Polysomnographic measures of nocturnal sleep in patients on chronic, intermittent daytime haemodialysis vs those with chronic kidney disease

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1 Nephrol Dial Transplant (2005) 20: doi: /ndt/gfh816 Advance Access publication 19 April 2005 Original Article Polysomnographic measures of nocturnal sleep in patients on chronic, intermittent daytime haemodialysis vs those with chronic kidney disease Kathy P. Parker 1,2,3, Donald L. Bliwise 2,3,1, James L. Bailey 4 and David B. Rye 2,3,1 1 Nell Hodgson Woodruff School of Nursing, 2 Department of Neurology, 3 Program in Sleep Medicine and 4 Department of Medicine, Renal Division, Emory University, Atlanta, GA, USA Abstract Background. Numerous factors probably contribute to the high prevalence of sleep problems in haemodialysis (HD) patients including metabolic changes and treatment-related factors. In contrast, the sleep problems of patients with chronic kidney disease (CKD) may be more related to psychological factors rather than the metabolic changes associated with renal disease. Thus, the objective of this study was to compare polysomnographic measures of nocturnal sleep in a group of stable patients on chronic, intermittent daytime HD and an age- and gendermatched, metabolically comparable group with CKD, and evaluate the role that quality of life (including psychological factors) and the effects of treatment may play in sleep outcomes. Methods. The sample included 16 patients on HD and eight patients with CKD all of whom were free from other significant physical and psychological morbidity. To assess for psychological, functional, family and economic responses to the disease and treatment, all subjects took the Ferrans and Powers Quality of Life Index. HD subjects received treatment three times a week and were adequately dialysed [Kt/V >1.2, equivalent to a weekly glomerular filtration rate (GFR) of ml/min]; CKD subjects had an estimated GFR of 14.5 (±7.2; range ) ml/min. All subjects underwent one night of laboratory-based polysomnography. Appropriate statistical procedures were used to explore group differences in sleep variables and their relationship to quality of life dimensions and the effect of treatment. Results. The CKD patients reported significantly poorer functional and psychological quality of life; both groups had reduced total sleep time and sleep Correspondence and offprint requests to: Kathy P. Parker, PhD, RN, FAAN, Nell Hodgson Woodruff School of Nursing, Emory University, 1520 Clifton Road, Atlanta, GA , USA. kpark04@emory.edu efficiency in comparison with normative data. However, HD subjects had less rapid eye movement sleep (P ¼ 0.032). They also had a higher brief arousal index (P ¼ 0.000), an independent predictor of which was treatment with HD, and respiratory disturbance index (P ¼ 0.061). Less total sleep time, increased wake after sleep onset, lower sleep efficiency, higher periodic limb movement index, and longer latencies to sleep onset and rapid eye movement sleep were also noted in the HD group. Quality of life scores did not predict sleep variables in this small sample. Conclusions. The results suggest that the sleep problems of patients with CKD and those receiving chronic, intermittent daytime HD may have different aetiologies; functional and psychological factors may play a more prominent role in the former group, while intrinsic sleep disruption (arousals, apnoeas and limb movements) secondary to the effects of chronic, intermittent daytime HD may play a more significant role in the latter. The findings suggest that further exploration is warranted and that population-specific sleep-promoting interventions may be indicated. Keywords: chronic kidney disease; haemodialysis; nocturnal sleep; quality of life Introduction Fifty to 85% of patients on haemodialysis (HD) have sleep complaints characterized by difficulties initiating and maintaining sleep. Polysomnographic studies reveal that sleep apnoea (SA) is common in this population and the prevalence of periodic limb movement disorder (PLMD), restless legs syndrome (RLS) and excessive daytime sleepiness (EDS) is also high. Numerous factors probably contribute to the high prevalence of sleep problems in HD patients ß The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please journals.permissions@oupjournals.org

