diagnostics

Review
Uremic Pruritus: From Diagnosis to Treatment
An-Yu Cheng and Lai-San Wong *

Department of Dermatology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of
Medicine, Kaohsiung 833, Taiwan; amandacheng26@gmail.com
* Correspondence: laisan7@hotmail.com; Tel.: +886-7-731-7123 (ext. 2299)

Abstract: Uremic pruritus, or chronic kidney disease-associated pruritus, is common, bothersome,

and sometimes debilitating in patients with chronic kidney disease or end-stage renal disease. Due to
its variable clinical manifestations, the diagnosis of uremic pruritus requires exquisite evaluation.
Excluding itch resulting from other dermatological causes as well as other systemic conditions
is essential for a proper diagnosis. The pathophysiology of uremic pruritus remains uncertain.
Hypotheses including toxin deposition, immune system dysregulation, peripheral neuropathy, and
opioid imbalance are supposed. This review summarizes the way to accurately diagnose uremic
pruritus and describes the latest treatment options.

Keywords: uremic pruritus; chronic kidney disease associated pruritus; chronic pruritus

1. Introduction
Uremic pruritus, also known as chronic kidney disease-associated pruritus (CKD-aP),
is a common, bothersome, and sometimes debilitating symptom in patients with chronic
kidney disease (CKD) or end-stage renal disease (ESRD).
Citation: Cheng, A.-Y.; Wong, L.-S. One large international cohort study of adult dialysis patients (Dialysis Outcomes
Uremic Pruritus: From Diagnosis to and Practice Patterns Study (DOPPS)) reported that around 70% of hemodialysis patients
Treatment. Diagnostics 2022, 12, 1108. suffered from pruritus and 40% of them were bothered by at least moderate pruritus.
https://doi.org/10.3390/
Notably, not only in patients with dialysis, the prevalence of moderate to severe pruritus
diagnostics12051108
in non-dialysis CKD patients was around 25% [1]. The prevalence of moderate to severe
Academic Editors: Chyi-Chia pruritus decreased from 46% in 1996 to 37% in 2015 [2,3], supposedly associated with the
Richard Lee and Mauro refinement of dialysis adequacy.
Giuseppe Mastropasqua Risk factors of uremic pruritus in hemodialysis patients have been reported to be old
age, gender, calcium–phosphate imbalance, longer duration of dialysis, and comorbidities
Received: 31 March 2022
such as concurrent cardiovascular disease, congestive cardiac failure, lung disease, liver
Accepted: 26 April 2022
Published: 28 April 2022
disease, neurological disease, hepatitis C infection, and anemia [4]. However, some results
were inconsistent in different studies [5–8]. Risk factors of developing pruritus in non-
Publisher’s Note: MDPI stays neutral dialysis CKD patients include old age, female sex, advanced stage of CKD, lung disease,
with regard to jurisdictional claims in diabetes mellitus, and depression [1].
published maps and institutional affil-
Pruritus in these patients dramatically affects their quality of life. Around half of them
iations.
were bothered by pruritus all day long, and one-third were most bothered at night. The
high percentage of night-time pruritus may lead to sleep disturbance. Sixty percent of
patients with severe pruritus also frequently suffered from restless sleep [3]. Patients with
pruritus also reported poor quality of life by appearance, mental distress, decreasing desire
Copyright: © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
for social interaction, and ability to work. Notably, the bothersome symptoms not only
This article is an open access article
decrease quality of life but also cause poorer medical outcomes. Pruritus in these patients
distributed under the terms and was associated with significantly higher mortality, with a 13% higher risk in DOPPS phase
conditions of the Creative Commons I (1996–2001), a 21% higher risk in DOPPS phase II (2002–2004), and 37% higher risk in
Attribution (CC BY) license (https:// Japanese patients, and was suggested to be related to poor sleep quality [2,9]. One recent
creativecommons.org/licenses/by/ study using Taiwan’s national health insurance database revealed a higher risk of all-cause
4.0/).

