Dreams disrupted: a comprehensive review of sleep disorders in chronic kidney disease

Insomnia in chronic kidney disease

Insomnia is defined as difficulty initiating or maintaining sleep, early morning awakenings, or poor sleep quality despite adequate sleep opportunity, leading to daytime impairment [9]. It is classified as chronic insomnia disorder when symptoms persist for at least 3 months, occurring at least three times per week [10]. If symptoms last for less than 3 months and are often triggered by stress or medical conditions, it is considered short-term insomnia disorder [11]. In CKD, insomnia is often secondary to factors such as uremic toxins, pruritus, metabolic acidosis, pain, and psychological distress [12].

Sleep-related breathing disorders in chronic kidney disease

This category includes OSA and central sleep apnea (CSA), both of which are highly prevalent in CKD. OSA is characterized by recurrent episodes of upper airway obstruction during sleep, leading to intermittent hypoxia and sleep fragmentation [13]. It is diagnosed when the apnea-hypopnea index (AHI) ≥5 events/hour with symptoms or AHI ≥15 events/hour regardless of symptoms [14]. CSA occurs due to a failure of central respiratory drive, leading to cyclic reductions in ventilatory effort and periodic breathing [15]. It is common in CKD due to fluid shifts, autonomic dysfunction, and metabolic disturbances [16].

Restless legs syndrome and periodic limb movement disorder in chronic kidney disease

RLS is a sensorimotor disorder characterized by an uncontrollable urge to move the legs, often worsening at night and relieved by movement [17]. It can be primary (Idiopathic, often genetic in origin) or secondary RLS, which is more common in CKD and linked to iron deficiency, uremia, and dopamine dysregulation [18]. Periodic limb movement disorder (PLMD) is a repetitive, involuntary leg movements during sleep, often disrupting sleep architecture [19]. It is common in CKD and frequently coexists with RLS, contributing to insomnia and daytime fatigue [20].

Circadian rhythm sleep-wake disorders in chronic kidney disease

These disorders result from misalignment between the endogenous circadian rhythm and external environmental cues [21]. Delayed sleep phase disorder is characterized by difficulty falling asleep and waking up late, frequently reported in CKD patients undergoing nighttime dialysis [22]. Non-24-hour sleep-wake disorder occurs due to irregular melatonin secretion patterns, observed in advanced CKD [23].

Insomnia in chronic kidney disease

Insomnia, characterized by difficulty initiating or maintaining sleep, affects a substantial proportion of CKD patients. Studies estimate that 40% to 60% of non-dialysis CKD patients and 50% to 70% of dialysis-dependent patients experience insomnia compared to 10% to 30% in the general population [12]. A large cross-sectional study reported that 57.4% of CKD patients had sleep disturbances, with 37% meeting the criteria for clinical insomnia [25]. Insomnia is more prevalent in end-stage renal disease (ESRD) patients, especially those on hemodialysis (55%–70%) and peritoneal dialysis (40%–60%) [26].

Obstructive sleep apnea in chronic kidney disease

OSA is one of the most common sleep disorders in CKD, with prevalence rates between 30% and 80%, depending on disease severity [27]. OSA is observed in 30% to 40% of patients with moderate kidney dysfunction [28], whereas in ESRD on hemodialysis the prevalence increases to between 50% and 60%, with a higher frequency of CSA in addition to OSA [29]. In patients on nocturnal dialysis, OSA prevalence remains 40% to 50%, although nocturnal hemodialysis may improve AHI scores by reducing fluid overload and upper airway narrowing [29].

Restless legs syndrome in chronic kidney disease

RLS is significantly more common in CKD than in the general population, affecting 20% to 50% of CKD patients, compared to 5% to 10% in the general population [30]. In non-dialysis CKD, RLS is present in 15% to 30% of patients. Among dialysis patients, prevalence reaches 30% to 50%, with studies reporting even higher rates in certain populations [31].

Excessive daytime sleepiness in chronic kidney disease

EDS is reported in 12% to 50% of CKD patients, depending on disease stage and dialysis modality [32]. In non-dialysis CKD patients, approximately 15% to 25% experience significant daytime sleepiness. For hemodialysis patients, rates range from 35% to 50%, with increased risk due to fragmented sleep, OSA, and metabolic imbalances [33]. Peritoneal dialysis patients report similar or slightly lower rates of EDS compared to hemodialysis, but they still experience high fatigue levels [34].

