**2. Sleep problems in hemodialysis patients**

Sleep complaints and sleep disorders are common in patients with end-stage renal disease. Although variable, their prevalence has been reported to be higher when compared to the general population (Merlino et al., 2006). The experiences of sleep alteration in ESRD patients have been studied. Interestingly, 80% of hemodialysis patients suffer from sleep abnormalities and the prevalence is higher than that in the general population (Gul et al., 2006). Holley et al. (1992) surveyed 70 dialysis patients, and reported sleep disturbance experienced mainly included trouble falling asleep (67%), nighttime waking (80%), early morning waking (72%), restless legs (83%), and jerking legs (28%). However, Walker et al. (1995) found daytime sleepiness was the most commonly reported problem (66.7%) followed by restless legs syndrome (57.4%). Generally, the most prominent sleep disorders among hemodialysis patients are sleep apnea syndrome, restless leg syndrome, periodic limb movement disorders, and insomnia (De Santo et al., 2005; Holley et al., 1992; Sabry et al., 2010).

### **2.1 Sleep apnea syndrome**

The prevalence of sleep apnea syndrome in hemodialysis patients is at least 10 times higher (Kraus & Hamburger, 1997) than those values reported in the general population (Young et al., 1993). In another recent investigation, an apnea/hypopnea index higher than 5 was found in 31% of the (young) non-diabetic HD patients studied (Rodriquez et al, 2005).

Sleep apnea syndrome (SAS) is a major clinical disturbance defined as an intermittent interruption of air flow at the level of nose and mouth during sleep. These abnormalities cause frequent decreases in O**2** saturation and awakenings. Episodes of apnea are considered clinically significant if they persist for more than 10 s; however, apnea episodes may last up to 2 min. SAS is the clinical consequence of frequent (at least 10 events per hour) episodes of apnea during sleep (Tatomir et al., 2007). There are three major types of sleep apnea: obstructive sleep apnea (OSA), the central type (CSA), and the mixed type, which includes features of both obstructive and central apnea. OSA is characterized by obstruction of the air flow determined by the occlusion of the oropharyngeal tract (Zoccali et al., 2001).

cues such as light and ambient temperature (Rosenthal, 1998). Melatonin, a physiologic sleep promoter, is inhibited by ambient light, and its circulation is decreased during daylight hours. The adrenal secretion of cortisol, which is associated with wakefulness, follows a circadian pattern. Regulated by the hypothalamic-pituitary axis, cortisol levels peak in the early morning hours in preparation for the increased metabolic demands during

Some medical illnesses, such as congestive heart failure (CHF), diabetes mellitus, chronic obstructive pulmonary disease and renal disease, can directly impair sleep physiology, leading to a cyclical interaction (Ballard, 2005). End-stage renal disease (ESRD) is one of these diseases. Approximately 50% of patients with chronic end-stage renal disease undergoing hemodialysis (HD) have insomnia and other sleep disorders (Hanly, 2007). Patients often complain of restless leg syndrome (RLS), periodic limb movement disorder (PLMD), bone pain, nausea, and pruritus (Merlino et al., 2006). The etiology of sleep disorders appears to be related to metabolic derangements associated with ESRD or from

Sleep complaints and sleep disorders are common in patients with end-stage renal disease. Although variable, their prevalence has been reported to be higher when compared to the general population (Merlino et al., 2006). The experiences of sleep alteration in ESRD patients have been studied. Interestingly, 80% of hemodialysis patients suffer from sleep abnormalities and the prevalence is higher than that in the general population (Gul et al., 2006). Holley et al. (1992) surveyed 70 dialysis patients, and reported sleep disturbance experienced mainly included trouble falling asleep (67%), nighttime waking (80%), early morning waking (72%), restless legs (83%), and jerking legs (28%). However, Walker et al. (1995) found daytime sleepiness was the most commonly reported problem (66.7%) followed by restless legs syndrome (57.4%). Generally, the most prominent sleep disorders among hemodialysis patients are sleep apnea syndrome, restless leg syndrome, periodic limb movement disorders, and insomnia (De Santo et al., 2005; Holley et al., 1992; Sabry et