2 Polysomnographic measures in patients on HD vs those with CKD 1423 including psychological responses, metabolic changes and treatment-related factors. In contrast, the sleep of patients with chronic kidney disease (CKD) not yet receiving treatment has received little attention. However, a recent report suggests that poor sleep quality is also prevalent in this group, but may be more related to psychological factors rather than metabolic changes associated with renal disease [1]. Thus, the available information suggests that psychological, and potentially treatment-related, factors may be particularly relevant with regard to sleep in these two groups. Therefore, the objective of this study was to compare polysomnographic measures of nocturnal sleep in a group of stable patients on chronic, intermittent daytime HD in comparison with an age- and gendermatched, metabolically comparable group with CKD and evaluate the role that quality of life (including the psychological dimension) and the physiological effects of treatment may play in sleep outcomes. Subjects and methods The University s Institutional Review Board and other appropriate dialysis unit physicians, nephrologists and administrators approved the study. Sample HD and CKD subjects were recruited from dialysis units in the Atlanta metropolitan area and a university-based out-patient nephrology clinic. Because of the relatively small sample size possibly due to financial constraints, consideration of those factors that might confound the study results led to an extensive set of exclusion criteria. Potential subjects on medications (e.g. centrally acting, including antidepressants and antihypertensives) with known effects on sleeprelated measures were excluded from participation. Also excluded were those with neurological disorders, significant mental illness requiring psychiatric treatment (including those previously diagnosed with anxiety or depression and/or taking medications for those conditions), or other co-morbidities associated with nocturnal symptoms (congestive heart failure, unstable angina, arthritis and chronic obstructive pulmonary disease). Finally, those subjects with a history of previously diagnosed and/or treated sleep disorders (SA, PLMD and/or RLS) were eliminated from participation. As a comparison group, we recruited patients who had been diagnosed with stage IV V CKD but were not yet receiving treatment. Renal function was assessed by calculating their estimated glomerular filtration rate (GFR) using the Modified Diet in Renal Disease (extended) equation, which is as follows: GFR ¼ 170 serum creatinine concentration 0:999 age 0:176 0:762 ðif femaleþ1:18 ðif race is blackþ blood urea nitrogen concentration 0:17 serum albumin concentration 0:318 This method of assessing renal function is currently recommended in the National Kidney Foundation s Kidney/Dialysis Outcome Quality Initiative, and a GFR calculator is readily available at their website ( kidney.org/professionals/kdoqi/gfr_ page.cfm). The estimated GFR of the CKD group was 14.5 ml/cmin (±7.2; range ml/min). All HD subjects received treatment thrice weekly (beginning between the hours of 6 a.m. and 4 p.m.) for a minimum of 5 months. They were adequately dialysed (Kt/V >1.2, all subjects), a level at which intermittent therapy provides an average weekly clearance comparable with a residual GFR of ml/min [4]. In order to eliminate the effects of age and gender (two demographic variables shown to have significant effects on sleep-related variables) in group comparisons, HD subjects were selected from those participating in a larger study [5] and were matched to recruited CKD subjects on these variables. Out of the 46 available HD subjects in the original study, only 16 could be matched to the eight CKD subjects on both age and gender (2:1 ratio; HD:CKD). The 30 subjects who were eliminated from the sample were significantly older than the study sample (55.2±9.7 vs 44.6±9.2; z ¼ 3.05, P ¼ 0.002); 17 were male and 13 were female, while six were white