Clinical history and validated questionnaires

A comprehensive sleep history, including sleep onset latency, nocturnal awakenings, daytime fatigue, and nocturnal symptoms such as snoring or leg discomfort, provides initial diagnostic clues. Several standardized questionnaires have been validated for screening sleep disorders in CKD patients.

Objective sleep studies

Polysomnography (PSG) is the gold standard. Full-night attended PSG is the definitive diagnostic tool for sleep disorders, particularly OSA and PLMD, which frequently coexists with RLS in CKD patients [42].

PSG records multiple physiological parameters:

• Electroencephalography (EEG): Assesses sleep architecture, disruptions, and microarousals [43]

• Electromyography: Detects periodic limb movements, a hallmark of PLMD [19]

• Electrooculography: Monitors rapid eye movement (REM) sleep abnormalities, often altered in CKD [2]

• Pulse oximetry and capnography: Identifies desaturations and hypercapnia, critical in detecting OSA and CSA [44]

• Respiratory effort and airflow sensors: Differentiate between obstructive and central events in sleep apnea [45]

Pathophysiology of sleep disorders in chronic kidney disease

The pathophysiology of sleep disorders in CKD is complex and multifactorial, involving a combination of metabolic, biochemical, hormonal, and inflammatory factors (Table 4). The progression of CKD leads to an array of systemic changes that disrupt sleep regulation and contribute to disorders such as insomnia, RLS, sleep-disordered breathing (SDB), and EDS [53]. These sleep disturbances, in turn, may accelerate the decline of renal function and exacerbate CKD complications, creating a vicious cycle that further challenges disease management [54].

Table 4.

Pathophysiology of sleep disorders in CKD

Melatonin supplementation

Melatonin is a hormone naturally produced by the pineal gland, which regulates circadian rhythms and the sleep-wake cycle. CKD patients often exhibit lower levels of melatonin due to disrupted renal metabolism, contributing to insomnia and other sleep disturbances [6]. Melatonin supplementation has shown promise as a treatment for insomnia in this population. Studies indicate that a dose of 3 mg of melatonin taken 30 minutes before bedtime can significantly improve various aspects of sleep quality, including sleep onset latency, sleep duration, and overall sleep efficiency as measured by the PSQI [63]. In addition to improving sleep metrics, melatonin supplementation has been associated with reductions in anxiety and depressive symptoms among hemodialysis patients. The anxiolytic and antidepressant properties of melatonin offer dual benefits, addressing not only insomnia but also the mental health comorbidities often present in CKD patients [68]. Prolonged-release formulations of melatonin may provide further benefits by sustaining melatonin levels throughout the night, thus helping to prevent nocturnal awakenings and enhancing overall sleep maintenance [20]. Melatonin is generally well-tolerated with minimal side effects, making it a viable first-line treatment option for insomnia in CKD, particularly for those looking to avoid traditional sedative-hypnotics [52].

Cognitive-behavioral therapy for insomnia

CBT-I is a structured, non-pharmacologic intervention that focuses on changing thoughts and behaviors contributing to poor sleep. CBT-I has proven effective for insomnia in the general population and is increasingly recognized as a beneficial approach for CKD patients [69]. CBT-I combines several therapeutic techniques, including sleep restriction (limiting time in bed to increase sleep efficiency), stimulus control (associating the bed only with sleep), cognitive restructuring (challenging negative thoughts about sleep), and relaxation training [70]. Through these techniques, CBT-I addresses both the psychological and behavioral aspects of insomnia, making it particularly well-suited for CKD patients who may suffer from stress, anxiety, and other psychological stressors related to their illness [63]. Studies have demonstrated that CBT-I can significantly improve sleep quality and reduce the number of awakenings in CKD patients, resulting in a marked improvement in overall quality of life [6].

Digital and remote CBT-I programs, which can be accessed via computers or tablets, have shown promise in improving sleep outcomes for patients undergoing hemodialysis, providing a feasible and accessible option for this population [71]. A notable advantage of CBT-I is its long-lasting effects; unlike pharmacologic treatments, which may require ongoing use, the benefits of CBT-I can persist beyond the treatment period, offering sustained relief from insomnia [72].

