Identification and Management of CKD-Associated Pruritus: Current Insights

Introduction

Among the various systemic disorders associated with itching, chronic kidney disease (CKD) requires particular attention.¹ Defined in 2002 by the National Kidney Foundation, CKD is characterized by structural or functional abnormalities of the kidneys that persist for at least three months, with significant implications for a patient’s health.² The prevalence of CKD is around 13%, making it a major public health concern.^3,4 CKD is associated with numerous complications, many of which involve the skin.⁵ Common dermatological manifestations in end-stage renal disease (ESRD) include changes in skin color, elastosis, bruising, dry skin (xerosis), uremic frost, acquired perforating disorders, metastatic calcification, and bullous dermatosis of hemodialysis.^1,5 One of the most prevalent and distressing skin symptoms in dialysis patients, first documented in 1932, is CKD-associated pruritus (CKD-aP).¹ The terminology for this condition evolved over time; while it was once called “uremic pruritus”, the term CKD-aP or “CKD-associated itch” is now preferred due to the lack of direct correlation between uremia and itching.⁶ This condition not only worsens sleep, mood, daily activities, and overall quality of life (QoL) but also elevates the mortality risk for patients undergoing hemodialysis (HD).^7,8

Table 1 Assessment of the Intensity of Itching

The clinical presentation of CKD-aP is highly variable, making diagnosis and treatment challenging.^9,10 Currently, there is a scare number of up-to-date guidelines established for managing CKD-aP in dialyzed patients.^11–13 The limited number of guidelines for its diagnosis and management leads to under-diagnosis and suboptimal treatment approaches.^10,12,13 European Medicines Agency (EMA) and Federal Drug Administration (FDA) approved difelikefalin, the first drug specifically indicated for CKD-aP in dialyzed patients, which demonstrated efficacy in two Phase 3 clinical trials.¹⁴ The development of this targeted medication, supported by solid evidence of its effectiveness and safety, increased awareness and understanding of this condition.¹¹ According to the most current expert recommendations, difelikefalin should be first-line medication for patients with moderate-to-severe CKD-aP undergoing dialysis.¹³ Other therapies should only be considered as first-line choice for those patients only if difelikefalin is not available.¹³ Although, difelikefalin showed promise as a treatment for CKD-aP in dialyzed patients, particularly through its selective κ-opioid receptor agonist activity, the current body of evidence has limitations. Several studies, including the pivotal KALM-1 and KALM-2 trials, demonstrated significant efficacy in reducing itch intensity and improving quality of life in hemodialysed patients.¹⁴ However, these studies were conducted in relatively controlled settings and focused predominantly on specific patient subsets, primarily those undergoing dialysis.

A notable gap remains in the form of large-scale, multicenter randomized controlled trials (RCTs) with diverse CKD populations, including those not on dialysis or with varying comorbidities. Additionally, long-term safety and efficacy data for difelikefalin are still emerging, highlighting the need for extended follow-up studies to assess sustained benefits and potential risks.

Addressing this gap with well-powered trials would not only validate the utility of difelikefalin across broader patient populations but also facilitate a deeper understanding of its comparative effectiveness against other pruritus management strategies. This need underscores an essential area for future research, particularly as CKD-aP remains a significant unmet need impacting patient well-being and treatment adherence. This narrative review aims to provide updated insights into the diagnostic and therapeutic management of dialyzed CKD-aP patients.

Epidemiology

Prevalence

The prevalence of CKD-aP among adult patients with ESRD decreased due to improvements in dialysis.⁶ While prevalence rates ranged from 50 to 90% between 1980 and 1993,^15,16 more recent studies reported lower rates, between 22% and 57%.^17–20 A prospective cohort study, the Dialysis Outcomes and Practice Patterns Study (DOPPS), which included over 20,000 hemodialysis patients, found that 37% experienced at least moderate pruritus consistently from 2009 to 2018, with 7% of participants being severely affected by pruritus.²¹ Pruritus often goes unreported by patients and underestimated by healthcare providers.^19,21 Among DOPPS participants with severe pruritus, 18% did not receive treatment, and 17% did not disclose their symptoms to medical staff.^19,21 Additionally, more than two-thirds of medical directors underestimated the prevalence of pruritus in their facilities.^19,21

Although research on the prevalence of pruritus among patients on peritoneal dialysis and children is limited, a cross-sectional study revealed that approximately 20% of children with CKD had CKD-aP (18% of non-HD and 24% of those on HD).^21–24 Earlier studies suggested that the prevalence in children is lower (around 9%) and similar between patients on hemodialysis and peritoneal dialysis.^21–23 However, two studies from Korea and Taiwan revealed differing results.^25,26 The Korean study found higher pruritus rates in patients on peritoneal dialysis (68.2%) compared to hemodialysis (48.3%), but the Taiwanese study found no significant difference between the two groups.^25,26