The prevalence of sleep apnea syndrome in hemodialysis patients is at least 10 times higher (Kraus & Hamburger, 1997) than those values reported in the general population (Young et al., 1993). In another recent investigation, an apnea/hypopnea index higher than 5 was

Sleep apnea syndrome (SAS) is a major clinical disturbance defined as an intermittent interruption of air flow at the level of nose and mouth during sleep. These abnormalities cause frequent decreases in O**2** saturation and awakenings. Episodes of apnea are considered clinically significant if they persist for more than 10 s; however, apnea episodes may last up to 2 min. SAS is the clinical consequence of frequent (at least 10 events per hour) episodes of apnea during sleep (Tatomir et al., 2007). There are three major types of sleep apnea: obstructive sleep apnea (OSA), the central type (CSA), and the mixed type, which includes features of both obstructive and central apnea. OSA is characterized by obstruction of the air

found in 31% of the (young) non-diabetic HD patients studied (Rodriquez et al, 2005).

flow determined by the occlusion of the oropharyngeal tract (Zoccali et al., 2001).

wakefulness (Mahowald, & Schenk, 1989).

coexisting diabetes mellitus (Ballard, 2005).

al., 2010).

**2.1 Sleep apnea syndrome** 

**2. Sleep problems in hemodialysis patients** 

OSA occurs when the patient no longer has airflow but there is respiratory effort. CSA is determined by the transient abolition of nerve conduction to the respiratory muscles. Central apnea is defined when the patient has both cessation of airflow and the lack of respiratory effort followed by spontaneous resumption of breathing. Mixed apnea is the combination of central and obstructive apneas. All of these conditions can cause arterial oxygen desaturation and they may even be present in the same person (Tatomir et al., 2007; Zoccali et al., 2001). Researchers have speculated that the chronic metabolic acidosis suffered by patients with hemodialysis causes these sleep disorders; as the body attempts to correct the acidosis, the patient exhales more carbon dioxide and the hypocapnia that results may be inadequate to fuel respiration (Kimmel, 1989). Another theory is that these patients frequently have peripheral neuropathy, either from the ESRD or diabetes mellitus, and if the neuropathy affects the nerves innervating the upper airway, then SAS will occur (Fletcher, 1993). There is also evidence that SAS is associated with increased morbidity, and mortality, as the patient with ESRD who suffers with SAS is looking at a future with probable pulmonary hypertension and right heart failure, as well as a shortened lifespan (Fletcher, 1993; Parker, 1997). While, there are no ready answers for the causes of these sleep disorders seen in patients with ESRD undergoing HD, it is crucial that the health care provider be aware of the syndrome.

The awareness of SAS as a potent cardiovascular risk factor in ESRD undergoing HD has generated new enthusiasm in examining novel therapeutic strategies to modify sleep apnea in the patient population. To date, conservative non-pharmacological treatments (e.g. weight loss and avoidance of potentiating medications) have yielded limited success. Nasal continuous positive airway pressure therapy remains a mainstay of treatment of SAS in the non-ESRD population. Continuous positive airway pressure involves a mask fitting over the nose or mouth in which positive pressure is administered to the airway keeping the upper airway patent during sleep. In the general population, the treatment of sleep apnea with continuous positive airway pressure improves quality of life ( D'Ambrosio et al.,1999), vigilance, cognition, sexual performance, and normalizes nocturnal blood pressure profile (Faccenda et al., 2001). In the HD population, continuous positive airway pressure was used in a small study of eight patients with some improvement in nocturnal oxygenation, and five of six patients reporting improved daytime alertness (Pressman, 1993). Finally, given the contribution of uremia in the pathogenesis of SAS in ESRD, attempts in optimizing uremia control in the forms of nocturnal hemodialysis (NHD) and renal transplantation have shown early clinical success (Auckley et al, 1999;Hanly & Pierratos, 2001). It is tempting to speculate that similar to those with refractory hypertension, the treatment of sleep apnea in the HD population would improve their quality of life, augment rehabilitation, and perhaps impact on the poor survival of patients.