Diagnostics 2022, 12, 1108. https://doi.org/10.3390/diagnostics12051108 https://www.mdpi.com/journal/diagnostics

Diagnostics 2022, 12, 1108 2 of 14

death and long-term morbidities including infection-associated hospitalization and major

adverse cardiac and cerebrovascular events in patients with uremic pruritus [10,11].
Despite its high prevalence, disease burden, and even higher risk of mortality, pruritus
is often underreported by patients and is underestimated by health care providers. Some
69% of medical facilities directors underestimated the prevalence of pruritus in their
facilities, and 17% of patients who were frequently bothered by itchiness never reported
their symptoms to any member of the medical facility. Among those who did report, they
were more likely to report to nephrologists and staff of the dialysis facility, followed by
dermatologists [3].
Therefore, raising awareness of uremic pruritus is crucial for both patients and health
care providers. Health care providers should also be careful about making an accurate
diagnosis in CKD patients with chronic pruritus. At the same time, understanding its
pathophysiology to develop proper treatment is essential to improve patients’ quality of
life and medical outcomes. In this review, we focus on current advances in diagnosis and
treatment to overcome the unmet needs of patients with uremic pruritus.

2. Clinical Features
The clinical manifestations of uremic pruritus are variable. The severity varies from
somewhat uncomfortable to extremely disturbing and inducing restlessness. About 20% of
patients experienced being very much and extremely itchy in the DOPPS study [3]. The
distribution is usually generalized and symmetric, but may be localized and is more com-
mon on the back, face, and shunt arm [12]. However, there is no dermatomal distribution.
Pruritus is aggravated by dryness, heat, cold, stress, and showering. The skin is often
lacking prominent lesions in the affected patients. However, in addition to xerosis, there
may be skin lesions secondary to repetitive scratching, such as excoriation, crusts, impetigo,
and prurigo nodularis. Most patients (61%) reported that pruritus has no relation to the
timing of dialysis, but some reported that the pruritus was more severe during dialysis
(15%), or soon after dialysis (9%), or on non-dialysis days (14%) [3].
Chronic pruritus also developed in patients receiving peritoneal dialysis, although
it is less studied compared to patients with hemodialysis. A meta-analysis study showed
comparable prevalence of CKD-aP in patients with hemodialysis and peritoneal dialysis
(55% vs. 56%) [13]. However, Min et al. reported a higher prevalence of pruritus in patients
with peritoneal dialysis compared to patients with hemodialysis (62.6% vs. 48.3%) [14].
The intensity of pruritus was higher in patients undergoing peritoneal dialysis and was
associated with lower total weekly Kt/V, longer duration of dialysis, higher dietary protein
intake, higher parathyroid hormone, and higher high-sensitivity C-reactive protein [13,15].
Several observations have shown that the prevalence of pruritus declined after renal
transplantation [16,17]. A recent large study revealed that pruritus resolved completely
in 73.7% (56/76) of renal transplant recipients [18]. Furthermore, pruritus improved or
totally resolved in 97.3% of patients (74/76) with renal transplantation. Intriguingly, new
onset of pruritus was found in 18.2% (22/121) of patients with renal transplantation with
undetermined reasons [18].

3. Diagnosis
Uremic pruritus is defined by itching directly resulting from CKD, without other
explainable conditions [19]. Due to its variability and the lack of specific skin lesions,
there are no well-established criteria nor laboratory tests for the diagnosis of uremic pru-
ritus. Accurate diagnosis of uremic pruritus may be challenging. Diagnosis requires
thorough consideration including dermatologic, renal, hepatobiliary, endocrine, rheumato-
logic, hematologic or oncologic, neuropathic, and psychogenic causes. The initial approach
is to evaluate whether there is primary or inflamed skin lesions to exclude other dermatolog-
ical causes of pruritus. Common dermatological causes of chronic pruritus include atopic
dermatitis, psoriasis, chronic urticaria, dermatophytosis, scabies infestations, and bullous
pemphigoid [20]. To be noted, skin lesions secondary to scratching and rubbing, such as
Diagnostics 2022, 12, 1108 3 of 14

crusts, erosions, ulcerations, and prurigo nodularis, should not be counted. Personal drug
history should also be reviewed to exclude drug-induced pruritus without visible skin
lesions. Angiotensin-converting enzyme inhibitors, clonidine, calcium antagonists, beta
blockers, diuretics, and allopurinol may induce itch by activating mu-opioid receptors [21].
Whether patients have chronic pruritus before deteriorating renal function helps to clar-
ify the diagnosis of uremic pruritus. Referring to dermatologists may help to reach an
appropriate diagnosis of uremic pruritus.

