Impact of Pruritus on Sleep Quality of Hemodialysis Patients: A Systematic Review and Meta-Analysis

Background and objectives: Chronic kidney disease (CKD)-associated pruritus is a common and disturbing condition which has a negative impact on sleep quality, as well as overall health-related quality of life of patients receiving hemodialysis. To date, no systematic review has been undertaken, and there is a lack of concise evidence that statistically quantifies the impact of pruritus based on published data. Materials and Methods: A systematic search was done for original articles published in peer-reviewed English journals from database inception on 20 December, 2018, in the following databases: PubMed, MEDLINE, EMBASE, Ovid, CINHAL, ProQuest, and Scopus. Results: A total of 9217 research articles were identified. After removal of duplicates and screening for titles and abstracts, 28 articles were selected. The prevalence of disturbed sleep was 4–94%, while the pooled proportion on random effect in the study was 40% (95% CI = 0.30 to 0.49); I2 = 99.8%. However, the prevalence of disturbed sleep quality and quantity due to pruritus was 9–76%, and the pooled proportion on random effect in the study was 50% (95% CI = 0.37 to 0.64); I2 = 99.8%. Conclusions: Patients undergoing hemodialysis who are affected by CKD-associated pruritus have a higher chance of experiencing sleep disturbances. The prevalence of disturbed sleep due to CKD-associated pruritus was found to be 9–76% in the included studies for patients receiving hemodialysis therapy.


Introduction
Chronic kidney disease (CKD) is a major public health dilemma worldwide [1]. CKD-associated pruritus (CKD-aP) contributes to patient complications [2,3], and is a common and troublesome complication experienced by CKD patients undergoing hemodialysis which has a major and distressing effect on their health-related quality of life (HRQOL) [4,5]. The prevalence of CKD-aP ranges from 22-84% among patients undergoing hemodialysis [5][6][7], and is more frequent at night and affects patient's sleep and moods [8]. CKD-aP may be episodic or constant, generalized or localized, and its intensity may vary from mild to severe [9]. It is quite often overlooked in hemodialysis patients, leading to worsening itchiness, which then results in poor HRQOL, and sleep disturbances in patients with chronic renal failure [10][11][12]. Sleep quality affected by CKD-aP varies in different studies, ranging from 11-26% [13][14][15][16]. Previous literature established that CKD-aP leads to compromised physical and mental wellbeing, and poor HRQOL in CKD patients [14,17]. Approximately 20-50% of patients report that CKD-aP has a negative effect on their lives [18,19]. Although a lot of treatment options

Search Strategies
The strategic search terms used medical subject headings (MeSH) and keywords, and the following text terms were combined with Boolean operators: (uremic* OR Skin Disorder OR Rash* OR Itch* OR Pruritus OR Uremia*) AND (Sleep* OR Disturb* sleep OR insomnia OR sleep quality OR lack of sleep OR no sleep) AND (Kidney OR Renal OR CKD OR ESRD OR end stage renal disease OR chronic kidney failure OR chronic kidney disease OR renal impair* OR Renal insuff*) AND (dialysis OR hemodialysis).

Inclusion Criteria
Original research articles using observational or experimental designs, published in peer-reviewed English journals and exploring the impact of CKD-aP on sleep quality among CKD patients undergoing hemodialysis.

Exclusion Criteria
All systematic reviews, case reports, advertisements, thesis, opinions, letters to the editor, and qualitative studies, were excluded. In addition, studies which reported on, or data on any other form of pruritus due to factors other than CKD, were excluded.

Data Extraction and Quality Assessment
Data were extracted using a standardized extraction form designed for this systematic review. The following information was extracted: author's name, publication year, study design, country, respondent's information, inclusion/exclusion criteria for the selection of respondents, sample size, statistical analysis used, and outcome measurements of the impact of CKD-aP on sleep quality and quantity. The Cochrane risk of bias [22] criteria was used to assess the risk of bias for randomized clinical trials (RCTs), while the Newcastle Ottawa Scale (NOS) [23] was selected for quality appraisal of observational studies. Any disagreement was resolved through discussion.

