**1. Introduction**

406 Progress in Hemodialysis – From Emergent Biotechnology to Clinical Practice

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Sleep has been identified as an essential human need; this is partly because of the metabolic activities that occur while the individual is sleeping. Normal sleep is divided into non–rapid eye movement (NREM) and rapid eye movement (REM) sleep. NREM sleep comprises 75% to 80% of total sleep time (TST), and is characterized by relatively quiescent brain activity and decreased metabolic rate (Carskadon & Dement, 2000). NREM sleep consists of four stages (S1-S4), with each stage leading to a progressively deeper sleep. REM sleep follows slow wave sleep (SWS), or deep sleep, and increases over the night, comprising 20% to 25% of TST. REM sleep is characterized by an activated EEG pattern, muscle atonia, and episodic bursts of rapid eye movements. Normal sleep provides a period of physiologic and mental rest. During sleep, sympathetic tone decreases and parasympathetic tone increases, leading to a reduction in heart rate, arterial blood pressure, and cardiac output (Rosenthal, 1998). Deep sleep is theorized to be necessary for physiologic restoration. REM sleep is associated with dreaming, and is essential for maintaining emotional and cognitive well-being (Redline et al., 2004).

Waking and consciousness depend on the activity, of neurons in the ascending reticular activating system of the brainstem. These neurons project into the thalamus, hypothalamus and basal forebrain and eventually send projections to the cortex. There are particular neurotransmitters, such as the catecholamines, acetylcholine, histamine, glutamate and aspartate, that are localized within the reticular formation and have important roles in cortical activation and arousal (Jones, 1989). Sleep-promoting neurotransmitters include gamma aminobutyric acid (GABA), adenosine, and melatonin. Specific stages of sleep are regulated by the turning "on" and "off" of various neurons. REM "on" cells use GABA, acetylcholine, and glutamine, whereas REM "off" cells use norepinephrine and serotonin." REM On cells" are cholinergic cells in the lateral pontine and medial medullary reticular areas that innervate the thalamus, hippocampus and hypothalamus. These cells discharge at high rates during REM and show little or no activity during NREM."REM Off cells" are noradrenergic and serotonergic cells found in the locus coeruleus and raphe. These are cells which are slow or silent during REM sleep. Affecting levels of norepinephirne or serotonin can have an effect on REM sleep (Hoyt, 2005).

Sleep regulation is a balance between a homeostatic sleep need and an intrinsic body clock, or circadian pacemaker. Located in the suprachiasmic nucleus, the circadian pacemaker determines the onset and termination of sleep, and is partially regulated by environmental

Sleep in Patients with ESRD Undergoing Hemodialysis 409

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

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

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

rehabilitation, and perhaps impact on the poor survival of patients.

aware of the syndrome.

**2.2 Restless Legs Syndrome** 

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 wakefulness (Mahowald, & Schenk, 1989).

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 coexisting diabetes mellitus (Ballard, 2005).