4. Pathogenesis
Generally, itch transmission can be defined as histaminergic and non-histaminergic
pathways [22]. Due to the insufficient response to antihistamine treatment in uremic pruri-
tus, the non-histaminergic pathway is suggested to be important in uremic pruritus. The
pathogenesis of uremic pruritus is not completely understood. The possible pathogenesis
of uremic pruritus is multifactorial and includes uremic toxins, immune dysregulation,
neuropathy, and opioid imbalance [19,23–27].
The most studied potential pruritogens in the pathogenesis of uremic pruritus include
histamine, calcium, phosphate, magnesium, parathyroid hormone, and vitamin A [28–31].
Uremic toxins, substances accumulating due to impaired renal function, are supposed to
participate in uremic pruritus. This is supported by evidence of decreased severity and
prevalence of uremic pruritus with the improvement in dialysis efficiency [18,19]. Uremic
toxins are further classified as water-soluble small molecules, protein-bound compounds,
and middle molecules [32]. Among them, beta-2 microglobulin, indoxyl sulfate, and p-
Cresyl sulfate draw researchers’ attention to their possible roles in uremic pruritus [33].
However, a recent metabolomic analysis failed to show different concentrations of water-
soluble small molecules in hemodialysis patients with and without itch [34].
The immune system may also participate in the pathogenesis of uremic pruritus.
Studies comparing hemodialysis patients with and without uremic pruritus showed sig-
nificantly enhanced T helper 1 cells and serum interleukin (IL)-6, IL-2, and IL-31 levels
in patients with uremic pruritus [23–25,35]. Partial responses with immunomodulatory
treatments such as calcineurin inhibitors, phototherapy, and mast cell stabilizers in uremic
pruritus indicate the role of subclinical inflammation in uremic pruritus [26,36].
Both peripheral neuropathy and central neuropathy are believed to participate in
uremic pruritus. One study showed a reduction in innervation in the skin of patients
with uremic pruritus [37]. The association of uremic pruritus and restless leg syndrome in
dialysis patients and successful treatment with gabapentin implies the role of neuropathy
in uremic pruritus [19]. In addition, increasing evidence suggests that both central and
peripheral opioid receptors contribute to uremic pruritus. Among three types of opioid
receptors, mu-opioid receptor agonists induce itching, and kappa-opioid receptor agonists
attenuate itching. Delta-opioid receptor has a limited impact on itching [27]. Recent
successful trials of nalbuphine, nalfurafine, and difelikefalin support the hypothesis of
opioid system imbalance in uremic pruritus [38–40].

5. Treatment
Due to the limited understanding of the pathogenesis of uremic pruritus, current
treatments for uremic pruritus remain elusive. There was no Food and Drug Administra-
tion (FDA)-approved treatment for uremic pruritus until difelikefalin was approved in the
United States in 2021 [41,42]. Conventional treatments including emollient, topical agents,
antihistamine, dialysis modification, phototherapy, and serotonin receptor antagonists are
reviewed here. Recently, more evidence suggests that gabapentin, pregabalin, opioid recep-
tor agonists and antagonists, and biologics play roles in uremic pruritus. We summarize
updated treatment options for uremic pruritus in this review. (Table 1)
Diagnostics 2022, 12, 1108 4 of 14

5.1. Moisturizers
Xerosis is found in 50–85% of patients with uremic pruritus and is an aggravating
factor of pruritus [43]. Multiple trials using different emollients including glycerol and
paraffin, 10% urea and dexpanthenol, physiological lipids, and baby oil decrease xerosis
and pruritus in patients with uremic pruritus [44–48]. Emollient is suggested as first-line
therapy in patients with uremic pruritus, especially for those with less severity [19].

