Sleep disorders in end-stage renal disease: Markers of inadequate dialysis?

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1 & 2006 International Society of Nephrology Sleep disorders in end-stage renal disease: Markers of inadequate dialysis? J Perl 1, ML Unruh 2 and CT Chan 1 1 Division of Nephrology, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada and 2 Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA Excessive daytime sleepiness and sleep disorders, including sleep apnea syndrome, restless legs syndrome, and periodic limb movement disorder, occur with increased frequency in patients with end-stage renal disease (ESRD). The detection and management of sleep disorders in ESRD patients is often challenging but may have significant clinical benefits. Some of the poor quality of life in ESRD may be attributed to the presence of concomitant sleep disorders, yet the classical symptoms of sleep disorders (poor concentration, daytime sleepiness, and insomnia) are often ascribed to the uremic syndrome itself. Conventional risk factors and screening tools used in the diagnosis of sleep disorders seem to have limited applicability in dialysis patients implicating the unique pathophysiology of sleep disorders in ESRD. Emerging evidence suggests that sleep apnea may contribute to the augmented cardiovascular event rates and to the accelerated development of atherosclerosis in ESRD. Whether treatment of sleep disorders in ESRD patients can affect the high morbidity and mortality of ESRD patients has yet to be elucidated. To date, conventional renal replacement therapies do not appear to have a significant impact on the treatment of sleep disorders in ESRD. The promising therapeutic effects of optimal uremia control in the forms of nocturnal hemodialysis and renal transplantation on sleep disorders require further mechanistic and clinical studies. Kidney International (2006) 70, doi: /sj.ki ; published online 13 September 2006 KEYWORDS: end-stage renal disease; sleep disorders; sleep apnea; restless leg syndrome; nocturnal hemodialysis; renal transplantation Correspondence: CT Chan, Division of Nephrology, University Health Network, Toronto General Hospital, 200 Elizabeth Street, 8N Room 842, Toronto, Ontario, Canada M5G 2C4. christopher.chan@uhn.on.ca Received 30 March 2006; revised 6 June 2006; accepted 11 July 2006; published online 13 September 2006 The purpose of the present is to examine the interactions between end-stage renal disease (ESRD) and sleep disorders. We will summarize the present knowledge on the epidemiology, pathogenesis, clinical sequelae, and treatment options for these specific uremia-associated sleep disorders. We speculate that uremia is critical in the development of sleep disorders in ESRD and that manipulation of uremia control represents a promising therapeutic approach. DAYTIME SLEEPINESS IS PREVALENT IN UREMIA ASSOCIATED SLEEP DISORDERS Sleep complaints are highly prevalent in ESRD patients with sleep disorders. Subjective assessments using standardized questionnaires have demonstrated a prevalence of daytime sleepiness in 52 67% of patients with ESRD. 1,2 Intriguingly, in addition to the high rate of excessive daytime sleepiness (EDS), up to 50% of ESRD patients complained of concomitant insomnia compared to 12% in control subjects. 3 Diagnosis of daytime sleepiness may be made by selfreport questionnaires. Although standardized questionnaires have been used widely in the non-esrd population, these instruments have not been well validated in ESRD patients. In a study by Unruh et al., 4 two commonly used sleep questionnaires: the Epworth Sleepiness Scale and the Sleep Problems Index were administered to control subjects and ESRD patients. The Epworth Sleepiness Scale provides a measure of daytime sleepiness and the Sleep Problems Index aims to assess sleep quality. Although the Epworth Sleepiness Scale scores were not significantly different between the two groups, the Sleep Problems Index scores demonstrated impaired subjective sleep quality in ESRD patients compared to control subjects. These results highlight the complexity of sleep complaints in the ESRD population and illustrate some of the limitations of subjective testing in detecting the presence of poor sleep quality and a potential underlying sleep disorder. Comprehensive screening for sleep disorders and complaints in the ESRD population should therefore require the use of validated objective testing. Multiple sleep latency test (MSLT) is an objective, validated measure of daytime sleepiness. 5 7 MSLT is typically performed following a sleep study, where a patient is asked to take five naps throughout the day. Sleep latency is defined as Kidney International (2006) 70,