and 24 were black. The eliminated subjects also had a significantly higher blood urea nitrogen (BUN) than the HD group used in this analysis (69.4±14.4 vs 57.0±18.3; z ¼ 2.78, P ¼ 0.005). Thus, the final sample included 24 subjects, 16 on chronic, intermittent daytime HD and eight with advanced CKD. Fifty percent of each group was female. Protocol Demographic, clinical and metabolic information was obtained via chart review (see Tables 1 and 2). For HD subjects, monthly laboratory reports were collected for 3 months immediately prior to inclusion, and the values cited in Table 2 represent the mean (±SD) for this time period. For CKD subjects, the values represent a minimum of one and a maximum of three measurements taken within the 3 months immediately prior to inclusion (values used to estimate the GFR were the most recent within that time period). In order to assess the association among several dimensions of quality of life and the sleep measures of interest, all subjects completed the Quality of Life Index (QLI, comparable Dialysis and Generic Versions) developed by Ferrans and Powers. Overall quality of life scores and four subscale scores were calculated: Health & Functioning, Social & Economic, Psychological & Spiritual, and Family. Scores are calculated by weighting each satisfaction response with its paired importance response. Thus, the scores reflect not only satisfaction with various aspects of life, but also how much the subject values those aspects. The range of scores on the overall scale and the subscales scores is 0 30, with a higher score indicating a better quality of life. The instrument has excellent validity and reliability [6]. All subjects underwent one night of laboratory-based polysomnography (PSG) consisting of a standard montage of electroencephalography (EEG) (C3/A2 or C4/A1 and O2/C3 or O1/C4), monopolar left and right electrooculography (EOG) referenced to the opposite mastoid, surface mentalis electromyography (EMG), respiratory airflow (measured by thermistor) and effort (piezoelectric sensors),

3 1424 K. P. Parker et al. Table 1. Demographic features by group (number or mean±sd) Parameter HD group CKD group n 16 8 Age (years) 44.6 (9.3) 43.1 (11.8) Male/female 8/8 4/4 Black/white 11/5 4/4 Marital status Married 8 5 Divorced 1 1 Single 7 2 Aetiology of renal failure Diabetes 6 2 Hypertension 7 2 Glomerulonephritis 1 1 Other 2 3 Years of education a 12.6 (1.7) 14.5 (1.9) Months of HD 36.4 (27.8) N/A Length of HD treatment (min) (27.4) N/A Time until institution of renal replacement therapy (months) N/A 19.4 (12.1) a The difference between groups was significant at a<0.05; Mann Whitney U-test; two-tailed test; P-value reported corrected for ties; HD mean rank vs CKD mean rank 16.94, z ¼ 2.25, P ¼ N/A ¼ not applicable. Table 2. Metabolic and dialysis parameters by group (mean±sd) Parameter HD group CKD group n 16 8 Body mass index (kg/m 2 ) 27.0 (5.6) 25.7 (3.2) <25 (normal) and <30 (overweight) (obese) 5 1 BUN (mg%) 57.9 (18.3) 58.4 (13.4) Creatinine (mg%) a 11.9 (2.4) 5.3 (2.6) Sodium (meq/l) (2.3) (2.2) Potassium (meq/l) 4.7 (0.6) 4.7 (0.4) CO 2 (meq/l) 20.7 (2.7) 21.0 (3.1) Glucose (mg%) (38.5) (55.5) Calcium (mg%) 9.5 (1.0) 9.1 (0.7) Phosphate (mg%) 5.4 (1.5) 4.7 (1.6) Albumin (g/l) 4.4 (0.4) 3.6 (0.4) Haematocrit (%) a 35.7 (3.4) 31.4 (4.1) Ferritin (mg/l) (473.4) (4.2) Kt/V b 1.6 (0.4) N/A GFR c (ml/min) N/A 14.5 (7.2) a The difference between groups was significant at a<0.05; Mann Whitney U-test; two-tailed test; P-value reported corrected for ties; creatinine, HD mean rank vs CKD mean rank 5.25, z ¼ 3.55, P<0.000; hematocrit, HD mean rank vs CKD mean rank 7.88, z ¼ 2.27, P ¼ b Kt/V is a measure of dialysis adequacy. c GFR ¼ calculated glomerular filtration rate using the Modified Diet in Renal Disease (extended) equation. electrocardiography (ECG), anterior tibialis EMG and pulse oximetry. For HD subjects, this study was performed on a night immediately following HD treatment (i.e h later). All recordings were made on a Grass Model 78 polysomnograph recorded with a paper speed of 10 mm/s. Manual scoring of sleep stages [7], apnoeas/hypopnoeas [8], periodic leg movements [9] and brief arousals [10] were