5.2. Topical Calcineurin Inhibitor (Tacrolimus, Pimecrolimus)

Tacrolimus, a calcineurin inhibitor, is used for its anti-inflammatory effects in atopic
dermatitis and vitiligo [49,50]. A case study reported that 0.03% tacrolimus ointment
reduced pruritus intensity in three cases with severe uremic pruritus [51]. However, a
randomized, double-blind, vehicle-controlled study demonstrated that 0.1% tacrolimus
applied twice daily for 4 weeks was not more efficacious than the vehicle [52]. Another
8-week, randomized, double-blind study of 1% pimecrolimus also revealed a lack of efficacy
compared to the placebo group [53].

5.3. Other Topical Agents

Capsaicin, a compound found in chili pepper and transient receptor potential vanilloid
member 1 (TRPV1) agonist, was used to relieve pain and neuropathy [54]. Three random-
ized controlled trials of capsaicin cream for uremic pruritus showed limited efficacy [55].
Pramoxine is a topical anesthetic with antipruritic effects. A randomized, double-blind,
controlled comparative trial with 28 patients using 1% pramoxine lotion showed a 61%
decrease in pruritus intensity compared to 12% in the placebo group [56].

5.4. High Quality of Dialysis

Since uremic toxins are suggested as potential pruritogens, increasing the efficiency of
dialysis and modification of hemodialysis prescription is a potential strategy for the treat-
ment of uremic pruritus. One randomized trial found that increased dialysis efficiency with
mean Kt/V up to 1.28 resulted in pruritus improvement compared to mean Kt/V of around
1.09 [57]. Dialysis modification to remove more middle molecules also showed improve-
ment in pruritus intensity. Hemodialysis modifications including high-flux hemodialy-
sis [58], hemodiafiltration with hemodialysis [59], and high-permeability hemodialysis [60]
have shown significant decreases in pruritus intensity. Therefore, increasing dialysis effi-
ciency as well as modulating dialysis parameters are suggested as first-line treatments in
patients with uremic pruritus [12].

5.5. Phototherapy
Phototherapy has been widely used in inflammatory skin diseases such as psori-
asis, atopic dermatitis, and vitiligo [49,50,61] by modulating Th1 and Th2 lymphocyte
differentiation and attenuating Th1-mediated responses [62,63]. Broadband ultraviolet
B phototherapy was found to be effective in patients with uremic pruritus compared to
ultraviolet A phototherapy [64]. One single-blind, randomized, controlled trial of 21 pa-
tients with uremic pruritus showed a significant improvement in pruritus by narrowband
ultraviolet B phototherapy and long-wave ultraviolet A phototherapy compared to the
non-treated group [62]. A recent controlled trial of narrowband ultraviolet B phototherapy
revealed a significant reduction in visual analog scale (VAS) from 9.1 to 1.9 compared to
treatment with antihistamine and emollients. In addition, the effect was sustained for up to
6 months in most of the study group [65]. Due to its wide adoption in pruritic dermatoses,
narrowband ultraviolet B is considered an efficacious treatment in uremic pruritus.

5.6. Antihistamine
Antihistamine, mainly targeting histamine H1 receptor, has been widely used for anti-
pruritus. It has been reported that over half of physicians prescribed an oral anti-histamine
and one-fourth of them prescribed a topical anti-histamine as first-line therapy for uremic
Diagnostics 2022, 12, 1108 5 of 14

pruritus; however, anti-histamines were generally unsatisfactory for the treatment of uremic
pruritus [3,19,66]. In addition, side effects of anti-histamines such as dizziness, sedation,
and urine retention are concerns in patients with CKD [19].

5.7. Gabapentin, Pregabalin

Both pregabalin and gabapentin, analogs of gamma-aminobutyric acid, are modulators
of neurotransmitters, acting possibly by decreasing neurotransmitter release [67]. The
neuropathic role was implicated in the pathogenesis of various pruritic disorders such as
brachioradial pruritus and pruritus in patients with diabetic neuropathic pain [68]. Several
clinical trials of gabapentin and pregabalin have shown them to be statistically significant
in the reduction in pruritus intensity in patients with uremic pruritus [69–72]. One recent
systematic review showed decreased severity of pruritus after treatment with gabapentin in
four out of seven studies (n = 171). Incidences of adverse effects with gabapentin including
dizziness, drowsiness, and somnolence were higher but not significant in a pooled analysis
(n = 290) [73]. Another clinical trial demonstrated that pruritus was relieved in 85% of
71 patients by gabapentin or pregabalin and that patients intolerant to gabapentin might
tolerate pregabalin [74]. One study comparing the effects of gabapentin after each dialysis
session and pregabalin daily showed a significant improvement in the reduction in pruritus
and neuropathic pain in both groups [72]. A systematic review concluded that gabapentin
is the most reliable and effective treatment as an off-label treatment for uremic pruritus [75].