CKD-aP is less frequent in patients with no-dialysis CKD.²⁷ A study involving over 5,600 patients with stages 3, 4, and 5 no-dialysis CKD reported that 24% had at least moderate pruritus, and less than 5% experienced extreme pruritus.²⁷ The prevalence and severity of pruritus increased with the progression of CKD stages.²⁷

Risk Factors

No single cause of CKD-aP was identified, but various factors were associated with its occurrence in observational studies.¹ Treatments often target these factors.¹ Dysregulation between μ-opioid and κ-opioid receptor activity plays a critical role in modulating itch sensations. Specifically, reduced μ-opioid receptor activity and heightened κ-opioid receptor signaling are crucial in pruritus pathogenesis.²⁸ Current treatments, such as difelikefalin, support this understanding by selectively targeting peripheral κ-opioid receptors, thereby reducing itch intensity without central nervous system effects.²⁸ Other notable risk factors, which were suggested including:

• Inadequate dialysis^17,29,30
• Hyperparathyroidism^31–33
• High levels of serum calcium or phosphorus^31,34,35
• Xerosis (dry skin from sweat gland atrophy)^36,37
• Elevated serum magnesium and aluminum levels^38–40
• Peripheral neuropathy^28,41,42
• Microinflammation^13,43

However, some studies did not find a consistent association between high parathyroid hormone or phosphorus levels and pruritus.^23,44 Other potential risk factors include anemia, male sex, hypervitaminosis-A, increased beta-2 microglobulin, certain human leukocyte antigen (HLA) types, and comorbid conditions like congestive heart failure, and ascites.^{19,35,45–47} The risk of pruritus appears independent of ethnicity, dialysis type, and the underlying kidney condition.⁶

Pathophysiology of CKD-aP

The exact pathophysiology of CKD-aP remains incompletely understood, but emerging evidence highlights metabolic, immunological, and neurological factors.^9,28

In CKD, the accumulation of uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, contributes to systemic inflammation and neurotoxicity.^9,28 These toxins can sensitize peripheral and central nervous systems, amplifying itch perception.^9,28 Dysregulated calcium-phosphate metabolism, hyperparathyroidism, and increased phosphorus levels found in pruritus, potentially influence on skin homeostasis and nerve excitability.^9,28

CKD-aP is increasingly recognized as an inflammatory condition.^27,44 Elevated levels of pro-inflammatory cytokines such as interleukin-6 (IL-6), interleukin-31 (IL-31), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP) are frequently observed in CKD patients with pruritus.^27,44 IL-31 plays a significant role in promoting itch through its receptor, expressed on sensory neurons and keratinocytes.^27,44 Dysregulation of Th1/Th2 cytokine balance and increased activation of mast cells further exacerbate skin inflammation and pruritus.^27,44

Neurological disturbances in CKD-aP involve both peripheral and central pathways.^8,10 Peripheral sensory neurons, particularly C-fibers, become hypersensitive to pruritogenic stimuli due to chronic inflammation and metabolic imbalances.^8,10 At the central level, imbalance in the opioid system plays a critical role.^8,10 An imbalance between μ-opioid receptor activation (which suppresses itch) and κ-opioid receptor activity (which promotes itch) was noted in CKD-aP patients.^8,10 This imbalance could result from the reduced expression of μ-opioid receptors or increased κ-opioid activity, both of which are influenced by the uremic environment.^8,10

Although CKD-aP is not only a dermatological condition, changes in skin integrity also contribute significantly to its presentation.^48,49 Xerosis (dry skin) is prevalent in CKD and exacerbates itch.^48,49 Reduced hydration, altered lipid composition, and impaired barrier proteins (eg, filaggrin) compromise the skin’s defense, allowing pruritogens to penetrate more easily and stimulate sensory nerves.^48,49

Endogenous pruritogens, such as histamine, serotonin, and proteases, play diverse roles in CKD-aP.^48,49 While histamine-independent pathways are predominant, histamine could still contribute via mast cell degranulation.^48,49 Other mediators, such as bile acids and lysophosphatidic acid (LPA), are thought to activate specific receptors (eg, TGR5 and LPARs) on sensory neurons, leading to itch sensation.^48,49 Elevated β-endorphins and dynorphins in CKD patients also interact with opioid receptors, further modulating pruritus.^48,49

Diagnosis

Clinical Characteristic

CKD-aP most often affects the back but can also impact the arms, forearms with arteriovenous shunts, head, and abdomen, with many patients experiencing generalized itching.^19,50 The intensity varies: some patients experience brief episodes each day, others suffer from near-continuous itching.⁵¹

Other characteristics of CKD-aP include:

• Symptoms typically worsen at night, leading to sleep disturbances.^{19,20,50–52} This problem is more severe in patients with intense pruritus, often causing fatigue and depression.^19,21,23
• Pruritus tends to increase with heat, especially with excessive sweating, and stress.⁶ It may decrease with physical activity, cooler temperatures, and either hot or cold showers.⁶
• Some patients experience worsening of pruritus during hemodialysis sessions, while others find relief during these sessions.^34,50