2 J Perl et al.: Sleep disorders in ESRD the time from lights out to the onset of sleep. A sleep latency of less than 5 min is considered to be pathological sleepiness. 7,8 Three studies have reported on the results of MSLT among ESRD patients. 1,9,10 Although all studies document a high prevalence of abnormal MSLT in ESRD patients, some disparity exists in the severity and associated risk factors of daytime sleepiness. Stepanski et al. 1 evaluated 18 peritoneal dialysis patients with sleep complaints. As a whole, the cohort s MSLT was min. Of interest, patients with co-existing sleep apnea were found to have lower MSLT of min. In another study, 24 consecutive ESRD patients were studied. 9 The MSLT was abnormal in 50% of patients and was directly associated with plasma urea concentrations and the frequency of periodic limb movements but not to the presence of apnea. In comparison, Parker et al. 10 studied 46 ESRD patients and found that 13% had abnormal MSLT whereas 33% had mildly abnormal MSLT (5 10 min). Intriguingly, these investigators also reported that 48% of the studied population had at least one sleep-onset rapid eye movement sleep during the five MSLT nap opportunities. In addition, the number of sleep-onset rapid eye movements was negatively related to MSLT scores. 10 It is important to note that this study excluded those ESRD patients thought to have sleep disorders and therefore the somewhat divergent findings may reflect the different populations. In contrast to previous study, MSLT did not correlate with the degree of apnea. One explanation for the EDS in ESRD is the notion of day/night sleep reversal, which has often been cited as a cardinal feature of uremia Multiple hypotheses have been proposed to account for uremia-induced daytime sleepiness including (1) subclinical uremic encephalopathy, 15 (2) abnormal metabolism and retention of melatonin, 16 (3) tyrosine deficiency leading to diminished neurotransmitters associated with arousal, 17 (4) alteration in body temperature rhythm resulting in a perturbation of the sleep-wakefulness cycle, 18 (5) release of sleep-inducing inflammatory cytokines during dialysis, 19,20 (6) the effects of dialysate temperature on sleep, 18 and (7) co-existent sleep apnea syndrome (SAS). 11 EDS and sleep complaints are common in ESRD patients with or without sleep disorders. 4 The pathogenesis of daytime sleepiness is likely multifactorial and may be common to a number of the uremia-associated sleep disorders. 14 At present, multiple proposed mechanisms have been hypothesized for the development of EDS. Moreover, daytime sleepiness may contribute to the poor vocational and rehabilitation potential traditionally associated with ESRD. 21 A mechanistic analysis of the biology underlying the development of day/night reversal and EDS will likely enhance our understanding of uremia-associated sleep disorders. SLEEP DISORDERED BREATHING IN ESRD The SAS is characterized by repetitive cessation of respiration during sleep resulting in oxygen desaturation and arousal. A definitive diagnosis is made by overnight polysomnography (PSG). However, because of significant night to night variability, a repeat PSG may be required in the setting of one normal study if a high index of suspicion is present. 22 An apnea is defined as the absence of airflow for 10 s or greater. If apnea is accompanied by evidence of continued respiratory effort, it is defined as obstructive apnea. In contrast, if there is no evidence of respiratory effort during apnea, it is termed central apnea. Apneas may also be classified as mixed if respiratory effort is present, but delayed. A hypopneic episode occurs when airflow decreases by 50% for 10 s or decreases by 30% if there is an associated decrease in the oxygen saturation or an arousal from sleep. 23 The apnea - hypopnea index (AHI) is determined by the total number of apneas and hypopneas during sleep divided by the total number of hours of sleep. An AHI of 5 15 is considered mild apnea. An AHI of is usually categorized as moderate apnea. An AHI of greater than 30 is classified as severe apnea. Another commonly used parameter is the respiratory disturbance index. The respiratory disturbance index also includes those respiratory events which result in arousal and is also used in certain diagnostic criteria. 24 PREVALENCE AND CLINICAL FEATURES OF SLEEP APNEA IN ESRD The prevalence of SAS in the middle-aged, general population has been reported to be 2 4%. 25 In contrast, studies in the dialysis population using survey questionnaires and overnight PSG have demonstrated a prevalence rate of greater than 50%. 