done using conventional criteria. The baseline and lowest oxygen saturation observed during the study were also recorded and an oxygen desaturation index (number of desaturations 4% lasting s; events/h [11]) was calculated. General sleep measures obtained for each subject included: total sleep time (min); the percentage of total sleep time spent in non-rapid eye movement (NREM) stages 1 and 2, slow wave sleep (NREM stages 3 and 4 collectively) and REM; the latency to three consecutive epochs of sleep (sleep latency, min), and the latency to the first epoch of REM sleep (REM latency, min). Sleep measures associated with sleep stability and quality included sleep efficiency (total sleep time/time in bed 100); wake after sleep onset (%); and brief arousal index (events/h). Respiratory disturbance index (events/h) and periodic limb movement index (events/h) were also calculated. Data analysis Descriptive statistics were used to summarize all data. Because the data did not meet the criteria for the use of parametric statistics, non-parametric procedures were used in most cases. Differences in demographic, clinical and PSG variables between the two groups were detected using a 2 analysis (categorical variables) and the Mann Whitney U-test (continuous variables). Analysis of covariance was used to examine the impact of selected variables on dependent measures and to determine if these variables needed to be controlled in subsequent analyses. Simple regression, with appropriate log transformations as indicated, was used to explore predictors of sleep variables. The significance level was set at a < 0.05 (two-tailed tests). Because of the exploratory nature of this study and small sample size, we chose not to use a familywise adjustment of the alpha level and to accept the greater possibility of making a type I error [12]. As the brief arousal index was considered a major variable associated with sleep stability and quality, we conducted a post hoc power analysis to determine our ability to detect a difference between groups 20 events/h [13]. For group sizes of 16 and eight with an SD of 22.1 and 4.0 in the HD and CKD groups, respectively, the power to detect a difference in brief arousal index 20 events/h was 91%. When a common SD of 15 was used instead, the power to detect this difference was 82%. Results Demographic, clinical and metabolic parameters The demographic features of the HD and CKD groups appear in Table 1. The mean age of the entire sample was 44.1 (10.0) years. Collectively, the subjects had an average of 12.6 (2.1) years of education; the CKD group had 2 years more education than the HD group (P ¼ 0.025; see Table 1). Fifteen subjects were black and nine were white. Thirteen were married, nine were single and two were divorced. The causes of renal failure included diabetes (n ¼ 8), hypertension (n ¼ 9), glomerulonephritis (n ¼ 2), and other causes including polycystic kidney disease (n ¼ 5). There were no

4 Polysomnographic measures in patients on HD vs those with CKD 1425 significant differences noted between the HD and CKD groups with regard to any of these categorical variables. The HD group had been on treatment (vintage) for an average of 36.4±27.8 months; the mean duration of treatment was 219.7±27.4 min. Post study follow-up revealed that the mean time until subjects in the CKD group required renal replacement therapy was 19.4±12.1 months. The clinical and metabolic features of the two groups appear in Table 2. There were no significant differences in the two groups with regard to body mass index (BMI; Mann Whitney U) or the number of subjects in NIH categories of obesity (BMI <25 ¼ normal weight; BMI 25 and <30 ¼ overweight; BMI 30 ¼ obese; 2 analysis). As previously mentioned, the mean estimated GFR for control subjects was 14.5±7.2 ml/min and the HD subjects were adequately dialysed (Kt/V >1.2 in all subjects; mean 1.6±0.4; comparable with a weekly GFR of ml/min). When the HD subjects were compared with the CKD subjects in terms of other clinical parameters, only creatinine [HD 11.9 mg/% (2.4) vs CKD 5.3 mg/% (2.6); P < 0.000] and haematocrit [HD 35.7% (3.4) vs CKD 31.4% (4.1); P ¼ 0.023] significantly differed; both