Needs Assessment: Patients with chronic kidney disease represent a substantial and growing segment of the population. This group has a high rate of sleep complaints and has recently been shown to have a high prevalence of insomnia, sleep apnea, restless legs, and periodic limb movements.

Learning Objectives:
• Recognize the prevalence of sleep disorders among those with end-stage renal disease.
• Recognize the impact of sleep disorders on sleep quality, quality of life, and mood.
• Assess potential treatments of common sleep disorders.

Target Audience: Primary care physicians and psychiatrists.

CME Accreditation Statement: This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation: The Mount Sinai School of Medicine designates this educational activity for a maximum of 3 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement: It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or devices. This information will be available as part of the course material.

This activity has been peer-reviewed and approved by Eric Hollander, MD, chair and professor of psychiatry at the Mount Sinai School of Medicine, and Norman Sussman, MD, editor of Primary Psychiatry and professor of psychiatry at New York University School of Medicine. Review Date: November 5, 2007.

Drs. Hollander and Sussman report no affiliation with or financial interest in any organization that may pose a conflict of interest.

To receive credit for this activity: Read this article and the two CME-designated accompanying articles, reflect on the information presented, and then complete the CME posttest and evaluation. To obtain credits, you should score 70% or better. Early submission of this posttest is encouraged: please submit this posttest by January 1, 2010 to be eligible for credit. Release date: January 1, 2008. Termination date: January 31, 2010. The estimated time to complete all three articles and the posttest is 3 hours.

Dr. Unruh is assistant professor of medicine in the Renal-Electrolyte Division at the University of Pittsburgh School of Medicine in Pennsylvania.

Disclosure: Dr. Unruh is a consultant to Qualitymetric and receives grant support from the National Institute of Health, the National Kidney Foundation, and the Paul Teschan Research Fund.

Please direct all correspondence to: Mark Unruh, MD, MSc, Assistant Professor of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, A915 Scaife Hall, 3550 Terrace St, Pittsburgh, PA 15261; Tel: 412-647-2571; Fax: 412-647-6891; E-mail: unruhm@dom.pitt.edu.

 


 

Abstract

In the chronic kidney disease (CKD) population, problems with sleep have been linked to disability days, healthcare utilization, and quality of life (QOL) for dialysis patients. The health burden associated with sleep disturbances is significant. Studies in the general population have linked these problems to greater use of health services, increased use of hypnotics, and reduced functional capabilities. The need to address sleep quality in the CKD population is highlighted by the 15% to 31% prevalence of hypnotic use. Among incident dialysis patients, patients with poor sleep quality were more likely to report poor physical and mental well being, decreased vitality, and more bodily pain. While there are many causes for poor sleep in patients with kidney disease, such as depression, insomnia, restless legs, and periodic limb movements, sleep apnea may be the most common. A significant percentage of end-stage renal disease  patients report hypersomnolence, snoring, and even witnessed apneas. Those undergoing thrice-weekly hemodialysis have been shown to have a high rate of sleep apnea, insomnia, restless legs syndrome, and excessive daytime sleepiness. In the general population, sleep disorders such as sleep apnea have been associated with premature death, cardiovascular disease, depression, and poor QOL. Emerging evidence suggests that sleep disorders may contribute to the high rates of medical and psychological comorbidity in CKD patients. The diagnosis and treatment of sleep disorders among this high-risk population remains understudied. The recommendations for therapy have been largely based on findings in the general population since studies of the CKD population have been limited in scope.

 

Introduction

Patients with kidney failure have a high rate of sleep apnea, insomnia, restless legs syndrome (RLS), and excessive daytime sleepiness.1-3 Kidney failure, or end-stage renal disease (ESRD), has been defined as having the kidney function <15 ml/minute/1.73 m2. It is associated with the inability to excrete waste products, control serum electrolytes, handle the daily dietary and metabolic acid load, and maintain fluid balance. In addition, kidney failure causes inadequate production of erythropoietin, deranged calcium and phosphorous metabolism, difficulties with high blood pressure, and accelerated progression of cardiovascular disease. In parts of the world with access to dialysis and kidney transplantation (KTx), renal replacement therapy (RRT) has been thought to be necessary when the glomerular filtration rate (GFR) decreases to <15 ml/minute. Chronic kidney disease (CKD), the term used to describe a chronic decrease in GFR, has different levels. Its prevalence is rapidly increasing worldwide, and the projections are that the number of patients with kidney failure will double in the next 10–15 years. Both sleep disorders and poor sleep quality have a negative impact on daytime symptoms of sleepiness and fatigue. Daytime sleepiness and fatigue are frequent and bothersome problems for the chronic dialysis population.4 One-hundred hemodialysis patients were surveyed regarding their willingness to perform hemodialysis more frequently. A increase in energy level (94%) and improvement in sleep (57%) were the most commonly cited potential benefits that would justify more frequent hemodialysis.5 This finding highlights the importance of sleepiness and fatigue in patients undergoing RRT. This article examines the association between kidney failure and sleep disorders, highlighting the impact of sleep disorders on health-related quality of life (HRQOL) and mood.