Short-term pharmacologic agents: Z-drugs and benzodiazepines

For CKD patients who require immediate relief from severe insomnia, short-term pharmacologic agents such as Z-drugs (non-benzodiazepine hypnotics like zolpidem and eszopiclone) and benzodiazepines may be considered. These drugs act by enhancing gamma-aminobutyric acid activity, promoting relaxation and sedation, thereby facilitating sleep [73]. Z-drugs, in particular, are often preferred due to their relatively favorable safety profile and lower risk of dependency compared to benzodiazepines [74]. However, due to impaired renal clearance, CKD patients are at an increased risk of prolonged sedation and side effects, including dizziness, confusion, and falls, especially in older adults [75]. Z-drugs are typically considered safer than benzodiazepines for short-term use, as they are less likely to affect respiratory function, which is crucial in CKD patients who may also have sleep apnea [76]. Nonetheless, their use should be limited to the lowest effective dose and shortest duration possible, generally recommended for no longer than 2 weeks, to mitigate the risk of dependence and withdrawal symptoms.

Benzodiazepines, such as lorazepam and temazepam, may be effective for acute insomnia but carry a higher risk of dependence and are associated with a range of adverse effects, including respiratory depression, especially in patients with concurrent sleep apnea [76].

Dopaminergic agents

Dopaminergic agents, such as pramipexole and ropinirole, are commonly used to manage RLS symptoms in both the general population and CKD patients. These medications work by stimulating dopamine receptors in the brain, which helps to alleviate the uncomfortable sensations associated with RLS [40]. Dopamine dysregulation is believed to play a role in RLS pathophysiology, and dopaminergic agents can restore some balance, thereby reducing the urge to move and improving sleep quality in CKD patients [77]. The efficacy of dopaminergic agents in reducing RLS severity and improving sleep quality in CKD patients is well-documented. Studies indicate that pramipexole and ropinirole are effective in reducing RLS symptoms and improving patient-reported sleep quality [78]. However, these medications must be used with caution in CKD due to potential side effects such as nausea, dizziness, and, importantly, augmentation—where symptoms worsen over time with long-term use [65,79].

Iron supplementation

Iron deficiency is a well-known contributor to RLS in CKD, as iron plays a crucial role in dopamine synthesis. Low serum ferritin and transferrin saturation levels are often found in CKD patients with RLS, exacerbating symptoms [60]. Iron supplementation, particularly intravenous iron, is recommended for CKD patients with RLS and low iron stores, as it bypasses the issues of reduced gastrointestinal absorption that are common in CKD [80]. Intravenous iron sucrose and ferric carboxymaltose are common options, with studies demonstrating that they can significantly reduce RLS severity and improve sleep quality in hemodialysis patients [56]. Oral iron supplements may also be used; however, they are generally less effective in CKD patients due to impaired gastrointestinal absorption and may not achieve adequate iron levels for symptom control [81].

Physical and alternative therapies

Non-pharmacological therapies, including physical and alternative treatments, provide additional options for RLS management in CKD. Physical activity, particularly intradialytic exercise (exercise performed during dialysis sessions), has been shown to alleviate RLS symptoms and improve sleep quality. Intradialytic exercise may include activities such as cycling or resistance exercises, which help reduce the frequency and severity of RLS episodes, likely by enhancing blood flow and reducing uremic toxin buildup in the muscles [61]. Alternative therapies, such as acupuncture and acupressure, have been explored for their potential to relieve RLS symptoms. These techniques involve stimulating specific points on the body, which is thought to modulate pain pathways and enhance relaxation [82]. Though the evidence is limited, preliminary studies suggest that acupuncture may reduce leg discomfort and improve sleep quality in CKD patients with RLS [83].

Fluid management: dietary and dialysis modifications

Fluid overload is a common issue in advanced CKD and is particularly problematic for patients with SDB and OSA. Fluid retention can contribute to the collapse of the upper airway during sleep, worsening OSA and other forms of SDB [57].

Dietary modifications are often the first step in managing fluid overload. CKD patients are typically advised to follow a low-sodium diet to limit fluid retention, as sodium intake is directly related to fluid volume control. Studies indicate that reducing sodium intake can help minimize fluid shifts, decreasing the likelihood of upper airway obstruction during sleep [84].

Dialysis-related modifications, particularly adjusting the timing and frequency of dialysis sessions, play a significant role in fluid management for CKD patients with SDB. Increasing the frequency of dialysis sessions, or opting for daily or nocturnal dialysis, helps achieve better fluid removal and prevents fluid overload between sessions [85]. Frequent dialysis has been shown to reduce edema and improve upper airway patency, thus decreasing the frequency of apnea episodes and improving oxygenation levels during sleep [86].

