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Sleep Apnea and the Kidney Is Sleep Apnea a Risk Factor for Chronic Kidney Disease? Patrick J. Hanly, MD; and Sofia B. Ahmed, MD, MMSc The prevalence of chronic kidney disease (CKD) is increasing, which presents challenges for both patients and health-care budgets. Although this phenomenon has been attributed to the growth in diabetes, hypertension, and obesity, sleep apnea and nocturnal hypoxemia may also contribute to the pathogenesis of CKD and its progression to kidney failure. Two pathophysiologic mechanisms responsible for CKD are glomerular hyperfiltration and chronic intrarenal hypoxia, resulting in tubulointerstitial injury, the final common pathway to endstage kidney disease (ESKD). Multiple descriptive studies have demonstrated an association between CKD and sleep apnea. Although sleep apnea is common in patients with CKD and associated with significant nocturnal hypoxemia, it is often relatively free of sleep-related symptoms, making it difficult to detect without objective nocturnal monitoring. Nevertheless, sleep apnea and nocturnal hypoxemia have been associated with loss of kidney function and kidney injury, suggesting that they contribute to the pathogenesis of continued deterioration in kidney function. There are several pathways through which sleep apnea may achieve this, including a direct effect of intrarenal hypoxia and activation of the systemic and renal reninangiotensin system. Further research is required to better understand these relationships and determine whether specific interventions in patients with sleep apnea have an impact on clinical outcomes, such as reducing the prevalence of CKD and delaying its progression to ESKD. CHEST 2014; 146 (4):1114-1122

AHI 5 apnea-hypopnea index; AngII 5 angiotensin II; CKD 5 chronic kidney disease; eGFR 5 estimated glomerular filtration rate; ESKD 5 end-stage kidney disease; FF 5 filtration fraction; GFR 5 glomerular filtration rate; PSG 5 polysomnography ; RAS 5 renin-angiotensin system; RDI 5 respiratory disturbance index; RPF 5 renal plasma flow ; PSQI 5 Pittsburg Sleep Quality Index; Sao2 5 arterial oxygen saturation ABBREVIATIONS:

It is well recognized that end-stage kidney disease (ESKD) is associated with an increased prevalence and severity of sleep apnea,1-4 the pathophysiology of which is related to both destabilization of central ventilatory control and upper airway occlusion during sleep.5-7 Sleep apnea is an

Manuscript received March 11, 2014; revision accepted May 27, 2014. AFFILIATIONS: From the Division of Respiratory Medicine (Dr Hanly), Sleep Centre, Foothills Medical Centre; and Division of Nephrology (Dr Ahmed), Department of Medicine, Faculty of Medicine, University of Calgary, Calgary, AB, Canada. FUNDING/SUPPORT: This study was supported by the Faculty of Medicine, Sleep Research Program, University of Calgary; Canadian Institutes of Health Research; and Alberta Innovates-Health Solutions.

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important comorbidity in patients with ESKD and contributes to the pathogenesis of excessive daytime sleepiness8 and has the potential to increase cardiovascular morbidity and mortality.9 More recently, the potential impact of OSA on the development of chronic kidney disease (CKD) has

CORRESPONDENCE TO:

Patrick J. Hanly, MD, 1421 Health Sciences Centre, 3330 Hospital Dr NW, Calgary, AB, T2N 4N1, Canada; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0596

