Sleep in Hemodialysis

PLMS are a common disorder in HD patients and are described as repetitive, stereotypical, and unconscious leg movements that occur during sleep. PLMS are present in up to 80% of patients with RLS. PLMS cause significant sleep disturbance, result in nonrestorative sleep, and interfere with the expected sleep-associated dipping of BP. Therefore PLMS may constitute a risk factor for CVD and mortality. An interesting study investigated the association of PLMS with indices of heart structure and function in 19 HD patients with RLS. They found that severe PLMS seems to contribute further impairments in left ventricular mass and left ventricular internal diameter in diastole in HD patients with RLS. Therefore successful treatment of PLMS could result to reduced CVD risk and lower mortality rates in HD.

In ESRD patients, the presence of OSA is associated with elevated BP, left ventricular hypertrophy, and increased mortality. The high prevalence of OSA in ESRD has been attributed partly to instability of the respiratory control system due to uremia. In patients with ESRD, fluid overload may contribute to their high prevalence of OSA by increasing the amount of fluid displaced from the legs into the neck overnight, and possibly compressing the upper airway. Indeed, in ESRD patients, the amount of overnight rostral fluid displaced from the legs is related to the frequency of apneas and hypopneas per hour of sleep (AHI). Fluid overload via increased internal jugular vein volume, along with upper airway mucosal water content, contributes to the pathogenesis of OSA in ESRD patients. This may explain the attenuation of OSA in association with nocturnal HD. Fig. 15.2 depicts representative magnet resonance images of internal jugular veins from a subject with OSA (A) and another without OSA (B).

Representative magnet resonance images of internal jugular veins from a subject with OSA (A) and another without OSA (B). The segment of the left internal jugular vein adjacent to the upper airway (UA) from the posterior aspect of the hard palate to the glottis is shown in green in both the subjects. Note that the internal jugular vein volume is greater in the subject with OSA (2.1 cm ³ ) than the subject without OSA (1.0 cm ³ ).

Reproduced with permission from Elias RM, Chan CT, Paul N, et al. Relationship of pharyngeal water content and jugular volume with severity of obstructive sleep apnea in kidney failure. Nephrol Dial Transplant . 2013;28(4):937-944.

Poor SQ has been associated with both QOL and mortality risk among patients undergoing thrice-weekly HD. Data on SQ were collected from 11,351 patients in 308 dialysis units in seven countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS) between 1996 and 2001 through a patient self-reported SQ scale, ranging from 0 (worst) to 10 (best). A score less than 6 reflected poor SQ. Nearly half (49%) of patients experienced poor SQ, which was independently associated with several QOL indices, medication use patterns, and mortality. Patients with poor SQ were more likely to be prescribed antihistamines, antidepressants, antiinflammatories, narcotics, gastrointestinal medications, antiasthmatics, or hypnotics. Physical exercise at least once a week (versus <1/week) was associated with 0.55 to 0.85 points lower odds of poor SQ ( P < .05). Poorer SQ was associated with significantly lower mental and physical component summary scores (mental component summary scores 1.9 to 13.2 points lower and physical component summary scores 1.5 to 7.7 points lower when SQ scores were <10 vs. 10). The reduction ratio of mortality was 16% higher for HD patients with poor SQ.

The nocturnal endogenous melatonin rise is associated with the onset of sleep propensity and is largely absent in patients on thrice-weekly HD. Exogenous melatonin administration can improve sleep in HD patients. One of the first studies examining the effects of exogenous melatonin on the sleep–wake rhythm of HD patients was the EMSCAP study. This was a randomized, double-blind, placebo-controlled, crossover study of 3 × 6 weeks melatonin 3 mg at 22.00 hours every night. In the first 6 weeks melatonin 3-mg tablets or placebo tablets were taken. In the second period of 6 weeks, placebo and melatonin tablets were reversed. All patients received melatonin 3-mg tablets for the last 6 weeks. HD patients were asked to fill out a sleep questionnaire and wore a wrist actigraph to determine their sleep patterns. Melatonin concentrations in saliva were sampled the night after daytime HD and the consecutive night. On nights after daytime dialysis, objective sleep onset latency decreased significantly from a median of 44.5 (placebo) to a median of 15.5 min with melatonin ( P < 0.01). Sleep efficiency increased from 67.3% to 73.1% with melatonin ( P < 0.05). Actual sleep time increased from 376 min (placebo) to 388 min with melatonin ( P < 0.01), and sleep fragmentation decreased from 4.5 to 3.1 ( P < 0.01). Furthermore, subjective sleep parameters improved also. Patients reported less time needed to fall asleep ( P < 0.05) and fewer wake periods ( P < 0.05) on the nights with and without daytime dialysis and an increase in sleep time on the night of daytime dialysis ( P < 0.05). Furthermore, the nocturnal melatonin rise was recovered. Fig. 15.3 displays a week’s actogram of a patient from the EMSCAP study, at baseline.

