Sleep disorders in patients with end-stage renal disease undergoing dialysis therapy

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1 Nephrol Dial Transplant (2006) 21: doi: /ndt/gfi144 Advance Access publication 6 September 2005 Original Article Sleep disorders in patients with end-stage renal disease undergoing dialysis therapy Giovanni Merlino 1, Antonella Piani 1, Pierluigi Dolso 1, Massimo Adorati 2, Iacopo Cancelli 1, Mariarosaria Valente 1 and Gian Luigi Gigli 1 1 Sleep Disorder Center, Neurology Unit, S. Maria della Misericordia Hospital and Udine University Hospital, Udine, Italy and 2 Dialysis Center, ASS 4 Medio Friuli, Udine, Italy Abstract Background. Many patients with end stage renal disease (ESRD) undergoing dialysis therapy suffer from sleep disturbances. The aim of this study was to investigate the prevalence of sleep disorders in a large population of uraemic patients recruited from 20 different dialytic centres in Triveneto. Methods. 883 patients on maintenance dialysis were enrolled in the study. Demographic, lifestyle, renal and dialysis data were recorded. Renal parameters were compared with the database of the Veneto Dialysis Register. Using a self-administered questionnaire we assessed the presence of the following sleep disorders: insomnia, restless leg syndrome (RLS), obstructive sleep apnoea syndrome (OSAS), excessive daytime sleepiness (EDS), possible narcolepsy, sleepwalking, nightmares and possible rapid eye movement behaviour disorders (RBD). Moreover, in order to determine the prevalence of sleep disturbances and the possible effect of demographic or clinical data on sleep, we divided our population into two groups: with (SLEEPþ) and without (SLEEP ) sleep disorders. Results. The questionnaire revealed the presence of insomnia (69.1%), RLS (18.4%), OSAS (23.6%), EDS (11.8%), possible narcolepsy (1.4%), sleepwalking (2.1%), nightmares (13.3%) and possible RBD (2.3%). Eighty percent demonstrated SLEEPþ, having at least one sleep disorder. Independent risk factors for sleep disorders were advanced age (P<0.001), excessive alcohol intake (P<0.04), cigarette smoking (P<0.006), polyneuropathy (P<0.05) and dialysis shift in the morning (P<0.001). Conclusions. The questionnaire showed a high presence of sleep disruption in dialytic populations. Awareness by Italian nephrologists regarding sleep disruption seems to be insufficient. Our data might help nephrologists to deal with uraemic patients Correspondence and offprint requests to: Gian Luigi Gigli, Neurology Unit, S. Maria della Misericordia Hospital, Udine, Italy. gigli.gianluigi@aoud.sanita.fvg.it with possible sleep disorders. Concerning the high prevalence of possible narcolepsy, further studies using polysomnographic records are necessary to confirm our results. Keywords: dialysis; end-stage renal disease; excessive daytime sleepiness; insomnia; restless legs syndrome; sleep apnoea Introduction Sleep disorders are common among patients undergoing dialysis in end stage renal disease (ESRD). Although variable, their prevalence has been reported to be higher when compared to the general population. The most frequently reported complaints are insomnia, restless leg syndrome (RLS), sleep-disordered breathing and excessive daytime sleepiness (EDS). Many studies have been carried out recently to understand the real impact of sleep disorders in dialytic patients and 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 [1,2]. Therefore, the results obtained could have been influenced by the specific dialytic techniques used in the individual units and/or by demographic or clinical peculiarities. Only one study was performed on a large population of dialysis patients coming from different dialysis units, but the questionnaire used in this investigation did not include recognized criteria for diagnosis of common sleep disorders [3]. The aim of this study was to re-evaluate the prevalence of sleep disorders (i) in a large population of patients with ESRD undergoing dialysis in 20 different centres, (ii) using, whenever possible, internationally recognized questionnaires, (iii) also exploring types of sleep disturbances not addressed previously. ß The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 Sleep disorders in dialytic patients 185 Subjects and methods Patients Patients were selected in 20 dialysis centres in Triveneto (a large geographic area in the north-east of Italy) in a 4 month period. Inclusion criteria were (i) willingness and ability to participate, and (ii) receiving chronic dialysis for at least 6 months. 883 patients satisfied our inclusion criteria and were enrolled in our study. 