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Keywords:

  • endothelial dysfunction;
  • microalbuminuria;
  • obstructive sleep apnea

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Small urinary protein loss (low-grade albuminuria or microalbuminuria) may reflect altered permeability of the glomerular filtration barrier. In the present study, it was hypothesized that children with obstructive sleep apnea have an increased risk of microalbuminuria compared with control subjects without sleep-disordered breathing. Albumin-to-creatinine ratio was measured in morning spot urine specimens collected from consecutive children with or without snoring who were referred for polysomnography. Three groups were studied: (i) control subjects (no snoring, apnea–hypopnea index < 1 episode h−1; = 31); (ii) mild obstructive sleep apnea (snoring, apnea–hypopnea index = 1–5 episodes h−1; = 71); and (iii) moderate-to-severe obstructive sleep apnea (snoring, apnea–hypopnea index > 5 episodes∙h−1; = 27). Indications for polysomnography in control subjects included nightmares, somnambulism and morning headaches. An albumin-to-creatinine ratio > median value in the control group (1.85 mg of albumin per g of creatinine) was defined as elevated. Logistic regression analysis revealed that children with moderate-to-severe obstructive sleep apnea, but not those with mild obstructive sleep apnea, had increased risk of elevated albumin-to-creatinine ratio relative to controls (reference) after adjustment for age, gender and presence of obesity: odds ratio 3.8 (95% confidence interval 1.1–12.6); = 0.04 and 1.5 (0.6–3.7); > 0.05, respectively. Oxygen desaturation of hemoglobin and respiratory arousal indices were significant predictors of albumin-to-creatinine ratio (= 0.31, = 0.01; and = 0.43, < 0.01, respectively). In conclusion, children with moderate-to-severe obstructive sleep apnea are at significantly higher risk of increased low-grade excretion of albumin in the morning urine as compared with control subjects without obstructive sleep apnea. These findings may reflect altered permeability of the glomerular filtration barrier related to nocturnal hypoxemia and sympathetic activation which are induced by obstructive sleep apnea.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Obstructive sleep apnea (OSA) has been recognized as an independent risk factor for systemic and pulmonary hypertension, heart failure, coronary heart disease, ventricular arrhythmias, stroke and end-stage renal disease in adults (Somers et al., 2008). Despite the paucity of evidence for overt cardiovascular morbidity in the pediatric population, children with OSA exhibit subtle manifestations of cardiovascular derangements, such as increased heart rate (Kaditis et al., 2011), blood pressure and blood pressure variability (Amin et al., 2004, 2008). Such abnormalities are probably related to obstructive events and the associated sympathetic nervous system overflow (Kaditis et al., 2009; O'Driscoll et al., 2009). Repetitive hypoxia-reoxygenation events accompanying apneas and hypopneas may predispose to endothelial dysfunction, which can be reversible after treatment (Gozal et al., 2007; Kaditis et al., 2010).

‘Microalbuminuria’ can be one of the subclinical manifestations of endothelial dysfunction. The term refers to a relatively small and clinically non-apparent, protein urinary loss via the glomerular filtration barrier. It is measured either in a 24-h urine collection or by calculating the albumin-to-creatinine ratio (ACR) in a spot urine sample. Evidence from the Third Copenhagen City Heart Study indicates that adults with microalbuminuria above the upper quartile have increased risk of coronary heart disease and death even after adjustment for the presence of diabetes mellitus and hypertension (Klausen et al., 2004).

Age and body weight, puberty, female gender, exercise and African-American descent are all physiological factors affecting urinary albumin excretion in childhood (Rademacher and Sinaiko, 2009). In pediatric patients with diabetes, the degree of microalbuminuria correlates positively with high blood pressure and lipid levels (Ettinger et al., 2005). It is conceivable that OSA-induced intermittent hypoxemia has adverse effects on the glomerular filtration barrier. Thus, in the current investigation, it was hypothesized that children with OSA have an increased risk of elevated ACR in morning spot urine specimens compared with control subjects without OSA or primary snoring.

Patients and Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Participants

Consecutive children referred to the Sleep Disorders Laboratory for polysomnography due to history of snoring and adenotonsillar hypertrophy with an age range of 2–14 years and with an apnea–hypopnea index (AHI) > 1 episode h−1 were enrolled in the study. Subjects without snoring, who underwent polysomnography for other reasons (nightmares, somnambulism, morning headaches) and had AHI < 1 episode h−1 were included as controls. Children with primary snoring (history of snoring and AHI < 1 episode h−1) were not recruited.