Physical examination usually shows minimal findings unless there are additional skin conditions caused by scratching, such as excoriations, lichen simplex, prurigo nodularis, keratotic papules, or follicular hyperkeratosis.¹⁶ Xerosis (dry skin) is common in those with CKD-aP, though it might only become apparent upon close inspection, showing skin scaling and cracking.⁵³

Laboratory findings in patients with pruritus can include elevated levels of blood urea nitrogen (BUN), parathyroid hormone (PTH), phosphate, calcium, and magnesium compared to those without pruritus.¹⁷ A study involving 1,773 adult hemodialysis patients found that those with severe pruritus were more likely to have BUN levels >81 mg/dL, calcium >9.5 mg/dL, phosphate >6.6 mg/dL, and less likely to have a PTH level <200 pg/mL.¹⁷ Although laboratory abnormalities could be observed, there are no reliable markers established for patients with CKD-aP.¹³

Screening

Pruritus in CKD patients is often assessed using questionnaires, like the The Kidney Disease Quality of Life 36-item short-form survey (KDQoL-36) and Worst Itch Numeric Rating Scale (WI-NRS), chosen for their simplicity and ease of use.^54–56 Initial screening for chronic pruritus focuses on a specific question (question 20) of the KDQoL-36, which asks about discomfort due to itching over the past 4 weeks, with responses ranging from “none” to “very much”.⁵⁴ This screening is typically done by nephrologists or nursing staff every three months for patients without a CKD-aP diagnosis.⁵⁴ If a patient reports significant discomfort, a more thorough differential diagnosis is conducted to rule out other potential causes.⁵⁴ WI-NRS is a simple-to-use, single-item, monodimensional patient-related outcome.⁵⁷ Patients indicate the intensity of the worst itching they have experienced over the past 24 h by marking one of 11 numbers—from 0 to 10—that best describe the worst itching experiences (‘0’ labeled with the anchor phrase ‘no itching’ and ‘10’ labelled ‘worst itching imaginable’).⁵⁷ This WI-NRS was validated for multiple dermatologic conditions, including CKD-aP.^57–59 After identifying potential CKD-aP patients, pruritus severity is assessed using the WI-NRS.^11,52,53 WI-NRS ≥ 3 < 4 corresponds to mild, WI-NRS ≥ 4 < 7 to moderate and WI-NRS ≥ 7 to severe intensity of itching, Table 1.¹¹ Apart from WI-NRS and KDQoL-36 in the clinical trials multiple scales that assess impact of itch on quality of life are utilized. For example, the Skindex-10 is a dermatology-specific instrument designed to measure the emotional, functional, and symptomatic burden of skin conditions, including pruritus.⁶⁰ The 5-D Itch Scale (duration, degree, direction, disability, and distribution) is another valuable tool that captures the multidimensional aspects of pruritus.⁶¹ Incorporating these scales into clinical assessments provides a more comprehensive understanding of how pruritus affects patients’ daily lives and facilitates standardized comparisons of treatment efficacy across studies.⁶⁰

Differential Diagnosis

The differential diagnosis process involves evaluation for skin lesions, which may be primary or secondary¹² Figure 1. Primary lesions are not associated with CKD-aP, whereas secondary ones could be.¹² A thorough skin examination, ideally done in a private consultation room, is needed.¹² If primary lesions are found, these are diagnosed and treated by a dermatologist.¹² In the absence of primary lesions, other possible causes of pruritus, such as hematological, liver, neurological, or psychiatric conditions, as well as certain medications or malignancies, should be ruled out.^11,12 Patients are then referred to the appropriate specialist for further treatment if another cause is identified.^11,12 CKD-aP is diagnosed if no other cause is found, though xerosis could coexist with CKD-aP despite being a primary skin condition.^11,12

Figure 1 Itch classification according to International Forum for the Study of Itch (IFSI).

Management

The treatment of CKD-aP follows a stepwise approach, tailored to symptom severity and patient response to each stage of therapy.^10,62–65 Given the scarcity of high-quality evidence, most recommendations originate from anecdotal experiences and small-scale, observational studies.^10,62–65 The interpretation of available studies is further complicated by varying scoring systems for pruritus severity and a lack of direct comparisons between treatments.^10,62–65 Additionally, some studied treatments could not be commercially accessible, and the placebo effect was notably stronger in many trials.^10,62–65 Most research was focused on hemodialysis patients, leaving limited data for those on peritoneal dialysis or with non-dialysis CKD.^10,62–65

Baseline treatment of all CKD-aP patients rely on three therapeutic pillars:

