Sleep Apnea and Chronic Kidney Disease

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Contemporary Reviews in Sleep Medicine

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Sleep Apnea and Chronic Kidney Disease

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A State-of-the-Art Review

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Chou-Han Lin, MD; Renee C. Lurie, BScH; and Owen D. Lyons, MBBCh

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Patients with chronic kidney disease have increased morbidity and mortality, mainly due to

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cardiovascular disease. Compared with the general population, patients with chronic kidney

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disease have an increased prevalence of both OSA and central sleep apnea, and the presence of

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sleep apnea in this population has been associated with an increased risk of cardiovascular

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events and mortality. Although OSA can lead to an increase in the rate of kidney function

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decline, there is also evidence that the presence of end-stage renal disease can lead to wors-

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ening of sleep apnea, indicating a bidirectional relation between sleep apnea and chronic kidney

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disease. The objective of this review was to describe the epidemiology of sleep apnea in chronic

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kidney disease, understand the pathophysiological mechanisms by which OSA can lead to

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progression of chronic kidney disease, and consider the role of treatment with CPAP in this

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regard. The review also explores the pathophysiological mechanism by which end-stage renal

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disease can lead to sleep apnea and considers how intensification of renal replacement therapy

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or extra fluid removal by ultrafiltration may attenuate the degree of sleep apnea severity in this

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population.

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KEY WORDS:

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Chronic kidney disease (CKD) is a leading cause of morbidity and mortality.1 CKD also has a profound deleterious effect on patients’ quality of life and leads to a dramatic increase in the use of health-care resources.2,3 In Canada, the care of patients with CKD undergoing dialysis accounts for approximately 1.2% of overall Canadian health-care expenditures,2 and in the United States, annual Medicare spending on CKD and end-stage renal disease (ESRD) is more than $98 billion.4

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Compared with the general population, individuals with CKD have an increased prevalence of sleep apnea, both OSA and

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central sleep apnea; dialysis; kidney; OSA; sleep apnea

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central sleep apnea (CSA).5-7 The presence of sleep apnea in this population has been associated with an increased risk of cardiovascular events and all-cause mortality across the spectrum of CKD, including those not undergoing dialysis as well as those undergoing peritoneal dialysis and hemodialysis.1,8,9 Even in patients undergoing hemodialysis who have low cardiovascular risk, the incidence of developing cardiovascular events is higher in those with OSA compared with those without OSA.10 Furthermore, the presence of OSA can lead to the progression of CKD and a decline in glomerular filtration rate (GFR)

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ABBREVIATIONS: AHI = apnea-hypopnea index; CKD = chronic kidney disease; CSA = central sleep apnea; ESRD = end-stage renal disease; GFR = glomerular filtration rate; PAP = positive airway pressure; RAS = renin-angiotensin system; UA = upper airway AFFILIATIONS: From the Department of Medicine, Women’s College Hospital, Toronto, ON, Canada.

CORRESPONDENCE TO: Owen D. Lyons, MBBCh, Department of Medicine, Women’s College Hospital, 76 Grenville St, Toronto, ON, M5S 1B2, Canada; e-mail: [email protected] Q3 Copyright Ó 2019 Published by Elsevier Inc under license from the American College of Chest Physicians. DOI: https://doi.org/10.1016/j.chest.2019.09.004

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mediated by intermittent hypoxia and various other mechanisms, including the effects of OSA on BP and sympathetic nervous system activity.11-13 However, despite the high prevalence of sleep apnea in CKD, and its negative impact on disease progression and mortality, its presence often goes unrecognized, in part due to its clinical presentation in the CKD population, which differs significantly from its clinical presentation in the general population.14,15 Although OSA contributes to CKD progression, there is also evidence that the underlying kidney disease itself can contribute to development or worsening of sleep apnea, especially in the latter stages of CKD when patients require renal replacement therapy/dialysis. The prevalence of sleep apnea increases as CKD progresses and GFR declines, to the extent that prevalence rates of sleep apnea in ESRD are as high as 60%.6 Mechanisms by which ESRD could predispose to sleep apnea include uremia-induced neuropathy or myopathy, altered chemosensitivity, and hypervolemia.16,17 In patients with ESRD, increased fluid overload predicts severity of sleep apnea, and intensification of renal replacement therapy or increased fluid removal by ultrafiltration attenuates sleep apnea severity.18-21 The objective of the current review was to consider the bidirectional relation between sleep apnea and CKD. The first part of this review focuses on descriptions of the epidemiology and clinical presentation of OSA and CSA in CKD, understanding the pathophysiological mechanisms by which OSA can lead to progression of CKD, and consideration of the potential role of CPAP in preventing accelerated GFR decline in patients with CKD and OSA. The second part of the review focuses on the pathophysiological mechanism by which ESRD can lead to sleep apnea and considers how intensification of renal replacement therapy and/or extra fluid removal by ultrafiltration may attenuate the degree of sleep apnea severity in this population.