 

Poor Sleep Quality in End-stage Renal Disease

Self-reported sleep quality is the subjective integration of sleep disturbances and satisfaction with sleep. Studies of patients on maintenance hemodialysis have found that 50% to 80% of dialysis patients experience some sleep complaint or excessive daytime somnolence.6 The patient perception of sleep quality is important since there is neither a laboratory variable nor a polysomnography (PSG) finding that can serve as a surrogate for telling how patients feel about their sleep. Neuroimaging studies have suggested that patient self reports may reflect neurophysiologic findings a PSG does not measure.7 Furthermore, those with insomnia complaints can have PSG findings comparable to normal sleepers. Self-reported outcomes may be the most critical in patients with chronic illness, and the impact treatments have on patient perception of fatigue and sleepiness may be the most important factor in their management.5

The hemodialysis population’s sleep quality has been linked to disability days, healthcare utilization, and quality of life (QOL) for dialysis patients. The health burden associated with sleep disturbances is significant. Studies in the general population have linked these problems to greater use of health services, increased use of hypnotics, and reduced functional capabilities.8-10 The need to address sleep quality in the kidney failure population is underscored by the 15% to 31% prevalence of hypnotic use in a sample of dialysis patients.6,11 The use of hypnotics to treat sleep complaints has an economic cost and exposes patients to the medications’ side-effects. Among incident dialysis patients, those with poor sleep quality were more likely to report poor physical and mental well being, decreased vitality, and more bodily pain.11 In addition, incident hemodialysis patients with a clinically significant decline in self-reported sleep quality have been shown to have a higher risk of mortality.11 While this risk may reflect acquired sleep disorders, the impact of sleep problems on mood, or the treatment of sleep complaints, studies have demonstrated that sleep quality may be reliably measured and is clinically meaningful for patients receiving dialysis.5,6,11

The Figure advocates the approach to this high-risk group’s sleep disorders in which clinicians recognize sleep disorders using patient interviews and screening tests. The interventions used to treat sleep disorders are both graded by the severity of the complaint and tailored to this special population. Sleep disorder treatment in ESRD patients should emphasize behavioral interventions. In addition, physicians should consider the removal of aggravating medications when possible since ESRD patients take a median of eight to 10 prescription drugs daily. The response to treatment should be monitored with sensitive instruments, medical follow-ups, and assessments of the patient’s overall well being.

 

 

Insomnia Highly Prevalent in End-stage Renal Disease

Insomnia, which involves difficulty falling asleep, maintaining sleep, or waking early in the morning with associated daytime difficulties, is very common among patients with ESRD. Up to 75% of dialysis patients experience insomnia,1 but the possible connection between insomnia and RLS in this population has not been investigated. Trials of insomnia treatment for patients undergoing dialysis have not been comducted. However, several approaches could optimize sleep hygiene, screen for other sleep disorders, use a brief trial of cognitive-behavioral therapy and hypnotics, or consider a sleep study in patients that remain symptomatic. For those undergoing hemodialysis, it may be reasonable to move the shift to earlier in the day, consider thermoneutral hemodialysis, and ask the patient to avoid napping during treatments. Those using overnight peritoneal dialysis may need to adapt their regimen to avoid both frequent alarms and abdominal discomfort. Numerous studies suggest that the timing of hemodialysis treatments may impact the severity of restless legs, cardiovascular risk, and survival.12,13 Parker and colleagues14 have shown that sleep propensity increases during coronary heart disease treatments, an effect they suggest may be related to treatment-induced alterations in arousal and/or thermoregulatory processes. Overnight dialysis may change daytime experience with respect to sleep, uremia, and free time for rest and activity.