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received increasing attention in the medical literature. These findings raise the possibility that a bidirectional relationship exists between sleep apnea and kidney disease. The global prevalence of CKD has increased significantly over the past decade,10-12 particularly in the older population. More than 10% of adults have CKD,13,14 and this figure rises to 20% in those aged . 60 years and to 35% in those aged . 70 years.10 Although this phenomenon has been largely attributed to the increasing prevalence of diabetes, hypertension, and obesity,12,15,16 these chronic medical disorders do not fully explain the growing prevalence of CKD.10 Undiagnosed sleep apnea is common,17 and its prevalence has increased dramatically in the past 2 decades.18 Sleep apnea may also contribute to the progression of kidney disease either directly through the effects of hypoxia on the kidney19,20 or indirectly by increasing oxidative stress and endothelial dysfunction, inflammatory cytokine levels, sympathetic nervous system activity, and systemic BP, all of which have been proposed to reduce kidney function.21-23 Because reduced kidney function increases the risk of cardiovascular morbidity and death24 and progression of CKD to renal replacement therapy carries an enormous economic burden,10,13,25 a better understanding of the potential role of sleep apnea in facilitating these changes is important to both clinicians and health policymakers. This article reviews the pathogenesis of kidney disease, summarizes the data on the prevalence of sleep apnea in the CKD population and its potential impact on kidney function, and outlines pathophysiologic mechanisms through which sleep apnea may damage the kidney.

Pathogenesis of Kidney Disease Conceptually, the kidney can be considered to consist of two functionally distinct but anatomically connected areas, namely the glomerulus, which is found predominantly in the cortex of the kidney, and the renal tubule, which is located predominantly in the renal medulla (Fig 126). Blood flows from the interlobular artery through the afferent arteriole to reach the capillary network within each glomerulus and leaves through the efferent arteriole to pass through the peritubular capillaries before exiting the kidney through the interlobular vein. Urine is produced by filtration at the glomerulus and reabsorption at the kidney tubule and is transported through the collecting system to the ureter. CKD is believed to start with an initial injury arising from a variety of sources.12,27 Once the injury has

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reached a critical threshold, additional physiologic processes within the kidney, which are largely independent of the initial insult, drive the progression to kidney failure.12,19 These mechanisms occur at the glomerulus (glomerular hyperfiltration theory)25 and the renal tubule (chronic hypoxia hypothesis).19,20,27 The glomerular hyperfiltration theory was proposed by Brenner et al28 in 1982, who suggested that a critical loss of nephrons from the initial injury results in a compensatory increase in activity in the remaining nephrons to maintain adequate clearance and glomerular filtration rate (GFR). Glomerular hyperfiltration is achieved largely by vasodilation of the afferent arteriole, which increases renal plasma flow and glomerular capillary pressure. Although this maintains GFR in the short term, it damages the glomerulus in the long term, resulting in the development of glomerulosclerosis. Furthermore, glomerular capillary hypertension impairs the sieving function of the glomerulus, resulting in protein overload that stimulates inflammation and fibrosis in the interstitium of the kidney.29 Although glomerular hypertension remains an important mechanism in the pathogenesis of CKD, damage to the kidney tubule and interstitium that surrounds it (tubulointerstitial injury) correlate better with the degree of kidney dysfunction. In fact, it has been proposed that tubulointerstitial injury, partly due to chronic hypoxia, is the final common pathway to ESKD.27 Although the kidney receives 20% of the total cardiac output, the supply of oxygen to the renal medulla, which receives only 10% of total renal blood flow,30 is compromised by both anatomic and physiologic factors. Anatomically, the renal medulla is relatively remote from the blood vessels that supply oxygen to the kidney. Physiologically, the countercurrent mechanism through which the renal tubule operates effectively provides an arteriovenous shunt for oxygen through the vasa recta. This compromised oxygen supply is further aggravated by an intermittently high oxygen consumption promoted by normal renal physiologic activities, such as active sodium reabsorption. The imbalance between limited oxygen supply and heavy demand in the renal medulla makes the kidney vulnerable to hypoxic injury.31 Intrarenal hypoxia has been demonstrated in humans with CKD32 (Fig 2), and renal tissue hypoxia in experimental animal models causes proteinuria independently of other hemodynamic or biochemical changes.33 It has been proposed that the renal parenchyma can respond to hypoxia through both protective pathways mediated by hypoxia-inducible factor and potentially harmful

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Figure 1 – Anatomy of the kidney. (Reprinted with permission from Openstax College.26)

pathways, such as the renin-angiotensin system (RAS),30,34 which are nonhypoxia-inducible factor-mediated mechanisms.