### **2.2 Restless Legs Syndrome**

Restless Legs Syndrome (RLS) is a neurological movement disorder that is common, underdiagnosed, under-treated, and has a poorly understood etiology (Patrick,2007). Restless legs syndrome (RLS) is a sensorimotor movement disorder characterized by the irresistible need to move associated with feelings of discomfort and parasthesias (International Restless Legs Syndrome Study Group, 2003). The incidence of idiopathic RLS (iRLS) varies between 5– 15% in the general population (Nicholas et al., 2003). In the HD population, the prevalence of secondary RLS may be greater, reported to be between 6–62% (Takaki et al., 2003;Unruh et al.,2004) with some geographic variability (Kavanagh et al., 2004). With employment of

Sleep in Patients with ESRD Undergoing Hemodialysis 411

information from case reports of significant symptom reduction in pediatric RLS using

Periodic limb movement disorder (PLMD) is a condition characterized by periodic episodes of repetitive and highly stereotyped limb movements that occur either during sleep (PLMS) or in wakefulness (PLMW) (Walker et al., 1995). This syndrome is more often seen in the patient with ESRD than in the general population (Pressman et al., 1995). The presence of PLMS is responsible for sleep problems in up to 72% of patients with ESRD (Benz et al., 2000) and the presence of PLMS is a more accurate predictor of mortality than coexisting diseases, serum albumin, or urea reduction ratio (Winkelman et al., 1996). A high correlation

Treatments with high-dose iron dextran and normalization of hematocrit with recombinant human erythropoietin have been demonstrated to improve RLPLMD in ESRD patients (Benz et al, 1999; Sloand et al., 2004). Alterations in dopamine and opioid synthesis may also play a role in the high prevalence of RLS and PLMD in uremia; however, data are limited. Indirect evidence stems from the notion that treatment with dopamine agonists, dopamine precursors in ESRD patients may improve RLS and PLMD symptoms (Sandyk et al.1987;

Insomnia is defined as a disorder of difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), and/or early morning awakening (EMA). Insomnia is commonly defined as the subjective sensation of short, unsatisfying sleep, despite the ability to sleep (Sabbatini et al., 2002). It may be secondary either to trouble falling asleep and/or to night‐time waking, which must be persistently present (i.e. three to four times a week for several weeks) ( Leger et al.,2002). The prevalence estimates of insomnia vary because of differences in definition, diagnosis, population characteristics, and research methodologies. Insomnia is a common sleep problem, however, and its prevalence in the general population ranges from 4% to 64% (Terzano et al., 2004; Chesson et al., 2000). The prevalence of insomnia is substantially greater in dialysis patients and has been reported to range from 45% to 59% (İliescu et al.,

Insomnia is characterized by one or more of the following symptoms: difficulty falling asleep ("sleep onset insomnia"), difficulty staying asleep ("sleep maintenance insomnia"), early awakening or poor sleep quality ("non-restorative sleep") (Ohayon et al., 2002; Meyer, 1998). Insomnia is primarily a clinical diagnosis and it is most frequently diagnosed from data obtained from the history and from sleep diaries. PSG is not indicated in the initial evaluation of insomnia but may be necessary in chronic treatment-resistant cases and in patients in whom

Insomnia may be caused by a variety of reasons, with the most frequent causes listed by researchers as: restless legs syndrome (RLS), periodic leg movements during sleep (PLMS), sleep apnea syndrome (SAS) and depression (Kimmel, 1989; Parker, 1997; Welch & Austin, 2001). The prevalence of insomnia due to RLS in dialysis patients ranges from 57% to 83% ( Holley et al., 1992; Sabbatini et al., 2002; Walker et al., 1995). Elderly patients, those with longer dialysis durations, dialysis shift, and those with high levels of parathyroid hormone (PTH) or diabetes mellitus are at higher risk of insomnia; however, the dialysis type and biochemical parameters are not important determinants of insomnia (Han et al., 2002; Sabbatini et al., 2002).

specific sleep disorders (SASRLSPLMS) are suspected (Bonner et al., 2008).

dopaminergic agents (Konofal et al.,2005)

**2.3 Periodic Limb Movement Disorder** 

Trenkwalder et al., 1995; Walker, 1996).