73 patients were excluded because of refusal, intercurrent illness, psychiatric disorders or cognitive dysfunction. statistically significant difference concerning demographic and dialytic parameters was found between patients included in the study and those who were not. Enrolled patients completed our questionnaire during the dialysis sessions or while waiting for their treatment. The questionnaire was explained to patients and, when required, assistance was given in reading and understanding the questions. Information regarding the demographic and clinical data (including type of renal replacement) of our population was given by the attending nephrologists and is summarized in Table 1. The nephrologists reported the following percentages as causes of ESRD: glomerulonephritis (28%), vascular (20%), interstitial (14%), diabetic (10%), hereditary (6%) and autoimmune (2%) nephropathy. Other and unknown kidney diseases were reported for 4 and 16% of our sample, respectively. The renal data collected by our nephrologists seem to be reliable, being quite similar to those of the Veneto Dialysis Register [4]. This register includes data coming from all the dialysis units of the Veneto Region (constituting a large part of the Triveneto macroregion). Our population was divided into two groups: patients with at least one sleep disorder (defined as SLEEPþ) and those without sleep disorders (defined as SLEEP ). Insomnia, RLS, obstructive sleep apnoea syndrome (OSAS), EDS, possible narcolepsy, sleepwalking, nightmares and possible rapid eye movement (REM) behaviour disorder (RBD) were considered as sleep disorders. Patients were classified as positive for each disorder according to their responses to the questionnaire (see below). Questionnaire Our questionnaire consisted of two parts. The first part was completed by the nephrologists at the dialysis unit and included: demographic data, some information about patient s lifestyle (i.e. smoking, daily intake of coffee or Table 1. Demographic and clinical data Number of patients 883 Sex (M%) 61.2 Age (years) 64.95±12.85 (range 17 95) Age >45 (%) 91.6 Body mass index 24.06±4.12 Type of dialysis (%) 91 HD 9 HDF Dialysis dependence 68.73±74.88 months (range 1 420) Previous transplant (%) Dialysis on the morning shift (%) 11.5 (86 patients) 49.7 (439 patients) HD, haemodialysis; HDF, haemodiafiltration. alcohol), general medical history and pharmacological therapy. The following drugs were tabulated: antihypertensive, clonidine, immunosuppressive and gastroprotective agents, antiplatelets, anticoagulants, antidiabetics, calcitriol, other vitamins, phosphorus binders, erythropoietin, iron, benzodiazepines, L-Dopa or dopamine-agonists. Moreover, for each patient the nephrologist had to fill in supplemental data regarding renal disease history, type and time on dialysis, previous transplantation (if applicable) and dialysis shift. The second part of the questionnaire contained questions exploring the presence of sleep disorders and was completed by the patients. Assessment of individual sleep disorders Insomnia. Difficulty in falling asleep, frequent awakening with difficulty in falling asleep once again and early morning wakefulness (questions 1, 2 and 3) were considered as insomnia symptoms. According to Ohayon et al. [5] and Terzano et al. [6], patients were asked two more questions that investigated tiredness and mood affected consequent to sleep loss (questions 4 and 5), in order to divide insomnia into two levels: level 1, insomnia without day-time dysfunction; and level 2, insomnia with day-time dysfunction. Dialysis patients were considered positive for level 1 insomnia if they responded yes to any of questions 1 3 and no to questions 4 and 5. Instead, patients were considered positive for level 2 insomnia if they reported yes to any of questions 1 3 and yes to questions 4 or 5 (level 2). The frequency cut-off for a positive answer was three times or more per week. RLS. We included the four questions proposed by The International Restless Legs Syndrome Study Group (IRLSSG) for the clinical diagnosis of RLS [7]. Only patients who fulfilled all four criteria were requested to answer 10 additional questions in order to assess RLS severity using the IRLSSG Rating Scale (IRLS) [8]. We used the appropriate translation of the severity scale into Italian, obtained from Mapi Research Institute. OSAS. Using the Berlin Questionnaire we divided dialysis patients in two groups: at high risk for OSAS (considered OSASþ) and at low risk for OSAS (considered OSAS ) [9]. EDS. The Italian version of Epworth Sleepiness Scale (ESS) was used for the diagnosis of excessive daytime sleepiness. A score 9 was considered as a minimal criterion for diagnosis [10]. Possible narcolepsy. Possible narcolepsy was diagnosed using the minimal clinical criteria proposed by the International Classification of Sleep Disorders (ICSD) [11]: cataplexy and almost daily occurrence of recurrent daytime naps or lapses into sleep for at least 3 months. Cataplexy was investigated with the question: Do you feel or have you ever felt a sudden loss of muscle tone provoked by strong emotions, such as laugher, elation, anger or surprise. Sleepwalking and nightmares. We estimated the prevalence of sleepwalking and nightmares using the specific questions of Hatoum s sleep questionnaire [12].