Prevalence of Sleep Apnea in CKD The potential for hypoxia to modulate progressive kidney damage has stimulated research to identify the

prevalence of sleep apnea in patients with CKD. Broadly speaking, they can be divided into three groups based on how the subjects were recruited, namely (1) patients with CKD who were investigated for sleep apnea, (2) patients with sleep apnea who were investigated for CKD, and (3) administrative databases that were interrogated for an association between sleep apnea and CKD. Prevalence of Sleep Apnea in Patients With CKD

Figure 2 – Blood oxygen level-dependent MRI of the kidney. Representative series of T2 images in a healthy subject and in a patient with CKD. In healthy subjects, MRI signals were homogenous and gradually degraded over time. T2 signals in CKD are more heterogeneous. In many areas, the signals were rapidly lost (arrowhead), suggesting the presence of severe hypoxia in those areas. CKD 5 chronic kidney disease. (Reprinted with permission from Manotham et al.32)

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Markou et al35 recruited 35 patients with an estimated GFR (eGFR) of 26.8 ⫾ 9.2 mL/min/1.73 m2 and found that 31.4% had OSA as reflected by an apnea-hypopnea index (AHI) . 15 based on overnight polysomnography (PSG). AHI correlated with blood urea level (r 5 0.35, P 5 .037), and in patients without diabetes (n 5 25), it correlated with eGFR (r 5 20.50, P 5 .012). Sakaguchi et al36 studied 100 Japanese men who had CKD (eGFR, 28.5 mL/min/1.73 m2; range, 8-40 mL/min/1.73 m2) and found that 33% had moderate to severe OSA (AHI . 15) as assessed by a type 3 portable monitor.37 Multivariate logistic regression analysis revealed that a 10 mL/min decrease in eGFR was associated with a 42% increased odds of OSA after adjustment for age, BMI, and diabetes mellitus. Roumelioti et al38 recruited 89 patients with CKD (eGFR, 18.9 ⫾ 7.6 mL/min/1.73 m2) and compared them with a

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community cohort of 224 subjects (eGFR, 91.8 ⫾ 19.2 mL/min/1.73 m2). Sleep apnea was evaluated by in-home unattended PSG. The prevalence of severe sleep apnea (AHI ⱖ 30) was significantly higher in patients with CKD than in the control group (22.5% vs 11.5%) with an adjusted OR of 2.41 (1.2-4.9, P 5 .01). Subsequently, Nicholl et al39 evaluated 254 patients who represented the full spectrum of kidney function, ranging from those with an eGFR . 60 mL/min/1.73 m2, to CKD (eGFR , 60 mL/min/1.73 m2 but not on dialysis), to ESKD (on hemodialysis). Sleep apnea was defined as a respiratory disturbance index (RDI) ⱖ 15 based on type 3 portable monitoring. The prevalence of sleep apnea increased as eGFR declined (eGFR . 60 mL/min/1.73 m2, 27%; CKD, 41%; ESKD, 57%; P 5 .002) (Fig 3). Furthermore, the prevalence of nocturnal hypoxemia was higher in patients with CKD and ESKD (Fig 4). Prevalence of CKD in Patients With Sleep Apnea

Kanbay et al40 studied 175 patients referred for overnight PSG for suspected sleep apnea. eGFR was determined in all subjects, who were stratified into four groups based on AHI (group 1, , 5; group 2, 5-15; group 3, 15-30; group 4, . 30). The authors reported a significant decrease in eGFR across these four groups (50 ⫾ 11.8, 44.8 ⫾ 15.9, 40.8 ⫾ 14.7, and 33.8 ⫾ 16 mL/min/1.73 m2 for groups 1-4, respectively; P for trend , .001). Chou et al41 studied 40 patients referred for PSG to rule out sleep apnea. The mean AHI was 51.6 ⫾ 39.2, and the mean eGFR was 85.4 ⫾ 18.3 mL/min/1.73 m2. The prevalence of CKD in patients with severe OSA