were lower in the CKD group. The difference in serum creatinine was probably related to the continual glomerular filtration present in the CKD patients as opposed to the intermittent solute clearance provided in HD patients (routine blood work is drawn immediately prior to HD when values are typically highest). The lower haematocrit in the CKD group may reflect the fact that all HD subjects were receiving recombinant erythropoietin while those in the CKD group were not. Because analysis of covariance using the entire sample revealed that neither creatinine nor haematocrit significantly contributed to variability in sleep measures, they were not controlled for in subsequent statistical analyses. Further support for this decision lies in the fact that no consistent relationships between creatinine and objective measures of sleep have been reported [14]. In addition, although decreased haematocrit has been associated with increased limb movements [15], the HD group (which had a higher mean haematorcrit) actually had increased limb movements in comparison with the CKD group (see Table 4). Quality of life The mean total QLI and the four subscale scores for the HD and CKD groups are reported in Table 3. The CKD group, although selected according to the same criteria as the HD group, rated their quality of life lower in every domain. These differences were significant with regard to the Health & Functioning (mean rank vs 8.25, z ¼ 2.1, P ¼ 0.037) and Psychological & Spiritual (mean rank vs 8.13, z ¼ 2.1, P ¼ 0.032) subscale scores. The differences in the two groups with regard to the Family subscales scores and the total QLI scores approached significance (P ¼ and P ¼ 0.058, respectively). Table 3. Quality of life scores by group (mean±sd) Scale HD group CKD group P-value Health & Functioning 21.0 (4.6) 15.7 (6.7) subscale a Social & Economic subscale 21.5 (4.5) 20.3 (6.4) Psychological & Spiritual 24.1 (5.0) 18.9 (6.1) subscale a Family subscale 26.8 (4.1) 23.1 (6.3) Total QLI score 22.5 (4.2) 18.4 (5.7) a Differences between groups were significant at a < 0.05; Mann Whitney U-test; two-tailed test; P-value reported corrected for ties (higher scores ¼ higher quality of life). These results suggest that the CKD group had poorer quality of life, in particular more functional and psychological distress, than the HD group in spite of being age and gender matched, metabolically comparable and not yet exposed to the effects of treatment. Polysomnographic data Data (mean/sd, median, and range) for the observed PSG measures by group appear in Table 4. Both groups had reduced total sleep time (6h) in comparison with normative data for this age group. However, in comparison with the CKD group, the HD group had less total sleep time. The HD group had significantly less REM sleep (mean rank vs 16.81, z ¼ 2.11, P ¼ 0.032), but there were no differences between the groups with regard to the percentages of specific NREM sleep stages. Although not statistically significant, notably longer sleep onset and REM latencies were observed in the HD group. In comparison with the CKD group, the HD group had a significantly higher brief arousal index (mean rank vs 5.13, z ¼ 3.61, P < 0.000). Although not statistically significant, the percentage of waking after sleep onset and sleep efficiency were higher and lower, respectively. HD subjects also had a trend toward a higher respiratory disturbance index (mean rank vs 8.63, z ¼ 1.91, P ¼ 0.061); a significantly greater number of these apnoeas occurred in NREM sleep (Wilcoxon Signed Rank Test; mean rank 4.6 vs 10.27, z ¼ 2.33, P ¼ 0.020), a somewhat unusual observation given that apnoeas are often worse in number and length in REM because of the skeletal muscle paralysis associated with this state. No differences were noted in measures of oxygen saturation between the two groups. Although not correlated with overall apnoea index, a higher BMI was positively associated with desaturation index across all subjects (r s ¼ 0.438, P ¼ 0.032), suggesting that increased weight predisposed patients to more desaturations, possibly because of lower residual lung volumes [11]. HD subjects also had a higher periodic limb movement index.