Optimal Dialysis

Ensuring adequate dialysis is critical, as underdialysis is often linked to pruritus.^29,30,66 For patients on dialysis, adjusting the dialysis dose or membrane type can help reduce itching.^29,30,66 For those with non-dialysis CKD, chronic dialysis is not typically initiated solely to manage pruritus.^29,30,66 Adjusting dialysis parameters, such as the Kt/V values (a measure of dialysis adequacy), could improve pruritus.^29,30,66 Some studies suggested that increasing the dose of dialysis could reduce itching, although results are inconclusive.^29,35 For example, a 1995 study found that patients receiving a higher dose of dialysis reported less pruritus.²⁹ However, other studies yielded conflicting results, indicating that factors like contact with dialysis equipment or other underlying conditions could influence pruritus.^35,66,67 Switching from bioincompatible or low-flux membranes to biocompatible, high-flux ones might decrease pruritus in certain patients.^68–70 For instance, studies indicate that patients who transitioned to membranes made with materials like polymethylmethacrylate (PMMA) experienced reduced itching.^68–70

Managing Hyperparathyroidism and Hyperphosphatemia

Proper control of these conditions is essential for managing CKD-aP.^13,34,35 Treatment goals on maintaining targeted levels of parathyroid hormone (PTH) and phosphate, although specific values for controlling CKD-aP were not established.^13,34,35 Controlling PTH levels is important as elevated levels could lead to secondary hyperparathyroidism, a common complication in CKD that contributes to itching.^13,34,35 Similarly, managing serum phosphate levels is critical because hyperphosphatemia was associated with increased skin deposition of calcium-phosphate crystals, which might exacerbate pruritus.^13,34,35 Maintaining balanced PTH and phosphate levels through appropriate medication, dietary restrictions, and dialysis adjustments is one of key strategies in the comprehensive management of CKD-aP.^13,34,35

Emollients

Applying emollients is recommended, especially for patients with dry skin, to help alleviate symptoms. Emollients that have a high-water content are preferred.⁷¹ Since xerosis is common and could be challenging to detect, emollient therapy should be used even for patients without visible signs of xerosis. Typically, patients administer an emollient for a minimum of two weeks to assess its effectiveness before considering other medical treatments.⁷¹ However, in adequately dialyzed patients with severe pruritus, additional therapy should not be delayed.⁷¹ Patients continue to use emollients indefinitely, regardless of the initial response, as insufficiently treated xerosis could hinder the effectiveness of other treatments.⁷¹

Balaskas et al⁷⁰ conducted a randomized, double-blind study involving 99 patients with uremic xerosis, treated with an oil-in-water emulsion containing 15% glycerol and 10% paraffin. Itch levels were assessed using a 100-mm Visual Analog Scale (VAS), starting at a baseline of 40.64 ± 3.36 mm.⁷² By days 28 and 56, there was a significant reduction in itch scores, measuring 13.39 ± 2.19 mm and 10.66 ± 2.14 mm, respectively.⁷² On day 56, there was also notable improvement in quality of life (QoL) based on the DLQI and SF-12 questionnaires.⁷² In the recent three periods study, this topical agent was evaluated on 235 dialysis patients with CKD and uremic xerosis.⁷³ The first one was double blind RCT in which patients with moderate-to-severe uremic xerosis were randomized to once-daily application of the lotion or vehicle control for 28 days.⁷³ This was followed by a treatment-free period ≤21 days (period II), then all patients received open-label treatment with lotion for ≥84 days.⁷³ Mean ± SEM pruritus VAS scores were comparable between the lotion (16.9 ± 2.2) and vehicle control groups (15.1 ± 2.0) at the end of period I.⁷³ After a slight rebound during period II and up to the start of period III (20.2 ± 2.7 vs 19.3 ± 2.5 mm), pruritus was significantly decreased in both groups through to the end of period III (10.4 ± 1.9 vs 7.5 ± 1.4 mm).⁷³ DLQI scores showed a significant reduction versus baseline at the end of period I and II in both groups, what indicated an improvement in QoL.⁷³ Although no additional antipruritic benefit of glycerol and paraffin was shown, the main antipruritic effect of this product could be caused by its oil-in-water emulsion base.⁷³ Significant improvements in DLQI scores in both groups suggested that relief of pruritus is an important determinant of QoL in patients with uremic xerosis.⁷³

Previous study explored the potential of endocannabinoids in managing ESRD-associated chronic itch (ESRDCI), proposing that these compounds could alleviate itching through mechanisms which include histamine reduction, vasodilation, and downregulation of mast cells (MCs).⁷⁴ Thirty-one ESRDCI patients undergoing HD were treated with a cream containing structural physiologic lipids and endogenous cannabinoids, applied twice daily for three weeks.⁷⁴ Of these, 21 patients were included in the final analysis. The baseline itch intensity, measured with a Visual Analog Scale (VAS), was 6.24 ± 2.19.⁷⁴ After 21 days of therapy, the score significantly decreased to 1.29 ± 1.41.⁷⁴ At a follow-up visit, conducted 14 days after discontinuing the therapy, itch levels increased to 2.43 ± 2.82 (P = 0.02), but the values remained significantly lower than the baseline (P < 0.001).⁷⁴ Additionally, more than 90% of patients considered the therapy to be at least “satisfactory”.⁷⁴