 

High Rates of Sleep Apnea in End-stage Renal Disease May Contribute to Morbidity

Sleep apnea leads to repetitive episodes of hypoxemia, hypercapnia, sleep disruption, and sympathetic nervous system activation. Sleep apnea can be obstructive if respiratory effort persists during upper airway occlusion, central if both respiratory effort and airflow cease, or a combination of the two. The most common metric for sleep apnea is the apnea-hypopnea index (AHI), which is the number of apneas and hypopneas in 1 hour of sleep. Sleep apnea causes gas exchange abnormalities, sleep fragmentation, and autonomic activation, all implicated causes of substantial adverse health effects.15 This disease commonly produces daytime sleepiness, decreased QOL, and impaired cognitive ability. In the general population, the treatment of sleep apnea with continuous positive airway pressure (CPAP) improves QOL, daytime symptoms, and blood pressure.16

Severe sleep apnea has a higher prevalence among dialysis patients than the general population. The prevalence of severe sleep apnea among a community-based sample of hemodialysis patients was four-fold higher than an age-, sex-, race-, and body mass index (BMI)-matched comparison group.17 Sleep apnea in ESRD is likely due to factors related to uremia and volume overload. In a community-based study of the general population, the risk factors for sleep apnea were obesity, male sex, and neck circumference.18 These risk factors have not been associated with sleep apnea among patients with ESRD,19 perhaps due in part to the small number of patients studied. In 49 ESRD patients, those with sleep apnea had a higher apneic threshold and a higher sensitivity to hypercapnia.20 These results suggest that central and peripheral chemoreceptor sensitivity is increased in patients with sleep apnea and ESRD, leading to destabilization of respiratory control during sleep. While alteration in chemosensitivity during sleep may explain the development of sleep apnea in ESRD patients, other factors such as extracellular fluid volume overload leading to upper airway edema21 and reduced upper airway muscle tone due to uremia compromising upper airway patency in ESRD22 likely contribute to the severity of sleep apnea in uremic patients. The contribution of uremia and volume overload to sleep apnea pathogenesis in ESRD patients has been supported by the improvement in sleep apnea following changes from hemodialysis to nocturnal hemodialysis, use of automated peritoneal dialysis, and KTx.

Sleep apnea contributes to the CKD population’s substantial morbidity and mortality. It leads to the poor daytime experiences of those on dialysis19 by causing excessive daytime sleepiness and diminished QOL.3 Among patients with ESRD, sleep apnea may contribute to fatigue, tiredness, and lack of energy. These debilitating symptoms may improve when sleep apnea is treated. Investigators have demonstrated that sleep apnea causes restless sleep and daytime somnolence as well as complaints of memory difficulties and inability to concentrate. As a result of sleepiness, the cognitive disturbances may lead to increased use of sick days at work.

Sleep apnea has been associated with decreased HRQOL, mood disturbances, and reduced libido. The high rate of sleep apnea among patients undergoing hemodialysis has been proposed to negatively impact HRQOL and cognitive function performance measures of cognitive function. Daytine functioning aspects have shown to be diminished in ESRD patients.23 Furthermore, these aspects are thought to be intimately linked to sleep and are negatively impacted by sleep apnea. Sleep apnea has been associated with lower HRQOL in patients on hemodialysis in a single study with small sample size and limited PSG.24 In this study, 21 of 31 participants had an AHI of >5 with a median AHI of 13.3. The vitality, social functioning, and mental health domains in the 36-item short-form health survey (SF-36) and the emotional reactions from the Nottingham Health Profile (NHP) were significantly higher in those without sleep apnea. Both poor social functioning from the SF-36 and emotional reactions from the NHP were independently associated with the AHI after adjusting for BMI. However, this report was limited by a small sample size and a minimal adjustment for age, gender, and comorbidity in relating the QOL results to sleep apnea. Most importantly, the eight-channel ambulatory PSG recording unit utilized in this study does not document actual sleep time; therefore, the AHI used was only an estimate. Nonetheless, these findings support the position that sleep disorders impact this population’s daytime functioning. In chronic illnesses such as kidney failure, self-reported HRQOL may be the most important treatment outcome. Despite improved medical management and increasing technologic gains in dialysis therapy, patients on hemodialysis still reported a substantially lower HRQOL than the general population.23