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Definitions and Diagnosis The GFR is a mathematically derived entity based on a patient’s serum creatinine level, age, sex, and race. It can be calculated by using one of several well-validated formulas available such as the Modification of Diet in Renal Disease Study equation or the Chronic Kidney Disease Epidemiology Collaboration equation. CKD is defined as kidney damage or decreased kidney function (GFR < 60 mL/min/1.73 m2) for $ 3 months.22 Kidney damage is signified by pathologic abnormalities or signs

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of damage (eg, markers in the blood and urine, imaging tests). There are five stages of CKD, with GFR progressively decreasing as the stages increase. Stage 5 or ESRD is defined as a GFR < 15 mL/min/1.73 m2 or if the patient is undergoing dialysis therapy.

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Apneas and hypopneas are defined according to the American Academy of Sleep Medicine Scoring manual.23 Classification of sleep apnea severity is based on the apnea-hypopnea index (AHI), which is the average number of apneas and hypopneas per hour of sleep; no sleep apnea is defined as an AHI < 5, mild as an AHI 5 to 15, moderate as an AHI 15 to 30, and severe as an AHI > 30.24

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Prevalence of Sleep Apnea in CKD and ESRD

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In the general population, the overall prevalence of moderate to severe OSA (AHI > 15) is estimated to be 10%,25 with the prevalence of CSA < 1%.26 Both types of sleep apnea are far more common in patients with CKD than in the general population (Fig 1). The reported prevalence rates of OSA in CKD vary widely, from 25% to 70%, depending on the AHI cutoff used, but even when using a strict cutoff of AHI > 15, (ie, moderate or severe OSA), OSA is very common in CKD.6,18,27 This increased prevalence is not explained by age, elevated BMI, or comorbidities, suggesting that the underlying kidney disease itself is the main cause.18,28,29 Furthermore, Nicholl et al6 reported that as kidney function worsens and GFR declines, OSA prevalence and severity increase. In a study of 254 patients from outpatient nephrology clinics and hemodialysis units, the prevalence of moderate to severe OSA was found to be 27%, 41%, and 57% in groups with GFR > 60 mL/ min/1.73 m2, CKD, and ESRD, respectively. Although there is a dearth of studies evaluating the prevalence of

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General Population

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Figure 1 – Prevalence of moderate to severe sleep apnea (apnea-hypopnea index > 15) in the general, CKD, and ESRD populations. CKD ¼ chronic kidney disease; ESRD ¼ end-stage renal disease.

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CSA in CKD, and those available studies are limited by the heterogeneity of the patients’ characteristics and comorbidities, it is estimated that about 10% of patients with CKD have CSA.30

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Clinical Presentation of Sleep Apnea in CKD

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Despite the high prevalence rates of sleep apnea in CKD and ESRD, the presence of sleep apnea in these patients often goes unrecognized.14 This is likely due to several factors. First, although an elevated BMI remains a risk factor for OSA in the CKD population, patients with ESRD and OSA tend to have lower BMI and smaller neck circumference compared with patients with OSA who do not have CKD. In a study of 76 patients with OSA and ESRD undergoing conventional hemodialysis, matched for sleep apnea severity to 380 control subjects with OSA from the Sleep Heart Health study, there was no difference in mean AHI (44.2  27.7 vs 44.2  27.7) or age (53 13 years vs 51 13 years) between the groups, as per study design; however, the ESRD group had a dramatically lower BMI (28.1 5.3 kg/m2 vs 33.0  13.8 kg/m2; P ¼ .003).29 Second, symptoms that characterize the clinical presentation of OSA in the general population are less evident in the CKD and ESRD populations.15,29 Beecroft et al29 reported that patients with ESRD and OSA reported fewer instances of snoring, witnessed apneas, and morning headaches than patients with OSA but without kidney disease. It has also been shown that although the prevalence of daytime sleepiness is higher in patients with CKD and OSA compared with patients with CKD but no OSA, daytime sleepiness is less frequent than in patients with OSA without CKD.15 Furthermore, patients with ESRD often have symptoms of daytime fatigue and poor sleep quality related to the kidney disease itself, comorbidities, or medications, which may mask the presence of true excessive daytime sleepiness and thus OSA.31,32 The presence of other sleep disorders such as insomnia and periodic leg movements may further overshadow the presence of OSA in this population.33 Consequently, the presence of sleep apnea may often not be clinically apparent.