Displays a week’s actogram of a patient, at baseline.

The graph shows the movements of the wrist during night and day. All days are double plotted, as on all lines two consequent 24-hour periods are shown. The black lines reflect the movement of the wrist. The lighter colored areas represent the light input on the Actiwatch of the patient. This patient dialyzed on Tuesday, Thursday, and Saturday afternoon. As can be seen, there are often low-light conditions during the day. Daytime napping does occur based on the absence of wrist movements, which can indicate sleep.

Reproduced with permission from Koch BC, Nagtegaal JE, Hagen EC, et al. The effects of melatonin on sleep-wake rhythm of daytime haemodialysis patients: a randomized, placebo-controlled, cross-over study (EMSCAP study). Br J Clin Pharmacol . 2009;67(1):68-75.

Treatment with melatonin may improve objective sleep parameters, such as sleep fragmentation, sleep onset latency, and subjective SQ, and may recover the nocturnal melatonin rhythm. This finding was supported by a 6-week double-blind crossover randomized controlled trial, where 3 mg of melatonin or placebo were administered to 68 patients at bedtime. Lipid profile and the required dose of erythropoietin are also reported as secondary outcomes. Melatonin treatment significantly improved the global Pittsburgh Sleep Quality Index (PSQI) scores ( P < 0.001), particularly subjective SQ ( P < 0.001), sleep efficiency ( P = 0.005), and sleep duration ( P < 0.001). No differences in sleep latency and daytime sleepiness were observed. Melatonin also increased the high-density lipoprotein cholesterol ( P = 0.003). The need for erythropoietin prescription decreased after melatonin treatment ( P < 0.001).

Many nonpharmacological interventions have been examined in HD patients to alleviate symptoms related to sleep disturbances. A randomized controlled trial evaluated the effects of a yoga-based exercise program (30 min session, twice per week for 3 months) on pain, fatigue, sleep disturbance, and biochemical markers in 37 stable HD patients. They found that a simplified yoga-based rehabilitation program is a complementary, safe, and effective clinical treatment modality in patients with ESRD and improved all those symptoms and parameters. A noninvasive alternative therapy such as acupressure and its effects on SQ in 48 HD patients were investigated in another randomized controlled trial. Patients who scored 5 points or higher on the PSQI were enrolled. The main outcome measures of this study were subjective SQ, latency and duration, habitual sleep efficiency, sleep disorders, daytime functional status, and use of sleeping medications. All outcome measures improved significantly in the acupressure group and the results supported the effectiveness of this therapy in improving SQ of HD patients.

Cognitive-behavioral therapy has also been shown to improve SQ and to reduce chronic inflammation. Within this interventional randomized controlled trial, 37 sleep disturbed HD patients received tri-weekly cognitive-behavioral therapy lasting 6 weeks and the remaining 35 HD patients served as controls receiving sleep hygiene education. The adjusted posttrial primary outcome scores of the PSQI, the Fatigue Severity Scale, the Beck Depression Inventory, and the Beck Anxiety Inventory were all significantly improved from baseline by cognitive-behavioral therapy compared with the control group. High-sensitivity C-reactive protein, interleukin (IL)-18, and oxidized low-density lipoprotein levels also significantly declined with cognitive-behavioral therapy compared with the control group. Thus cognitive-behavioral therapy improved SQ, inflammation, and oxidative stress among HD patients with insomnia.

The beneficial effects of intradialytic aerobic exercise training were examined in a pilot study of 14 HD patients with RLS that aimed to evaluate the effect of 16-weeks supervised aerobic exercise training in the severity of RLS and QOL. Exercise training reduced the International RLS score by 42% and improved QOL and SQ. In this study, aerobic exercise training was safe and efficacious in reducing RLS symptoms and improving QOL and SQ in patients with RLS on HD.

Five years later the same group of investigators conducted an exercise randomized controlled trial to investigate whether the reduction of RLS severity, often seen after training, is due to expected systemic exercise adaptations or it is mainly due to the relief that leg movements confer during exercise training on a cycle ergometer. Twenty-four HD patients with RLS were randomly assigned to two groups: the progressive exercise training group ( n = 12) and the control exercise with no resistance group ( n = 12). The exercise session in both groups included intradialytic cycling for 45 min at 50 rpm. Only in the progressive exercise training group was resistance applied, at 60% to 65% of maximum exercise capacity, which was reassessed every 4 weeks to account for the patients’ improvement. A 6-month intradialytic progressive exercise training program was found a safe and effective approach in reducing RLS symptom severity and improving SQ in HD patients. Because the exercise with no applied resistance protocol failed to improve the RLS severity status of the patients, it seems that resistance-applied exercise induced body adaptations that were largely responsible for the reduction in RLS severity score.

