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Sleep disorders in end-stage kidney disease

Sleep disorders in end-stage kidney disease
Literature review current through: Jan 2024.
This topic last updated: Oct 09, 2023.

INTRODUCTION — Sleep disorders are common in patients with end-stage kidney disease (ESKD). A systematic review of 17 studies in patients with ESKD indicated that "sleep disturbance" was one of their most common symptoms, with a mean prevalence of 44 percent [1]. Sleep disorders tend to be under-recognized by renal health care providers [2].

This topic reviews sleep disorders among patients with ESKD, including insomnia, excessive sleepiness, sleep apnea, restless legs syndrome (RLS), and periodic limb movement (PLM) disorder. Sleep disorders in the general population are discussed elsewhere. (See "Classification of sleep disorders" and "Risk factors, comorbidities, and consequences of insomnia in adults" and "Approach to the patient with excessive daytime sleepiness".)

INSOMNIA — The reported prevalence of insomnia among patients with ESKD treated with conventional hemodialysis or chronic ambulatory peritoneal dialysis (CAPD) ranges from 19 to 71 percent [3-14]. A meta-analysis reported that the prevalence of insomnia was 46 percent in patients on hemodialysis and 61 percent in patients on peritoneal dialysis [15]. Insomnia is a significant source of stress [5,16] and is associated with an increased risk of nocturnal blood pressure variability [17] and mortality [14,18] in these patients. The mechanism by which insomnia may increase mortality among such patients is not clear, but may be via an increase in systemic inflammation, which has been associated both with increased risk of incident ESKD and with poor cardiovascular outcomes among patients with ESKD [19,20].

Pathogenesis — Contributors to insomnia include restless leg syndrome (RLS); periodic limb movement (PLM); sleep apnea [21-23]; metabolic factors, including uremia, anemia, hypercalcemia [24,25], bone pain, and pruritus; anxiety and depression [26,27]; circadian rhythm disorders, such as delayed-sleep phase syndrome [4,28]; the use of medications that prevent sleep; and poor sleep hygiene, including frequent napping during daytime dialysis.

Elevated plasma levels of orexin (a neuropeptide that promotes wakefulness) [29] and systemic inflammation [19,20] may also contribute to poor sleep among patients with ESKD. The diurnal rhythm of melatonin is disturbed in patients with ESKD, and it is also related to the degree of kidney dysfunction in patients with chronic kidney disease (CKD) [30]. Some studies have suggested that the timing of the dialysis shift alters the severity of insomnia such that insomnia is worse among patients who are dialyzed in the morning [6,31], but this has not been shown in all studies [32].

Clinical features — Patients complain of difficulty initiating and maintaining sleep and early-morning awakening. In addition to subjective sleep complaints, there is objective evidence of both sleep loss and sleep disruption among patients with ESKD who are treated with conventional hemodialysis (defined by three times weekly in-center hemodialysis). Polysomnographic studies have reported lower than normal total sleep time (4.4 to 6 hours per night), fragmented by a high frequency of arousals (up to 30 per hour), resulting in low sleep efficiency among patients with ESKD [22,33,34].

In one study that compared patients with ESKD treated with conventional hemodialysis with otherwise matched non-ESKD controls, patients with ESKD were more likely to have short sleep (odds ratio [OR] 3.27, 95% CI 1.16-9.25) and less efficient sleep (OR 5.5, 95% CI 1.5-19.6), even after adjustment for cardiovascular disease, diabetes, and known sleep apnea [35]. Sleep architecture varies between studies, but, generally, stages 1 and 2 nonrapid eye movement (NREM) sleep are increased, whereas slow-wave sleep and REM sleep are reduced among patients on hemodialysis compared with the non-ESKD population [22].

Diagnosis — The evaluation of insomnia is not different among patients with ESKD than in the general population and is discussed elsewhere. (See "Evaluation and diagnosis of insomnia in adults".)