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Unsurprisingly, clinical prediction scores used for screening for sleep apnea (eg, the snoring, tiredness, observed apnea, high BP, BMI, age, neck circumference, and male sex [STOP-Bang] questionnaire, adjusted neck circumference, the Berlin questionnaire), which are based on characteristic clinical features of the “traditional phenotype” of OSA, do not perform well in the CKD and ESRD populations as they have poor

specificity and accuracy.34 Therefore, given the atypical presentation and high prevalence of sleep apnea in these populations, a low threshold for diagnostic testing with polysomnography or some form of cardiopulmonary monitoring during sleep should be considered. This approach is of particular relevance, given that the presence of OSA in this population is associated with a significantly higher risk of cardiovascular events and increased mortality.9,10

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Association Between OSA and Incident CKD A retrospective cohort substudy of the Wisconsin sleep cohort study did not show an association between severity of sleep apnea and decline in kidney function.35 Sleep apnea was defined as an AHI $ 15 or positive airway pressure (PAP) use at baseline. A total of 855 subjects were followed up over an average of 13.9 years. The rate of GFR decline in the group with sleep apnea was not significantly different compared with the group without sleep apnea (–0.7 vs –0.9 mL/min/1.73 m2 per year; P ¼ .134). The prevalence of sleep apnea in this population was relatively low at 11%, the population was relatively young (mean age, 50.4 years) and healthy, and the mean GFR at baseline was normal (89.3  13.8 mL/ min/1.73 m2). These factors raise the possibility that this population did not represent an at-risk group for the development of kidney damage. However, in studies of older populations, studies with subjects referred for diagnostic tests for possible sleep apnea, or studies in patients with preexisting kidney damage, there seems to be a link between OSA and incident CKD and accelerated decline in kidney function. In a cohort study of > 3 million US veterans, the majority of whom were male with a mean age of 60.5 years, a diagnosis of incident OSA was associated with a higher incidence of CKD and a faster decline in kidney function over time compared with those without OSA.36 Similarly, in a retrospective, longitudinal populationbased cohort study from the Taiwan Longitudinal Health Insurance Database, those with sleep apnea had an increased risk of developing CKD with an adjusted OR of 1.37 (95% CI, 1.05-1.77; P ¼ .019); this increased risk was observed not just in men but also in women (hazard ratio, 1.41; 95% CI, 1.12-1.78; P ¼ .0036).37 In a Q6 study of older subjects (age S65 years) recruited from the general population (277 of whom underwent overnight polysomnography), there was an increased risk of rapid kidney decline, over an 11-year follow-up, in those with an AHI S 30 (OR, 2.80; 95% CI, 1.216.44); the results remained significant following

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adjustments for age, sex, BMI, smoking status, diabetes mellitus, hypertension, and history of cardiovascular disease (OR, 2.50; 95% CI, 1.01-6.20).38

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In a prospective observational study of 858 subjects referred for diagnostic sleep testing, unselected for the presence or absence of CKD, GFR was measured at baseline and followed up for 2 years.39 At baseline, the mean GFR of the cohort was mildly reduced (71  12 mL/min/1.73 m2), 18% had a GFR < 60 mL/min/1.73 m2, and 44% had nocturnal hypoxia (oxygen saturation < 90% for $ 12% of the nocturnal monitoring time). Compared with control patients without hypoxia, patients with hypoxia had an increased risk of rapid loss of kidney function (defined as a decline in GFR $ 4 mL/min/1.73 m2 per year) with an OR of 2.89 (1.25-6.67) following adjustment for respiratory disturbance index, age, BMI, diabetes, and heart failure. In studies of subjects with established CKD or diabetic nephropathy, similar accelerated rates of decline in GFR have been shown in those with nocturnal hypoxia compared with those without hypoxia.40,41 In a study of 161 patients with stage 3 to 4 CKD, the decline in GFR over 1 year was three to four times greater in patients with a 4% oxygen desaturation index $ 15 than in those with a 4% oxygen desaturation index < 15 following adjustment for baseline characteristics (including BMI) (135). Similar results were also seen in a cross-sectional study of 7,700 subjects from the European Sleep Apnoea Database (ESADA) cohort, in which the overnight minimum oxygen saturation was found to be a predictor of the presence of CKD, with a 2% higher probability of CKD for every unit decrease in the minimum oxygen saturation.42