Figure 4 – Prevalence of nocturnal hypoxemia in CKD. Nocturnal hypoxemia was defined as mean arterial oxygen saturation of , 90% for ⱖ 12% of the recording time. Patient groups: eGFR ⱖ 60 mL/min/1.73 m2, CKD, and ESRD. The prevalence of nocturnal hypoxemia was 16% in patients with eGFR ⱖ 60 mL/min/1.73 m2, 47% in patients with CKD, and 48% in patients with ESRD (P , .001). See Figure 2 and 3 legends for expansion of abbreviations. (Reprinted with permission from Nicholl et al.39)

(AHI . 30) was 18%. Multivariate regression analysis revealed a significant association between AHI and eGFR (r2 5 0.32, P , .01). Iseki et al42 evaluated 4,056 patients in a sleep apnea syndrome registry of whom all had an AHI ⱖ 5 based on PSG. Of these patients, 1,624 had serum creatinine data from which the eGFR was determined. CKD, defined as an eGFR , 60 mL/min/1.73 m2, was found in 30.5% of patients with sleep apnea (AHI, 45.3 ⫾ 33.3). Furthermore, comparison of these patients with an age- and sex-matched control group (n 5 7,454) from the community showed an adjusted OR for CKD of 4.542 (3.922-5.260; P , .0001). Fleischmann et al43 determined the eGFR in 158 patients referred for overnight PSG for suspected sleep apnea and found it to be lower in patients with sleep apnea (AHI . 5) than in those without sleep apnea (84.5 ⫾ 7 mL/min/1.73 m2 vs 94.6 ⫾ 7 mL/min/1.73 m2, respectively; P 5 .037). Association Between Sleep Apnea and CKD in Administrative Databases

Figure 3 – Prevalence of sleep apnea in CKD and ESRD. Patient groups: eGFR ⱖ 60 mL/min/1.73 m2, CKD, and ESRD. The prevalence of sleep apnea increased as eGFR declined (eGFR ⱖ 60, 27%; CKD, 41%; ESRD, 57%; P 5 .002). CSR 5 Cheyne-Stokes respiration (defined as nasal pressure recording with a characteristic crescendo/decrescendo pattern without airflow limitation); eGFR 5 estimated glomerular filtration rate; ESRD 5 end-stage renal disease. See Figure 2 legend for expansion of other abbreviation. (Reprinted with permission from Nicholl et al.39)

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Canales et al44 investigated the prevalence of sleep apnea by in-home unattended PSG and the eGFR in 2,696 older men (mean age, 73 ⫾ 5.5 years) who were enrolled in the Outcomes of Sleep Disorders in Older Men (MrOS Sleep) study. Although 27% had sleep apnea (AHI ⱖ 15) and 15% had an eGFR , 60 mL/min/1.73 m2, no association was found between eGFR and AHI. Sim et al45 performed a cross-sectional study on a very large administrative health-care database comprising 1,377,427 adults, all of whom had one or more serum creatinine measurements taken over a 3-year period. Sleep apnea diagnosis was determined from administrative data, and eGFR was used as an estimation of kidney function. The overall prevalence of sleep apnea was low (2.5%) because the population included both subjects 1117

with normal renal function (eGFR . 60 mL/min/1.73 m2) and subjects with CKD. However, the OR for sleep apnea in subjects with an eGFR between 45 and 59 mL/min/1.73 m2 was 1.42 compared with subjects with normal renal function after adjustment for age, sex, and relevant comorbidities (diabetes, heart failure, and hypertension).