3 186 G. Merlino et al. Possible RBD. Patients who reported in their questionnaires the presence of movements of the body or limbs associated with dreaming and potentially harmful sleep behaviour were classified as possible RBD. Statistical analysis Data are displayed as mean and standard deviation (SD) if not otherwise specified. The Kolmogorov Smirnov test with Lilliefors significant correction was used to assess normal distribution of data and Levene s test was performed to evaluate equality of variances. Student s t-test for independent samples was used for normally distributed continuous variables. The Mann Whitney U-test was performed for non-normally distributed continuous variables. One-way analysis of variance was used when the grouping variable had more than two levels. Bonferroni test was used for post-hoc analysis. minal variables were analysed by means of contingency tables and c 2 test. Likelihood Ratio was performed when minimum expected count in cells was <5 in N M contingency tables. Odds ratios (OR) were computed using logistic regression. For multivariate analysis, multiple logistic regression models where used. Each model included age, sex and dialysis centres. A P-value of <0.05 was considered statistically significant. Statistical analysis was carried out using SPSS 9.0.software. Results In Figure 1 we present the sleep complaints reported by dialysis patients. Sleep disorders (total population) According to the proposed criteria, 708 patients (80.2%) were considered to have at least one sleep disorder (SLEEPþ group). The prevalence of sleep disorders was not significantly different among dialysis centres (range %, P ¼ 0.20). SLEEPþ and SLEEP groups did not differ as to sex, weight, BMI, caffeine intake and drug use. The aetiology of ESRD, type and time on dialysis and percentage of previous transplants were similar between the two groups. However, sleep disorders were significantly associated with age (OR for 1 year increment in age, 1.02; CI 95, ; P<0.0006), alcohol intake (OR for >1 l daily, 8.69; CI 95, ; P<0.03), cigarette smoking (OR, 1.49; CI 95, ; P<0.02), diabetes (OR, 1.75; CI 95, ; P<0.04), polyneuropathy (OR, 2.40; CI 95, ; P<0.009) and dialysis shift in the morning (OR, 2.02; CI 95, ; P<0.001). Age, alcohol intake, cigarette smoking, polyneuropathy and dialysis shift in the morning were also confirmed to be significant and independent predictors of sleep disorders in the multivariate model (see Table 2). Insomnia 69.1% gave a positive response to at least one of the three questions proposed for the diagnosis of insomnia. Most of them (54.2%) reported more than one insomnia symptom. Difficulty in maintaining sleep was reported by 88.9% of insomniac patients, while difficulty in falling asleep (42.5%) and early morning awakening (44.7%) were less frequent. Table 3 shows insomnia characteristics in patients reporting sleep loss in their questionnaires. Restlessness (26.9%), pain (24%), cough (20.8%), worry (18.9%) and burst of heat (5.8%) were the possible causes of insomnia as subjectively identified by patients. Between dialytic parameters only dialysis shift was related to insomnia (OR, 2.02; CI 95, ; P<0.001). We did not observe significant differences regarding sleep hygiene Table 2. Association of age, alcohol intake, cigarette smoking, diabetes and polyneuropathy with sleep disorders OR a 95% CI a P Age Alcohol intake intake 50 cl cl cl Smokers/ex-smokers Yes Diabetes Yes Polyneuropathy Yes Dialysis shift Afternoon Morning Fig. 1. Prevalence of sleep disorders in dialytic patients. a OR and CI 95 calculated using multivariate logistic regression. b Reference category.