It was also reported that balneological therapy using polidocanol in bath oil could be successful for ESRDCI patients on HD.⁶² Thirty-one patients received 150-L baths with 30 mL of polidocanol every two days, each lasting 10 to 15 minutes.⁶² After four weeks, 87% of patients experienced complete relief from itching, with 10% showing marked improvement, and 3% reporting moderate improvement.⁶²

Several randomized, double-blind, placebo-controlled studies tested emollients for CKD-aP including gamma-linolenic acid 2.2% cream and sericin cream, all of which showed statistically significant effects in treated patients.^75,76

For patients who do not respond sufficiently to emollients, more targeted therapies could be introduced one by one.

Topical Analgesics

For patients with mild CKD-aP who continue to experience symptoms despite using a skin moisturizer, a topical analgesic could be recommended. These should be applied to the specific areas of itching and discontinued if no improvement is seen after about one week.⁷⁷ Preferred topical analgesic could be lotion containing 1% pramoxine hydrochloride, which is available over the counter and generally safe.⁷⁷ In a randomized study involving 28 hemodialysis patients, using pramoxine twice daily significantly reduced itching compared to a vehicle (61% vs 12%).⁷⁷ Topical NSAIDs or capsaicin should not be recommended for patients with CKD-aP.^78–80 Topical NSAIDs were not evaluated for this condition and could negatively impact residual kidney function.^78–80 Although capsaicin showed some effectiveness for localized itching,^78–80 it often causes an uncomfortable burning or stinging sensation. Additionally, the design of existing capsaicin studies has limitations that make the results difficult to interpret.⁸¹

Phototherapy

Phototherapy using narrow – band ultraviolet B (UVB) irradiation could be proposed for moderate-to-severe CKD-aP as a next step in the therapeutic ladder. However, it carries risks, such as increased cancer risk, especially in patients on immunosuppressive therapy.⁸² Narrow band UVB is not recommended for patients with conditions like lupus erythematosus due to photosensitivity.⁸² The positive effects of UVB therapy are believed to result from a reduction in proinflammatory cytokine levels and the promotion of mast cell apoptosis.⁸³ UVB irradiation could be effective for treating CKD-aP, as indicated by findings from small or uncontrolled studies.^48,84–87 For instance, in one study, 8 out of 10 patients with persistent pruritus experienced symptom relief after undergoing UVB therapy.⁸⁵ The treatment started with a UVB dose of 200 to 400 mJ/cm², increasing by 100 mJ/cm² with each session, up to a maximum of 1500 mJ/cm² per session.⁸⁵ However, the return of symptoms after stopping the therapy could be a concern.⁸⁵ In this study, four patients who initially responded experienced a recurrence of symptoms.⁸⁵ Patients with CKD-aP should be irradiated at least 2–3 times a week to get a satisfactory outcome.⁸⁸ Most of the UVB therapy centers are localized in the tertiary clinics.⁸⁸ Number of the phototherapy centers is limited and scare in rural areas.⁸⁸ All these severely limits the usefulness of UVB therapy in CKD-aP patients.⁸⁸

Difelikefalin

According to recent expert recommendations difelikefalin, a highly selective agonist of the κ-opioid receptor, should be administered as a first-line treatment for moderate-to-severe CKD-aP.^11,13 Difelikefalin was approved by FDA in 2021 and by EMA in 2022 as the first medication specifically for CKD-aP.¹¹ Its effectiveness in treating CKD-aP was demonstrated through two Phase 3 clinical trials (KALM-1 and KALM-2), each lasting 12 weeks, as well as an additional 52-week open-label extension study involving hemodialysis patients.¹⁴ The reduction in the intensity of itching resulted in significant long-term improvements in patients’ health-related quality of life (HRQoL), as seen in KALM-1 and its open-label extension phase.¹⁴ In both KALM-1 and KALM-2, a significantly larger percentage of patients treated with difelikefalin showed an improvement of at least 3 points on the WI-NRS scale compared to those who received a placebo.¹⁴ During the double-blind phase, those in the difelikefalin group continued to experience improvements in both pruritus severity and HRQoL (as measured by the 5-D Itch Scale and Skindex-10).¹⁴ Additionally, patients who initially received a placebo during the double-blind phase and later switched to difelikefalin in the KALM-1 open-label extension showed an average improvement of 6.9 points (95% CI −7.7 to −6.2) on the 5-D Itch Scale from the start to week 52 of the extension phase.¹⁴

Difelikefalin is administered three times a week via a quick intravenous injection into the venous line of the dialysis circuit at the end of a hemodialysis session, either during or after returning the blood to the patient.¹¹ This method of administration ensures that difelikefalin does not require additional visits, making it convenient and potentially improving patient adherence.¹¹ Furthermore, it does not require extra monitoring, which simplifies its use. The recommended dose is 0.5 μg/kg of the patient’s dry body weight (the target weight after dialysis).¹¹