Treatment — The treatment of insomnia among patients with ESKD is generally the same as in the non-ESKD population (see "Overview of the treatment of insomnia in adults"). For example, cognitive behavioral therapy for insomnia (CBT-I), the preferred form of treatment for chronic insomnia in the general population, also has been effective in patients on dialysis [36]. Nonpharmacologic therapy is the treatment of choice, particularly in view of the increased risk of fall-related fractures and mortality associated with hypnotic medications in patients with ESKD [37,38].

However, an important component of treatment that is specific to patients with ESKD is the optimization of kidney replacement therapy.

The benefit of kidney replacement therapy in insomnia has been evaluated in a few studies. In one retrospective study that utilized a 10-symptom questionnaire called the Pittsburgh Symptom Score to assess uremic symptoms among 45 patients, symptoms including "trouble sleeping" and "restless legs" improved nine months after the initiation of CAPD [39].

The optimal modality of kidney replacement therapy for the treatment of insomnia among patients with ESKD is not clear. A single, randomized, multicenter study compared the effect of automated peritoneal dialysis (APD) with CAPD on subjectively described sleep quality [40]. Among 25 patients who completed the study, 13 were allocated to CAPD and 12 to APD. APD consisted of nightly intermittent peritoneal dialysis supplemented by additional daytime manual exchanges, if required, to meet a minimum dialysis target. Both groups achieved the same mean weekly Kt/V (of approximately 2.3) over a six-month period. There was no difference in sleep quality at baseline or at six months.

Nocturnal hemodialysis improves sleep apnea but has the potential to cause sleep disruption for other reasons. This was suggested by one study that included 14 patients who were switched from conventional hemodialysis to nocturnal hemodialysis [22]. Although all patients had improved sleep apnea, there was no improvement in polysomnographic features of sleep fragmentation [22]. One reason for the persistent sleep disruption observed in this study is that the reduction in respiratory arousals, associated with improvement of sleep apnea, was replaced by an increase in spontaneous arousals and in arousals associated with PLM [22]. Experience from clinical practice has also suggested that home dialysis has the potential to disrupt sleep in some patients, most often due to technical difficulties with the mode of dialysis (eg, alarms or discomfort due to body or arm positions), as well as to anxiety about receiving dialysis during the night.

The effect of kidney transplantation on sleep quality has been evaluated in a few studies. Among 115 transplant recipients, poor sleep, assessed by the Pittsburgh Sleep Quality Index (PSQI), was reported in 30 percent [41]. However, it is not known whether transplantation (which was performed at least six months prior to the study) caused any change in sleep quality since a baseline assessment prior to transplantation was not obtained. Another study, which assessed insomnia with the Athens Insomnia Scale, reported a lower prevalence of insomnia (8 percent) among kidney transplant recipients compared with waitlisted patients on dialysis [42]. A more recent study reported that poor sleep quality, assessed by the PSQI, was common in patients with ESKD and that it improved following kidney transplant in males but not in females [43].

EXCESSIVE SLEEPINESS — Excessive sleepiness is defined as the inability to stay awake or alert during the major waking episodes of the day, resulting in unintended lapses into drowsiness or sleep [44]. It is a common problem among patients with ESKD, with a frequency ranging from 31 to 86 percent across various studies [4,8,33,45-48].

Excessive sleepiness can result from chronic medical conditions associated with sleep disruption, central nervous system medications, and/or a sleep disorder. The sleep disorders that are often implicated among patients with ESKD include sleep apnea and periodic limb movements [34]. Additional details regarding these conditions in the general population are presented separately. (See "Approach to the patient with excessive daytime sleepiness" and "Excessive daytime sleepiness due to medical disorders and medications".)

Pathogenesis — Multiple ESKD-related factors contribute to sleepiness. Insufficient sleep, poor sleep hygiene, and irregular sleep schedules, often related to the dialysis schedule and/or sleeping during dialysis, can contribute to daytime sleepiness. Patients assigned to the earliest and latest dialysis treatments exhibit the greatest sleepiness, as measured using the Epworth Sleepiness Scale (ESS) [49].

