Tools
Uremic Pruritus Evaluation and Treatment
Introduction
Uremic pruritus, also called chronic kidney disease (CKD)-associated pruritus (CKD-aP), is a common and debilitating symptom experienced by patients with CKD and end-stage renal disease (ESRD), which causes significant discomfort to patients. The condition is characterized by itching related to CKD and end-stage renal disease (ESRD). Uremic pruritus is commonly defined as the daily or near-daily experience of itching without a primary dermatologic finding. It is a common symptom that causes significant discomfort to patients with ESRD. However, other conditions that cause itching, such as eczema, liver disease, atopy, and thyroid diseases, should be excluded before diagnosing uremic pruritus.
More than 40% of hemodialysis patients suffer from chronic pruritus, with half experiencing generalized pruritus.[1] The underlying pathogenic mechanism of CKD-aP remains obscure. Histamine, parathyroid hormone (PTH), magnesium, and calcium have been associated with its pathogenesis. Newer studies are evaluating opioid-receptor abnormalities and microinflammation as potential causes of CKD-aP, although more data are required.[2]
Pruritus can be extremely difficult to manage due to limited treatment options. Stepwise management is recommended, starting with topical emollients, gabapentin, and phototherapy. More novel options, such as μ-opioid receptor antagonists or κ-opioid receptor agonists, may be chosen in refractory cases. In advanced cases, patients may undergo transplantation, as a successful renal transplant will relieve patients from CKD-aP.[3][4]
Etiology
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Etiology
The etiopathogenesis of uremic pruritus is poorly understood.[5] In the pathogenesis of itching, compounds such as histamine, prostaglandins, cytokines, neuropeptides, and proteases activate neurons to send itch signals to the central nervous system via secondary neurons in the dorsal horn of the spinal cord. Proposed pruritogenic toxins in CKD include aluminum, calcium, phosphate, and parathyroid hormone (PTH). However, the Dialysis Outcomes and Practice Patterns Study (DOPPS; 2012-2015) did not show any association between pruritus and serum calcium or phosphorus levels.[6]
Other contributory factors are increased blood urea, β2-microglobulin, magnesium, and vitamin A.[7][8] Some studies have found that lower serum albumin levels and higher white blood cell counts are significantly associated with moderate-to-extreme pruritus.[8][9] In addition, anemia, low erythropoietin levels, elevated ferritin, and low transferrin have also been explored as potential risks for CKD-aP.[10] Current proposed pathophysiological mechanisms for uremic pruritus include skin alterations, inflammation, nociceptive receptor dysfunction, and opioid receptor dysfunction. Although many patients with CKD experience dry skin (xerosis), not all individuals with severely dry skin have itching.[11] Nociceptive receptor dysfunction and peripheral neuropathy resulting from diseased sensory neurons and interneurons are also believed to contribute to itching.[8] Skin microinflammation is also proposed to contribute to uremic pruritus, as a study revealed elevated C-reactive protein levels have been observed in ESRD patients on hemodialysis with the condition. In addition, the opioid pathway is increasingly linked to itch sensation.[12] A theory postulates that an imbalance between μ-opioid and κ-opioid receptors (specifically, μ-overstimulation and κ-antagonism) may cause itching.[8] Moreover, other potential triggering factors include uremic toxins, cutaneous xerosis, systemic inflammation, and common comorbid conditions, including diabetes mellitus, viral hepatitis, and endocrinopathies.[13][14]
Epidemiology
Pruritus is a common complaint among patients with progressive kidney disease. The reported prevalence of uremic pruritus varies between 18% and 98%, with an overall prevalence of 55%.[15] Uremic pruritus affects both males and females, with no consistent gender preference, although a few studies have reported a higher prevalence in males.[7] However, uremic pruritus is less frequent in children and occurs in both patients on hemodialysis and those on peritoneal dialysis. Despite the high prevalence of CKD-aP, nephrologists often underestimate its prevalence.[16]