5.8. Opioid Receptor Agonist/Antagonist

5.8.1. Naloxone
Intravenous injection of naloxone, a mu-receptor antagonist, was firstly reported to
be efficacious in treating uremic pruritus in 1984 [76]. However, inconsistent results were
found in subsequent large studies of oral naltrexone for uremic pruritus. In addition, some
studies revealed frequent adverse effects such as nausea and sleep disturbance [77–79].

5.8.2. Nalfurafine
Nalfurafine, a selective kappa agonist, was found to be effective in uremic pruritus
in a multicenter, randomized, double-blind, placebo-controlled clinical study [80]. A
phase III randomized, double-blind, placebo-controlled study of 337 patients also revealed
that nalfurafine significantly reduce the itch severity in intractable uremic pruritus [38].
Nalfurafine was officially approved for clinical use for uremic pruritus in Japan.

5.8.3. Difelikefalin
Recently, difelikefalin, a peripheral restricted and selective kappa opioid receptor
agonist, proved its efficacy in the treatment of uremic pruritus in a large double-blind,
placebo-controlled, multicenter phase III trial [40]. A total of 378 hemodialysis patients with
moderate to severe pruritus were randomly treated with intravenous difelikefalin at the
dose of 0.5 µg per kilogram or placebo for 12 weeks. Difelikefalin significantly decreased
the intensity of pruritus (at least 3 points from baseline according to a 24-h worst itching
intensity numerical rating scale) in 51.9% of patients compared to 30.9% of patients in the
placebo group. Itch-related quality of life also improved significantly compared to the
placebo group. Common adverse events include diarrhea, dizziness, and vomiting, but no
adverse events of dysphoria, hallucination, euphoria, or discontinuation-related discomfort
were reported in the difelikefalin group. Based on the successful results of the phase III
trial, difelikefalin was approved by the FDA in the United States in 2021. A regulatory
review is ongoing in Europe and a phase III trial is in progress in Japan. Oral difelikefalin
is under investigation [41].

5.8.4. Nalbuphine
Nalbuphine, a combination of kappa-opioid receptor antagonist and mu-opioid recep-
tor agonist, has been reported to be beneficial for morphine-related itch [81]. In addition,
Diagnostics 2022, 12, 1108 6 of 14

nalbuphine also decreased the intensity of uremic pruritus [39]. A multicenter, randomized,
double-blind, placebo-controlled trial of 373 hemodialysis patients with moderate to severe
pruritus demonstrated that the group receiving nalbuphine 120 mg twice daily for 8 weeks
reported significantly decreased pruritus. However, there was no significant difference
between nalbuphine at the dose of 60 mg twice daily and the placebo group.

5.9. Mast Cell Stabilizer

Mast cell stabilizers, which prevent degranulation of inflammatory mediators from
mast cells, have been shown to be effective in uremic pruritus, and include topical cromolyn
sodium [82], oral cromolyn sodium [83], ketotifen [70], and zinc sulfate [84]. One double-
blind, randomized clinical trial of 52 patients revealed similar efficacy in decreasing pruritus
severity and no significant difference in adverse effect with gabapentin and ketotifen [70].
However, one randomized control trial of 36 patients with 4-week duration of zinc sulfate
showed non-significant reduction in pruritus in hemodialysis patients [85]. Mast cell
stabilizer is safe and potentially efficacious in uremic pruritus, but more studies are needed.

5.10. Montelukast
Leukotriene B4, primarily released by macrophage and leukocytes, is involved in itch
and may induce scratching [86,87]. Montelukast, a leukotriene receptor antagonist, is used
in atopic dermatitis, asthma, allergic rhinitis, and idiopathic urticaria. One randomized
double-blind controlled trial of 80 hemodialysis patients receiving 10 mg montelukast
daily for 30 days revealed that montelukast significantly decreased pruritus compared to
the placebo group. The authors concluded that montelukast might serve as an add-on
treatment in intractable uremic pruritus [88].