Other factors include uremia, high prevalence of PLM, and high prevalence of sleep apnea. In the study cited above, analysis of the MSLT data indicated that sleepiness was associated with both higher blood urea nitrogen (BUN) and higher frequency of PLM, suggesting that uremia and sleep disruption associated with PLM contribute to the pathogenesis of sleepiness [33].

Sleep apnea contributes to daytime sleepiness among patients with ESKD. In one study cited above, objective sleepiness correlated with the severity of sleep apnea and the frequency of arousals on the overnight polysomnogram [34]. However, although mild sleep apnea was present in some patients, the respiratory disturbance index, which is a measure of apnea frequency, accounted for only 11 percent of the variability in the measures of sleepiness, which suggested that nonrespiratory factors may contribute to sleepiness.

Other contributors to daytime sleepiness may include subclinical uremic encephalopathy; deficiency of tyrosine, which is an important precursor in the metabolism of dopamine; release of sleep-inducing inflammatory cytokines during dialysis; persistence of melatonin during the daytime; and alteration of body temperature rhythm, which is closely associated with the sleep-wakefulness rhythm [34,50].

Other less common conditions unrelated to uremia or that can cause excessive sleepiness in these patients include narcolepsy, idiopathic hypersomnia, circadian rhythm sleep disorders, hypothyroidism, and depression [49].

Clinical features — Excessive daytime sleepiness is manifested by falling asleep involuntarily in either passive (eg, reading, watching television) or active (eg, driving, during conversation) situations. (See "Approach to the patient with excessive daytime sleepiness", section on 'History'.)

Increased daytime sleepiness may lead to decreased productivity at work or even to an increased risk of motor vehicle accidents [51]. Its potential clinical significance varies depending on each individual patient's circumstances. Excessive sleepiness has been correlated with increased mortality in a cohort of patients with ESKD receiving treatment with chronic hemodialysis [52]. (See "Drowsy driving: Risks, evaluation, and management".)

Diagnosis — The evaluation of sleepiness among patients with ESKD is the same as in the general population and is discussed elsewhere. (See "Approach to the patient with excessive daytime sleepiness".)

Treatment — The treatment of excessive sleepiness is generally not different among patients with ESKD as in the general population. (See "Treatment of narcolepsy in adults".)

However, among patients with ESKD, the modality of kidney replacement therapy may influence daytime sleepiness. Nocturnal hemodialysis may have a beneficial effect on daytime sleepiness. This was suggested by one study in which 15 patients with ESKD were assessed by overnight polysomnography and MSLT before and after they were converted from conventional to nocturnal hemodialysis [33]. Prior to conversion of their dialysis treatment, patients were categorized into a somnolent group and an alert group based on the results of an MSLT. In the somnolent group, there was a trend for the frequency of PLM to fall and a corresponding trend for sleep latency to increase; whereas, in the alert group, there was a trend for the frequency of PLM to increase and a corresponding trend for sleep latency to fall. When the data from these two groups were combined, a significant correlation was found between the change in PLM and the change in sleep latency. These data suggest that sleepiness may improve following conversion to nocturnal hemodialysis, possibly related to reduced sleep disruption associated with PLM.

SLEEP APNEA — Sleep apnea is a chronic medical disorder in which patients stop breathing during sleep. There are two types of sleep apnea, both of which are found in patients with ESKD. Obstructive sleep apnea (OSA) occurs due to intermittent closure of the upper airway during sleep.

Central sleep apnea (CSA) occurs due to intermittent loss of respiratory drive. (See "Central sleep apnea: Risk factors, clinical presentation, and diagnosis".)

The term "mixed apnea" is used by polysomnographic technologists when they score apneas that start as a central event and finish as an obstructive one. It is not a distinct clinical entity, nor should it be confused with patients who have both OSA and CSA that occur separately on the same sleep study.