Data analysis
For the risk of bias, RevManger 5.3®was used to generate a graphical presentation of the included trials. A meta-analysis was performed using STATA version 14 using the random effects model. All p-values were set at <0.05 with 95% confidence intervals. Subgroup analysis was performed to address heterogeneity. I 2 statistic was used to interpret the heterogeneity at a confidence interval of 95% among the included studies.

Study Selection
A total of 9217 related research articles were identified. After removal of duplicates, the final count reduced to 8054. After reviewing titles and abstracts, 777 were selected, and from these, 28 articles were included in this systematic review after the application of the inclusion and exclusion criteria [13][14][15][16]18, (Figure 1). clinical trials (RCTs), while the Newcastle Ottawa Scale (NOS) [23] was selected for quality appraisal of observational studies. Any disagreement was resolved through discussion.

Data analysis
For the risk of bias, RevManger 5.3® was used to generate a graphical presentation of the included trials. A meta-analysis was performed using STATA version 14 using the random effects model. All p-values were set at <0.05 with 95% confidence intervals. Subgroup analysis was performed to address heterogeneity. I 2 statistic was used to interpret the heterogeneity at a confidence interval of 95% among the included studies.

Study Selection
A total of 9217 related research articles were identified. After removal of duplicates, the final count reduced to 8054. After reviewing titles and abstracts, 777 were selected, and from these, 28 articles were included in this systematic review after the application of the inclusion and exclusion criteria [13][14][15][16]18, (Figure 1).

Study Characteristics
The study characteristics are shown in Table 1. Patients undergoing hemodialysis who developed CKD-aP experienced delays in sleep, awakenings due to CKD-aP, and nocturnal awakenings (Table 1).

Study Characteristics
The study characteristics are shown in Table 1. Patients undergoing hemodialysis who developed CKD-aP experienced delays in sleep, awakenings due to CKD-aP, and nocturnal awakenings (Table 1).

Sub Group Analysis
The pooled proportion on random effects revealed the prevalence of sleep disturbance in cross sectional studies was 32% (95% CI = 0.19 to 0.45); I 2 = 99.8%; while in prospective observational studies it was 49% (95% CI = 0.33 to 0.65), and in clinical trials it was 74% (95% CI = 0.52 to 0.96). The pooled proportion on random effect found prevalence of sleep disturbance for studies conducted in Asia was 50% (95% CI = 0.38 to 0.62) and the heterogeneity was 99.0%; whereas the pooled proportion on random effect for studies conducted in Europe was 25% (95% CI = 0.19 to 0.32) and the heterogeneity was 80.1%.

Sub Group Analysis
The pooled proportion on random effects revealed the prevalence of sleep disturbance in cross sectional studies was 32% (95% CI = 0.19 to 0.45); I 2 = 99.8%; while in prospective observational studies it was 49% (95% CI = 0.33 to 0.65), and in clinical trials it was 74% (95% CI = 0.52 to 0.96). The pooled proportion on random effect found prevalence of sleep disturbance for studies conducted in Asia was 50% (95% CI = 0.38 to 0.62) and the heterogeneity was 99.0%; whereas the pooled proportion on random effect for studies conducted in Europe was 25% (95% CI = 0.19 to 0.32) and the heterogeneity was 80.1%.