5 1426 K. P. Parker et al. Table 4. Polysomnographic sleep measures by group Parameter HD group (n ¼ 16) CKD group (n ¼ 8) P-value Mean (SD) Median Range Mean (SD) Median Range General sleep architecture Total sleep time (min) (57.3) (81.8) Sleep latency (min) 35.0 (36.9) (17.1) REM latency (min) (101.4) (55.6) % Stage (14.2) (9.6) % Stage (13.1) (5.6) % Slow wave sleep 17.8 (14.2) (8.2) % NREM sleep 82.8 (9.4) (4.6) a % REM sleep 17.2 (9.4) (4.6) a Measures of sleep stability and quality Sleep efficiency (%) 77.5 (13.9) (11.7) Wake after sleep onset (%) 19.7 (17.0) (20.1) Brief arousal index (events/h) 30.7 (22.1) (4.0) a Respiratory and limb movement indices Respiratory disturbance index (events/h) 9.9 (18.4) (3.4) RDI in REM (total no.) 7.4 (9.7) (7.9) RDI in NREM (total no.) 46.6 (12.5) (3.2) Baseline O 2 saturation 93.4 (2.3) (1.1) Lowest O 2 saturation 85.9 (5.6) (8.4) Desaturation index 3.7 (5.3) (0.2) Periodic limb movement index (events/h) 29.4 (43.9) (8.2) NREM ¼ non-rapid eye movement sleep; REM ¼ rapid eye movement sleep. a Differences between groups were significant at a<0.05; Mann Whitney U-test; two-tailed test; P-value reported corrected for ties. Additional analyses Given that major clinical and metabolic variables were controlled, the two major differences between the groups were measures of quality of life (in particular Health & Functioning and Psychological & Spiritual) and exposure to chronic, intermittent daytime HD vs medical management (HD vs CKD). Thus, we further examined the impact of these variables on sleep measures across all subjects. The Health & Functioning and Psychological & Spiritual scores were highly correlated. Thus, a simple regression model was developed that included Psychological & Spiritual scores (as psychological factors have been associated with poor subjective sleep quality in both HD and CKD patients [1]) and group assignment with the dependent variables including measures of general sleep architecture (total sleep time, sleep latency, REM latency and REM sleep percentage), measures of sleep stability and quality (sleep efficiency, percentage of wake after sleep onset and brief arousal index), and respiratory and limb movement indices. A separate regression was performed for each sleep variable. Log transformations were done on those sleep measures that were not normally distributed. The model did not significantly predict measures of general sleep architecture. However, with regard to measures of sleep stability and quality, Psychological & Spiritual scores and group assignment predicted 26% of the variance in brief arousal index (R 2 ¼ 0.26, F ¼ 3.64, P ¼ 0.044), with group assignment (treatment with HD) being the only significant independent predictor (b ¼ 0.541, t ¼ 2.601, P ¼ 0.017). The model did not significantly predict sleep efficiency, wake after sleep onset, respiratory disturbance index or periodic limb movement index. Discussion The high prevalence of sleep complaints, SA and PLMD in the HD population is well described. In comparison, the sleep of CKD patients is less well characterized. Although CKD patients also have a high prevalence of sleep complaints, previous work suggests that these problems appear early in the course of the disease, do not seem to increase with disease progression and may be related to psychological factors [1]; the prevalence of SA and PLMD in this group is unknown. To our knowledge, we are the first to compare polysomnographic measures of sleep in wellcharacterized samples of these two groups, while specifically focusing on dimensions of quality of life and treatment effects. We found that both groups had reduced total sleep time and sleep efficiency in comparison with normative data, an observation consistent with the reported complaints of poor sleep. Other than those similarities, the sleep features of the two groups differed. The CKD group had a normal average sleep latency, while that of the HD group was almost twice as long. We also found that significantly less REM sleep and increased numbers of brief arousals, group assignment being the only independent predictor of the latter, characterized the sleep of HD

6 Polysomnographic measures in patients on HD vs those with CKD 1427 patients. HD subjects also had more frequent apnoeas and limb movements. These findings suggest that the mechanisms underlying the poor sleep reported by patients on chronic, intermittent daytime HD and CKD may differ. Despite elimination of potential subjects with significant physical and psychological morbidities in both groups, CKD subjects reported poorer quality of life especially with regard to functional and psychological status. This observation is consistent with previous reports that have found that the illness impact of CKD itself is marked and not necessarily associated with the degree of renal impairment [16]. It may be that the prospect of disease progression and eventual need for treatment may adversely affect selected measures of sleep such as total sleep time and sleep efficiency. Stress, anxiety and depression have been shown to have such effects in the general population. In contrast, the HD group may have reported higher quality of life because of the opportunity to adjust to