The severity of sleep apnea is defined by the apnea-hypopnea index (AHI) [53]. The AHI is calculated from a sleep study and describes the frequency of apneas (complete absence of airflow for 10 seconds or more) and hypopneas (partial reduction in airflow for 10 seconds or more) per hour of sleep [53]. (See "Polysomnography in the evaluation of sleep-disordered breathing in adults", section on 'Measures of sleep-disordered breathing severity'.)

Untreated sleep apnea has many potential clinical consequences among patients with ESKD. Sleep apnea may exacerbate the symptoms of chronic kidney disease (CKD), such as daytime fatigue, sleepiness, and impaired neurocognitive function, which could impair health-related quality of life [54]. Similar effects on cognitive function have been described in CKD stages 4 and 5 [55]. The prevalence of OSA and nocturnal hypoxemia increases with declining kidney function [56].

In addition, sleep apnea may exacerbate the cardiovascular complications of CKD, as well as ESKD, which are the leading causes of morbidity and mortality among such patients [57-59]. In patients with normal kidney function, OSA independently increases the prevalence of systemic hypertension [60], coronary artery disease [61], and cerebrovascular disease [62] and also exacerbates myocardial ischemia in patients with coexisting coronary artery disease [63]. (See "Obstructive sleep apnea and cardiovascular disease in adults".) In a study of stable kidney transplant recipients, the presence of sleep apnea was associated with hypertension and increased cardiovascular risk [64].

OSA has been identified as a source of increased oxidative stress [65] and systemic inflammation [66], which may accelerate the development of atherosclerosis [67]. Published data about the association between sleep disorders and inflammation among CKD patients, however, are conflicting, with some studies reporting no association between sleep disorders, including sleep apnea, and inflammatory markers [68]. Among patients with ESKD, hypoxemia during sleep is associated with nocturnal hypertension, left ventricular hypertrophy, impaired sympathovagal balance, and an increased risk of cardiovascular complications [69-72].

Sleep apnea may increase the risk of death among patients with ESKD (figure 1). In a 2020 meta-analysis of seven observational studies and 186,686 patients (over 99 percent with ESKD), sleep apnea was associated with an increased risk of mortality (odds ratio [OR] 2.1) [73]. A subsequent analysis of United States Renal Data System data included 858,131 patients with ESKD and reported that CSA was associated with a 42 percent increase in mortality risk and OSA was associated with a 35 percent increase in mortality risk [74].

Epidemiology — Sleep apnea is more common among patients with ESKD than in the general population. The reported prevalence of sleep apnea is >50 percent among patients with ESKD [48,75-77], which is higher than that reported in the general population (2 to 20 percent, depending upon defining criteria). Perhaps the best comparative data are provided by a study that compared 46 patients on hemodialysis with 137 patients with normal kidney function who were matched for age, sex, body mass index (BMI), and race [77]. Patients on hemodialysis were more likely to have severe sleep apnea as defined by the AHI (odds ratio [OR] 4.07, 95% CI 1.83-9.07) [53].

The prevalence of sleep apnea is similar among patients with ESKD who are treated with peritoneal dialysis or hemodialysis [75,76]. This suggests that the pathophysiology of sleep apnea in this population is related to kidney failure itself rather than the dialysis-related factors.

The prevalence and severity of sleep apnea are not altered by the temporal relationship to the patient's last dialysis [22,78].

Patients with ESKD more commonly have OSA rather than CSA, although CSA and mixed apnea are also more commonly observed among patients with ESKD than in the general population [79].

Risk factors — Definite risk factors for OSA in the general population include obesity, craniofacial abnormalities, and upper-airway soft-tissue abnormalities. Potential risk factors include heredity, smoking, nasal congestion, diabetes, age, and sex [80,81].

Some investigators have identified similar risk factors among patients with ESKD [82-85]. However, others have reported that these associations are weak in the ESKD population [48,75,86-88]. In a study that compared 76 patients on hemodialysis with an AHI-matched, non-ESKD control group, the age and sex distribution were similar between groups, patients with ESKD were generally not obese, and the BMI of patients with ESKD was significantly lower than those with normal kidney function (approximately 28 versus 33 kg/m2, respectively) [79].