The most comprehensive epidemiologic data on uremic pruritis comes from DOPPS, which surveyed patients across various countries—including France, Canada, Australia, Germany, Italy, Japan, the United Kingdom, Sweden, New Zealand, and the United States—between 2002 and 2003. In this study, 42% of patients reported experiencing moderate to extreme pruritus.[17] Additionally, 23 studies conducted in 11 countries between 1973 and 2012 reported a mean weighted prevalence of 35% for pruritus in ESRD patients.[18][19][20] Combining these data with DOPPS-I and DOPPS-II yields a mean weighted prevalence of 41%. The latest substantial study, DOPPS-III, particularly from Japan, observed an incidence of moderate-to-extreme uremic pruritus of 44% between 1996 and 2008.[21]
Pathophysiology
In pruritus, specialized cutaneous somatosensory nerve fibers detect various stimuli, resulting in itch. While the physiology underlying pruritus has been increasingly described over the past few decades, much remains to be understood. The primary neuron type responsible for itch was initially identified as the slow-conducting, histamine-dependent, unmyelinated C fiber. Various recently discovered nonhistaminergic neurons are also involved in the neural pathways that produce itch, which likely explains the common finding of pruritus being unresponsive to antihistamines.[22]
Uremic pruritus has not been studied as extensively as pruritus in general. Furthermore, pruritus in kidney disease may be caused by mechanisms distinct from those underlying pruritus from other causes. In uremia, itching can be secondary to profound changes such as hyperparathyroidism-associated bone disease, structural changes in the skin due to dehydration, and systemic inflammation and immune dysfunction. These factors collectively contribute to morbidity in CKD patients.[23]
Emerging evidence suggests that patients with CKD may also experience primary changes in nociceptive sensory pathways in the central or peripheral nervous system. A study observed that pruritus in CKD patients often occurs in large, non-dermatomal areas with "striking mirror symmetry," suggesting a potential central neurogenic etiology.[18] Additionally, an imbalance of opioid receptors is observed in both the central and peripheral nervous systems in CKD, suggesting that uremic pruritus may result from a neuropathic mechanism rather than the pruritus seen in other conditions. Therefore, opioid modulators and gabapentin are effective in treating uremic pruritus, as detailed further below. CKD-aP correlates more strongly with uremic toxins than with the glomerular filtration rate, indicating that these toxins play a more significant role in the pathophysiology of uremic pruritus.[13][24]
History and Physical
The clinical presentation of pruritus in patients with CKD varies significantly in terms of severity and pattern. Some patients experience mild and intermittent itching, while others suffer from persistently irritating symptoms. In a survey assessing symptom distress, quality of sleep, and quality of life in 301 maintenance hemodialysis patients, itching was ranked as the most severe symptom.[25]
Itching may be localized or generalized. Localized uremic pruritus predominantly affects the face, back, or shunt arm, although any body part can be affected.[8] The relationship between itching and dialysis is variable. Some patients report worsening symptoms during and after dialysis, while others experience itching before dialysis.
A study reports that uremic patients experience itching daily or nearly daily, with most patients having itching on large, discontinuous, bilateral, and symmetric areas of skin.[18] The itching is generally worse at night than during the day. Another study notes that commonly affected areas include the back and arms, though other areas of the body can also be bothersome. The affected area may remain constant or migrate over time. Aggravating factors vary significantly, including heat, stress, dialysis, cold, physical activity, and showering.[26][27][28] Unfortunately, most patients continue to experience pruritus for months to years.
Due to the variable presentation of pruritus in CKD, distinguishing it from other causes of itching can be challenging. If a suitable treatment trial fails, a nonuremic cause of pruritus should be considered, particularly in patients with asymmetric symptoms, ulcerating or bullous lesions, or clinical findings suggestive of other systemic diseases. Additionally, pruritus may present as an adverse drug reaction from recently started or long-standing pharmacological therapy. The skin may appear normal morphologically. Alternatively, there may be evidence of chronic itching, such as excoriations, scars, and linear crusts. Other findings can include impetigo, papules, and prurigo nodularis.