Another study evaluated the effects of aerobic training on SQ, inflammatory status, and serum leptin and C-reactive protein levels in 28 HD patients randomly assigned into control and training groups (14 patients per group). They found that aerobic exercise with moderate intensity during the first 2 hours of a dialysis session could improve SQ and inflammatory status of HD patients.

One metaanalysis summarized and quantified the effects of three identified nonpharmacological interventions (cognitive-behavioral therapy, physical training, and acupressure) on SQ improvement in uremic patients on dialysis (HD, PD). The primary outcome was the change of SQ before and after interventions (evaluated by PSG or subjective questionnaires such as the PSQI). They included 12 eligible randomized controlled trials and one prospective cohort study. All three interventions could result in a greater PSQI score reduction compared with controls: (1) cognitive-behavioral therapy versus sleep hygiene education (standardized mean difference 0.85; 95% CI, 0.37 to .34), (2) physical training versus no training (standardized mean difference 3.36; 95% CI, 2.16 to 4.57), and (3) acupressure (including other acupoints massages) versus control (standardized mean difference 1.77; 95% CI, 0.80 to 2.73). The finding of the cohort study suggested that intradialytic aerobic exercise training improved SQ in HD patients with RLS. This metaanalysis concluded that: (1) in dialysis-dependent patients, cognitive-behavioral therapy could shorten sleep latency, alleviate sleep disturbance, and reduce the use of sleep medications; and (2) acupressure and exercise training are promising interventions but the results in these subgroups should be interpreted cautiously due to the concern of methodological quality and potential confounding factors.

Sleep in Peritoneal Dialysis

Some sleep disorders may present differently depending on the dialysis modality used. Many important studies have attempted to evaluate sleep in PD patients (both in automated peritoneal dialysis [APD] and continuous ambulatory peritoneal dialysis [CAPD]) with objective and/or subjective measures and sometimes compared with HD patients as controls.

In a large cohort study, data from the Comprehensive Dialysis Study (CDS) were used to examine the association of self-reported physical activity with self-reported symptoms of insomnia, RLS, and depression in 1678 patients new to dialysis (169 PD and 1509 HD patients). Sleep and mood disturbances were commonly reported (53% reported 1 of 3 insomnia symptoms, 29% symptoms of RLS and 28% symptoms of depression). Patients who reported lower levels of activity were more likely to report symptoms of insomnia, RLS, and depression.

In another interesting study, 166 clinically stable dialysis patients were randomly selected and divided into HD, CAPD, or APD. Self-administered questionnaires were collected for the investigation of insomnia, RLS, bruxism, rapid-eye-movement sleep behavior disorder, excessive daytime sleepiness, OSA syndrome, sleepwalking, sleep hygiene, depression, and anxiety. Insomnia was detected in more than 80% of patients in all three dialysis modalities. OSA syndrome was lower for patients on HD (36%) than on CAPD (65%) or APD (60%) and this was attributed most likely to their lower body mass indices. Patients on APD were more likely to have RLS compared with those on HD or CAPD (50% vs. 23% vs. 33%; P < 0.04) for unknown reasons. No differences among the modalities were found in bruxism, excessive daytime sleepiness, sleepwalking, sleep hygiene, depression, or anxiety.

Another cross-sectional study aimed to investigate the association between SQ, health-related QOL, and depression, and to define independent predictors of SQ and depression in 64 PD and 90 HD patients receiving kidney replacement therapy for at least 3 months. This study showed that despite similar SQ scores between the two groups, HD patients had better health-related QOL and less depression than PD patients. However, another study that assessed SQ in 90 HD and PD patients seemed to favor PD over HD. These investigators found that poor SQ was frequent in 86.6% of the cases in each group of HD and PD patients. Anxiety, depression, and being on HD were independent predictors of overall poor SQ.