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Pathophysiology: Effect of OSA on CKD Progression Two key pathological mechanisms are believed to contribute to progression of damage to kidney tissue, namely hypoxia and glomerular hypertension/ hyperfiltration.43,44 It is clear that OSA could contribute to both these mechanisms directly due to intermittent hypoxia and also by its effects on hypertension, increased sympathetic nervous system, and activation of the renin-angiotensin-aldosterone system (Fig 2). Despite receiving approximately one-quarter of resting cardiac output, renal oxygen tension is relatively low due to low renal oxygen consumption.23 The kidney medulla is particularly sensitive to hypoxia.44 The chronic hypoxia hypothesis postulates several mechanisms by

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which hypoxia leads to tubulointerstitial injury, the harbinger of CKD.45 Intermittent hypoxia can cause reactive oxygen species to form, subsequently leading to oxidative stress, inflammation, and systemic endothelial dysfunction.46-49 Together, these processes can cause structural and functional damage to the kidney, leading to CKD.16,50-52 Hypoxia also causes the renal tubular cells to undergo an epithelial-to-mesenchymal transformation and activates fibroblasts, causing interstitial fibrosis and damage to the peritubular capillaries.16,53 Chronic hypoxia also causes defects in the renal tubular mitochondrial cells with subsequent activation of apoptosis.16 These actions all lead to degeneration of the renal tubules. A recent study in a rat model showed that intermittent hypoxia caused hyperplasia of the glomerular mesangial cells, edema of the tubular epithelial cells, and loss of the Q10 renal cell brush border.54 Recent data from a mouse model of sleep apnea suggest that treatment with the antioxidant a-lipoic acid could attenuate intermittent Q11 hypoxia-related kidney damage. Also, animal and human experiments have shown that intermittent hypoxia can also increase the renin-angiotensin system (RAS).55,56 RAS, acting systemically and locally, can together cause increased hypertension, hyperfiltration, inflammation, and fibrosis in the renal tissues, leading to CKD.44,48 In a study of 31 patients with OSA and 13 control subjects, Zalucky et al57 aimed to determine the relationship between OSA/hypoxia and RAS activity by measuring the effective renal plasma flow response to angiotensin II challenge, which is a recognized marker of renal RAS activity. The patients with OSA were divided Q12 into a severe hypoxia group (mean nocturnal oxygen saturation $ 90%) and a moderate hypoxia group (mean nocturnal oxygen saturation $ 90%). Compared with control subjects, patients with OSA had greater baseline glomerular pressure, a measure of increased renal risk. Also, those patients with OSA and severe hypoxia had greater RAS activity compared with those with moderate hypoxia and control subjects in a dose-dependent manner. Furthermore, the severity of hypoxia was not associated with the BP or the systemic circulating RAS component response to angiotensin II, suggesting a direct effect on renal RAS activation. Hypertension is one of the most common causes of CKD. It can cause kidney damage through various pathological mechanisms, including diffuse glomerulosclerosis, mesangial hypertrophy, nephrosclerotic glomerulonephropathy, glomerular fibrosis, and renal interstitial fibrosis.13 The role of OSA

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Figure 2 – Effect of OSA on chronic kidney disease progression: pathophysiological mechanisms. RAS ¼ renin-angiotensin system; SNS ¼ sympathetic nervous system.

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in causing hypertension is now well established from experimental studies in animals and from epidemiologic studies in humans.58-61 The main mechanism is the effect of repeated cycles of hypoxia/hypercapnia leading to sympathetically mediated vasoconstriction.62 Arousals that terminate apneas also lead to surges in sympathetic activity.63 OSA can also increase arterial wall stiffness, which in itself can damage the kidneys by leading to microvascular damage and ischemia of the renal tissues.64-66

Effect of OSA Treatment With CPAP on Kidney Function and Progression of CKD By abolishing OSA, CPAP may prevent downstream effects of OSA that are potentially deleterious to kidney function. In subjects with normal kidney function, treatment of OSA with CPAP therapy has a positive effect on renal hemodynamics. In 20 normotensive

patients (predominantly men, mean age of 50 years) with newly diagnosed OSA (mean AHI, 42  4), it was shown that 1 month of treatment with CPAP led to an augmented renal plasma flow response to angiotensin II; this response indicates a downregulation of RAS activity, as well as reductions in mean arterial pressure, plasma aldosterone, and urinary protein excretion.67 Other studies have shown similar effects of CPAP on renal hemodynamics, reducing hyperfiltration, decreasing the filtration fraction, and increasing renal blood flow, and Q13 ultimately slowing kidney damage.43,48,68 In a recent prospective, nonrandomized study from the ESADA cohort, it was shown that fixed CPAP had an attenuating effect on the rate of kidney function decline, whereas auto-PAP did not,69 with the authors postulating that fixed CPAP may have had a more significant beneficial effect on BP control and sympathetic nervous system activation, as previously reported.70