Clinical Profile of Patients With CKD and Sleep Apnea Sleep-related symptoms are common in patients with CKD. Murtagh et al46 performed a cross-sectional study of 66 patients with stage 5 CKD (eGFR, 11.2 ⫾ 2.8 mL/min/1.73 m2) who were managed conservatively (ie, not on dialysis), using a self-report questionnaire (Memorial Symptom Assessment Scale Short Form) to which renal symptoms were added. Forty-one percent of patients reported difficulty sleeping, and 65% reported drowsiness during the daytime. It should be noted that the study was in an elderly population (age, 82 ⫾ 6.6 years) with significantly impaired kidney function. A subsequent study by Kumar et al47 investigated sleep symptoms in 689 patients with stage 3 to 5 CKD (eGFR, 24.9 ⫾ 10.6 mL/min/1.73 m2). They constructed a sleep quality score (0-100) from a self-report questionnaire (Kidney Disease Quality of Life Instrument). Poor sleep quality (defined as a sleep quality score ⱕ 60) was reported by 57% of patients with CKD. The authors concluded that self-reported poor sleep quality was common in patients with CKD. Although the etiology of poor sleep in patients with CKD is multifactorial, it can be partly attributed to restless legs syndrome, the prevalence of which in patients with CKD has been reported to be as high as 26% and is independently associated with poor sleep quality as reflected by the Pittsburg Sleep Quality Index (PSQI).48 How does OSA present clinically in patients with CKD, and is OSA clinically apparent in this population? Nicholl et al49 evaluated 119 patients with CKD and compared those with and without OSA using a sleep history questionnaire, the Epworth Sleepiness Scale and the PSQI. Sleep apnea was determined by type 3 portable monitoring, with an RDI ⱖ 15 considered diagnostic of OSA. The prevalence of OSA symptoms (snoring, witnessed apnea, and unrefreshing sleep) and PSQI scores did not differ between patients with CKD with OSA and patients with CKD without apnea. The prevalence of daytime sleepiness (reflected by an Epworth Sleepiness Scale score of . 10) was higher in patients with CKD with OSA than in patients with CKD without apnea (39% vs 19%, P 5 .033). However, both 1118 Contemporary Reviews in Sleep Medicine

daytime sleepiness and symptoms of sleep apnea outlined previously were considerably less frequent than in patients with OSA without a history of kidney disease. Consequently, many patients with CKD can have OSA without the typical symptoms of this disorder. The investigators concluded that the presence of OSA in patients with CKD is unlikely to be clinically apparent and that objective nocturnal monitoring is required to reliably identify this comorbidity. The same authors evaluated three common screening questionnaires for OSA in patients with CKD, namely, the Berlin questionnaire, adjusted neck circumference, and the STOP-BANG (snoring, tiredness during daytime, observed apnea, high BP, BMI, age, neck circumference, sex) questionnaire.50 This study included patients with CKD (n 5 109) and ESKD (n 5 63). OSA was present in 38% of patients with CKD and 51% of those with ESKD. All screening instruments had a satisfactory sensitivity (56%-94%) but poor specificity (29%-77%) and low accuracy (51%-69%) in both patients with CKD and those with ESKD with sleep apnea (RDI ⱖ 15). Accuracy was defined as the total number of correct risk assessments divided by the total number of risk assessments. The results were unchanged if a more conservative RDI (RDI ⱖ 30) was used to define sleep apnea. The authors concluded that current screening questionnaires for OSA do not accurately identify patients at risk for OSA or rule out the presence of OSA in patients with CKD (and ESKD). Based on this literature, it appears that patients with CKD have a high prevalence of sleep-related complaints, but their clinical presentation is not specific enough to reliably identify those who have sleep apnea.