1,26 29 Co-morbid conditions such as cardiovascular disease, diabetes mellitus, and obesity coupled with selection bias in these studies may explain in part the high prevalence of SAS in ESRD. In comparison to the non-esrd population, several clinical features are thought to be unique to the SAS in ESRD. In the general population, obstructive sleep apnea is the predominant phenotype. In contrast, SAS seen in ESRD patients has been characterized by varying degrees of obstructive, mixed, and central sleep apnea Also in contrast to the general population, higher body mass index and male sex are not consistently associated with SAS in ESRD patients. 1,28,33,34 The lack of association between SAS and usual risk factors may in part reflect the limitations of previous studies of ESRD patients. Previous studies have been small and may suffer from a lack of power to detect an association of SAS with conventional risk factors. In addition, the classical symptoms of sleep apnea such as snoring are less commonly encountered in apneic ESRD patients. 33,34 Taken together, the clinical presentation of SAS in ESRD presents a difficult diagnostic and therapeutic challenge. PATHOPHYSIOLOGY OF SLEEP APNEA IN UREMIA Although the pathogenesis of SAS in ESRD requires further elucidation, several uremic risk factors have been proposed. From a simplistic viewpoint, uremia may exacerbate sleep apnea in ESRD by accumulation of uremic toxins, by volume 1688 Kidney International (2006) 70,

3 J Perl et al.: Sleep disorders in ESRD overload, or both. Suggestion that the accumulation of toxic products and the altered biochemical milieu may contribute to uremia-related sleep disorders stems from the observation that infusion with branched chain amino acids has been associated with (1) a return of rapid eye movement (REM) sleep to normal and (2) a significant decrease in end-tidal carbon dioxide during both REM and non-rem sleep. 35 It is particularly interesting to note that respiratory stimulation via alteration in biochemical milieu in ESRD patient is uniquely associated with an increased amount of REM sleep in contrast to other therapeutic attempts. This observation is consistent with the working hypothesis that improvement with uremia clearance may be associated with changes in the sleep architecture in ESRD patients. The notion that sleep apnea in ESRD is composed of an even distribution of the obstructive, central, and mixed types, implies that both upper airway occlusion and destabilization of central ventilatory control play key roles in the pathogenesis of SAS in ESRD. Respiratory drive during sleep operates under chemoreflex control. Hypocapnia resulting from respiratory adaptation to chronic metabolic acidosis or to the uremic state itself may be central to the development of SAS in ESRD. As a result, it was proposed that ESRD patients with SAS may have an altered chemoresponsiveness. Recently, chemoreceptor activity was studied by Beecroft et al. 36 In 49 ESRD patients, central and peripheral chemoresponsiveness was measured under isoxic hypoxia and hyperoxia conditions. These investigators found that basal ventilation was similar in all subjects. However, patients with SAS were found to have a higher ventilatory threshold and a higher sensitivity to hypercapnia. These results suggest that sensitivities of both central and peripheral chemoreceptors are increased in patients with SAS and ESRD leading to destabilization of respiratory control during sleep. Although alteration in chemosensitivity during sleep may largely explain the development of SAS in ESRD, other factors compromising upper airway patency in ESRD may also contribute to sleep apnea in uremic patients. These include extracellular fluid volume overload leading to upper airway edema and reduced upper airway muscle tone as a consequence of uremic neuropathy. 11,37 CLINICAL IMPLICATIONS OF SAS IN ESRD Sleep apnea is characterized by repetitive cycles of apnea, hypoxia, hypercapnia, and arousal. 38,39 Subjects with upper airway obstruction endure, in addition, sudden and profound changes in cardiac loading conditions, secondary to the abrupt generation of negative intra-thoracic pressure. Acutely, each of these stimuli acts independently to trigger central sympathetic outflow to the heart and periphery. The gas exchange abnormalities, sleep fragmentation, and autonomic activation have all been implicated as causes of the substantial adverse health effects attributed to SAS. 40 Because sleep disturbance leads to daytime sleepiness and decreased mental acuity, disturbed sleep may lead to decreased quality of life, 41 impaired cognitive ability, 42 poor vocational abilities, and increased illness intrusiveness. 28,43 From a cardiovascular point of view, SAS is linked with the development of hypertension, accelerated atherosclerosis, heart failure, and ischemic strokes in the general population Given that cardiovascular mortality remains the leading cause of death in ESRD, further characterization of SAS in ESRD as a cardiovascular risk factor is of great clinical interest. 