4 Sleep disorders in dialytic patients 187 Table 3. Insomnia symptoms Questions a Level 1 insomnia (n ¼ 269, 48.7%) Level 2 insomnia (n ¼ 283, 51.3%) 1. Do you often have difficulty falling asleep? 31.6% 55% 2. If you frequently awaken during the night, do you 86.6% 90.8% have difficulty going back to sleep? 3. Do you awaken too early in the morning? 36% 54.3% 4. Do you often feel tired when you awaken in the morning? 0% 56% 5. Does sleep loss affect your mood during the day, making you feel tense, irritable or depressed? 0% 82.9% a More than one answer per patient could be given. and use of benzodiazepines between patients with and without insomnia. Restless leg syndrome 152 patients (18.4%, IRLS score 21.20±8.25) responded yes to all four questions proposed by IRLSSG for clinical diagnosis of RLS and were considered as RLSþ. With regard to the prevalence of sleep disorder and use of L-dopa or dopamineagonists, RLSþ patients were compared only to those patients who did not match any question proposed by the IRLSSG questionnaire. RLS was found to be related to EDS and insomnia (see Table 4). Conversely, there was no statistically significant difference concerning use of L-dopa or dopamine agonists between the two groups (1.6 vs 0.3%). Furthermore, the IRLS score was used to subdivide RLSþ patients according to the severity of the RLS. 40.9% RLSþ patients had a moderate RLS, 31.4% had a severe form, and 16.1% had very severe symptoms. tably, only 11.7% of patients with RLS had a mild form. RLS severity was not associated with dialytic and renal parameters or with demographic data (data not displayed). OSAS Half of our dialysis population (50.1%) displayed habitual snoring and 24.9% of them reported extremely loud snoring. 136 patients (23.6%) were included in the OSASþ group, corresponding to the cases considered at high risk for sleep apnoea according to the Berlin Questionnaire [10]. Sex and age were not linked with OSAS. Rather, OSASþ patients showed a significant association with EDS, frequent nocturnal awakening, morning headache and transient memory or concentration disturbances (see Table 5). Daytime sleepiness Patients having an ESS score 9 (indicating the presence of excessive daytime sleepiness) were 11.8% of the total sample. The presence of somnolence was not related to the use of clonidine and benzodiazepines (9.7 vs 10.7%, n.s., and 4.2 vs 3.5%, n.s., respectively). Similarly, we did not find significant differences regarding the type and the time on dialysis. Table 4. Association of EDS and insomnia with RLS OR a 95% CI a P EDS Yes Insomnia Yes a OR and CI 95 calculated using multivariate logistic regression. b Reference category. Table 5. Association of EDS, frequent nocturnal awakening, morning headache and transient memory or concentration disturbances (TMCD) with OSAS OR a 95% CI a P EDS Yes Frequent nocturnal awakening Yes Morning headache Yes TMCD Yes a OR and CI 95 calculated using multivariate logistic regression. b Reference category. Other sleep disorders The symptoms that we utilized to diagnose possible narcolepsy were observed in 1.4% of our patients. Among them, 27% suffered from hypnagogic hallucinations, 36% suffered from sleep paralysis, while 18% presented with a combination of both complaints. The prevalence of symptoms suggesting sleepwalking, nightmares and possible RBD were 2.1, 13.3 and 2.3%, respectively. Nightmares were related to frequent awakening during sleep (OR, 2.08; CI 95, ; P<0.004). Patients with possible RBD were commonly males (73.7 vs 26.3%) and tended to

5 188 G. Merlino et al. be older (69 vs 65 years); however, these differences were not statistically significant. Discussion To our knowledge, this study was the largest carried out in a sample of uraemic patients coming from different dialysis centres, in order to evaluate the prevalence and features of sleep disorders in this specific population. Unlike previous studies, in the first part of our survey we decided to assess the impact of sleep disorders as a whole, rather than concentrate our attention on a specific sleep complaint. Using a simple questionnaire and examining a limited number of patients. Holley et al. [1] and Walker et al. [2] reported a high prevalence of sleep disorders in dialysis units. Our data confirm these results and furthermore suggest that awareness regarding sleep disorders in dialysis patients is insufficient, at least in Italy. In fact, the use of hypnotic drugs for insomnia (3.6%) or the use of L-Dopa or dopamine agonists (1.6%) for RLS was very low in our population, despite the high prevalence of these potentially curable disturbances. Our results should be considered by nephrologists in order to identify factors predisposing patients to sleep complaint in dialysis centres. We underline that