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There are few studies assessing the effects of CPAP on rate of kidney function decline in patients with established CKD, but some short- to medium-term nonrandomized studies have suggested a beneficial effect of CPAP on kidney function in this population. In a retrospective cohort study of 42 patients with OSA and CKD stage 3 to 5, followed up over a median of 2.3 years following commencement of CPAP, those who were more compliant to CPAP therapy (nightly usage > 4 h) had a slower decline of GFR and reduced levels of proteinuria than those who were not as compliant (nightly usage < 4 h).71 Similar results have been shown in patients with moderate to severe OSA and diabetic nephropathy, with a faster decline in GFR seen in those noncompliant with CPAP compared with those who were compliant.41 However, these results have not been consistently seen in other studies, reflected in a metaanalysis of eight studies (with a total of 240 subjects) that aimed to evaluate the effect of PAP, CPAP, or adaptive servo-ventilation on GFR.72 Overall, there was no change in GFR prior to and following PAP treatment in patients with sleep apnea. However, longer duration of PAP treatment and increased age were associated with significantly improved GFR. There has only been one randomized controlled study to date that has aimed to assess the effects of CPAP on renal function. In a post hoc analysis of the Sleep Apnea Cardiovascular Endpoints (SAVE) randomized controlled trial, it was shown that in subjects with moderate to severe OSA and an established history of coronary or cerebrovascular disease, randomized to receive CPAP or usual care, there was no difference in the rate of GFR decline in the CPAP group (–1.64 [–3.45 to –0.740] mL/min/1.73 m2 per year) compared with in the usual care group (–2.30 [–4.53 to –0.71 mL/min/1.73 m2 per year]; P ¼ .21) after a median follow-up of 4.4 years.73 However, the study was powered for cardiac outcomes and was not adequately powered to assess renal outcomes. Furthermore, adherence to CPAP was low, the mean GFR was normal at baseline, the majority of patients in the study did not have CKD at baseline, subjects with severe nocturnal hypoxia were excluded, and, based on baseline characteristics, they were unlikely to be at high risk for loss of kidney function.74 Therefore, although the results of this study do not support the use of CPAP for renal protection in patients with sleep apnea, future randomized controlled trials that aim to assess the effect of CPAP on kidney function will need to be performed in patients at risk for CKD or indeed who already have abnormal renal function. One

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such study, currently underway, aims to specifically address the effect of CPAP on the rate of GFR decline in patients with established CKD.75

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ESRD describes the stage when kidney function has deteriorated to the point where the GFR is < 15 mL/ min/1.73 m2 or renal replacement therapy (renal transplantation or chronic dialysis) is required. As discussed earlier, sleep apnea is very common in ESRD, with prevalence rates of 50% to 60%, and this increased prevalence is not explained by age, sex, BMI, or the presence of cardiovascular disease.28,76 Furthermore, several studies have shown that intensification of dialysis treatment attenuates the severity of sleep apnea in patients with ESRD,21,77 and a meta-analysis of nine studies that assessed the impact of renal replacement therapies on sleep quality and disturbances favored intensive renal replacement therapy vs conventional renal replacement therapy in AHI reduction (OR, 0.66; 95% CI, 0.51-0.84; P < .001).78 Taken together, these findings suggest it is the underlying renal disease itself that causes sleep apnea or indeed leads to worsening of preexisting sleep apnea.

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Impaired upper airway (UA) sensory function and denervation of the UA dilator muscles, associated with inflammation, have been shown to play a role in the pathogenesis of UA obstruction in patients with OSA and normal kidney function.79 In ESRD, uremic neuropathy is common and may affect sensory function of the UA, increasing UA collapsibility.80 Furthermore, uremic myopathy, which has been shown to increase fatigability of the respiratory muscles,81 could also potentially lead to reduced tone of the UA dilator muscles, with a subsequent increase in UA collapsibility during sleep.

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In non-rapid eye movement sleep, ventilatory drive is predominantly under metabolic or chemoreflex control.82 Increases in chemosensitivity can lead to destabilization of respiratory control and periodic breathing.83 Although ventilatory instability and

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There are several proposed pathophysiological mechanisms by which ESRD could potentially predispose to sleep apnea, including uremia-induced neuropathy or myopathy, altered chemosensitivity, and hypervolemia (Fig 3).

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Pathophysiology: the Role of ESRD in the Pathogenesis of Sleep Apnea

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OSA and central sleep apnea Figure 3 – The role of end-stage renal disease in the pathogenesis of sleep apnea: pathophysiological mechanisms.