2003; İliescu et al., 2004; Sabbatini et al., 2002).

**2.4 Insomnia** 

between RLS and PLMS has also been noted (Allen et al. 2003).

standardized criteria by IRLSSG, this decreased to 12–48% (Siddiqui et al.,2005; Takaki et al, 2003;Unruh et al., 2004). RLS is observed more commonly in women than men, more commonly with increasing age and with co-morbid diabetes. Other potential correlates of RLS include lower socio-economic status, worse somatic and mental health and diabetes (Berger et al., 2004; Siddiqui et al.,2005). A high correlation between RLS and PLMS has also been noted (Allen et al. 2003, Liao et al.,2008).

The pathophysiology of RLS in uremia remains unknown however, several theories have been proposed. Potential risk factors include anemia, iron deficiency, dialysis vintage, calcium/phosphate imbalance, and peripheral and central nervous system abnormalities(Berger et al., 2004;Unruh et al.,2004).

Evidence for a possible relationship of iron deficiency to RLS in this patient population has been explained by the universal occurrence of anemia, which is commonly acquired in patients with end-stage renal disease due to inadequate production of erythropoietin (Gigli et al.,2004). Anemia in ESRD is associated with several co-morbid conditions, including congestive heart failure, stroke, cognitive dysfunction, left ventricular hypertrophy,and worsening iron deficiency due to loss from hemodialysis (Allen,2004; Gigli et al.,2004) Ferritin levels under 100 ng/mL reflect depletion of iron stores and complicate the treatment of anemia in patients on dialysis (Easom, 2006; Patrick ,2007)

Multiple causes of secondary RLS including iron deficiency anemia, diabetes mellitus, Parkinsons disease, pregnancy, rheumatic disease, venous insufficiency and less commonly in association with peripheral neuropathies, vitamin deficiencies, lumbosacral radiculopathy, spinal stenosis, excess caffeine intake, administration of some tricyclic antidepressants, hypoglycemia and hypothyroidism (Nichols et al.,2003; Siddiqui et al.,2005;Unruh et al.,2004). The revised IRLSSG criteria (Allen et al. 2003) for RLS included four essential diagnostic criteria additional supportive features. The criteria include unpleasant and uncomfortable sensations associated with an urge to move the limbs with symptoms worsened by rest, relieved by activity and typically worse toward the evening. Positive family history, initial therapeutic response to L-dopa or a dopamine-receptor agonist are supportive evidence. At least 85% of patients with RLS may also have concomitant periodic limb movements (PLMS) though this may be the result of other disorders such as obstructive sleep apnea.

Treatment of ESRD-associated anemia with erythropoietin has been shown to decrease arousal due to PLMS and produce trends toward higher sleep quality (Benz et al 2000). As will be reviewed later, intravenous (I.V.) iron in ESRD patients has been shown to be highly effective in causing remission of RLS symptoms (Sloand et al., 2004).

Given that alterations of the dopaminergic pathways may contribute to the development of RLS in ESRD, pharmacological treatment of RLS with Levodopa (L-DOPA) has been studied and was shown to improve sleep and reduce nocturnal limb movements in three prospective trials (Sandyk et al.1987; Trenkwalder et al., 1995; Walker, 1996). Recently, treatment with pergolide, a dopamine agonist was also examined in a double-blind placebocontrolled crossover study in ESRD patients (Pieta et al., 1998). In contrast to the use of L-DOPA, pergolide resulted in decreased symptoms without objective improvements in nocturnal limb movement or sleep architecture. Limited beneficial data regarding the use of other dopamine agonists have also been reported (Miranda et AL., 2004; Pellecchia et al., 2004). Folate is also involved in the production of dopamine in the CNS. Folate, as 5 methyltetrahydrofolate, increases production of CNS tetrahydrobiopterin, a cofactor in tyrosine hydroxylase production significant reduction in RLS symptoms and decreased leg movements during sleep (p=0.018). With the exception of this one trial, there is only limited information from case reports of significant symptom reduction in pediatric RLS using dopaminergic agents (Konofal et al.,2005)