5.11. Serotonin Receptor Antagonist: Ondansetron

5-HT3 receptor antagonists have been studied for their treatment efficacy in uremic
pruritus. Ondansetron, a selective 5-HT3 receptor antagonist, had an insignificant effect on
uremic pruritus in two randomized controlled trials [89,90].

5.12. Nemolizumab
Due to the higher concentration of IL-31 in hemodialysis patients with uremic pruritus,
the role of nemolizumab, an IL-31 receptor alpha antibody, in the treatment of uremic
pruritus is suggested [23]. A randomized, double-blind, placebo-controlled phase IIB trial
of a single dose of nemolizumab was conducted in 69 patients with uremic pruritus but
failed to meet the primary efficacy endpoint [91].

5.13. Dupilumab
As the possible involvement of IL-31 was implicated in uremic pruritus, the role of
T-helper 2, which is the upstream regulator of IL-31, in uremic pruritus has been suggested.
Dupilumab, an IL-4 receptor alpha-blocker, was reported to successfully treat cases with
intractable uremic pruritus [92,93]. More studies are necessary.

5.14. Acupuncture, Acupressure

Acupuncture, defined by acupuncture needle insertion into specific points of the skin
as treatment, has long been used for a variety of symptoms, such as acute or chronic pain,
sleep disturbance, and poor quality of life in East Asia [94]. Acupuncture was believed to act
through modulating the endogenous opioid system [95], which accounts for the hypothesis
of it treating uremic treatment. Similarly, acupressure stimulates the acupuncture points with
body parts of practitioners or designed equipment. A systematic review including six trials
showed that acupuncture and acupressure were effective for uremic pruritus [96]. Recent
studies comparing Zolpidem and acupressure revealed that both improved sleep quality and
quality of life in patients with uremic pruritus-associated sleep disturbance [97,98]. However,
more evidence is needed to affirm this as a recommended treatment for uremic pruritus.
Diagnostics 2022, 12, 1108 7 of 14

5.15. Charcoal
Given the hypothesis of non-dialyzable uremic toxins as possible pruritogens, the ade-
quate removal of potential toxins by charcoal is a reasonable therapeutic option. Activated
charcoal, a non-selective absorbent, is usually used for detoxication in certain kinds of
poisoning. An 11-patient, placebo-controlled, double-blind, crossover study showed that a
daily dose of 6 g of activated charcoal for 8 weeks decreased pruritus in most patients with
uremic pruritus [99]. In addition, coated charcoal in extracorporeal techniques showed
decreased levels of parathyroid hormone and pruritus in a study of 12 patients [100]. Al-
though evidence with large case numbers and well-designed studies are lacking, a recent
review showed a promising role of charcoal in uremic pruritus [101].

5.16. Other Treatment

Early studies have proposed the association of uremic pruritus with hyperthyroidism,
calcium, and phosphate. It is reported that the level of calcium multiplied by phosphate
is correlated with the extent of pruritus after parathyroidectomy, and intractable pruritus
improved after parathyroidectomy in some cases [102,103].
Thalidomide, an immunomodulator and neuromodulator, was initially observed to
reduce pruritus in dialysis patients with leprosy [104]. One early randomized, crossover
study with 29 patients found a statistically significant decrease in pruritus in the thalido-
mide group [105].
Gamma-linolenic acid (GLA), an essential acid, is thought to modulate T lymphocytes
and lymphokines. In one small-sized, randomized control trial, GLA-enriched cream
significantly improved the pruritus severity in dialysis patients [106].
Cannabinoids act on the endocannabinoid system to modulate pruritus and shed light
on the treatment of chronic and refractory pruritus with legalized medical marijuana [107].
In a study of 21 patients applying topical cream containing structured physiological lipids,
anandamide, and palmitoylethanoamine twice daily for 3 weeks, 8 out of 21 patients with
uremic pruritus were completely free from pruritus [45]. However, randomized trials for
cannabinoids are lacking [108].
Kidney transplantation, a kidney replacement therapy, largely decreased or cured
chronic pruritus in patients with uremic pruritus [12,18,109]. Other medical considerations
remain issues due to the shortage of human kidneys.
Catabolism of exogenous protein may lead to the retention of protein-bound molecules.
Therefore, protein-restrictive diets and probiotics may serve as a potential treatments for
uremic pruritus [101]. Omega-3 supplements were found to be effective to decrease pruritus
in a cross-randomized trial [110].