Discussion
This systematic review and meta-analysis is perhaps the first systematic and quantitative assessment to assess the impact of CKD-aP on sleep quality among CKD patients undergoing hemodialysis. Results from the meta-analysis revealed the proportion of hemodialysis patients suffering from sleep disturbance, regardless of whether they have CKD-aP or not, was 40% (95% CI = 0.30 to 0.49); I 2 = 99.8%, while in patients suffering from CKD-aP, 50% of them were observed to have sleep disturbances with a pooled proportion of 50% (95% CI = 0.37 to 0.64); I 2 = 99.8%. This emphasizes the need to routinely assess CKD-aP and sleep quality. This is to allow suitable and timely interventions to be carried out to address these problems, which are very frequent among CKD patients on hemodialysis.
The heterogeneity in the prevalence data may be due to the different study design, selection of participants (e.g., study populations, races, and sample sizes), and the definition of CKD-aP in the included studies. Another meta-analysis on the prevalence of CKD-aP among adult hemodialysis patients also previously reported high heterogeneity in the subgroup analysis [49].
Studies showed a high prevalence of CKD-aP with 85.4% [50] and 53.4% [51], and CKD-aP led to sleep disturbances in 33.8% of patients [51]. Furthermore, patients with CKD-aP have a poorer quality of sleep or more serious depression as compared to patients without CKD-aP [52][53][54].
Therefore, from a clinical practice point of view it is important to assess patients for the severity of CKD-aP and intervene therapeutically to improve the HRQOL and overall wellbeing of the patients. CKD-aP is often overlooked by nephrologists, primary care physicians, and other health

Discussion
This systematic review and meta-analysis is perhaps the first systematic and quantitative assessment to assess the impact of CKD-aP on sleep quality among CKD patients undergoing hemodialysis. Results from the meta-analysis revealed the proportion of hemodialysis patients suffering from sleep disturbance, regardless of whether they have CKD-aP or not, was 40% (95% CI = 0.30 to 0.49); I 2 = 99.8%, while in patients suffering from CKD-aP, 50% of them were observed to have sleep disturbances with a pooled proportion of 50% (95% CI = 0.37 to 0.64); I 2 = 99.8%. This emphasizes the need to routinely assess CKD-aP and sleep quality. This is to allow suitable and timely interventions to be carried out to address these problems, which are very frequent among CKD patients on hemodialysis.
The heterogeneity in the prevalence data may be due to the different study design, selection of participants (e.g., study populations, races, and sample sizes), and the definition of CKD-aP in the included studies. Another meta-analysis on the prevalence of CKD-aP among adult hemodialysis patients also previously reported high heterogeneity in the subgroup analysis [49].
Studies showed a high prevalence of CKD-aP with 85.4% [50] and 53.4% [51], and CKD-aP led to sleep disturbances in 33.8% of patients [51]. Furthermore, patients with CKD-aP have a poorer quality of sleep or more serious depression as compared to patients without CKD-aP [52][53][54].
Therefore, from a clinical practice point of view it is important to assess patients for the severity of CKD-aP and intervene therapeutically to improve the HRQOL and overall wellbeing of the patients. CKD-aP is often overlooked by nephrologists, primary care physicians, and other health care professionals [20] and this negligence can be curtailed by training the nephrologist on how to interpret tools to quantify the severity of CKD-aP and sleep. Moreover, it is essential to provoke awareness among physicians, nephrologists, and researchers for formulations of coherent and suitable therapeutic strategies and guidelines to manage CKD-aP. Indeed, CKD-aP should be treated with equal importance as other symptoms because scratching to relieve CKD-aP may impair sleep quality as well as other QOL aspects of the patients, and this can cause other medical related complications like secondary infections.

Strength and Limitation
There was high heterogeneity in the pooled analysis; this could be due to varied sample size, population characteristics, race, difference in study designs, diverse tools/questionnaire (validated and self-designed) used for assessment of CKD-aP as well as sleep assessment and the definition of CKD-aP in the included studies. Despite performing sub-group analysis, the heterogeneity remained high and that is the major limitation of this study.

Conclusions
In conclusion, sleep quality is disturbed to a great extent by CKD-aP in patients receiving hemodialysis. The prevalence of disturbed sleep due to CKD-aP was found to be 9-76% in the included studies; establishing evidence of impaired sleep quality. More research is needed to establish suitable data using specific tools for determining CKD-aP and sleep quality for quantitative analysis. Among health care providers, CKD-aP should be treated with equal importance as other complications to improve patient's HRQOL, and to relieve itching to avoid secondary infections due to persistent scratching.

Conflicts of Interest:
The authors declare no conflict of interest.