The prevalence of end-stage chronic renal disease (ESRD) in Egypt has been rising from 225 per 1 million population in 1996 to 483 per 1 million population in 2004 . Sleep complaints are common in patients with ESRD on dialysis and include delayed sleep onset, frequent awakening, restlessness, and daytime sleepiness .
Many studies have been carried out recently to understand the real impact of sleep disorders on dialytic patients and to discover whether these complaints are correlated with clinical and/or demographic data. However, most of these studies were conducted on small groups of patients recruited from single dialysis units [3,4]. Therefore, the results obtained could have been influenced by the specific dialysis techniques used in the individual units and/or by demographic or clinical peculiarities. Only one study was performed on a large population of dialytic patients coming from different dialysis units, but the questionnaire used in this investigation did not include recognized criteria for diagnosis of common sleep disorders .
The objectives of this study were to determine the prevalence of sleep disorders in patients with ESRD on maintenance dialysis and to determine the risk factors underlying these disorders.
Patients and methods
Study design and setting
A cross-sectional survey was conducted during the period from September to November 2010. All dialysis units were pooled from all the districts of Cairo (capital of Egypt) and categorized into private and public units. A random sample was then selected from each category to include 16 hemodialysis units, as nine from public and seven from private units.
The calculated sample size was at least 234 patients, based on the prevalence of insomnia, in patients with chronic renal failure, of 65.9 and 60.8% reported in Mansoura University, Egypt , and Saudi Arabia,  respectively.
A proportionate sample was then calculated to include at least 131 patients from public units and 103 patients from private units.
An 80% power, 5% significance level, and 95% confidence interval (CI) were used in the sample size calculation by Epi Info, 6 software (CDC, Atlanta, USA).
Patients were randomly selected from the patients' list to include every other patient. Dialysis units were visited three times weekly, on alternative days and shifts. Patients' inclusion criteria included adults (age: >18 years) of both sexes, who were stable, who were on regular dialysis three times per week for at least 3 months, and who accepted to participate in the survey.
Our population was divided into two groups: patients with at least one sleep disorder and those without sleep disorders. Patients were classified as positive for each disorder according to their responses to the questionnaire.
A questionnaire-based survey was used to examine the prevalence of symptoms that reflect sleep disorders, which included insomnia, restless leg syndrome (RLS), and obstructive sleep apnea syndrome (OSAS). Personal professional interviews were carried out by trained medical students. Enrolled patients completed our questionnaire during the dialysis sessions or while waiting for their treatment.
Data on medical history, laboratory, and pharmacological information were collected by careful inspection of the patients' files. The questionnaire consisted of the following parts:
- (1) Demographic characteristics: age, sex, marital status, and employment;
- (2) Medical history: patients were asked about underlying causes of chronic renal disease and clinical data (including type of renal replacement);
- (3) Laboratory and pharmacological data included main biochemical and hematological parameters as well as current medications;
- (4) Evaluation of insomnia was made by the Athens Insomnia Scale (AIS), which is a self-administered psychometric instrument, based on the International Classification of Diseases, tenth version (ICD-10) [WHO (1994) insomnia criteria]. It consists of eight items AIS and the total score ranges from 0 to 24. The original validation study demonstrated good internal test–retest reliability and external validity . A cut-off value of six to determine those suffering from insomnia among the general population was chosen following the creators' recommendations as it provides us with the highest positive predictive value of 90%, while still offering a high-negative predictive value of 94% .
- (5) Evaluation of RLS was made by the International Restless Legs Syndrome Study Group  for the clinical diagnosis of RLS. The International Restless Legs Syndrome Study Group Rating Scale describes severity of RLS as mild: 1–10 points, moderate: 11–20 points, severe: 21–30 points, and very severe: 31–40 points;
- (6) Evaluation of OSAS was made by using Berlin Questionnaire  for sleep apnea (high-risk group score=1, low-risk group score=0).
Data management and analysis
Data were stored and analyzed using SPSS software version 13 (Chicago, Illinois, USA). Data were summarized as mean±standard deviation or number and percentage as appropriate. Nominal variables were analyzed by means of contingency tables and the χ2-test. Likelihood ratio was performed when minimum expected count in cells was less than 5 in contingency tables. Spearman's rank correlation (r) test was used to examine the relationship between levels of insomnia and other parameters as well as between grades of RLS and other parameters.