both the illness and treatment. We did not find direct evidence that functional and psychological status predicted sleep measures, quite possibly because the study was underpowered to do so. Nonetheless, the observation that the CKD subjects reported poorer functional and psychological quality of life in comparison with those already on treatment indicates that sleep-promoting psychological and behavioural interventions may be a promising area for future research in this population. The greater number of brief arousals, apnoeas and limb movements noted in the HD group suggests that the chronic, intermittent daytime form of this treatment may have iatrogenic effects on sleep. This observation is consistent with the findings recently reported by Hanley [17] who found that administration of slow, nightly HD significantly decreased apnoea (although it did not decrease arousals and limb movements), possible due to enhancement of ventilatory stability. Collectively, these results suggest that administration of the treatment in a more stable, consistent manner, and/or having stable residual renal function may have beneficial effects on sleep. Treatment time of day may also be a contributing factor. In contrast, there are several mechanisms via which chronic, intermittent daytime HD a form of treatment that induces very rapid physiological changes may alter biological systems controlling sleep stability and quality. For example, this type of treatment has been associated with increased daytime sleep that can decrease the quantity and quality of subsequent nocturnal sleep. The rapid fluid, electrolyte and acid/base changes that occur are often associated with central nervous system symptoms such as changes in arousal and fatigue during or immediately after treatment. A fall in cerebral spinal fluid ph during dialysis and slow movement of bicarbonate across the blood brain barrier may also be contributing factors causing daytime somnolence and subsequent decreased nocturnal sleep quality and ventilatory instability. In addition, several studies have reported an increase in cytokine production secondary to blood interactions with the bioincompatible equipment used in the HD procedure [18]. These substances have both somnogenic and pyrogenic properties, and have been linked to a number of post-dialytic symptoms including daytime sleepiness and sleep disturbances [19]. In particular, the somnogenic effects of cytokines are most pronounced during the day when receptor binding of these substances to brain receptor sites is typically much lower than during the night. Dialysis-associated changes in melatonin levels and pattern of secretion may play a role in disrupting circadian systems [3]. HD treatment time of day may also affect circadian systems by altering exposure to zeitgebers such as wake-up and bed times, activity patterns, meal times, light exposure and social activity. In addition, HD induces a heat load, and patients often respond with an increase in body temperature of C and this increase in body temperature may persist for several hours following treatment [20]. These changes may disrupt the circadian regulation of sleep and explain the increased sleep onset and REM latencies and decreased percentage of REM sleep, measures that are specifically linked to body temperature rhythms in the HD subjects. One might argue that the increase in brief arousals noted in the HD group in comparison with the CKD group was related to the greater numbers of limb movements and apnoeas observed. However, the interactions among arousals and both apnoeas and limb movements are complex, and causality cannot be assumed to be unidirectional (intermittent events causing brief arousals). Experimentally induced sleep fragmentation can increase both apnoeas and limb movements, while the temporal relationship between apnoeas and limb movements and arousals may vary. Thus, it is not clear whether apnoeas and limb movement always trigger arousals and sleep instability or, alternatively, whether sleep state instability underlies the extent to which these disorders are expressed. In summary, our results imply that the sleep problems and complaints of patients with CKD and those receiving chronic, intermittent daytime HD may have different aetiologies; functional and psychological factors may play a more prominent role in the former group while intrinsic sleep disruption (arousals, apnoeas and limb movements) may play a more significant role in the latter. The study is limited by the small sample size and the possibility that other confounding variables not controlled, such as disease trajectory, may have affected the results. Nonetheless, the findings suggest that further exploration is warranted and that population-specific interventions may be indicated. Research in this area provides opportunities to develop and test such interventions, and has the potential to increase our understanding of the basic mechanisms that regulate sleep and waking. It may well be that the association of sleep complaints and problems with co-morbidities, such as renal failure, may be mediated differentially by the condition itself and the therapies for those conditions.

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