**3.1 Uremic toxins**

Several studies in the past 30 years have shown that uremic patients are at great risk for disordered sleep. A study by Millman et al. (1985) noticed a slight but significant relationship between sleep apnea syndrome and azotemia. In a recent prospective study of incident HD patients followed-up for 1 year, higher dialysis efficiency was associated with fewer sleep disturbances (Unruh et al., 2006). These latter data are further supported by the results of Hanly et al. (2001), who studied patients on conventional hemodialysis (4 h three times a week) who then switched to nocturnal (intensive) dialysis (8 h for 6 or 7 days/week). A spectacular correction of sleep apnea was recorded in this small-scale study (Hanly et al., 2001). Finally, the impact of uremic toxins is highlighted by the fact that sleep disorders are more frequent and more severe in dialyzed patients compared with subjects with pre-dialysis CKD (Merlino et al., 2006).

### **3.2 Interdialytic weight gain and hypertension**

Excessive interdialytic weight gain has been associated with poor compliance and high blood pressure (Rahman et al., 2000). While the mechanism of the association between interdialytic weight gain and sleep problems is unclear, we speculate that large interdialytic weight gains result in expanded intravascular volume, which has been associated with upper airway obstruction (Chiu et al., 2006).

The length of sleep during the night before a hemodialysis session after a long interdialytic interval (3 days, the "weekend interval") is significantly shorter compared to the usual sleep length following a short interdialytic interval. This led to some speculation regarding the possible effect of interdialytic weight gain (IWG) on sleep (Bertini et al., 1999). Furthermore, patients with uncontrolled pre-dialysis systolic pressure (usually a sign of hypervolemia in these patients) experience clinically overt insomnia more frequently (De Santo et al., 2001); in patients with chronic diseases, systolic hypertension appears to be a cause of sleep disturbances (Katz & McHorney 1998; Sabbatini et al., 2002; Thase, 2005).

### **3.3 Dialysis shift**

412 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

Most studies assessing the effectiveness of different treatment modalities in insomniacs address short-term treatment of insomnia (Montgomery &Dennis., 2004; Morgan et al., 2003; Smith et al., 2002). Extra care and caution has to be exercised when treating insomnia in patients with renal impairment. Most hypnotics should be administered in appropriately reduced doses and interactions with the numerous medications used in the different HD populations should be considered carefully when prescribing a hypnotic to patients with renal failure (Novak et al., 2006). Surprisingly there is an almost complete lack of pharmacologic studies in renal patients suffering from insomnia. In a small randomized study using the PSQI Sabbatini et al. (2003). suggested that zaleplon improved sleep efficacy

Nonpharmacologic interventions include sleep hygiene measures relaxation therapy and biofeedback stimulus control therapy sleep restriction and cognitive behavioral therapy (Montgomery &Dennis., 2004; Morgan et al., 2003). These interventions have been shown to be beneficial in the long-term management of patients with chronic hypnotic use. Cognitive behavioral therapy for insomnia in the routine general practice setting improved sleep quality reduced hypnotic drug use and improved health-related quality of life at a favorable

A multitude of causes including anemia, blood urea levels, plasma creatinine levels, parathyroid hormone (PTH) concentrations, increased blood pressure, quality of life, and illness intrusiveness may contribute to sleep disturbances in patients on maintenance hemodialysis (Hanly et al., 2003; Iliescu et al., 2004; Sabbatini et al.,2003). Furthermore, there is a positive correlation between sleep disturbances and increased morbidity and mortality related to cardiovascular disease and infectious complications, the 2 major causes of death in hemodialysis patients (De Santo et al., 2005). Sleep disorders in hemodialysis patients is a multifactorial complaint, stemming from Uremic toxins and dialysis procedure, other

Several studies in the past 30 years have shown that uremic patients are at great risk for disordered sleep. A study by Millman et al. (1985) noticed a slight but significant relationship between sleep apnea syndrome and azotemia. In a recent prospective study of incident HD patients followed-up for 1 year, higher dialysis efficiency was associated with fewer sleep disturbances (Unruh et al., 2006). These latter data are further supported by the results of Hanly et al. (2001), who studied patients on conventional hemodialysis (4 h three times a week) who then switched to nocturnal (intensive) dialysis (8 h for 6 or 7 days/week). A spectacular correction of sleep apnea was recorded in this small-scale study (Hanly et al., 2001). Finally, the impact of uremic toxins is highlighted by the fact that sleep disorders are more frequent and more severe in dialyzed patients compared with

Excessive interdialytic weight gain has been associated with poor compliance and high blood pressure (Rahman et al., 2000). While the mechanism of the association between

**3. Related factors with sleep problems in hemodialysis patients** 

medical problems, psychiatric or psychosocial background.

subjects with pre-dialysis CKD (Merlino et al., 2006).

**3.2 Interdialytic weight gain and hypertension** 

in maintenance hemodialysis patients.

cost in chronic insomniacs.

**3.1 Uremic toxins** 

The dialysis shift has several effects on patients with ESRD. Morning-shift HD patients experience more insomnia (Sabbatini et al., 2002), but also have longer survival times (Bliwise., 2001) than patients on other dialysis shifts. In according to another study (Merlino et al., 2006), for patients undergoing HD in the morning shift, the risk of subclinical insomnia is up to 18 times higher than for those who have their dialysis session in the afternoon. However, morning-shift HD patients have higher intradialytic sleepiness, which is associated with more decreased body temperature during HD, than patients on other dialysis shifts (Parker et al., 2003).