Sleep apnea has also been shown to increase risk of cardiovascular disease in ESRD patients. Sleep apnea in those with ESRD disrupts the normal non-rapid eye movement (REM) sleep, and vagal heart rate modulation is attenuated while sympathetic modulation predominates. Increased cardiac and peripheral adrenergic drive may help explain why sleep apnea and nocturnal hypoxemia have been associated with the ESRD population’s left ventricular hypertrophy, hypertension, and increased cardiovascular events in the ESRD population.25

A study on when to initiate therapy for sleep apnea in the ESRD population has never been conducted. Similar to the general population, one should consider the severity of sleep apnea, hypoxemia, hypertension, and daytime symptoms. In the ESRD population, CPAP was used in a very preliminary study. Eight patients showed some improvement in nocturnal oxygenation and five of six patients reported improved daytime alertness.26 It is interesting that CPAP is not widely used among patients with ESRD; <2% of patients with ESRD have the sleep apnea diagnosis (D Gilbertson PhD, United States Renal Data System; personal communication; Dec 13, 2007).

Since the sleep apnea associated with uremia may be secondary to the effects of uremic toxins, some investigators have examined dialysis’ impact on sleep apnea. Quotidian nocturnal hemodialysis partially corrects sleep apnea.27 One study examined 14 patients undergoing conventional hemodialysis who subsequently switched over to nocturnal hemodialysis.27 The patients underwent PSG before and after they switched dialysis modes, demonstrating a marked reduction in sleep apnea among seven patients.27 However, the study demonstrated that these patients continued to have frequent arousals from sleep, diminished REM time, and diminished sleep time and sleep efficiency with nocturnal hemodialysis. In addition, the study neglected to report patient-assessed outcomes. While sleep apnea was diminished, these findings suggested that overall sleep architecture did not improve with intensive nocturnal hemodialysis.27

 

Restless Legs Common Among Patients with End-stage Renal Disease

RLS is a sleep disorder common among people on dialysis. RLS is characterized by paresthesias and dysesthesias, conditions improved through the movement of the affected limb, usually in the evening.28 RLS is diagnosed based on the criteria of the International Restless Legs Syndrome Study Group (IRLSSG), including an urge to move usually due to uncomfortable sensations, motor restlessness, worsening of symptoms during relaxation, and worsening symptoms in the evening.29 Studies using a gold standard neurologist interview have found that approximately 23% to 33% of patients undergoing chronic hemodialysis have RLS.30,31 The data show a 33% prevalence of RLS among ESRD patients using a questionnaire based on IRLSSG criteria. While the estimates of RLS among the hemodialysis population range up to 10 times more frequent than the general population,30 the etiology and risk factors for RLS in those with ESRD remain unclear. In the general population, a blockade of the dopamine-2 receptor in the diencephalon has been suggested to cause RLS, while among ESRD patients other factors such as under dialysis and with hypoparathyroidism may be predisposed to the syndrome.31,32 Iron has been used to treat RLS, and ferritin has been found to be a useful marker relating RLS to iron deficiency.33 The mechanism relating iron metabolism to RLS is probably central as iron is a key catalyst in brain dopamine metabolism and serum iron levels correlate poorly with central nervous system concentrations.34

RLS has been associated with substantial morbidity and mortality in the ESRD population. In both the general population and the hemodialysis population, however, RLS has been associated with poor mental health.32 RLS symptoms were associated with a lower HRQOL among a nation-wide sample of 900 incident dialysis patients.35 In hemodialysis patients, RLS has been associated with shorter survival when the age, sex, and duration of dialysis were controlled.32,35 RLS was associated with hemodialysis nonadherence, and poor adherence to the dialysis prescription in patients with RLS may lead to increased mortality risk.32