A cross-sectional study studied 42 CAPD patients and evaluated the relationship of SQ with RLS and depression and other potential risk factors. The prevalence of sleep disorders was 47.6% in the CAPD patients. RLS, depression, and low serum albumin were identified as risk factors for sleep disorders in this study. A cross-sectional study explored the possible impact factors on excessive daytime sleepiness among 98 prevalent PD patients using both the PSQI and the Epworth Sleepiness Scale questionnaire. This study reported a high prevalence of poor SQ in PD patients and a correlation of excessive daytime sleepiness with low residual kidney function, poor nighttime SQ, and hypermagnesemia. Another study attempted to assess the prevalence and relative risk factors of sleep disorders among 212 CAPD patients from a single center in southern China. PSQI was used to assess SQ. The average global PSQI score was 9.5 ± 5.2, with 171 (80.4%) poor sleepers (PSQI scores ≥5). This report demonstrated an important relationship of malnutrition and calcium to phosphate product with poor SQ in CAPD patients, which may partly explain the link between poor SQ and overall morbidity and mortality. Finally, a descriptive study was performed to determine SQ, fatigue levels and related factors in 105 CAPD patients, as well as the effect of their SQ on fatigue. The investigators confirmed the high prevalence of poor SQ and increasing with age and fatigue in this patient population.

A study from Sweden took a step further. These investigators aimed to describe the sleep–wake cycle, SQ, fatigue and health-related QOL measured with four questionnaires, actigraphy and a sleep diary during a 1-week period in 28 patients undergoing in-home PD. They also aimed to explore differences compared with 22 patients with coronary artery disease (CAD) and 18 individuals from the general population. Patients on PD had more fragmented sleep and worse sleep efficiency than patients with CAD or individuals from the general population. Pruritus (57%), RLS (46%), and fatigue (89%) were prevalent in PD patients. Pruritus correlated with fragmented sleep and sleep efficiency.

SA has been evaluated in the past both by subjective (questionnaires) and objective (in-home PSG) measures in the PD population alone or in combination with HD patients. Sleep studies on CAPD and APD patients have also been performed. A cross-sectional study assessed the prevalence of SA and excessive daytime sleepiness in 227 ESRD patients (both PD and HD) using questionnaires. The overall prevalence of SA as defined by the Berlin Questionnaire was 37% in males and 34% in females, which was not a statistically significant difference ( P = 0.459). SA was significantly associated with age, neck size, afternoon and evening HD shift, obesity, diabetes, and hypertension ( P values: 0.001, 0.029, < 0.0001, < 0.0001, < 0.008, 0.002, and < 0.001, respectively). SA was also significantly associated with other sleep disorders such as RLS, insomnia, habitual snoring, and excessive daytime sleepiness ( P values: < 0.001, < 0.001, < 0.001, and < 0.001, respectively). The prevalence of excessive daytime sleepiness was 44%, and excessive daytime sleepiness was significantly more prevalent in patients undergoing PD ( P < 0.001); it was also associated with older age, diabetes mellitus, and other sleep disorders.

An important study explored SA as a novel risk predictor of CVD events and death in patients receiving PD. This group of investigators prospectively followed the clinical outcome of 93 PD patients with baseline PSG. Of these, 51 were diagnosed with the syndrome defined by an AHI of at least 15 per hour. During a median follow-up of 41 months, there were 30 deaths, of which 17 were due to CVD causes. Patients with SA at baseline had significantly higher all-cause and CVD mortality during follow-up compared with those without SA. Minimal nocturnal saturation and desaturation indices were predictors of mortality and CVD events at univariate analysis. Multivariable Cox regression analysis identified significant SA syndrome at baseline as an independent predictor of increased all-cause mortality independent of age, male gender, and diabetes status. An absolute increase in the AHI was associated with an incremental risk of CVD events. Thus SA syndrome, detected at the start of PD, is a novel risk predictor for subsequent mortality and CVD events.

It is well known that abnormal patterns of heart rate variability are associated with an increased risk of sudden cardiac death, stroke, and diabetes mellitus. In addition, dialysis patients and patients with CKD experience a substantial risk for abnormal autonomic function and abnormal heart rate variability. This was shown in a study where in-home PSG was performed in 95 patients with stages 4 to 5 CKD or ESRD on HD or PD. They found that patients with CKD and ESRD exhibited dysregulation of the autonomous nervous system tone manifesting as a failure to increase heart rate variability during wakefulness and sleep. Different patient characteristics were associated with changes in heart rate variability at different sleep stages. Patients with advanced CKD did not differ from dialysis patients in their inability to increase vagal tone during sleep.