Table 1. Summary of studies of interventions for uremic pruritus.

Authors Study Design Participants Enrollment Intervention Comparator Efficacy

Randomized,
0.1% tacrolimus
double-blind,
Duque et al. ointment twice
vehicle- HD N = 22 Vehicle No significant effect.
(2005) [52] daily for
controlled
4 weeks
study
Randomized Pimecrolimus
Ghorbani et al. Not
double-blind N = 60 1% twice daily Placebo No significant effect.
(2011) [53] mentioned
study for 8 weeks
NB-UVB Significant and
Single-blind, phototherapy comparable
Ko et al. Long-wave
randomized, HD, PD, CKD N = 21 three times a improvement in the
(2011) [62] UVA radiation
controlled trial week for VAS scores in both
6 weeks groups.
Diagnostics 2022, 12, 1108 8 of 14

Table 1. Cont.

Authors Study Design Participants Enrollment Intervention Comparator Efficacy

Significant effect.
NBUVB Topical liquid
VAS 9.13 to 1.9 at
Sherjeena et al. CKD, stage IV, phototherapy paraffin, 10 mg
Controlled trial N = 30 3 months (NBUVB).
(2017) [65] V every 3 days for oral cetirizine
VAS 9.1 to 8.8 at
15 sessions daily
3 months (control).
Zinc sulfate
Mapar et al. Pilot randomized,
HD N = 36 220 mg daily Placebo No significant effect.
(2015) [85] triple-blind study
for 4 weeks
Reduction in VAS
score was
Mahmudpour Randomized Montelukast significantly greater
et al. (2017) double-blind HD N = 80 10 mg daily for Placebo in the montelukast
[88] controlled trial 30 days group (2.73)
compared to placebo
group (5.47).
Significant reduction
Double-blind Gabapentin Ketotifen 1 mg in both groups (88.4%
Amirkhanlou
randomized HD N = 52 100 mg daily twice daily for in gabapentin group
(2016) [70]
clinical trial for 2 weeks 2 weeks vs. 76.9% in group
ketotifen group).
Gabapentin Gabapentin
Eusebio- 100 mg daily, Antihistamine, decreased the
Alpapara et al. Meta-analysis HD N = 315 100–400 mg pregabalin, pruritus severity
(2020) [73] 2–4 times per placebo compared to the
week placebo (n = 171).
Randomized, Significant reduction
Nalfurafine
double-blind, in VAS in both
Kumagai et al. hydrochloride
placebo- HD N = 337 Placebo dosages of
(2010) [38] 5 µg, 2.5 µg for
controlled nalfurafine
14 days
study compared to placebo.
Randomized,
Nalbuphine Significant effect with
double-blind,
Mathur et al. 120 mg, 60 mg nalbuphine 120 mg,
placebo- HD N = 373 Placebo
(2017) [39] twice daily for but not with
controlled
8 weeks nalbuphine 60 mg.
trial
Intravenous A decrease of at least
Double-blind, difelikefalin 3 points (WI-NRS
Fishbane et al. placebo- 0.5 µg per score) in 49.1% of the
HD N = 378 Placebo
(2020) [40] controlled, phase kilogram difelikefalin group
III trial per week for (27.9% of the placebo
12 weeks group).
Randomized,
Nemolizumab
double-blind,
Kinugasa et al. 0.125, 0.5,
placebo- HD N = 69 Placebo No significant effect.
(2021) [91] 2.0 mg/kg on
controlled clinical
day 1
study
HD, hemodialysis; PD, peritoneal dialysis; CKD, chronic kidney disease; VAS, visual analog scale; NB, narrow
band; WI-NRS, worst itch numeric rating scale. The data were retrieved by 25 March 2022.