The levels of insomnia were recoded dichotomously in ‘patients without insomnia’ for those scoring ‘0–6’ and ‘patients with insomnia’ for those scoring ‘7–24’. The levels of RLS were also dichotomized into ‘negative’ for those scoring ‘0’ and ‘positive’ for those scoring ‘1–40’. Multivariate logistic regression analysis was used to evaluate the risk of insomnia, RLS, and OSAS, while controlling for all other variables. A P value of less than 0.05 was considered statistically significant.
Risk factor analysis was completed for a summary score of sleep disorders. A score was developed based on giving one point for each sleep disorder. Bivariate analyses were completed examining each of the following groups: those who scored a three (i.e., having 3 sleep disorders, those who have two sleep disorders, and those who have one sleep disorder as compared those who scored a zero (i.e., do not have any sleep disorders). All variables with a P value less than 0.10 in the bivariate analyses were entered into the full model for each comparison. Only variables that were significant at P≤0.01 (to correct for multiple comparisons) were left in the final models.
The survey was reviewed and approved by the Research Ethics Committee of Ain Shams University, Cairo, Egypt.
The number of patients that satisfied our inclusion criteria and enrolled in our study was 264. Eighteen patients were excluded because of refusal or intercurrent illness. No statistically significant difference with regard to demographic and dialytic parameters was found between patients included in the study and in those who were not included.
The mean age of the patients was 50.83±14.48 years, 55.7% were men, 75.4% were married, and 39.4% were employed. Mean dialysis duration was 25.41±16.21 months (Table 1).
Sleep disorders (total population)
According to the proposed criteria, 162 patients (61.4%) were considered to have at least one sleep disorder. The prevalence of sleep disorders was not significantly different among dialysis centers (range: 51.6–83.8%, P=0.5).
Patients with at least one sleep disorder and those without sleep disorders did not significantly differ as regards age, sex, employment, dialysis shift, type, or duration. However, sleep disorders were significantly associated with marital status (χ2=4.1, P=0.03), diabetes mellitus (χ2=4.5, P=0.02) (Table 1).
Figure 1 presents the sleep disorders reported by dialysis patients.
The prevalence of insomnia was 57.6%. There were 92 (34.8%) low-grade patients with insomnia, 45 (17%) moderate-grade patients with insomnia, and 15 (5.7%) high-grade patients with insomnia. The grades of insomnia correlated with inadequate dialysis, as measured by the Kt/V index [Kt/V is a number used to quantify hemodialysis and peritoneal dialysis treatment adequacy. K, dialyzer clearance of urea; t, dialysis time; V, volume of distribution of urea, approximately equal to patient's total body water.] (r=0.8, P=0.000), hyperphosphatemia (r=0.6, P<0.001), hypoalbuminemia (r=0.5, P=0.001), and anemia (r=0.3, P<0.001).
Table 2 shows that there was significant association between the presence of insomnia and inadequate dialysis, (P<0.001), hyperphosphatemia (P=0.004), hypoalbuminemia (P=0.001), and anemia (P=0.002).
Restless leg syndrome
As shown in Table 2, 149 patients (56.4%) were considered to be RLS-positive. RLS was found to be significantly related to inadequate dialysis (P<0.001), hyperphosphatemia (P=0.001), hypoalbuminemia (P=0.003), and anemia (P=0.001).
Obstructive sleep apnea syndrome
According to the Berlin Questionnaire, 56 (21.2%) patients were considered to be at high risk for sleep apnea. There were significant associations between presence of OSAS and inadequate dialysis (P<0.001), hyperphosphatemia (P=0.002), and hypoalbuminemia (P<0.001) (Table 2). They also showed a significant association with obesity (BMI≥30), hypertension, and morning headache (P=0.002, 0.001, and 0.002, respectively) (Table 3).