Positive airway pressure therapy: continuous positive airway pressure and bilevel positive airway pressure

PAP therapy, which includes continuous PAP (CPAP) and bilevel PAP (BiPAP), is the standard treatment for OSA and is also effective for managing other forms of SDB in CKD patients [87]. PAP therapy works by delivering a constant flow of air through a mask, which keeps the upper airway open and prevents the collapse associated with apnea episodes. CPAP is generally recommended as the first-line treatment for OSA, while BiPAP may be more suitable for patients who have difficulty tolerating the higher pressures required with CPAP or who have concurrent conditions like heart failure that require variable pressure levels [88]. Studies have demonstrated that CPAP use in CKD patients with SDB can significantly reduce AHI scores, improve oxygen saturation, and enhance overall sleep quality [89]. Improved oxygenation from CPAP use has beneficial effects on cardiovascular health, reducing the sympathetic overactivity often triggered by nocturnal hypoxia in SDB patients. This reduction in sympathetic drive may also help stabilize blood pressure, a critical factor for CKD patients who are at high risk of hypertension [90]. While CPAP is effective, adherence can be a challenge in the CKD population. Factors such as discomfort, skin irritation, and nasal dryness can reduce CPAP compliance, making it important for healthcare providers to offer support and education on mask fitting, device maintenance, and managing side effects [91]. BiPAP is sometimes preferred in CKD patients with high pressures or those who experience CSA in addition to OSA, as it allows for different pressures during inhalation and exhalation, which can improve comfort and tolerance [92].

Nocturnal hemodialysis: effectiveness for sleep-disordered breathing and improvements in oxygenation and fluid management

Nocturnal hemodialysis, which involves longer dialysis sessions performed at night, is an effective alternative to conventional daytime dialysis for CKD patients with SDB. This approach has gained traction for its potential to improve both sleep quality and overall health outcomes by enhancing fluid management, reducing blood pressure, and minimizing toxin buildup [93]. Studies indicate that nocturnal hemodialysis can significantly reduce the AHI in CKD patients with OSA, suggesting that this approach can reduce the frequency of apnea episodes and improve sleep continuity [29]. Additionally, patients who switch to nocturnal dialysis often experience improved oxygenation levels [94]. Another advantage of nocturnal hemodialysis is its effect on blood pressure control. SDB and OSA are associated with elevated sympathetic activity and hypertension, both of which exacerbate CKD progression. Nocturnal hemodialysis has been shown to lower blood pressure, which can have additional benefits for CKD patients by reducing cardiovascular strain and potentially slowing disease progression [68]. Patients on nocturnal hemodialysis report fewer awakenings and less daytime fatigue, potentially due to reduced uremic symptoms and better control of fluid and electrolyte levels [95].

Light therapy: circadian rhythm regulation and reduction of daytime sleepiness

Light therapy is a noninvasive intervention that involves exposing patients to bright light at specific times of the day to help regulate circadian rhythms and improve sleep-wake cycles. CKD patients, especially those undergoing dialysis, often experience disrupted circadian rhythms due to treatment schedules and altered melatonin production, leading to fragmented sleep and subsequent daytime sleepiness [79]. Studies have shown that morning exposure to bright light, typically around 5,000 to 10,000 lux for 20 to 30 minutes, can significantly reduce EDS in CKD patients by enhancing alertness and supporting a healthier sleep-wake pattern [96]. This therapeutic approach has proven particularly beneficial for dialysis patients, who may struggle to maintain consistent circadian rhythms due to the disruptive nature of dialysis schedules [97,98]. Implementation of light therapy can be customized based on the patient’s daily routine and dialysis schedule. Home-based light therapy devices are available, allowing patients to undergo treatment at their convenience. Though generally safe, some patients may experience mild side effects such as headaches or eye strain; these can often be managed by adjusting light intensity or session duration [98].

Intradialytic exercise and physical activity: effects on fatigue, alertness, and sleep quality

Physical activity, particularly intradialytic exercise (exercise performed during dialysis sessions), has been shown to positively impact fatigue levels, alertness, and sleep quality in CKD patients. Exercise helps reduce uremic toxins, improves cardiovascular health, and enhances mood, all of which contribute to reduced EDS and improved overall well-being. Intradialytic exercise typically includes low-to-moderate intensity activities such as stationary cycling or resistance training, which are feasible to perform during dialysis without interrupting the treatment [99]. Research indicates that intradialytic exercise significantly improves alertness and reduces fatigue, as it stimulates blood circulation and increases oxygenation to the brain, which can enhance cognitive function and mental clarity [100]. Additionally, regular physical activity has been associated with improvements in nighttime sleep quality and duration, helping to establish a healthier sleep pattern and reducing the need for daytime napping [101].