among renal (i.e. causes of ESRD and previous kidney transplantation) and dialytic parameters (i.e. type and time on dialysis), only dialysis shift was associated with sleep disorders. This association is due to the link between the morning shift and insomnia. Indeed, psychological problems may disturb sleep in patients on the morning shift and cause symptoms of insomnia [3]. However, the possible interference of morning dialysis with metabolic factors able to modify circadian rhythms cannot be excluded. Besides dialysis shift, our findings suggest that age, excessive alcohol intake, cigarette smoking and polyneuropathy are independent predictors of sleep disorders. The multicentric study of Sabbatini et al. [3] reported that 45% of patients with ESRD were affected by insomnia. In our survey we observed an even higher percentage, confirming the strong impact of this specific complaint in dialysis patients. Unlike Sabbatini et al. [3], we used a questionnaire that evaluated both quantity (insomnia symptoms alone) and quality (insomnia with daytime consequences) of the sleep complaint. This should prevent any possible confusion between poor sleepers and insomnia patients. Level 2 insomnia (i.e. insomnia with daytime dysfunction) was present in a large number of the dialysis patients suffering from insomnia, while the occurrence of level 2 insomnia is lower in the general population [5]. These data suggest that insomnia in uraemic patients has greater daytime consequences than in the general population, and that nephrologists should investigate sleep complaints of all nephrological patients with tiredness on awakening, morning headache, transient memory and concentration disturbances, since these symptoms could be the expression of insomnia or OSAS and not only a direct consequence of dialysis. Regarding RLS, we confirm its high prevalence and its association with other sleep complaints such as insomnia and EDS in uraemic patients. To our knowledge, only a few studies evaluated the severity of RLS in dialysis patients using the IRLS. Hogl et al. [13] assessed the prevalence and the severity of RLS, using IRLS, in a general community, with the Bruneck study. In addition, they investigated all the possible causes of symptomatic RLS. The authors reported very severe and severe forms in only 21.6% of the individuals affected by RLS and they emphasized that the great majority of patients in the community seemed to have idiopathic RLS. In our study the percentage of very severe and severe forms was almost two-fold. Therefore, we suggest that uraemic RLS differ from idiopathic RLS regarding severity of the symptoms and not only regarding age onset and family history as previously reported. However, we were not able to evaluate how many dialysis patients reported RLS symptoms before the renal insufficiency, in order to differentiate idiopathic from uraemic forms. Despite this limitation, our previous statement seems to be notable. OSAS is a frequent disorder in patients with ESRD on dialysis. Using the Berlin Questionnaire, 23.6% of patients in our sample were classified as OSASþ. This percentage was lower than that reported in previously polysomnographic studies (53 61%) and raises concern about the validity of the Berlin Questionnaire as a screening tool in the uraemic population. Validation studies are needed. Regardless of this methodological limit, some considerations about our results can be made. Our study confirms that OSAS is not correlated with age and sex in the uraemic population. Instead, in the general population this correlation is well established. This may lead to speculation that mechanisms of OSAS are different in uraemic patients as compared to the general population, even if nocturnal and diurnal consequences of the respiratory complaint are the same. Daytime somnolence has been anecdotally reported in dialysis patients. This is the first study performed with the aim of quantifying subjective daytime sleepiness in a large number of patients with ESRD. The findings of our statistical analysis in this field were somewhat surprising. They revealed a prevalence of EDS much lower than that reported by other authors using the same questionnaire (ESS) [14,15]. Probably the very small number of patients included in Mucsi et al. [14] and Hanly et al. s [15] studies tended to overestimate the real impact of subjective EDS in ESRD. Moreover, Hanly et al. [15] reported a significant association between EDS and blood urea nitrogen (BUN) that represents a marker of severity of uraemia. In our study we did not consider metabolic variables and in particular levels of BUN. Consequently, it is not possible to determinate if the lower percentage of EDS that we found in our population could be explained as consequence of a better level of renal function. Finally, our results showed that RLS and OSAS were