Pathogenesis — The pathophysiology of OSA and CSA is discussed elsewhere.

Issues that pertain to the ESKD population are discussed here. The observation of both OSA and CSA in patients with ESKD supports the hypothesis that the pathogenesis of sleep apnea among patients with ESKD is due both to destabilization of central ventilatory control and upper-airway occlusion [22,86,89].

Enhanced ventilatory sensitivity to hypercapnia that correlates with apnea severity has been reported in patients with ESKD [86]. Enhanced ventilatory sensitivity to hypercapnia destabilizes respiratory control by increasing a phenomenon known as loop gain [90,91]. A reduction in ventilatory sensitivity to hypercapnia has been demonstrated among patients with ESKD whose apnea improved when they were switched from conventional to nocturnal hemodialysis (figure 2) [92]. Among such patients, the reduction in ventilatory sensitivity correlated with a reduction in apnea severity, as reflected by a fall in AHI.

Alternatively, patients with ESKD may develop sleep apnea through mechanisms that promote upper-airway occlusion during sleep. Such patients are vulnerable to fluid overload [93], which could contribute to pharyngeal narrowing by causing interstitial edema and/or increased fluid volume in the neck and peripharyngeal structures [94]. In healthy subjects, displacement of fluid from the lower limbs has been reported to increase neck circumference and pharyngeal resistance [95] and reduce upper-airway cross-sectional area [96]. This mechanism has been reported to contribute to the pathogenesis of OSA in patients with normal kidney function [97] and in patients with congestive heart failure [98].

Studies have suggested that a similar mechanism is operative among patients with ESKD. As an example, pharyngeal cross-sectional area was measured with acoustic pharyngometry in 44 patients on hemodialysis and compared with a control group with normal kidney function [99]. Pharyngeal area was smaller among the patients on hemodialysis, suggesting that such patients may be predisposed to upper-airway occlusion during sleep [99]. Furthermore, conversion of patients with ESKD from conventional hemodialysis to nocturnal hemodialysis was associated with an increase in pharyngeal cross-sectional area [100], possibly due to improved fluid removal. Conversion from CAPD to nocturnal peritoneal dialysis has also been shown to reduce the frequency of OSA [101]. The decreased prevalence of OSA among patients on nocturnal peritoneal dialysis was associated with better fluid clearance and reduced pharyngeal narrowing, as measured by magnetic resonance imaging [102]. In one study, the upper-airway mucosal water content and jugular volume correlated well with the severity of OSA [103]. Upper-airway mucosal water content was related to nocturnal rostral fluid shift [104], and improvement in fluid overload following hemodialysis was associated with a reduction in the severity of OSA [105]. (See 'Treatment' below.)

Another potential cause of pharyngeal narrowing is upper-airway dilator muscle dysfunction due to neuropathy or myopathy associated with chronic uremia or the underlying cause of ESKD, such as diabetes mellitus [78]. Both sensory neuropathy [106] and muscle denervation [107] have been demonstrated in the upper airway in OSA patients with normal kidney function and may exacerbate the disease process in patients with ESKD.

Clinical features — In the general population, common signs and symptoms of OSA include loud snoring, witnessed episodes of apnea, morning headaches, and sleepiness or poor concentration during the day. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults", section on 'Clinical features'.)

However, patients with ESKD may be less likely to report loud snoring, witnessed apneic episodes, and morning headaches [79]. In addition, other symptoms, such as fatigue and sleepiness, are often attributed to kidney failure. As a result, a high index of suspicion and objective monitoring may be required to make a diagnosis of sleep apnea in this population.

Diagnosis — The clinical diagnosis of sleep apnea is difficult among patients with ESKD since the characteristic clinical features of sleep apnea may be absent and since sleep-related symptoms, such as fatigue and sleepiness, may be attributed to kidney failure. However, the evaluation of patients with possible sleep apnea is the same among patients with ESKD as in the general population and is discussed elsewhere.