6. Proposed Algorithm from Diagnosis to Treatment

Based on the updated evidence, we propose the diagnosis and treatment algorithm
in CKD patients (Figure 1). Firstly, any pruritus and skin condition should be evaluated
in patients with CKD every visit. If primary skin lesions or acute pruritus are present,
physicians may refer patients to dermatologists to exclude other common causes of itch.
Diagnostics 2022, 12, 1108 9 of 14

Screening laboratory examinations including complete blood count, differential count, liver
function test, renal function test, thyroid function, and electrolytes should also be arranged
to exclude other systemic etiologies. Once an accurate diagnosis of uremic pruritus is made,
physicians may initiate an emollient for skin rehydration. The dialysis efficacy should also
be re-evaluated to increase efficiency and correct electrolytes in case of imbalance. Modifica-
tion with dialysis membrane is suggested to remove middle molecules and protein-bound
molecules [111]. Difelikefalin was the first FDA-approved medicine for uremic pruritus in
the United States. Gabapentin, NBUVB, and difelikefalin may be considered as first-line
treatments. Mast cell stabilizers, montelukast, nalbuphine, nalfurafine, acupuncture or
acupressure, and activated charcoal may be considered as alternative therapies. Diet adjust-
ment with low protein and probiotics also serve as potential treatment strategies. Treatment
Diagnostics 2022,
Diagnostics 2022, 12,
12, xx FOR
FOR PEER
PEER REVIEW
REVIEW 10 of
options are listed and classified according to potential targeted etiologies (Figure 2). 10 of 15
Kidney15
transplantation is considered in extreme cases.

Figure 1.
Figure
Figure 1. Proposed
1. Proposed diagnosis
Proposed diagnosis and treatment
diagnosis and
and treatment algorithm
treatment algorithm of
of uremic
uremic pruritus.
pruritus.

Figure 2.
Figure
Figure 2. Treatment
2. Treatment options
Treatment options for
for uremic
uremic pruritus
pruritus classified
classified by
by possible
possible targeted
targeted etiologies.
etiologies. The
The bold
The bold
bold
ones have
ones have
ones greater
have greater evidence in current literature.
greater evidence in current literature.

7. Conclusions
7. Conclusions
In this
In this review,
review, we
we summarized
summarized the the current
current evidence
evidence onon diagnosis
diagnosis and
and treatment
treatment of
of
uremic pruritus. Given the limitations of proper diagnosis of uremic pruritus,
uremic pruritus. Given the limitations of proper diagnosis of uremic pruritus, we pro- we pro-
posed an
posed an algorithm
algorithm for
for more
more accurate
accurate diagnosis
diagnosis of
of uremic
uremic pruritus.
pruritus. In
In summary,
summary, aa com-
com-
plete assessment to exclude occult itch origin and early diagnosis of uremic pruritus
plete assessment to exclude occult itch origin and early diagnosis of uremic pruritus are are
Diagnostics 2022, 12, 1108 10 of 14

7. Conclusions
In this review, we summarized the current evidence on diagnosis and treatment of
uremic pruritus. Given the limitations of proper diagnosis of uremic pruritus, we proposed
an algorithm for more accurate diagnosis of uremic pruritus. In summary, a complete
assessment to exclude occult itch origin and early diagnosis of uremic pruritus are essential.
Emollients and dialysis modification are general preventive guidance in the treatment of
uremic pruritus. Gabapentin, phototherapy, and FDA-approved difelikefalin are promising
treatment options for recalcitrant uremic pruritus. Other developing treatments are opioid
mediators, neural transmission mediators, and biologics targeting IL-31. Due to the high
prevalence and unsatisfactory treatment response, more research on uremic pruritus should
be prioritized.

Author Contributions: Conceptualization, A.-Y.C. and L.-S.W.; writing—original draft preparation,

A.-Y.C.; writing—review and editing, A.-Y.C. and L.-S.W. All authors have read and agreed to the
published version of the manuscript.
Funding: This research was funded by grants from the Chang Gung Medical Research Program
(CMRPG8K0731 and CMRPG8L0831) of Taiwan.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: We acknowledge the grant support from the Chang Gung Medical Research
Program (CMRPG8K0731 and CMRPG8L0831).
Conflicts of Interest: The authors declare no conflict of interest.

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