Gabapentinoids

If difelikefalin is not available, for patients with moderate-to-severe CKD-aP gabapentin or pregabalin could be recommended as first-line treatment.⁶² If there is no improvement after four to 6 weeks, the medication should be stopped.⁶² The starting dose for gabapentin is 100 mg after each dialysis session, and this can be gradually increased to 300 mg daily depending on the response.⁶² Pregabalin is initially prescribed at 25 mg daily, which can be increased to 75 mg daily if needed.⁶² Doses higher than 300 mg per day for gabapentin and 75 mg per day for pregabalin are not advised for patients with stage 5 CKD, whether on dialysis or not.⁶² Patients using these medications should be monitored for potential side effects, such as dizziness and drowsiness.⁶²

Gabapentinoids are often used for various neuropathic pain conditions and showed effectiveness in treating CKD-aP in several smaller studies.^89–97 A meta-analysis of randomized trials, which included five studies with a total of 297 CKD-aP patients, found that treatment with gabapentin or pregabalin reduced itching by about five points on a 11-point visual analog scale.⁹⁸

There are several therapies for CKD-aP of limited use, which could be found in available literature. Some of they are discussed below:

Opioid Receptor Agonists and Antagonists

Nalbuphine

Another opioid used in patients with moderate-to-severe CKD-aP with satisfactory outcomes is nalbuphine.^1,63 This drug acts as a mixed κ-agonist and µ-antagonist opioid modulator.^1,63 In a large, multicenter, randomized, double-blind, placebo-controlled study, 373 patients undergoing HD received extended-release nalbuphine tablets (either 60 mg or 120 mg) or a placebo over a period of 8 weeks.^1,63 The 120 mg group experienced a significant reduction in itch severity compared to the placebo group.^1,63 Additionally, this dose led to a significant improvement in sleep disturbances caused by itching compared to placebo.^1,63 However, the tolerance for nalbuphine was low, with a high dropout rate of about 25% in the treatment groups compared to the placebo group.⁶³ In a separate open-label study with 15 hemodialysis patients suffering from pruritus, a dose-escalation trial of nalbuphine showed a decrease in the mean visual analog scale score from 4 to 1.2 points at a dose of 180 mg/day and to 0.4 points at 240 mg/day.⁹⁹ The results suggested that nalbuphine administered as tablets was safe and well tolerated in HD patients.⁹⁹ It could be effective in reducing pruritus in HD patients, with particular benefit at doses of 60 mg or higher.⁹⁹

Butorphanol

Butorphanol showed promise for use in outpatient dermatology due to its effectiveness, ease of use, and generally favorable side effect profile.¹⁰⁰ In series of patients, intranasal butorphanol proved to be highly effective in managing severe, treatment-resistant pruritus.¹⁰⁰ It remains uncertain whether butorphanol is effective for all types of pruritus, particularly CKD-aP.¹⁰⁰ Further research through a large, prospective clinical trial would be valuable to assess its effectiveness.¹⁰⁰

Nalfurafine

Nalfurafine, a kappa-opioid receptor agonist, was proved to be effective in treating CKD-aP.^101,102 According to a meta-analysis of randomized controlled trials (RCTs), nalfurafine significantly reduced itching in 144 hD patients compared to a placebo over 2 and 4 weeks.¹⁰² In a separate 2-week study involving 337 hD patients with pruritus, randomized into three groups (1:1:1) receiving either 5 mg of nalfurafine, 2.5 mg of nalfurafine, or a placebo, both doses of nalfurafine (5 mg and 2.5 mg) led to a significant reduction in itching.¹⁰² Currently, oral nalfurafine is approved for the treatment of resistant pruritus in HD patients only in Japan.¹⁰³ A key distinction between nalfurafine and difelikefalin is in their mechanism of action and site of activity. Nalfurafine is a centrally acting κ-opioid receptor agonist, which crosses the blood–brain barrier acts on central nervous system (CNS).¹⁰⁴ This central mechanism is thought to modulate itch perception and reduce pruritus severity.¹⁰⁴ In contrast, difelikefalin is a peripherally acting κ-opioid receptor agonist that does not cross the blood–brain barrier, focusing its action on peripheral nerve terminals and immune cells.¹⁰⁴ This distinction is clinically significant as it could account for differences in efficacy, safety profiles, and side effects, with nalfurafine having potential CNS-related side effects like sedation and dizziness, while difelikefalin is less likely to cause such central effects.¹⁰⁴

Naltrexone

The effectiveness of the μ-receptor antagonist naltrexone in treating CKD-aP showed inconsistent results across studies.¹ In one study, a dose of 50 mg/day of naltrexone taken orally for 7 days significantly reduced CKD-aP symptoms in a group of 15 hD patients.¹⁰⁵ However, research by Pauli-Magnus et al¹⁰⁴ found that naltrexone was ineffective as an antipruritic treatment for CKD-aP and was associated with a high incidence of side effects.¹⁸