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periodic breathing are established mechanisms in the pathogenesis of CSA, there is also now evidence supporting the role of ventilatory instability or increased loop gain in the pathogenesis of OSA.84,85 Renal disease may lead to altered chemoreflex responsiveness and subsequent ventilatory instability. In a study of 58 subjects with ESRD, it was shown that those with sleep apnea (AHI > 10) had augmented responsiveness of both the peripheral and central chemoreflexes compared with those without OSA, suggesting that subsequent ventilatory instability caused sleep apnea in this population.17 It is not understood what precise ESRDrelated factors contribute to increased chemoreflex response in those with CKD. Some authors have suggested that metabolic acidosis or uremia may cause increased responsiveness.86 However, Beecroft et al17 reported increased chemosensitivity in the ESRD study population with no metabolic acidosis, suggesting other factors play a role. There is now an established and relatively large body of evidence supporting the role of fluid overload in the pathogenesis of sleep apnea (both OSA and CSA), particularly in conditions characterized by fluid overload such as heart failure and ESRD.19,87-89 The underlying mechanisms have been reviewed in-depth previously,90 but in brief, hypervolemia and rostral fluid shift from the legs overnight can both contribute to subsequent fluid accumulation in the neck, leading to a reduction in UA cross-sectional area and increased collapsibility predisposing to OSA; fluid accumulation in the lungs may stimulate pulmonary irritant receptor, leading to a

cycle of hyperventilation and apnea, and predisposing to CSA.87,88 In patients with ESRD, the degree of leg fluid volume from the legs overnight has been shown to correlate with severity of sleep apnea. It has also been shown that internal jugular vein volume and UA mucosal water content, measured by MRI of the neck, independently correlate with severity of sleep apnea in patients with ESRD; this outcome suggests that intravascular and extravascular fluid accumulation surrounding the UA leads to increased collapsibility of the airway and OSA.87 It is also possible that fluid overload contributes to OSA not only by its effects on UA collapsibility but also potentially by affecting ventilatory instability.91 In a cross-sectional study of patients with CKD and a GFR< 60 mL/min/1.7 m2 who were not receiving dialysis, severity of sleep apnea was independently associated with markers of fluid overload, including brain natriuretic peptide levels, the cardiothoracic ratio calculated from chest radiographs, and diameter of the inferior vena cava (P < .005).92 In a study of 42 patients with ESRD undergoing thrice-weekly conventional hemodialysis, the total body extracellular fluid volume, measured according to bioelectrical impedance, was 2.6 L greater in those subjects with moderate to severe sleep apnea (n ¼ 28) compared with those with mild or no sleep apnea (n ¼ 14) (P ¼ .006); there was no difference in BMI between the groups.18 Several other studies have shown that the degree of fluid overload is independently and directly related to severity of sleep apnea.10,20

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In a study of 14 patients with ESRD initially receiving conventional hemodialysis, there was an overall reduction in AHI from 25  25 to 8  8 following conversion to nocturnal hemodialysis, with a reduction in AHI from 46  19 to 9  9 (P ¼ .006) in those seven subjects with sleep apnea at baseline.21 Because fluid volumes were not measured, the extent to which improved uremic status or improved fluid volume status contributed to the reduction in sleep apnea severity was not elucidated. In a subsequent study, conversion to nocturnal hemodialysis led to an increase in pharyngeal area; however, this element alone did not explain the improvement in the AHI, suggesting that other factors must also be involved.93 It has been postulated that one mechanism by which

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The Effect of Intensified Renal Replacement Therapy and Ultrafiltration on Sleep Apnea Severity

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755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770

771

772

773

774

775

776

777

778

779

780

781

782

783

784

785

786

787

788

789

790

791

792

793

794

795

796

797

798

799

800

801

802

803

804

805

806

807

808

809

810

811

812

813

814

815

816

817

818

819

820

821

822

823

824

825

] Effect of Interventions on Sleep Apnea Severity in Patients With End-Stage Renal Disease

Author/Reference (Year)

Subjects

Intervention

n

21

CHD patients converting to NHD program

CHD/NHD

14

Hanly et al97 (2003)

CHD patients converting to NHD program

CHD/NHD

15

Chan et al98 (2004)

CHD patients converting to NHD program

CHD/NHD

9

Tang et al77 (2006)

PD patients

NPD/CAPD

24

Beecroft et al99 (2007)

Dialysisdependent or predialysis patients in a transplant clinic

Transplant

Beecroft et al93 (2008)

CHD patients from NHD program

CHD/ NHD

Hanly et al (2001)

Definition of SA

Q16

Outcome of SA Parameters

AHI S 15

Other Main Findings

Limitations

AHI, 25  25/8  8 (P ¼ .03)

AHI on night without NHD remained lower than on night with CHD

Limited number of patients with SA Not randomized

.