### **3.4 Dialysis vintage**

The longer the dialysis vintage, the more significant is the prevalence of sleep quality disorders (Veiga et al., 1997). In a study by De Santo et al., (2005), patients with subclinical or clinical sleep disorders had double the dialysis vintage of those without sleep complaints; in patients with a medium dialytic age of 75 months, the prevalence of sleep disorders is close to 80%. These data are not surprising, taking into account the accumulation of comorbidites, including peripheral neuropathy and CVD, whilst on dialysis on long-term. In a polysomnographic study by Tatomir et al.,(2007) in patients hemodialyzed for more than 10 years, all patients has disturbed sleep with frequent awakening and reduced sleep efficiency. One-half of these patients had sleep-related breathing disorders, i.e. sleep apnea syndrome.

### **3.5 Restless legs syndrome**

Restless legs syndrome (RLS) usually becomes apparent during resting and may significantly interfere with sleep. An association between RLS and insomnia in patients on maintenance hemodialysis has been suggested already by a few papers (Musci et al., 2005; Sabbatini et al., 2002; Walker et al., 1995). Moreover, RLS is associated with a low quality of sleep and lower quality of life.

### **3.6 Other medical factors**

Other medical factors include the pain and discomfort caused by illnesses such as arthritis, cardiovascular disease, chronic obstructive pulmonary disease (COPD), cerebrovascular disease, neurological disorders, asthma, headaches, and more. The prognosis of patients with chronic uremia is influenced by the presence of comorbidities, mainly by

Sleep in Patients with ESRD Undergoing Hemodialysis 415

ESRD patients compared to the general population. Moreover, according to recent data from the CHOICE incident dialysis population, use of benziodiazepines is associated with altered sleep quality during the first year of dialysis. Although this study was unable to distinguish between cause and effect, more effective dialysis and cognitive behavioral therapy have been suggested in patients with sleep disorders in need of sleep-inducing medication (Unruh et al., 2006). Moreover, many antidepressants actually cause paradoxical restlessness, therefore systematic administration of these drugs should be subjected to close

Alcohol is widely used as a sleep aid. Although it does shorten sleep latency, it also causes sleep fragmentation, decreased REM, REM rebound and early morning awakenings. The use of alcohol combined with hypnotics may exacerbate sleep difficulties even more (Rosenthal, 1998). Alcohol and (particularly) tobacco abuse is highly associated with increased prevalence of sleep disorders in ESRD (Merlino et al., 2006). Caffeine and other stimulants such as nicotine have been shown to increase sleep latency and sleep fragmentation, and to decrease total sleep time (Rosenthal, 1998). Current smoking is also related with decreases in sleep quality during the first year of dialysis therapy in incident patients (Unruh et al., 2006). Caffeine intake appears to have no significant impact on insomnia in ESRD (Sabbatini

Sleep quality is an important clinical construct for two major reasons. First, complaints about sleep quality are common; epidemiological surveys indicate that 15-35 % of the adult population complain of frequent sleep quality disturbance, such as difficulty falling asleep or difficulty maintaining sleep. Second, poor sleep quality can be an important symptom of

Sleep quality" is sometimes used to refer to a collection of sleep measures including total sleep time (TST), sleep onset latency (SOL), degree of fragmentation, total wake time, sleep efficiency, and sometimes sleep disruptive events such as spontaneous arousals or apnea. The widely employed Pittsburgh Sleep Quality Index (PSQI), for example, provides a measure of global sleep quality based on a respondent's retrospective appraisal (past month) of an array of sleep measures, including sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction (Krystal & Edinger, 2008). Sleep quality is also sometimes inferred from a collection of objective indices taken from polysomnography (PSG). PSG is the most valid and accurate way to assess sleep. Measures derived from PSG include: (a) total sleep time, (b) sleep efficiency (ratio of time spent asleep/time in bed), (c) sleep latency (time to fall asleep after lights out), (d) amount of wake time during sleep periods (waking after sleep onset, WASO), (e)

Among these objective indices are measures such as sleep onset latency, total sleep time, wake time after sleep onset, sleep efficiency, and number of awakenings that correspond to like measures taken from various available self-report instruments (e.g., sleep diaries, PSQI, etc.) (Buysse et al., 2006). However, PSG also provides a number of measures that reflect the architecture of sleep such as the percentage or temporal amounts of stage 1 sleep, stage 2 sleep, slow wave sleep or rapid eye movement (REM) sleep. Despite having no self-report analogues, these latter measures also have been employed by some as indices of sleep

clinical follow-up, which should be easy to accomplish in hemodialysis patients.

**4. Sleep quality and evaluation of sleep in hemodialysis patients** 

number of awakenings, and (f) amount of each sleep stage ( Landis al., 2002).

many sleep and medical disorders (Buysse et al., 1989).

quality (Krystal & Edinger, 2008).

et al., 2002).

cardiovascular disease (CVD), which causes roughly 50% of deaths (Covic et al., 2006). A study by Mucsi et al. (2004), demonstrated that comorbidities are independent predictors of sleep disturbances in patients on maintenance dialysis. According to another study, the average Charlson Comorbidity Index (CCI) in patients without sleep disorders was 4.10, while scores in patients with subclinical and clinically overt sleep disorders were 6.10 and 6.81, respectively (De Santo et al.,2005). This highly significant association in the Italian HD population was maintained regardless of age. To conclude so far, any in-depth research on the quality of sleep in renal patients must consider the magnitude of comorbidities.