### **2.3 Periodic Limb Movement Disorder**

Periodic limb movement disorder (PLMD) is a condition characterized by periodic episodes of repetitive and highly stereotyped limb movements that occur either during sleep (PLMS) or in wakefulness (PLMW) (Walker et al., 1995). This syndrome is more often seen in the patient with ESRD than in the general population (Pressman et al., 1995). The presence of PLMS is responsible for sleep problems in up to 72% of patients with ESRD (Benz et al., 2000) and the presence of PLMS is a more accurate predictor of mortality than coexisting diseases, serum albumin, or urea reduction ratio (Winkelman et al., 1996). A high correlation between RLS and PLMS has also been noted (Allen et al. 2003).

Treatments with high-dose iron dextran and normalization of hematocrit with recombinant human erythropoietin have been demonstrated to improve RLPLMD in ESRD patients (Benz et al, 1999; Sloand et al., 2004). Alterations in dopamine and opioid synthesis may also play a role in the high prevalence of RLS and PLMD in uremia; however, data are limited. Indirect evidence stems from the notion that treatment with dopamine agonists, dopamine precursors in ESRD patients may improve RLS and PLMD symptoms (Sandyk et al.1987; Trenkwalder et al., 1995; Walker, 1996).

### **2.4 Insomnia**

410 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

standardized criteria by IRLSSG, this decreased to 12–48% (Siddiqui et al.,2005; Takaki et al, 2003;Unruh et al., 2004). RLS is observed more commonly in women than men, more commonly with increasing age and with co-morbid diabetes. Other potential correlates of RLS include lower socio-economic status, worse somatic and mental health and diabetes (Berger et al., 2004; Siddiqui et al.,2005). A high correlation between RLS and PLMS has also

The pathophysiology of RLS in uremia remains unknown however, several theories have been proposed. Potential risk factors include anemia, iron deficiency, dialysis vintage, calcium/phosphate imbalance, and peripheral and central nervous system

Evidence for a possible relationship of iron deficiency to RLS in this patient population has been explained by the universal occurrence of anemia, which is commonly acquired in patients with end-stage renal disease due to inadequate production of erythropoietin (Gigli et al.,2004). Anemia in ESRD is associated with several co-morbid conditions, including congestive heart failure, stroke, cognitive dysfunction, left ventricular hypertrophy,and worsening iron deficiency due to loss from hemodialysis (Allen,2004; Gigli et al.,2004) Ferritin levels under 100 ng/mL reflect depletion of iron stores and complicate the treatment

Multiple causes of secondary RLS including iron deficiency anemia, diabetes mellitus, Parkinsons disease, pregnancy, rheumatic disease, venous insufficiency and less commonly in association with peripheral neuropathies, vitamin deficiencies, lumbosacral radiculopathy, spinal stenosis, excess caffeine intake, administration of some tricyclic antidepressants, hypoglycemia and hypothyroidism (Nichols et al.,2003; Siddiqui et al.,2005;Unruh et al.,2004). The revised IRLSSG criteria (Allen et al. 2003) for RLS included four essential diagnostic criteria additional supportive features. The criteria include unpleasant and uncomfortable sensations associated with an urge to move the limbs with symptoms worsened by rest, relieved by activity and typically worse toward the evening. Positive family history, initial therapeutic response to L-dopa or a dopamine-receptor agonist are supportive evidence. At least 85% of patients with RLS may also have concomitant periodic limb movements (PLMS)

though this may be the result of other disorders such as obstructive sleep apnea.

effective in causing remission of RLS symptoms (Sloand et al., 2004).