Associations among sleep disorders
The multivariate analysis showed a significant independent association between insomnia and both RLS [odds ratio (OR)=34.9, 95% CI=13.3–92.1, P<0.001] and OSAS (OR=4.8, 95% CI=2.2–10.2, P=0.000) and between RLS and OSAS (OR=4.2, 95% CI=2.1–8.4, P<0.001).
Table 4 presents the results of risk factor models comparing patients with three, two, and one sleep disorders with those who had no sleep disorder (i.e. zero). Only variables that were significant at P=0.01 were left in the final models. Across the three models, inadequate dialysis and hyperphosphatemia were significantly associated with an increased risk of having sleep disorders. Meanwhile, hypoalbuminemia and anemia were significantly associated with an increased risk of having three sleep disorders as well as having two sleep disorders, both compared with not having any sleep disorder (i.e. zero).
To our knowledge, this study was the only one carried out in a sample of patients with ESRD coming from different dialysis centers in Egypt, to evaluate the prevalence and risk factors of some sleep disorders in this specific population. The results of our study showed high prevalence of sleep disorders among dialytic patients. The multicentric study of Sabbatini et al.  reported that 45% of patients with ESRD were affected by insomnia. In other studies, conducted in single dialysis units, the prevalence of insomnia ranged between 45 and 59% [12–14].
In our survey, we observed an even higher percentage (61.4%) confirming the strong impact of this specific complaint in dialytic patients.
Our results should be considered by nephrologists to identify factors predisposing patients to sleep complaint in dialysis centers. We underline that among causes of ESRD only diabetes was associated with sleep disorders. In contrast, dialytic parameters (i.e. hematological and biochemical data) showed that inadequate dialysis, hyperphosphatemia, and hypoalbuminemia were associated with insomnia, OSAS, and RLS. Unruh et al.  noted that sleep disordered breathing was more common in dialytic patients with diabetes mellitus. In contrast, other studies found no difference between patients with diabetes and nondiabetic patients regarding the associated sleep disorders [6,7].
Multiple factors contribute to insomnia complaints in patients with diabetes. In type 1 diabetes, rapid changes in glucose levels during sleep have been postulated to cause awakenings . For individuals with type 2 diabetes, sleep disturbances may be related to obesity or obesity-associated sleep disorders, such as sleep apnea . Another common source of disturbed sleep in diabetics is discomfort or pain associated with peripheral neuropathy .
In consistency with our results, Sabry et al. , found that risk factors for insomnia among dialytic patients were inadequate dialysis and hypoalbuminemia.
Multiple hypotheses have been proposed to account for uremia-induced sleep disorders, including (a) subclinical uremic encephalopathy , (b) abnormal metabolism and retention of melatonin,  (c) tyrosine deficiency leading to diminished neurotransmitters associated with arousal , (d) alteration in body temperature rhythm resulting in a perturbation of the sleep–wakefulness cycle , (e) release of sleep-inducing inflammatory cytokines during dialysis , (f) the effects of dialysate temperature on sleep , and (g) coexistent OSAS .
In contrast, another study found no association between insomnia and dialysis adequacy and other biochemical parameters, including hemoglobin, ferritin, phosphorus, and calcium levels .
Our results showed that OSAS was also associated with a BMI>30, hypertension, and morning headache. Similarly, Merlino et al.  reported that patients with OSAS showed a significant association with frequent nocturnal awakening, morning headache, and transient memory or concentration disturbances. Moreover, Nieto et al.  found that mean systolic and diastolic blood pressure and prevalence of hypertension increased significantly with increasing sleep disordered breathing measures, and some of this association was explained by BMI.
One study found that risk factors for RLS included anemia, hypoalbuminemia, and hyperphosphatemia , which is comparable with our results. Another study found that there was no significant correlation between RLS and adequacy of dialysis .
Interestingly, our results showed a significant independent association between insomnia and both RLS and OSAS. Comparable results were obtained in other studies where RLS was found to be related to EDS and insomnia and other sleep measures [15,27].
Conclusion and recommendations
Patients with ESRD have a high prevalence of sleep disorders in dialysis centers. Considering that the most frequent sleep complaints such as insomnia, OSAS, and RLS are related to a significant negative impact on functional health status in patients with uremia, nephrologists should improve their recognition and treatment of these conditions to restore the quality of life of their patients.
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