50 Normal non-rem sleep is characterized by reductions in metabolic rate, sympathetic nervous system activity, heart rate, cardiac output, and total peripheral resistance. Vagal tone increases. This normal autonomic balance is disturbed in patients with ESRD, especially in those with coexistent SAS. 51 Vagal modulation of heart rate is attenuated, and sympathetic modulation predominates. Increased cardiac and peripheral adrenergic drive may help explain why sleep apnea and nocturnal hypoxemia have been associated with left ventricular hypertrophy, 52 hypertension, 53 and increased cardiovascular events in the chronic heart disease (CHD) population. 54 In addition to the neurohormonal hypothesis of SAS, recent literature has linked nocturnal hypoxemia with elevated oxidative stress and coronary calcification in CHD patients. Jung et al. 55 studied 26 CHD patients and documented their overnight PSG, spiral computed tomography-derived coronary artery calcification scores, and predialysis serum total antioxidant status. These investigators demonstrated an association between AHI and coronary calcification scores. Furthermore, the oxygen desaturation index, a marker of nocturnal hypoxemia was negatively correlated with total antioxidant status. The authors propose that nocturnal hypoxemia followed by reoxygenation may lead to free radical generation facilitating the process of coronary calcification. The awareness of SAS as a potent cardiovascular risk factor in ESRD has generated new enthusiasm in examining novel therapeutic strategies to modify sleep apnea in our 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, 56 vigilance, cognition, sexual performance, and normalizes nocturnal blood pressure profile. 57 In the ESRD 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. 31 Finally, given the contribution of uremia in the pathogenesis of SAS in ESRD, attempts in optimizing uremia control in the forms of nocturnal Kidney International (2006) 70,

4 J Perl et al.: Sleep disorders in ESRD hemodialysis (NHD) and renal transplantation have shown early clinical success. 32,58,59 It is tempting to speculate that similar to those with refractory hypertension, the treatment of sleep apnea in the ESRD population would improve their quality of life, augment rehabilitation, and perhaps impact on the poor survival of our patients. RESTLESS LEGS SYNDROME AND PERIODIC LEG MOVEMENTS OF SLEEP Restless legs syndrome (RLS) is a sensorimotor movement disorder characterized by the irresistible need to move associated with feelings of discomfort and parasthesias. In contrast, periodic limb movement disorder (PLMD) are sudden, repetitive, and highly stereotyped jerking leg movements occurring during sleep. PLMD are identified during sleep laboratory investigations. RLS is a diagnosis based on history with standardized clinical criteria. 60,61 (Table 1). Although both primary and secondary forms of RLS and PLMD exist, our discussion will be limited to secondary forms of RLS and PLMD as a consequence of uremia and/or concomitant iron deficiency. PREVALENCE AND CLINICAL FEATURES OF RLS IN ESRD In the general population, the prevalence of RLS has been demonstrated to be between 5 and 15% with approximately 80% of patients with RLS also having PLMD. 62,63 RLS have been associated with poor quality of life, neuropsychiatric symptoms, diminished cognition, and poor attention in both dialysis patients and the general population. 43,62 66 Defining the prevalence of RLS in both the ESRD and general population has been challenging as studies have been limited by small sample size and differing diagnostic criteria used. Similar to the unique clinical features of SAS in ESRD, established non-uremic risk factors such as age and gender are not often associated with the development of RLS in uremia. In addition, pharmacological co-interventions may also affect prevalence rates of RLS and PLMD. As a result, the reported prevalence of this syndrome in uremia has ranged between 6.6 and 83%. 2,3,64,67 70 PATHOPHYSIOLOGY OF RLS/PLMD IN ESRD The pathophysiology of RLS and PLMD 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. 71 As iron is a cofactor of dopamine production in the niagrostriatal areas of the brain, iron deficiency has long been associated with the development of RLS in the general population In contrast, the role of anemia and iron deficiency in the development of RLS in uremic patients have been conflicting with only some studies indicating an inverse association between iron deficiency and increasing risk of developing RLS. 67,69,76 Treatments with high-dose iron dextran and normalization of hematocrit with recombinant human erythropoietin have been demonstrated to improve RLS/PLMD in ESRD patients. 