Potential Impact of Sleep Apnea on Kidney Function Two clinical studies have evaluated the association between sleep apnea and loss of kidney function. Both focused on indexes of nocturnal hypoxemia, which was predominately due to OSA, and both showed an association between the severity of nocturnal hypoxemia and the rate of decline of kidney function. Ahmed et al51 studied 858 patients who were referred for diagnostic testing (PSG or type 3 portable monitoring) to rule out sleep apnea and who had serial measurements of eGFR over a mean study period of 2.1 years. Nocturnal hypoxemia was defined as arterial oxygen saturation (Sao2) , 90% for ⱖ 12% of the recording time based on the use of a similar metric in the Sleep Heart Health Study.52 The RDI was calculated based on a 4% oxygen desaturation, with stratification of the results according to the recommendation of the American

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Academy of Sleep Medicine53: RDI , 5, normal; 5 to 14.9, mild OSA; 15 to 30, moderate OSA; and . 30 severe OSA. Through self-administered questionnaires and administrative data, relevant covariates were measured, including diabetes, hypertension, cardiovascular disease (heart failure, stroke, and myocardial infarction), COPD and asthma, cardiac arrhythmia, and depression. The RDI was 23 ⫾ 25 and Sao2 , 90% for 22 ⫾ 27% of the sleep recording. Baseline eGFR was 71 ⫾ 12 mL/min/1.73 m2. Forty-four percent of the patients had nocturnal hypoxemia, as defined previously, and 5.7% of the population had an accelerated decline in eGFR defined as a fall in eGFR of ⱖ 4 mL/min/1.73 m2 per year (two to four times normal). Multivariate logistic regression showed a significant association between nocturnal hypoxemia and rapid loss of kidney function, with an OR of 6.32 (3.03-13.20) in the unadjusted model. This remained significant following adjustment for RDI, age, BMI, diabetes, and heart failure, with an OR of 2.89 (1.25-6.67). The authors concluded that nocturnal hypoxemia was independently associated with an increased risk of accelerated loss of kidney function. In contrast to this study in patients referred for sleep testing, of whom most did not have a history of CKD, Sakaguchi et al54 evaluated 161 patients with stage 3 to 4 CKD. The primary exposure was intermittent hypoxemia reflected by an oxygen desaturation index (ODI) calculated as a 4% decline in oxygen saturation. The severity of nocturnal hypoxemia was categorized as none (ODI , 5), mild (ODI, 5-14.9), or moderate to severe (ODI ⱖ 15). The decline in kidney function was estimated as the change in eGFR over 1 year. The mean eGFR at baseline was 31 mL/min/1.73 m2. Fifty percent of patients had nocturnal hypoxemia, of whom 20% had moderate to severe nocturnal hypoxemia. The decline in eGFR was three to four times greater in patients with moderate to severe nocturnal hypoxemia compared with those with no or mild nocturnal hypoxemia. They concluded that nocturnal hypoxemia was a significant predictor of decline in kidney function, even after adjustment for a variety of baseline clinical factors. The association between sleep apnea and kidney function has been further tested by studies that have measured the change in eGFR following treatment of sleep-disordered breathing with positive airway pressure. Koga et al55 evaluated 27 patients with OSA without CKD before and 3 months after CPAP therapy. They found a small, but significant improvement in eGFR (72.9 ⫾ 12 to 79.3 ⫾ 17.9 mL/min/1.73 m2, P 5 .014). However, the study was not designed to

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investigate the underlying mechanisms. Two additional studies have evaluated the impact of adaptive servoventilation in patients with heart failure with sleep apnea and CKD.56,57 The morphology and pathogenesis of these patients’ sleep apnea was predominantly central rather than obstructive. Nevertheless, both studies reported that adaptive servoventilation improved eGFR and attributed this to a combination of improved cardiac hemodynamics and reduced sympathetic nervous system activation and inflammation, all of which may have contributed to improved survival.57