Evaluation
Uremic pruritus is a clinical diagnosis. Due to the high prevalence of itching among patients with CKD, most instances of itching are attributed to uremic pruritus without considering alternate diagnoses. However, it is essential to rule out other causes of pruritus, including drug reactions, liver disease, thyroid disease, and dermatologic conditions.[29]
Before initiating treatment for pruritus, it is advisable to obtain objective information about its severity to monitor the response to treatment. A recent study recommended a set of methods for use in clinical trials to evaluate pruritus, including pruritus intensity scales, equipment to assess scratch lesions, quality of life measures, chronic pruritus course, and patient benefit from therapy.[30]
Assessing the severity of symptoms and their impact on sleep is also essential. Various tools are used to evaluate uremic pruritus, including the visual analog scale, verbal rating scale, numeric rating scale, 5-dimensional (5-D) itch scale, and Kidney Disease Quality of Life-Short Form.[8] Other psychometric tests, such as the Kidney Disease Quality of Life Short Form assessment and the Uremic Pruritus in Dialysis Patients scale, have also been used for evaluation.
The visual analog scale, numeric rating scale, and verbal rating scale are unidimensional tools used to measure symptom severity, including pruritus severity. The visual analog scale uses a graphic scale where patients select a point that describes the severity of their symptoms. For example, 0 represents no itching, and 10 illustrates the worst imaginable itching. The numeric rating scale is similar to the visual rating scale, but patients are asked to select a number representing itching severity. For example, it may be classified as none (0), mild (1-3), moderate (4-6), severe (7-8), and very severe (9 and above).
The 5-D itch scale is a multidimensional tool with 5 domains—duration, degree, direction, disability, and distribution. The disability domain assesses the effect of pruritus on sleep, leisure, housework, and work or school.[31] Pruritus is a subjective symptom, making its assessment challenging. Although scratch marks can be quantified, this method is often inaccurate when measuring the symptom's extent. Therefore, pruritus is typically assessed through patient-reported outcomes. Various patient-reported outcome scales are available for estimating pruritus intensity, including unidimensional scales that address one symptom at a time and multidimensional scales that monitor multiple symptoms, variations in symptoms, or different aspects of the symptom.[30]
Treatment / Management
Consensus recommendations for managing uremic pruritus are lacking, making it challenging for clinicians to treat these patients effectively. Some strategies are listed below.
Optimizing Serum Calcium and Phosphate Levels
Clinicians may attempt to alleviate itching symptoms by optimizing serum calcium and phosphate levels as part of the overall care for CKD patients. However, the DOPPS trial found no relationship between serum phosphate levels and uremic pruritus, raising questions about the efficacy of this strategy. Additionally, there are no established target levels to guide treatment.
Dialysis Optimization
This strategy is proposed to lower the levels of pruritogens in the body. Although no specific target Kt/V has been established for managing pruritus, it is recommended to use the Kt/V targets associated with optimal clinical outcomes. Dialysis optimization may include increasing the frequency of dialysis sessions and switching from low-flux to high-flux dialyzers.
Topical Agents
In addition to optimizing dialysis and managing serum calcium and phosphate levels, skin care—particularly hydration—is crucial for managing uremic pruritus. Topical treatments for uremic pruritus include:
- Emollients: These are widely recommended for managing uremic pruritus. Patients with CKD often experience xerosis, and emollients have demonstrated benefits in alleviating CKD-aP. Various types of emollients, such as paraffin and glycerol, have been studied and shown to provide relief.