Treatment — The decision to treat sleep apnea for the reduction of cardiovascular risk should be individualized for each patient. Although sleep apnea has been associated with increased cardiovascular risk and with mortality [72], no studies have assessed whether treatment reduces mortality in the ESKD population. The treatment of sleep apnea utilizes the same measures that have been shown to be effective in the general population. (See "Obstructive sleep apnea: Overview of management in adults" and "Central sleep apnea: Treatment".)

In addition to such measures, sleep apnea may be improved by changing the mode of kidney replacement therapy [22,100-102]. Although sleep apnea is not corrected by conventional hemodialysis or peritoneal dialysis, nocturnal hemodialysis, which enables patients to receive hemodialysis at home during sleep, may improve sleep apnea. In one study, among seven subjects changing from conventional three times weekly hemodialysis, nocturnal hemodialysis was associated with a reduction in the AHI (approximately 46 to 9 per hour, respectively) [22]. However, as noted previously, although nocturnal hemodialysis may reduce sleep apnea, it has the potential to cause sleep disruption for other reasons. More recently, fluid removal by a single night of ultrafiltration has been shown to improve OSA in ESKD [108]. (See 'Treatment' above.)

Patients treated with nocturnal cycler-assisted peritoneal dialysis have also been shown to have decreased prevalence and severity of sleep apnea compared with those on CAPD [101]. The improvement in sleep apnea was attributed to more effective fluid removal and its impact on the upper airway [102].

It is not clear whether transplantation improves sleep apnea. Case reports have suggested decreased sleep apnea following successful kidney transplantation [109,110]. However, results from case series have been mixed, with some indicating that sleep apnea improves [111] and others indicating that sleep apnea resolves in only a minority of patients following transplantation [64,87]. A meta-analysis including 401 patients with ESKD showed no significant benefit of kidney transplantation on OSA [112]. The persistence of sleep apnea following kidney transplantation may be related to nonrenal factors, such as weight gain and a medication effect on the upper airway [113]. In the transplant population, sleep apnea has also been associated with graft failure [113]. An observational study that used the Berlin questionnaire to assess the risk of OSA reported that a high risk of sleep apnea was associated with an increased risk of graft loss in kidney transplant recipients [114].

RESTLESS LEGS SYNDROME AND PERIODIC LIMB MOVEMENT DISORDER — Restless legs syndrome (RLS) is characterized by an unpleasant sensation in the legs (and occasionally in the arms), accompanied by an urge to move them, typically in the evening or early part of the night, that is worse during periods of inactivity and transiently relieved by movement [44,115]. The prevalence of RLS among patients on hemodialysis is approximately 20 to 30 percent [1,116].

The restlessness experienced by patients with RLS may be problematic both during the daytime, especially during inactivity, and at nighttime, when patients report difficulty initiating and maintaining sleep [117]. Periodic limb movement (PLM) disorder refers to involuntary, jerking movement of the legs (and occasionally the arms) during sleep that may be disruptive to the patients or bed partner [44]. RLS is almost always associated with PLM disorder, but PLM can occur in the absence of RLS.

Epidemiology — Based upon limited data, the reported prevalence of RLS among patients on hemodialysis ranges from 14 to 57 percent [4,7,117,118] compared with a prevalence of 5 to 15 percent in the general population.  

The variability in the reported prevalence of RLS may be due to the heterogeneity of the patient populations studied and differences in the criteria used to diagnose RLS.

The prevalence of PLM among patients with ESKD treated with conventional hemodialysis or chronic ambulatory peritoneal dialysis (CAPD) is >50 percent, which is higher than in the general population [4,8,22,33,34] (see "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults", section on 'Periodic limb movements of sleep'). In a large cohort of stable kidney transplant recipients, the prevalence of RLS was approximately 5 percent [119], which is similar to the observed prevalence in the general population.