Another cross-sectional, descriptive study focused on estimating sleep disorders in APD patients by objective (PSG) and subjective (PSQI; Patient Health Questionnaire-9) measures. In this report, the investigators aimed to describe and compare the prevalence of sleep-disordered breathing (SDB), PLMS, poor SQ, and depression among 22 APD patients compared with 89 patients with CKD stages 3b to 5 and 75 patients treated by HD. In univariate analyses, APD patients had significantly lower AHI compared with HD patients (likelihood ratio test P = 0.008) and revealed the least proportion of total sleep time with nocturnal hypoxemia compared with CKD patients, respectively (likelihood ratio test P = 0.01). In multivariate analyses and after adjustment for age, gender, race, and body mass index, both APD and HD patients had higher average PSQI scores (worse SQ) than CKD patients, respectively (likelihood ratio test P = 0.005). They found that APD patients had similar sleep parameters and sleep architecture and as poor SQ and symptoms of depression as HD patients.

Melatonin seems to play an important role in the sleep–wake rhythm of APD patients. It is well-known that this pineal hormone plays an important role in the synchronization of the circadian sleep–wake rhythm (defining periods of low and high sleep propensity), which may be negatively affected in dialysis patients, due to the pathology of ESRD and the dialysis process, causing daytime sleepiness and nocturnal insomnia. An absence of the nocturnal rise in melatonin concentration in daytime HD patients has been described in the past. Because little comparative data on sleep–wake rhythms in different dialysis groups existed, an innovative study aimed to investigate sleep–wake parameters measured with actigraphy and sleep questionnaires as well as melatonin rhythms in 6 APD, 20 conventional daytime HD, and 13 nocturnal HD patients. Melatonin in saliva was sampled at five time points (21:00, 23:00, 01:00, 07:00, and 09:00 hours). This study showed impaired sleep parameters in all dialysis patient groups. Conventional daytime HD patients had the worst sleep. In nocturnal HD patients, a normal nocturnal melatonin rise was found. In daytime HD and APD patients, this rise was absent. As APD is also performed during night time, the same effect on normalized melatonin was anticipated as was found in nocturnal HD.

Are there any differences between APD and CAPD on sleep? A cross-sectional study aimed to determine any differences between these two PD modalities with respect to health-related QOL, depression, and SQ. Twenty APD and 48 CAPD patients were included. Moderate or severe sleep problems were found in 60% and 69% of the APD and CAPD patients, respectively. There were no significant differences between APD and CAPD in any of the studied parameters. Similarly, a subsequent study compared 29 APD patients with 30 CAPD patients regarding their excessive daytime sleepiness and QOL. They found that the incidence of excessive daytime sleepiness was slightly higher in APD patients but not significantly different from the CAPD patients. Furthermore, the presence of excessive daytime sleepiness did not affect negatively daily activities or QOL.

Both studies evaluated sleep by subjective means. However, our report regarding the contribution of uremia and volume overload to the pathogenesis of SA in ESRD has been supported by the improvement in SA with use of nocturnal APD. In a small study performed at two PD centers in Hong Kong, the investigators demonstrated a reduction in the severity of SA (AHI) with the use of nocturnal cycler-assisted PD in 23 patients that transitioned from APD to CAPD. This hypothesis was further examined using MRI of the upper airway which demonstrated a reduction in cross-sectional space in the upper airway of 14 patients who transitioned from nocturnal PD to CAPD.

Cognitive-behavioral therapy is effective for treating chronic insomnia in the general population and seems useful among the PD population as well. A pilot randomized controlled trial with parallel-group design investigated the effectiveness of cognitive-behavioral therapy in 24 PD patients with insomnia without active medical and psychiatric illness by assessing changes in SQ and inflammatory cytokines. The intervention group ( n = 13) received cognitive-behavioral therapy from a psychiatrist for 4 weeks and sleep hygiene education, whereas the control group ( n = 11) received only sleep hygiene education. Primary outcomes were changes in the PSQI and Fatigue Severity Scale scores, and secondary outcomes were changes in serum IL-6, IL-1β, and tumor necrosis factor-α levels during the 4-week trial. This study found that cognitive-behavioral therapy may be effective for improving SQ and decreasing fatigue and inflammatory cytokine levels in PD patients.

Finally, a study evaluated the effects of nonpharmacological interventions; a pressure-relieving mattress and a 4-week individual sleep hygiene and sleep scheduling intervention on sleep, activity and fatigue in nine PD patients using both actigraphy and self-assessed questionnaires. Two women and seven men with sleep problems, 48 to 77 years old, treated with PD participated in a 17-week study. Physical activity advice was the element of the individual sleep hygiene and sleep scheduling intervention that yielded the most sleep improvements. This study demonstrated how a nonpharmacological treatment and self-management can be applied with kidney-supportive care to improve SQ in PD patients. This model can also reduce the pharmacological burden of these patients, because the current use of hypnotics can be replaced by sleep-hygiene self-care activities.