pharmacological management is a cornerstone of CKD-aP care. Among current options, gabapentinoids (gabapentin and pregabalin) are the most extensively studied, consistently demonstrating efficacy in symptom relief. In recent years, κ-opioid receptor agonists, particularly difelikefalin, have emerged as effective alternatives. Although no head-to-head trials have been conducted between gabapentinoids and difelikefalin, the latter’s approval in the United States and Europe supports its use in patients with treatment-resistant symptoms. Drug selection should be guided by shared decision-making and tailored to patient-specific factors, including comorbidities, tolerability, and functional status. For example, difelikefalin may be preferred in elderly dialysis patients who are at increased risk of sedation from gabapentinoids.
A proposed CKD-aP treatment algorithm (Figure 4) includes both first-line agents and escalation pathways. For patients with refractory pruritus, early referral to specialised pruritus clinics is recommended. Such centres can facilitate access to advanced treatments, including phototherapy, systemic immunomodulators, or emerging biologics.
Despite promising clinical trial results and regulatory approvals, access to newer therapies such as difelikefalin remains limited in Singapore. Key barriers include its absence from public hospital formularies, high cost, and a lack of local protocols or standard operating procedures for administration. In international practice, trained dialysis nurses routinely administer difelikefalin post-dialysis without physician supervision. However, Singapore’s initial adoption may necessitate physician-administered first doses and additional nursing protocol development. With structured training and established SOPs, nurse-led administration is both safe and feasible, and may facilitate broader uptake in the local setting.
Affordability poses a further challenge. Difelikefalin is estimated to cost approximately SGD 4200 per year in some international markets. Without health technology assessment endorsement or inclusion in subsidy schemes such as MediSave, patient access in Singapore is likely to be constrained by financial limitations. Even in countries with strong public funding mechanisms, such as Canada, similar cost-related access issues have been reported. Moreover, awareness of CKD-aP and its newer therapies among nephrologists and dialysis providers in Singapore remains variable. In the absence of national clinical guidelines or consensus statements, many patients may continue to receive off-label treatments with limited effectiveness and tolerability.
Globally, cost-effectiveness analyses have supported the use of difelikefalin. The United Kingdom’s National Institute for Health and Care Excellence (NICE) approved difelikefalin based on a favourable incremental cost-effectiveness ratio (ICER) of approximately GBP 22,000 per quality-adjusted life year (QALY), within the accepted cost-effectiveness threshold. 49 Similar endorsements have been reported in Australia and selected European nations. Another κ-opioid receptor agonist, nalfurafine, which is approved in Japan and South Korea, has also demonstrated efficacy and may warrant further consideration for wider international use. 19
In Singapore, improving CKD-aP management will require several coordinated efforts. These include enhancing clinician education on symptom recognition, integrating patient-reported outcome measures into routine care, strengthening interdisciplinary collaboration with dermatologists, and expanding access to novel therapies. Policymakers should consider evaluating difelikefalin through health technology assessment frameworks to support its subsidised availability. Patient education on the burden and treatment options for pruritus should also be prioritised to facilitate informed decision-making and better health outcomes.
Future research priorities in the local context should include epidemiological studies to assess CKD-aP prevalence, the integration of PROMs in dialysis settings, and evaluation of prescription trends and treatment satisfaction among Singapore’s dialysis population. Generating such evidence will be crucial in informing clinical guidelines, healthcare resource planning, and equitable access to effective pruritus therapies.
Conclusion
CKD-aP is a prevalent, underrecognized, and debilitating condition. A stepwise, algorithmic approach—including screening, exclusion, and PROM-based severity assessment—can enhance physician awareness and support personalized management plans. Interdisciplinary collaboration in optimizing patient-centered care via a combination of pharmacological and non-pharmacological interventions remains the cornerstone of CKD-aP management. Future research should focus on refining treatment guidelines such as head-to-head comparisons of existing treatments, exploring alternative administration routes, such as subcutaneous or oral κ-receptor agonists, could expand treatment options for patients on peritoneal dialysis, kidney transplant recipients, and those opting for conservative management.
Footnotes
Acknowledgements
We would like to thank Vifor Pharma for the technical assistance with the diagrams.
Author contributions
TSN and DA researched literature and conceived the study. TSN and LBC was involved in protocol development and data analysis. LBC wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Data Availability Statement
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.