Pathogenesis — The pathogenesis of RLS and PLM in patients with ESKD is not understood. Factors that have been associated with these sleep disorders include anemia, iron deficiency, elevated serum calcium, and peripheral and central nervous system abnormalities [44,118,120]. In addition, alterations of central nervous system dopamine and opioid activity may contribute.

Medications, including tricyclic antidepressants, serotonin reuptake inhibitors, and dopamine antagonists, may exacerbate symptoms, as may excessive caffeine, alcohol, and nicotine. An analysis of data from the United States Renal Data System reported that many medications that patients with ESKD frequently receive for relief of depression and psychological issues, pruritus, and gastroparesis are associated with a substantially increased risk of RLS [121]. Iron deficiency may contribute both by causing anemia and by altering central nervous system dopamine metabolism.

Peripheral neuropathy, secondary to uremia or the underlying cause of ESKD (such as diabetes), may also predispose patients to develop RLS and/or PLM.

Clinical features — As noted above, patients with RLS complain of an unpleasant sensation in the legs (and occasionally in the arms), accompanied by an urge to move them, typically in the evening or early part of the night, that is worse during periods of inactivity and transiently relieved by movement [44,115].

Patients with PLM disorder have involuntary, jerking movement of the legs (and occasionally the arms) during sleep [44]. Patients may report nocturnal awakenings associated with legs movements or, more commonly, rely on their bed partner to report them. Although both syndromes may present in the general population, RLS appears to progress more rapidly, is more severe, and is less responsive to dopaminergic medications among patients with ESKD [122].

Clinical significance — RLS is associated with difficulty initiating sleep, poor sleep quality, and impaired health-related quality of life [7,23,117,123]. Furthermore, RLS has been associated with depression in a cohort of patients with chronic kidney disease (CKD) [124]. RLS and PLM may also be associated with increased mortality among patients with ESKD [117,123,125-128]. In a carefully characterized cohort of stable kidney transplant recipients, PLM was associated with increased cardiovascular risk, assessed by the Framingham Score [129]. Although the mechanism underlying the increased mortality is not known, potential explanations include poor compliance with therapy, depression, and the psychological and hemodynamic consequences of recurrent sleep disruption [130-132].

Diagnosis — The diagnosis of RLS is the same among patients with ESKD as in the general population and is discussed elsewhere. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults".)

Treatment — Most pharmacologic and nonpharmacologic therapies for RLS are the same among patients with ESKD as in the general population and are described elsewhere. However, the benefit of such interventions in patients on hemodialysis remains uncertain [133]. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults".)

Interventions utilized in patients on dialysis include the following:

More frequent dialysis may improve RLS. A prospective, cohort study (FREEDOM study) suggested that short daily hemodialysis reduces the prevalence and severity of RLS, as assessed by the International Restless Leg Syndrome Study Group rating scale (IRLS) [134,135] (see "Short daily hemodialysis", section on 'Quality of life'). However, the percentage of patients prescribed medication for RLS did not decrease. Another study reported that nocturnal hemodialysis did not correct PLM [22].

A meta-analysis suggested that cool dialysate may reduce RLS symptoms for patients on hemodialysis [136].

Kidney transplantation has been associated with an improvement in both RLS and PLM in several small studies [119,129,137-139].

Correcting iron deficiency, which is quite prevalent in individuals on maintenance dialysis, with intravenous iron has been shown to improve RLS [140,141].

Moderate, regular exercise has been shown to improve symptoms of RLS in the non-ESKD population as well as patients with ESKD receiving hemodialysis [133,142] (see "Management of restless legs syndrome and periodic limb movement disorder in adults", section on 'Nonpharmacologic therapy'). In a trial that randomly assigned 25 stable patients on hemodialysis to a progressive exercise group (consisting of 45 minutes of intradialytic cycling against progressive resistance applied at 60 to 65 percent maximum exercise capacity) or control (intradialytic cycling without any resistance), there was an improvement in the IRLS score in the progressive exercise group, but not in the control group, at six months [143]. Another study has shown that exercise training is equivalent to dopamine agonists in relieving RLS symptoms [144]. Whether an improvement in RLS symptoms translates to better sleep quality and improved quality of life is not known.