- γ-Linoleic acid cream: This cream may provide relief for uremic pruritus.[32]
- Topical analgesics: Capsaicin and pramoxine lotion have demonstrated a superior response compared to placebo in studies.[33]
- Tacrolimus: This calcineurin inhibitor reduces interleukin-2 production and has shown benefits in treating uremic pruritus.[34] However, topical tacrolimus carries a black box warning for an increased risk of skin cancers. Therefore, it should be used with caution in renal transplant patients who already have an already elevated risk of skin cancers. (A1)
Antihistamines
Antihistamines are commonly used as a therapeutic strategy to manage uremic pruritis, but their effectiveness is uncertain. Sedating antihistamines may provide more symptom relief compared to nonsedating antihistamines. However, their use, particularly in older adults, raises safety concerns due to potential adverse effects.[8]
Gabapentin and Pregabalin
These anticonvulsants, which are commonly used to manage neuropathic pain, have also shown effectiveness in treating CKD-aP. A systematic review indicated that both gabapentin and pregabalin provide superior benefits compared to placebo.[35] Adverse effects of gabapentin include dizziness, somnolence, confusion, dry mouth, and an increased risk of suicidal thoughts, which can limit the use of gabapentin and pregabalin. Pregabalin may be better tolerated by some patients who do not respond well to gabapentin. Gabapentin can be initiated at 100 mg 3 times weekly (post-dialysis) and increased to 300 mg 3 times weekly, or started at 100 mg daily. (A1)
Mast Cell Stabilizers
Hydroxyzine, cromolyn sodium, and nicotinamide have been investigated as potential treatments for uremic pruritus. Hydroxyzine acts as a histamine-1 receptor antagonist, while nicotinamide and cromolyn sodium work by stabilizing mast cells.
In a randomized, double-blind, prospective 4-week study involving 60 patients with ESRD, cromolyn sodium cream showed some benefits compared to placebo.[36] In other studies, hydroxyzine and nicotinamide reduced pruritus, but they did not confer a statistically significant benefit compared to diluted vinegar or placebo, respectively.[37][38](A1)
Phototherapy
UV-B modulates the immune response by altering cytokine production. Narrowband UV-A, broadband UV-B, and narrowband UV-B therapy benefit patients with uremic pruritus. However, broadband UV-B treatment has demonstrated a superior response over UV-A therapy in treating uremic pruritus.[8] Although a study comparing narrowband UV-B therapy and long-wave UV-A therapy found improvement in symptoms in both groups, it did not find any difference in response.[39] Despite significant improvement in symptoms, a high drop-out rate has also been reported with narrowband UV-B therapy.[40] Adverse effects reported following UV-B treatment include sunburn and tanning.(A1)
Opioid Receptor Modulation
An imbalance in μ- and κ-opioid receptors is linked to pruritus. κ-Agonism and μ-antagonism have been found to relieve itching, and these mechanisms are being explored as potential therapeutic options.
Difelikefalin: This drug is a selective κ-opioid receptor agonist indicated for treating CKD-aP in adult hemodialysis patients. Difelikefalin does not cross the brain-blood barrier and thus does not cause the severe characteristic central nervous system adverse effects linked with opioids. The potential for abuse is low, as it does not act on the μ-receptors, which mediate euphoria.
In a randomized, double-blind, controlled trial involving 174 hemodialysis patients with moderate-to-severe pruritus, difelikefalin improved itching and sleep disturbance scores compared with patients on placebo.[41] However, patients in the difelikefalin arm also reported more adverse events, with diarrhea, dizziness, nausea, somnolence, and falls being the most frequent. Dizziness is typically transient and subsides within 3 weeks if treatment is continued.(A1)
Nalfurafine: This drug is another selective κ-opioid agonist that shows promise in treating uremic pruritus.[8] Studies did not show the benefits of nalfurafine hydrochloride infusion post-hemodialysis, but oral nalfurafine administered daily improved itching. Nalfurafine is associated with insomnia, but this resolves rapidly upon discontinuing the therapy. Nalfurafine is currently approved in Japan.