How Could Sleep Apnea Damage the Kidney? Potential Mechanisms OSA may be associated with CKD by virtue of overlapping comorbidities that are common to both conditions. Systemic hypertension, diabetes mellitus, and obesity are increasingly common, chronic disorders that are risk factors and consequences of OSA and CKD. Poor control of these disorders, especially hypertension and diabetes, are well known to hasten decline in kidney function in patients with CKD.14 However, OSA and nocturnal hypoxemia may also contribute to the progression of kidney disease independently of these comorbidities. If OSA does damage the kidney, it is likely to be modulated by intermittent hypoxia. It has been proposed that activation of the RAS leads to kidney damage58 by facilitating glomerular hyperfiltration and systemic hypertension, both of which can impair kidney function.29 Indeed, there is evidence from experimental animal59,60 and human61 models that the systemic RAS is activated by intermittent hypoxia. Notwithstanding this experimental evidence, studies that have evaluated the association between sleep apnea and the RAS in humans have yielded conflicting results.62-67 Activation of the RAS within the kidney (so-called renal RAS) in animal models has also been shown to have a variety of downstream effects, including glomerular hyperfiltration; inflammation; and ultimately, fibrosis within the kidney.68,69 A single study that evaluated renal hemodynamics in patients with OSA showed an improvement in filtration fraction (FF) (a marker of glomerular hypertension) associated with CPAP therapy.70 Furthermore, this effect was not seen in patients who were taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, which implicate a role for the RAS. We have evaluated the potential impact of OSA on the systemic and renal RAS and how this is altered by correction of OSA with CPAP.71 Twenty patients with OSA (RDI, 42 ⫾ 4) and significant nocturnal hypoxemia

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(Sao2 , 90% for 36 ⫾ 5% of the night) were studied before and after CPAP therapy. Systemic RAS activity was assessed by measurement of systemic BP and circulating components of the RAS and their response to an infusion of angiotensin II (AngII). Renal RAS was assessed by measurement of renal hemodynamics (GFR, renal plasma flow [RPF], and FF) and their response to AngII infusion. Following CPAP therapy, there was a significant reduction in BP and plasma aldosterone. Furthermore, the BP response to AngII increased after CPAP, which implies that systemic RAS was upregulated in untreated OSA.72 Regarding renal RAS activity, the FF fell significantly after CPAP, which reflects a reduction in glomerular pressure due to an increase in RPF. Furthermore, the sensitivity of the RPF response to AngII infusion increased after CPAP, which implies that renal RAS was upregulated in untreated OSA (Fig 5). These findings support a role for enhanced systemic and renal RAS activity in OSA, which could contribute to the progression of renal disease in patients with coexisting CKD. In summary, OSA is common in patients with CKD and may contribute to the pathogenesis of progressive kidney disease. There are multiple pathways through which this can occur that are initiated by the effect of nocturnal hypoxia on the RAS or directly on the kidney (Fig 6). Further research is required to understand how these pathways may be modified by specific therapies

Figure 6 – Schematic representation of the potential pathways for OSA to cause CKD and specific interventions (uppercase). ACEI 5 angiotensinconverting enzyme inhibitor; AngII 5 angiotensin II; Anti-HTN 5 antihypertensive medication; ARB 5 angiotensin receptor blocker; Glom..sclerosis 5 glomerulosclerosis; HIF 5 hypoxia-inducible factor; HTN 5 hypertension; Inflamm 5 inflammation; Pr uria 5 proteinuria; RAS 5 renin-angiotensin system; SNS 5 sympathetic nervous system. See Figure 2 legend for expansion of other abbreviation.

and whether this improves clinical outcomes, such as the prevalence of CKD and its progression to ESKD.

Acknowledgments Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Hanly reports receiving respiratory equipment donations from Philips Respironics (Koninklijke Philips NV) and Fisher & Paykel Healthcare Limited for research studies. Dr Ahmed has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript. Other contributions: The authors thank Leah Howson for clerical assistance.

References

Figure 5 – A and B, Change in FF (A) and response of RPF to angiotensin II infusion (B), pre- and post-CPAP therapy. *P , .05 vs pre-CPAP. FF 5 filtration fraction; RPF 5 renal plasma flow.

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