A meta-analysis that included 369 patients on hemodialysis reported that massage therapy may improve RLS symptoms in patients with ESKD [145].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dialysis".)

SUMMARY

Overview – Sleep disorders are common in patients with end-stage kidney disease (ESKD) and tend to be under-recognized by renal health care providers. Sleep disorders include insomnia, excessive sleepiness, sleep apnea, and restless legs syndrome (RLS). (See 'Introduction' above.)

Insomnia

Etiology and clinical features – Insomnia is a significant source of stress and may be associated with shorter survival among patients with ESKD. Causes of insomnia include RLS and periodic limb movements (PLM), sleep apnea, metabolic factors, bone pain and pruritus, anxiety and depression, circadian rhythm disorders, medications, and poor sleep hygiene, including frequent napping during daytime dialysis. Patients complain of difficulty initiating and maintaining sleep and early morning awakening. (See 'Pathogenesis' above and 'Clinical features' above.)

Treatment – Among patients with ESKD, the treatment of insomnia is directed at optimizing kidney replacement therapy, as well as utilizing interventions that are employed for the treatment of insomnia in the general population. Nonpharmacologic therapy is the treatment of choice because of the increased risk of fall-related fractures and mortality associated with hypnotic medications in patients with ESKD. (See 'Treatment' above and "Overview of the treatment of insomnia in adults".)

Excessive sleepiness – Excessive sleepiness is defined as the inability to stay awake or alert during the major waking episodes of the day, resulting in unintended lapses into drowsiness or sleep. Subjective daytime sleepiness has been associated with higher blood urea nitrogen (BUN), higher frequency of PLM disorders, and sleep apnea. (See 'Excessive sleepiness' above.)

Sleep apnea

Pathogenesis – Sleep apnea among patients with ESKD is due both to destabilization of central ventilatory control and upper-airway occlusion. Volume overload and neuropathy or myopathy associated with chronic uremia or the underlying cause of ESKD may contribute. (See 'Pathogenesis' above.)

Clinical features and evaluation – Patients with ESKD may not have the typical manifestations of sleep apnea, and objective monitoring may be required to exclude the diagnosis. The evaluation of patients with possible sleep apnea is the same among patients with ESKD as in the general population.

Treatment – The decision to treat sleep apnea for the reduction of cardiovascular risk should be individualized for each patient. In general, the treatment of sleep apnea is the same among patients with ESKD as in the general population. Among patients on conventional, three times weekly hemodialysis, sleep apnea may be improved by switching to nocturnal hemodialysis; however, nocturnal hemodialysis has the potential to cause sleep disruption for other reasons. Among patients on chronic ambulatory peritoneal dialysis (CAPD), switching to nocturnal peritoneal dialysis may improve sleep apnea. (See "Obstructive sleep apnea: Overview of management in adults" and "Central sleep apnea: Treatment".)

Restless leg syndrome – Restless leg syndrome (RLS) refers to complaints of an unpleasant sensation in the legs (and occasionally in the arms), accompanied by an urge to move them, typically in the evening or early part of the night, that is worse during periods of inactivity and transiently relieved by movement. Factors that exacerbate, if not cause, these sleep disorders among patients with ESKD include anemia, iron deficiency, elevated serum calcium, and peripheral and central nervous system abnormalities. RLS is associated with difficulty initiating sleep, poor sleep quality, impaired health-related quality of life, and depression. (See 'Restless legs syndrome and periodic limb movement disorder' above.)

ACKNOWLEDGMENT

We are saddened by the death of Andreas Pierratos, MD, FRCPC, who passed away in November 2022. UpToDate acknowledges Dr. Pierratos's past work as an author for this topic.

The UpToDate editorial staff acknowledges Marta Novak, MD, PhD, who contributed to an earlier version of this topic review.

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Topic 16197 Version 29.0

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