Treatment of ESRD-associated anemia with erythropoietin has been shown to decrease arousal due to PLMS and produce trends toward higher sleep quality (Benz et al 2000). As will be reviewed later, intravenous (I.V.) iron in ESRD patients has been shown to be highly

Given that alterations of the dopaminergic pathways may contribute to the development of RLS in ESRD, pharmacological treatment of RLS with Levodopa (L-DOPA) has been studied and was shown to improve sleep and reduce nocturnal limb movements in three prospective trials (Sandyk et al.1987; Trenkwalder et al., 1995; Walker, 1996). Recently, treatment with pergolide, a dopamine agonist was also examined in a double-blind placebocontrolled crossover study in ESRD patients (Pieta et al., 1998). In contrast to the use of L-DOPA, pergolide resulted in decreased symptoms without objective improvements in nocturnal limb movement or sleep architecture. Limited beneficial data regarding the use of other dopamine agonists have also been reported (Miranda et AL., 2004; Pellecchia et al., 2004). Folate is also involved in the production of dopamine in the CNS. Folate, as 5 methyltetrahydrofolate, increases production of CNS tetrahydrobiopterin, a cofactor in tyrosine hydroxylase production significant reduction in RLS symptoms and decreased leg movements during sleep (p=0.018). With the exception of this one trial, there is only limited

been noted (Allen et al. 2003, Liao et al.,2008).

abnormalities(Berger et al., 2004;Unruh et al.,2004).

of anemia in patients on dialysis (Easom, 2006; Patrick ,2007)

Insomnia is defined as a disorder of difficulty initiating sleep (DIS), difficulty maintaining sleep (DMS), and/or early morning awakening (EMA). Insomnia is commonly defined as the subjective sensation of short, unsatisfying sleep, despite the ability to sleep (Sabbatini et al., 2002). It may be secondary either to trouble falling asleep and/or to night‐time waking, which must be persistently present (i.e. three to four times a week for several weeks) ( Leger et al.,2002). The prevalence estimates of insomnia vary because of differences in definition, diagnosis, population characteristics, and research methodologies. Insomnia is a common sleep problem, however, and its prevalence in the general population ranges from 4% to 64% (Terzano et al., 2004; Chesson et al., 2000). The prevalence of insomnia is substantially greater in dialysis patients and has been reported to range from 45% to 59% (İliescu et al., 2003; İliescu et al., 2004; Sabbatini et al., 2002).

Insomnia is characterized by one or more of the following symptoms: difficulty falling asleep ("sleep onset insomnia"), difficulty staying asleep ("sleep maintenance insomnia"), early awakening or poor sleep quality ("non-restorative sleep") (Ohayon et al., 2002; Meyer, 1998). Insomnia is primarily a clinical diagnosis and it is most frequently diagnosed from data obtained from the history and from sleep diaries. PSG is not indicated in the initial evaluation of insomnia but may be necessary in chronic treatment-resistant cases and in patients in whom specific sleep disorders (SASRLSPLMS) are suspected (Bonner et al., 2008).

Insomnia may be caused by a variety of reasons, with the most frequent causes listed by researchers as: restless legs syndrome (RLS), periodic leg movements during sleep (PLMS), sleep apnea syndrome (SAS) and depression (Kimmel, 1989; Parker, 1997; Welch & Austin, 2001). The prevalence of insomnia due to RLS in dialysis patients ranges from 57% to 83% ( Holley et al., 1992; Sabbatini et al., 2002; Walker et al., 1995). Elderly patients, those with longer dialysis durations, dialysis shift, and those with high levels of parathyroid hormone (PTH) or diabetes mellitus are at higher risk of insomnia; however, the dialysis type and biochemical parameters are not important determinants of insomnia (Han et al., 2002; Sabbatini et al., 2002).

Sleep in Patients with ESRD Undergoing Hemodialysis 413

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

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

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

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

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

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

disturbances (Katz & McHorney 1998; Sabbatini et al., 2002; Thase, 2005).

upper airway obstruction (Chiu et al., 2006).

**3.3 Dialysis shift** 

**3.4 Dialysis vintage** 

syndrome.

dialysis shifts (Parker et al., 2003).

**3.5 Restless legs syndrome** 

sleep and lower quality of life.

**3.6 Other medical factors** 

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 in maintenance hemodialysis patients.

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 cost in chronic insomniacs.