6 Sleep disorders in dialytic patients 189 the only risk factors associated with EDS in uraemic patients. This is not surprising since RLS and OSAS produce sleep arousal and disruption that may interfere with the sleep restorative effect. In our questionnaire we included sleep disturbances that have never been evaluated in previous studies. Since sleepwalking and RBD were detected similarly in uraemic and in the general population, we focused our attention on possible narcolepsy and nightmares. In fact, the prevalence of possible narcolepsy in our uraemic patients on dialysis was higher than that reported in the general population (1.4 vs %). This unexpected high prevalence of possible narcolepsy may be due to the intrinsic limitation of our study because of the lack of polysomnographic records. A clinical diagnosis of narcolepsy might have overestimated the prevalence of this syndrome in uraemic patients. In fact, this population frequently reports weakness and fatigue, which are clinical conditions that could be confused with cataplexy as defined in ICSD and in the question addressed to the patients in our questionnaire. For this reason, we are aware that these findings need to be confirmed by polysomnographic records. Regardless of this concern, a pathophysiological hypothesis to explain an increased prevalence of narcolepsy among uraemic patients can be constructed. Undetectable levels of cerebrospinal fluid hypocretin-1/ orexin-a and a dramatic decrease in hypocretin neurones, localized in the lateral hypothalamus/ perifornical area, were described in patients with sporadic narcolepsy associated with cataplexy. We wonder whether metabolic changes in ESRD are able to damage the hypocretin system and consequently to develop a secondary narcolepsy. Our hypothesis is supported by the recent observations of Li et al. [16,17], who observed a lowering of hypothalamus orexin-a levels in rats with chronic renal failure, and by Luger et al. [18] and Handelsman et al. [19] who showed abnormal function of the hypothalamus-pituitaryadrenocortical and the hypothalamus-pituitary-gonadal axis in uraemic patients, respectively. Actually, both endocrinol axis are regulated by orexinergic neurones. In contrast with such hypothesis, Sugimoto et al. [20] reported a statistically significant higher plasma concentration of orexin-a in patients with ESRD than in the control group. However, in uraemic patients this higher plasma concentration may be related to a decreased renal clearance of orexin-a rather than an increased hypothalamic synthesis. Indeed, the authors found a correlation between plasma level of the neuropeptide and creatinine plasma concentration. So, we may suppose that in patients with ESRD neuropeptide s plasma levels do not represent the real function of hypothalamic cells. Further studies are certainly needed to ascertain this point. Nightmares are a REM parasomnia. Approximately 50% of adults in the general population report an occasional frightening dream associated with awakening from sleep, while the prevalence of recurrent nightmares is much lower (1%). Frequent nightmares are the most defining symptoms of post-traumatic stress disorder and maybe associated with psychiatric illnesses and stressful events. Hatoum s sleep questionnaire, which we used in the study to evaluate nocturnal disturbances, asked dialysis patients to report frequent nightmares. Surprisingly, we observed a high prevalence (13.3%) of recurrent disturbing dreams in this specific population. Unfortunately, our questionnaire did not include questions that investigated psychiatric complaints, so we can only suppose that a stressful state associated with the uraemic condition could be a possible cause of frightening dreams in patients with chronic illnesses such as ESRD. Our data also showed that in these populations nightmares must be considered as a primary cause of frequent nocturnal awakening. In conclusion, we highlight the high prevalence of sleep disorders in dialysis centres. Despite this result, the level of attention of our nephrologists to these problems is still insufficient, as shown by the low use of specific drugs. 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 uraemic patients, Italian nephrologists should improve their recognition and treatment of these conditions to restore the quality of life of their patients. The interesting observation of frequent cases of possible narcolepsy in dialysis units should be confirmed by further studies using polysomnographic records. Acknowledgements. We thank Mrs Mary J. Di Giorgio for her assistance with English translation. Conflict of interest statement. ne declared. References 1. 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