Nalbuphine: This drug acts on both κ- and μ-opioid receptors and has also proved beneficial in hemodialysis patients with pruritus. Extended-release nalbuphine has been used at a dose of 120 mg to achieve a response among hemodialysis patients.[42](A1)
Differential Diagnosis
When CKD patients develop itching, it is important to rule out other causes. Differential diagnoses for non-uremic causes of pruritus in these patients include:
- Liver disease
- Thyroid disease
- Primary dermatologic conditions
- Drug reactions
- Infestations, including lice, scabies, and bed bugs
- Hypercalcemic states
- Hodgkin lymphoma
- Cutaneous T-cell lymphoma
- Polycythemia vera
- Post-herpetic neuralgia
- Human immunodeficiency virus
Pertinent Studies and Ongoing Trials
Table. Efficacy of Various Treatments in Patients With Uremic Pruritus
| Agents | Trials | Outcomes |
| γ-Linoleic acid cream | Crossover RCT involving 17 dialysis patients [32] | A cream containing γ-linoleic acid was applied 3 times daily for 2 weeks, effectively reducing the intensity of pruritus. One patient was withdrawn from the study because of an allergic reaction. |
| Capsaicin | Double-blind placebo-controlled crossover study [43] | A total of 14 of 17 hemodialysis patients reported marked relief of pruritus during capsaicin treatment. |
| Tacrolimus | Proof of concept study [34] | Treatment with tacrolimus ointment for 6 weeks reduced the severity of itching in chronic dialysis patients. |
| Tacrolimus | Double-blind RCT [44] | No difference is observed between the effectiveness of tacrolimus and the vehicle. |
| Gabapentin | RCT involving 54 patients [45] | A total of 88.9% of patients in the gabapentin group responded well to gabapentin, compared to 22.2% in the placebo group. |
| Gabapentin | Systematic review [46] | Gabapentin improved pruritus in 6 out of 7 studies included in the review. |
| Pregabalin | RCT involving 72 patients [47] | A total of 72 patients were randomly assigned to receive either pregabalin or doxepin, and a superior response was seen in the pregabalin group. |
| Difelikefalin | RCT involving 174 hemodialysis patients [41] | Difelikefalin improved itching and sleep disturbance scores compared with patients on placebo. |
| Nalfurafine | RCT involving 337 hemodialysis patients [48] | Nalfurafine (2.5 or 5 μg) resulted in improved VAS scores compared with placebo. A larger response was seen in the 5 μg group. |
| Nalbuphine | RCT involving 373 hemodialysis patients [42] | The group receiving 120 mg extended-release nalbuphine experienced a significant reduction in itching compared to the placebo group. |
Abbreviations: RCT, randomized controlled trial; VAS, Visual Analogue Scale.
Prognosis
Some studies have reported a worse prognosis for patients with severe CKD-aP, although the mechanism is unknown. A study reported that severe pruritus was independently associated with increased mortality, even after adjusting for various other clinical factors, such as diabetes mellitus, age, β2-microglobulin, and albumin.[7] Severe uremic pruritus not only affects quality of life but is also linked to poor outcomes in chronic hemodialysis patients.
Complications
Complications of uremic pruritus include:
- Poor adherence to treatment
- Poor sleep
- Depression
- Impaired quality of life
- Skin marks
- Suicidal ideation
Deterrence and Patient Education
Uremic pruritus negatively impacts clinical outcomes, yet patients often do not report this symptom to their healthcare team.[6] Some patients are unaware that the itching is related to CKD, while others may prioritize other complaints they perceive as more severe. Educating and encouraging patients to discuss pruritus with their healthcare team is crucial, given its significant impact on both physical and mental well-being.
Enhancing Healthcare Team Outcomes
Managing uremic pruritus is challenging due to the lack of consensus recommendations and the limited number of large randomized controlled trials. Optimal care necessitates an interprofessional approach involving nephrologists, dermatologists, nurses, pharmacists, and clinical psychologists. Dermatologists can help rule out other causes of itching and recommend treatment strategies. Pharmacists are responsible for verifying dosing, performing medication reconciliation, and reporting any concerns to the prescriber or nurse if they have any concerns. All healthcare team members are responsible for maintaining accurate records of interventions and patient interactions to ensure that everyone has access to up-to-date patient information.
Given the high rate of underreporting, clinicians, nurses, and dialysis technicians are crucial in detecting itching in patients and encouraging discussions about it. Nurses are also critical for educating and monitoring the patient. Pharmacists must ensure that drugs that could trigger, worsen, or exacerbate itching are not included in the patient's regimen. Considering the link between uremic pruritus and depression, consultation with a clinical psychologist may also be necessary.
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