77,78 In the SLEEPO study, normalization of the hematocrit was achieved with both (recombinant human erythropoietin) and concomitant increases in the dose of iron. It is therefore difficult to attribute the observed beneficial effects solely to the use of recombinant human erythropoietin. 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 DRUG THERAPY OF RLS 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 Recently, treatment with pergolide, a dopamine agonist was also examined in a double-blind placebo-controlled crossover study in ESRD patients. 83 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. 84,85 (Table 2) RLS/PLMD AND MORTALITY IN ESRD In addition to diminished quality of life, RLS has been associated with increased mortality in ESRD patients. Among incident CHD and peritoneal dialysis patients from the CHOICE cohort, severe symptoms of restless legs was associated with shorter survival with a hazard ratio of 1.39 (95% confidence interval: ). 62 Other observational data reported by Benz et al. 86 demonstrated higher mortality in 29 CHD patients affected by PLMD. Although the actual Table 1 The International RLS Study Group criteria a An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs. The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity, such as lying or sitting. The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, for at least as long as the activity continues. The urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night. RLS, restless legs syndrome. a All four criteria are required for the diagnosis of restless legs syndrome Kidney International (2006) 70,

5 J Perl et al.: Sleep disorders in ESRD Table 2 Stepwise therapeutic approach to RLS in dialysis patients 1. History and physical examination to exclude and treat non-uremia secondary causes of RLS. 2. Assess severity using standardized instruments: International Restless Legs Syndrome Study Group severity scale. 3. If patient complains of mild to moderate RLS, consider the use of non-pharmacological treatments. Mental alerting activities. Trial of caffeine, nicotine, and alcohol abstinence. Eliminate aggravating medications (e.g., anti-depressants). Consider change of dialysis time, dialysis modality or frequency. 4. Stepwise use of drug therapy. Dopamine agonist (on dialysis days). If unsuccessful consider an alternate dopamine agonist. If symptoms persist consider L-DOPA. If symptoms persist consider adjunct therapy: gabapentin. RLS, restless leg syndrome. mechanism underlying the heightened mortality in our patient population with RLS and PLMD remains unknown, potential contributors may include poor compliance with hemodialysis and sympathetic overactivity secondary to sleep fragmentation and recurrent arousals from sleep. RENAL REPLACEMENT THERAPY AND SLEEP DISORDERS IN ESRD Conventional renal replacement does not correct sleep disorders in ESRD Conventional renal replacement strategies (CHD and peritoneal dialysis) have not been shown to correct SAS associated with ESRD. 1,28,29 To date, the prevalence of sleep apnea is similar in ESRD patients receiving either conventional modalities. 1,28,29 In addition, both CHD and peritoneal dialysis have been postulated to alter sleep quality and have potential effects on the mechanics of respiration. Several reports have suggested that CHD is associated with the release and production of sleep-inducing cytokines during dialysis. 19,20 Other authors have postulated that the mechanical effects of peritoneal fluid on diaphragmatic excursion may decrease total lung capacity, thereby contributing to ventilatory instability. 26 Similarly, consistent but limited data also indicate that conventional renal replacement therapies do not have any impact on RLS/PLMD in ESRD. 3,71 Taken together, it is reasonable to conclude that the present target of uremia control remains ineffective for the treatment of EDS, SAS, and RLS in ESRD. OPTIMAL UREMIA CONTROL CORRECTS SLEEP DISORDERS IN ESRD Nocturnal hemodialysis Given that uremia may be directly related to the development of SAS in our patient population, it is reasonable to hypothesize that intensifying uremia control will ameliorate sleep disorders in ESRD. Hanly and Pierratos 32 showed that NHD was able to correct SAS in ESRD. These investigators studied 14 CHD patients before and after conversion to NHD with overnight PSG. They found a significant reduction in the severity of sleep apnea in all patients (AHI fell from to 878 per hour; Po0.05). The effects of NHD were even more dramatic in those patients with severe sleep apnea as AHI fell from