While RLS is a syndrome diagnosed using a validated questionnaire based on standard criteria, the periodic limb movements (PLMs) diagnosis requires monitoring of leg movements overnight. PLMs are characterized by periodic episodes of repetitive and highly stereotyped movement.36 PLMs have been associated with RLS, Parkinsonism, aging, and medication use.37 The PLMs may be either measured using PSG with anterior tibialis electromyogram or estimated using actigraphy on the lower extremities. However, the use of a single time point has been shown to be subject to bias from marked day-to-day variability in PLMs. While PLMs have been frequently documented in the general population, their impact on sleep has been unclear and controversial.38 In the dialysis population, PLMs have been associated with increased sleep tendency and shorter survival in small studies that accounted for neither comorbidities nor RLS.39,40 In a study that examined both RLS and PLMs in hemodialysis, a substantial difference between those with and those without PLMs in the domains of insomnia, daytime sleepiness, depression, and HRQOL was not present.41 The effects of normalizing hematocrit in sleep disorders, sleep patterns, and daytime ability to remain awake was examined in ESRD patients. While 10 patients with sleep complaints were on recombinant human erythropoietin (rHuEPO) therapy, they were studied by PSG while moderately anemic (mean hematocrit=32.3%). The patients were studied again when hematocrit was normalized (mean hematocrit=42.3%) through increased rHuEPO dosing. All 10 subjects experienced highly statistically significant reductions in the total number of arousing PLMs (P=.002). Nine of 10 subjects showed reductions in both the Arousing PLMs Index (P<.01) and the PLMS Index (P=.03) when hematocrit was normalized. Measures of sleep quality showed trends to improved quality of sleep. Molecular weight demonstrated significant improvement in the length of time patients were able to remain awake (9.7 minutes versus 17.1 minutes; P=.04).42

Studies examining the use of intravenous iron in idiopathic RLS treatment are ongoing. The use of intravenous iron in RLS treatment among ESRD patients has been studied in a small randomized study examining both short-term changes in symptoms and adverse effects of intravenous iron.43 Hemodialysis patients who were determined to have RLS by IRLSSG criteria were administered either 1,000 mg of iron dextran or normal saline intravenous (IV) in a blind fashion. Eleven patients were randomly assigned to the iron dextran administration, and 14 patients were randomly assigned to the saline IV administration. Iron infusion was associated with a significant yet transient reduction in RLS symptoms in patients with ESRD.43 It is important to assess intravenous iron therapy’s impact on sleep quality, QOL, and survival of this population at risk.

There is no particular dialysis type recommended for patients with RLS. The timing and type of dialysis should be individualized to minimize RLS. For example, patients undergoing hemodialysis in the evening with severe symptoms of RLS may benefit from a change to the morning shift during which symptoms of RLS may be less intense. Likewise, patients using continuous cycling peritoneal dialysis—a nocturnal peritoneal dialysis—may consider switching to continuous ambulatory peritoneal dialysis which is done predominately during the day. This change permits peritoneal dialysis patients more freedom to move in the late evening. Regardless of the type or timing of dialysis treatment, it is important to treat RLS. An approach to the treatment of RLS among patients with kidney failure has been recently outlined and adapted for the Table.44 RLS patients should have both a history and a physical examination that exclude causes of pain in the extremities such as peripheral vascular disease and neuropathy. RLS severity should be clinically assessed and the clinicians should consider using a validated instrument to document RLS severity. If the patient has mild-to-moderate RLS, the team should focus on non-pharmacologic interventions, ie, using a bicycle or distracting activities. If RLS is severe, it would be important to both use a pharmacologic intervention for the improved quality of life and encourage adherence with dialysis.

 

 

Conclusion

The substantial population of patients with CKD and kidney failure will continue to increase with the population’s age. This patient population has a remarkable rate of sleep complaints and has been shown to have a much higher prevalence of sleep disorders than the general population. It may be that poor sleep and sleep disorders contribute to the substantial morbidity and mortality found in patients with kidney failure. The psychiatric field may serve to recognize and treat patients’ sleep disorders. The treatment of insomnia, sleep apnea, short sleep, and RLS may improve this population’s QOL, functional status, and mood. The recommendations for sleep disorder treatment in this high risk population reflect an evolving understanding of sleep disorders, particularly in populations with medical comorbidities. They should also serve as points for future research.

Further work and refinement should be done on both the screening tools for sleep disorders and on the role of screening in this population with an exceedingly high prevalence of sleep disorders. In addition to screening, the management of patients with ESRD and comorbid sleep disorder needs further study. If a patient has severe sleep apnea, does CPAP or changing the dialysis prescription best serve the patient? Can patients with sleep disorders tolerate nocturnal dialysis, the seemingly best treatment for uremic sleep apnea? Does the treatment of sleep apnea improve the poor sleep quality, mood, and fatigue in patients with medical comorbidity? It is important to measure, monitor, and treat sleep disorders in CKD patients. It is also important for the psychiatric field to recognize both the role of medications as potential aggravators of RLS and PLMs and the role of behavioral and non-pharmacologic interventions in the management of sleep disorders. PP

 

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