Severity of SA significantly improved following conversion

Trend for somnolent patients to become less sleepy after conversion

Mechanism why NHD corrects SA not further investigated Not randomized

.

AHI, 29.7  9.3/8.2  2.0 (P ¼ .02)

Normalization of autonomic modulation following conversion (analysis of heart rate variability)

Limited numbers of patients Not randomized

AHI S 15

AHI, 3.4  1.34/14.0  3.46 (P < .001) Prevalence of SA, 4.2%/ 33.3% (P ¼ .016)

Lower total body water during NPD than CPAD with greater fluid removal in NPD during sleep

Incomplete data of fluid measurement (n ¼ 15) Not randomized

11

AHI S 10

AHI, 20.2  15.1/23.5  21.3 (not significant)

Three of 11 patients with SA responded to transplant with AHI reduction > 50%

Limited numbers of patients Timing of follow-up PSG following transplant not standardized Not randomized

24

AHI S 15

Only 3 of 16 patients with SA responded to NHD with AHI < 15 following conversion

Increase in pharyngeal cross-sectional area after conversion

Not randomized

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TABLE 1

(Continued)

] 827

826

829

828

831

830

832

833

835

834

837

836

839

838

841

840

842

843

845

844

847

846

849

848

851

850

852

853

855

854

857

856

859

858

861

860

862

863

865

864

867

866

869

868

871

870

872

873

875

874

877

876

879

878

880

881

882

883

884

885

886

887

888

889

890

891

892

893

894

895

896

897

898

899

900

901

902

903

904

905

906

907

908

909

910

911

912

913

914

915

916

917

918

919

920

921

922

923

924

925

926

927

928

929

930

931

932

933

934

935

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TABLE 1

] (Continued)

Author/Reference (Year)

Subjects

Intervention

n

Definition of SA

Outcome of SA Parameters

Other Main Findings

Limitations

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CHD patients converting to NHD program

CHD/ NHD

24

AHI S 15

Only 4 of 17 patients with SA responded to NHD with AHI < 15 following conversion

Decrease in chemoreflex responsiveness in SA patients responded to NHD

Not randomized

Tang et al95 (2009)

PD patients

NPD/CAPD

38

AHI S 15

AHI, 9.6  2.7/21.5  4.2 (P < .001) Prevalence of SA, 21.1%/ 42.1% (P ¼ .008)

Reduced pharyngeal volumes and cross-sectional area with enlarged tongue on MRI after switching to CAPD

Not randomized

Koch et al101 (2009)

CHD patients converting to NHD program

CHD/ NHD

13

AHI S 10

11.2 (7.0)/5.6 (6.8) (P ¼ .01)

Improvements in sleep efficiency and slow-wave sleep

Limited numbers of patients Not randomized

Lyons et al96 (2015)

CHD patients

Fluid removal by ultra-filtration

15

AHI S 20

AHI, 43.8  20.3/28.0  17.7 (P < .001)

Reduction of AHI correlated with reduction of extracellular fluid volume.

Limited numbers of patients Not randomized

Beecroft et al (2009)

100

Q17

AHI data are presented as mean  SD or median (interquartile range). AHI ¼ apnea-hypopnea index; CAPD ¼ continuous ambulatory peritoneal dialysis; CHD ¼ conventional hemodialysis; NHD ¼ nocturnal hemodialysis; NPD ¼ nocturnal peritoneal dialysis; PD ¼ peritoneal dialysis; PSG ¼ polysomnography; SA ¼ sleep apnea.

9 937

936

939

938

941

940

942

943

945

944

947

946

949

948

951

950

952

953

955

954

957

956

959

958

961

960

962

963

965

964

967

966

969

968

971

970

972

973

975

974

977

976

979

978

981

980

982

983

985

984

987

986

989

988

990

991 992 993 994 995 996 997 998 999 1000 1001 1002 1003 1004 1005 1006 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 1025 1026 1027 1028 1029 1030 1031 1032 1033 1034 1035 1036 1037 1038 1039 1040 1041 1042 1043 1044 1045