to 9715 per hour; Po0.05. Similarly, nocturnal hypoxemia was corrected with conversion to NHD. However, total night time arousals remained elevated in NHD patients. As nocturnal hypoxemia is related to sympathetic overactivity in ESRD, it is reasonable to propose that correction of SAS with NHD should accompany an improvement in the autonomic modulation of heart rate during sleep. To this aim, Chan et al. 87 studied nine ESRD patients before and after conversion to NHD and 10 control subjects. Power spectral analysis of heart rate variability was applied to test the hypothesis that NHD would lower sympathetic modulation of heart rate during sleep. AHI, nocturnal hypoxemia, and relative risk interval were significantly higher in ESRD patients when receiving CHD than in healthy controls. After conversion to NHD, there was a decrease in the frequency of apnea and hypopnea, a reduction in the extent of hypoxemia, and a fall in heart rate during sleep. Of specific interest, the low frequency/high frequency ratio (a marker of sympathetic to vagal balance) which was significantly higher in ESRD patients receiving CHD than in control subjects ( vs ; Po0.05) returned to control values ( , Po0.05 compared with CHD) after conversion to NHD. The results from this study add to the body of evidence that uremia-related sleep apnea with oxygen desaturation is a potent stimulus to cardiac adrenergic drive, and are consistent with the concept that the combination of improved uremic clearance and lessened nocturnal hypoxemia decreases cardiac sympathetic drive. Although NHD has been shown to dramatically correct SAS in ESRD patients, its therapeutic effect on daytime sleepiness and PLMD is not as definitive. Hanly et al. 9 studied 24 unselected CHD patients. Of the study cohort, 15 patients were subsequently trained on NHD. Although there was a direct association between uremia control (as indicated by plasma urea concentration) and MSLT, this group of investigators did not find a significant improvement in daytime sleepiness after conversion to NHD in the short term. Further studies are required to understand the influence of uremia control on daytime sleepiness over time. RENAL TRANSPLANTATION Although there is limited published data regarding the effect of renal transplantation on sleep disorders in ESRD, a consistent trend was found indicating that optimizing uremia control is associated with an improvement or correction of uremia associated sleep disorders. Observational cohort studies suggest that RLS improves after renal transplantation. 88 Additionally, there is a direct association between allograft function and RLS severity. 89 Finally, case report data have shown resolution of SAS after renal transplantation. 58,59 Kidney International (2006) 70,

6 J Perl et al.: Sleep disorders in ESRD Therapeutic and diagnostic challenges of sleep disorders in dialysis patients Diagnostic challenges Screen for sleep apnea, excessive daytime sleepiness, PLMD, RLS Research on treatment efficacy Kidney transplantation Nocturnal hemodialysis Use of CPAP Use of drug therapy Treatment goals Improved daytime functioning and QOL Improved cardiovascular outcomes Figure 1 Therapeutic and diagnostic challenges of sleep disorders in dialysis patients. CONCLUSION AND PERSPECTIVES ESRD patients have a high prevalence of sleep disorders. Recognition of the presence of sleep disorders in our patient population is often complicated by the presence of comorbid illness and/or the uremic syndrome itself. Standard sleep questionnaires have limited applicability in screening or diagnosing ESRD patients with sleep disorders. Novel screening tools or further refinement and validation of existing diagnostic techniques are therefore needed. Emerging evidence suggests that nocturnal hypoxemia and the SAS are novel cardiovascular risk factors in ESRD. Understanding of the increased morbidity and mortality of sleep disorders in ESRD continues to evolve and requires further characterization. Manipulation of uremia control and its influence on sleep disorders will likely redefine our therapeutic target for renal replacement therapy in the future. (Figure 1). REFERENCES 1. Stepanski E, Faber M, Zorick F et al. Sleep disorders in patients on continuous ambulatory peritoneal dialysis. J Am Soc Nephrol 1995; 6: Walker S, Fine A, Kryger MH. Sleep complaints are common in a dialysis unit. Am J Kidney Dis 1995; 26: Holley JL, Nespor S, Rault R. A comparison of reported sleep disorders in patients on chronic hemodialysis and continuous peritoneal dialysis. Am J Kidney Dis 1992; 19: Unruh ML, Hartunian MG, Chapman MM et al. Sleep quality and clinical correlates in patients on maintenance dialysis. 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