Antihistamine Drugs and Mast-Cell Stabilizers

The positive effects of antihistamines in relieving itching were thought to be due to their sedative properties and their ability to stabilize mast cell membranes.¹⁰⁶ Despite a solid theoretical basis for their use, studies on histamine receptor antagonists yielded poor results in treating CKD-aP.²⁸ Trial outcomes were disappointing, and the risk of serious side effects, such as over-sedation—particularly in elderly patients—makes these medications less suitable for CKD-aP treatment.^28,106–109 In contrast, mast cell stabilizers showed promising results.^96,110,111 In a 4-week randomized controlled trial (RCT) involving 60 hD patients, the use of 4% cromolyn sodium cream applied twice daily significantly reduced itch severity compared to a placebo.¹¹² Additionally, in a 2-month double-blind RCT with 40 hD patients, zinc sulfate significantly improved CKD-aP symptoms compared to a placebo.¹¹³ However, these results were not proved in a subsequent RCT.¹¹⁴ Montelukast, a leukotriene receptor antagonist commonly used to treat asthma, allergic rhinitis, atopic dermatitis, and idiopathic urticaria, showed positive outcomes in reducing CKD-aP in two randomized, placebo-controlled studies.^115,116 However, both studies had a limited number of participants, and the average age of the patients was under 65 years, whereas most hemodialysis patients are typically over 65.¹¹ In general, nowadays antihistamines and mast cell stabilizers are not recommended in CKD-aP.

Tacrolimus Cream

One of the most well-designed trials evaluating immunomodulators for CKD-aP was a RCT of tacrolimus cream, which ultimately yielded negative results.²⁸ Tacrolimus cream, a topical calcineurin inhibitor with anti-inflammatory effects and minimal systemic absorption,¹¹⁷ had previously shown promise in two uncontrolled trials that reported reduced itching.^118,119 However, in a 4-week, double-blind RCT involving 22 hemodialysis patients, the results indicated that while 0.1% tacrolimus cream reduced itching severity by around 80%, it was not significantly more effective than a placebo.¹¹⁷ The study was complicated by an unexpectedly high reduction in itching—about 80%—in the placebo group, making it difficult to demonstrate the cream’s superiority.¹¹⁷

Antidepressive Drugs

Mirtazapine, a serotonergic antagonist with antihistamine properties, showed effectiveness in reducing pruritus severity in a clinical trial involving 77 patients who were initially treated with gabapentin and then switched to mirtazapine.¹²⁰ Although mirtazapine appears to be beneficial in treating pruritus caused by intrathecal morphine, such as in CKD-aP, more high-quality studies are required to validate its effectiveness.¹²¹ Although, some small studies reported that CKD-aP intensity decreased significantly with sertraline use, larger RCT with longer follow-up periods are required to prove its beneficial effect.^64,122,123

Ondansetron

Ondansetron is a competitive antagonist of the serotonin 5-HT3 receptor and is commonly used to prevent and treat nausea and vomiting related to chemotherapy, radiotherapy, and surgery.^124,125 Additionally, it is used off-label, with varying degrees of success, to treat pruritus associated with cholestasis and to prevent opioid-induced itching.^126–131 Although Balaskas et al reported promising results for its use in managing CKD-aP, subsequent studies largely failed to confirm its efficacy.^{107,132–136}

Discussion

Side Effects of Difelikefalin: A Comprehensive Perspective

Difelikefalin clinical efficacy in reducing itch intensity and improving quality of life was well-documented, a thorough discussion of its side effect profile is essential to provide a balanced perspective.

Clinical trials, KALM-1 and KALM-2 reported that the most frequently observed adverse events associated with difelikefalin include: a mild-to-moderate diarrhea that typically resolved without intervention, dose dependent nausea and vomiting that was likely related to the drug’s systemic effects and dizziness that reported in a minority of patients.¹⁴ Difelikefalin’s action on the central nervous system (CNS) is limited due to its inability to cross the blood–brain barrier.¹⁴ However, peripheral κ-opioid receptor activation could still lead to certain neurological effects, such as sedation and somnolence.¹⁴ Although uncommon, hypotension was reported, likely due to peripheral receptor activation affecting vascular tone.¹⁴ Patients with pre-existing cardiovascular instability could require close monitoring.¹⁴

There was a slight increase in the risk of infectious complications, including catheter-related infections, in hemodialysis patients receiving difelikefalin.¹⁴

The long-term safety profile of difelikefalin is still under investigation.¹⁴ Current data from clinical trials and post-marketing surveillance suggest no major safety concerns, but ongoing studies will help determine the potential risks associated with chronic use, particularly in patients with multiple comorbidities.¹⁴

Understanding the side effects of difelikefalin is crucial for tailoring its use to individual patient needs. Proactive management of adverse effects—such as adjusting dosage, providing symptomatic relief, or monitoring high-risk patients—can optimize outcomes while minimizing discomfort. Moreover, these considerations emphasize the importance of shared decision-making, where the potential benefits of pruritus relief are weighed against the likelihood and severity of adverse effects.