intensification of dialysis leads to attenuation of sleep apnea severity could include enhanced UA dilator muscle function and/or stabilization of the chemical component of respiration by decreasing ventilatory sensitivity to hypercapnia.94 In a study of 24 patients with ESRD receiving peritoneal dialysis, the mean AHI increased from 3  1 to 14  3 (P < .001) following conversion from nocturnal peritoneal dialysis to continuous ambulatory peritoneal dialysis.77 With nocturnal dialysis, there was a 1.47 L greater reduction in total body water compared with continuous dialysis but no difference in urea or creatinine levels. The reduced frequency of events with nocturnal dialysis was due to reductions in both obstructive and central events, indicating that the lower AHI was not solely due to improved UA mechanics. A related study found that following conversion from nocturnal peritoneal dialysis to continuous ambulatory peritoneal dialysis, there was an increase in the mean AHI from 9.6  2.7 to 21.5  4.2, which was associated with an increase in tongue volume and a reduction in pharyngeal volumes, measured by volumetric MRI; this outcome suggests increased fluid accumulation in the tongue and peripharyngeal soft tissue.95 There was also an improvement in uremic clearance. In an interventional study of 15 subjects with sleep apnea with ESRD undergoing conventional hemodialysis, which included subjects with both OSA and CSA, the additional removal of 2.2 L of fluid during a single ultrafiltration session led to a 36% reduction in AHI, in the absence of any changes in uremic or metabolic status.96 The degree of reduction in AHI correlated with the degree of reduction in total body extracellular fluid volume (r2 ¼ 0.322; P ¼ .027). Furthermore, the reduction in fluid volumes was accompanied by a reduction in chest fluid volume, and an increase in transcutaneous PaCO2 into the normal range, potentially suggesting a reduction in respiratory drive and possibly an increase in ventilatory stability. These findings support a key role for fluid overload in the pathogenesis of sleep apnea in ESRD and show that fluid removal attenuates sleep apnea without altering uremic status. The exact mechanisms by which fluid removal works has yet to be elucidated but include an improvement in UA mechanics and/or improved ventilatory control stability. Finally, the degree to which uremia may independently contribute to the pathogenesis of SA has not yet been rigorously evaluated.

10 Contemporary Reviews in Sleep Medicine

1046

Conclusions

1047

A growing body of evidence supports a bidirectional relationship between sleep apnea and CKD. Given that the presence of OSA in CKD is associated with more rapid progression of the disease and increased cardiovascular mortality, and given that its presence is often clinically not apparent in this population, diagnostic testing for sleep apnea in all patients with CKD should be considered, particularly in those with more advanced stages of disease. The results of ongoing randomized controlled trials are needed to provide definitive evidence to delineate the role of CPAP in slowing GFR decline in select populations at risk of CKD. Further research to explore the potential role of certain medications to attenuate the deleterious effect of intermittent hypoxia on renal tissue is also needed and could potentially provide an alternative renoprotective therapeutic option to CPAP therapy.

1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 1060 1061 1062 1063 1064 1065 1066

Finally, although it is clear that fluid overload plays an important role in the pathogenesis of sleep apnea in ESRD, further studies designed to better understand the effect of fluid overload on key pathophysiological mechanisms such as airway collapsibility and ventilatory instability are needed, as well as studies to investigate the role of uremia. This research could ultimately allow for a personalized approach to treatment of sleep apnea in ESRD, as an alternative to CPAP, by optimizing fluid volume status and guiding tailored and nuanced modifications of renal replacement therapies.

1067 1068 1069 1070 1071 1072 1073 1074 1075 1076 1077 1078 1079

Acknowledgments Financial/nonfinancial disclosures: None declared.

Q14 Q18

1080

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1170

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1300 1302

64. Drager LF, Bortolotto LA, Figueiredo AC, Silva BC, Krieger EM, Lorenzi-Filho G. Obstructive sleep apnea, hypertension, and their interaction on arterial stiffness and heart remodeling. Chest. 2007;131(5):1379-1386.

83. Dempsey JA, Smith CA, Przybylowski T, et al. The ventilatory responsiveness to CO(2) below eupnoea as a determinant of ventilatory stability in sleep. J Physiol. 2004;560(pt 1):1-11. 84. Younes M, Ostrowski M, Thompson W, Leslie C, Shewchuk W. Chemical control stability in patients with obstructive sleep apnea. Am J Respir Crit Care Med. 2001;163(5):1181-1190.

1304

65. Sedaghat S, Mattace-Raso FU, Hoorn EJ, et al. Arterial stiffness and decline in kidney function. Clin J Am Soc Nephrol. 2015;10(12): 2190-2197.

85. Wellman A, Jordan AS, Malhotra A, et al. Ventilatory control and airway anatomy in obstructive sleep apnea. Am J Respir Crit Care Med. 2004;170(11):1225-1232.

66. Peralta CA, Jacobs DR Jr, Katz R, et al. Association of pulse pressure, arterial elasticity, and endothelial function with kidney function decline among adults with estimated GFR >60 mL/min/1. 73 m(2): the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Kidney Dis. 2012;59(1):41-49.

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