Future Perspectives

B-type natriuretic peptide (BNP), also known as natriuretic polypeptide B, functions as a neurotransmitter in the murine itch response to various triggers.^28,137 Research showed that blocking natriuretic peptide receptor 1 could reduce itching in animal models.¹³⁸ This finding is particularly significant for dialysis patients, who tend to have elevated BNP levels that are associated with increased itching.¹³⁷ Other potential receptors involved in itch responses include mas-related G-protein–coupled receptors, protease-activated receptors 2 and 4, and the histamine-4 receptor.¹³⁹ In CKD, the retention of uremic toxins and metabolic disturbances leads to a state of systemic inflammation, involving elevated levels of pro-inflammatory cytokines like interleukin-31 (IL-31) and C-reactive protein (CRP).¹⁴⁰ This chronic inflammatory state can cause nerve sensitization and dysfunction in the skin, contributing to the sensation of itch.¹⁴⁰ Additionally, the upregulation of immune cells, such as T cells, mast cells, and macrophages, further exacerbates this inflammatory environment, intensifying the itch sensation.¹⁴⁰ Targeting these inflammatory pathways is a focus of therapeutic research, including trials involving nemolizumab a monoclonal antibody against the IL-31 receptor A.¹⁴⁷ Nemolizumab blocks the IL-31 signaling pathway, which is thought to play a significant role in pruritus.¹⁴¹ Recent clinical trials of nemolizumab in CKD-aP patients showed promising results, with reductions in itch severity and improvement in quality of life compared to placebo.^9,65,140,141 These trials highlighted nemolizumab’s potential as a targeted therapy that addresses the underlying inflammatory mechanisms of CKD-aP.^9,65,140,141

The development of oral formulations of difelikefalin could be an exciting advancement in the management of CKD-aP and other pruritic conditions.^142,143 Although current evidence for difelikefalin primarily originate from studies of its intravenous formulation in hemodialysis patients, preliminary research into the oral form is underway.^142,143 Early-phase clinical trials suggested that oral difelikefalin demonstrates promising efficacy and safety profiles, expanding its potential use beyond dialysis-dependent patients to include those with earlier stages of chronic kidney disease or other pruritic disorders.^142,143 This oral formulation could improve patient convenience, adherence, and accessibility.^142,143 Further large-scale, randomized controlled trials are needed to confirm these findings and to explore its use in diverse populations.^142,143

Summary

Although mentioned studies and medications could not present all possible treatment options for patients with CKD-aP, the authors attempted to conclude certain guidelines. In accordance with Spanish recommendations, patients with CKD should be screened for associated pruritus with KDQoL-36 and WI-NRS.⁴⁴ The baseline of the CKD-aP management is continuous use of emollients, optimal dialysis and hyperparathyroidism and hyperphosphatemia management. Emollients should have high water content. Oil-in-water emulsion with 15% glycerol and 10% paraffin, baths in polidocanol and emollients containing gamma-linolenic acid and sericin could bring additional relief for patients with CKD-aP. In case, when emollients would be insufficient, for mild CKD-aP topical 1% pramoxine lotion could be recommended and UVB therapy could be additionally considered.¹³ If topical treatment and narrow band UVB do not bring relief, difelikefalin 0.5 μg/kg is recommended as first-line treatment for patients with moderate-to-severe CKD-aP. If difelikefalin is not available, pregabalin 25–75mg per day or gabapentin up to 300 mg per dialysis session could be administered in moderate-to-severe CKD-aP. This management approach, suitable for dialyzed patients, is visualized in Figure 2. Although similar management of non-dialyzed CKD-aP patients could be recommended, the difelikefalin should not be administrated. It does not have registration for non-dialyzed CKD-aP patients, and gabapentinoids should be recommended as a first-line systemic treatment. These CKD-aP management recommendations were supported by recent metanalysis, results of RCT’s and expert’s opinions.^11,13,123 Although, in KALM-1 and KALM-2 trials, difelikefalin was compared only to placebo, some expert opinions suggest that it should be first-line treatment in refractory CKD-aP.^11,144 Although, its efficacy was clearly demonstrated, approximately 20% of patients did not report clinically meaningful reductions in itch intensity, 30% did not present clinically relevant improvements in QoL.¹⁴⁵ Development of the new drugs targeting other neurotransmitters of the itch pathway or microinflmamation could bring a relief to the difelikefalin resistant CKD-aP patients.

Figure 2 Proposal of stepwise management in dialyzed patients with chronic kidney disease associated pruritus (CKD-aP).