Exclusion criteria for both patients and controls were: (i) renal disease or abnormal serum creatinine concentration; (ii) diabetes mellitus; (iii) symptoms or signs of acute respiratory tract infection; (iv) neuromuscular disorders or craniofacial abnormalities; (v) cardiac disease; (vi) abnormal urinalysis with overt proteinuria; (vii) current use of ACE inhibitors or angiotensin receptor blockers. The study was approved by the Institutional Review Board of the Larissa University Hospital, and written informed consent was provided by the caregivers.

Clinical evaluation and polysomnography

A detailed history was received from parents, and all participants had a physical examination. Weight and standing height were recorded, and body mass index (BMI) z-score was calculated. Obesity was defined as BMI z-score > 1.645 (Kuczmarski et al., 2002). Upon morning arousal from sleep and after the child had been sitting quietly for about 5 min, blood pressure was measured three times using the right arm and a cuff of appropriate size (Dinamap Pro 100; Criticon; Tampa, FL, USA). To adjust for the effects of age, gender and height, blood pressure z-scores were determined (National High Blood Pressure Education Program Working Group, 2004).

Overnight polysomnography was carried out in the Sleep Disorders Laboratory and the following signals were recorded: electroencephalogram (EEG; C3/M2, F4/M1, O1/M2, O2/M1); right and left oculogram; submental and tibial electromyogram; body position; electrocardiogram; thoracic and abdominal wall motion; oronasal airflow (three-pronged thermistor and nasal pressure transducer); and oxygen saturation of hemoglobin (SpO2). Arousals, sleep stages and respiratory events were scored, and polysomnography indices were defined according to the recent American Academy of Sleep Medicine recommendations (Iber and American Academy of Sleep Medicine, 2007). Similar to previous studies (Gozal et al., 2010), respiratory arousals were defined as suggested in the report of the American Sleep Disorders Association Task Force on scoring of EEG arousals, i.e. those occurring within 3 s following an apnea, hypopnea or snore (American Sleep Disorders Association, 1992).

Main outcome measure

Urinary albumin excretion was the primary outcome measure. All children voided around 22:00 h and prior to initiation of polysomnography, and a urine specimen was collected at 08:00 h after its completion. Levels of creatinine in urine were determined using a standard color-producing method (Jaffé method) with an analytical range of 1–400 mg dL−1. Albumin concentration was determined using an immunonephelometric assay appropriate for detection of low-grade albuminuria (microalbuminuria) and with an analytical range of 0.25–500 mg L−1 (Microalbumin; Medicon Hellas SA, Gerakas, Greece). Urinary albumin excretion was expressed as: ACR (mg g−1) = urine albumin concentration/urine creatinine concentration.

Data analysis

To assess the study hypothesis, participants were classified into three groups: (i) control group (no snoring and AHI < 1 episode h−1); (ii) mild OSA (snoring and AHI 1–5 episodes h−1); and (iii) moderate-to-severe OSA (snoring and AHI > 5 episodes∙h−1). This classification is based on previously published population studies that indicate that AHI > 1 episode h−1 is associated with increased risk of neurocognitive morbidity, and AHI > 5 episodes h−1 is related to elevated blood pressure (Bixler et al., 2008, 2009; Goodwin et al., 2003). Children without sleep-disordered breathing (no snoring and AHI < 1 episode h−1), and not subjects with primary snoring (snoring and AHI < 1 episode h−1), were recruited as the comparison group. This choice was made in order to increase the probability of demonstrating significant differences between the two OSA study groups and the control group.

The three study groups were compared in terms of subjects' characteristics, polysomnography indices and ACR. For continuous variables that approached the normal distribution one-way anova with post hoc tests for pair comparisons (Bonferroni's) was applied, whereas a non-parametric test (Kruskal–Wallis) was used for data that did not fulfil the condition of normality. The χ2-test (Yate's correction) was carried out for categorical variables.

Values of polysomnography indices and ACR were log-transformed (natural logarithm) to approach a normal distribution, and the Kolmogorov–Smirnov test was applied to test for normality. Pearson's correlation was carried out to identify associations between log-transformed ACR and: (i) log-transformed polysomnography indices; (ii) BMI z-score; and (iii) age. Multiple linear regression analysis was performed to identify significant predictors of ACR. Log-transformed ACR was the dependent variable, and age, gender, BMI z-score and log-transformed polysomnography indices that were significantly correlated with ACR (one polysomnography index in each model) were the independent variables (spss version 17.0; SPSS, Chicago, IL, USA).

Because the upper limit of normal for low-range albuminuria has not been defined in children clearly, an ACR was considered as elevated if it exceeded the median value for the control group. Univariate and multivariate logistic regression analysis was performed to determine the risk (odds ratio and 95% confidence interval) of elevated ACR in children with moderate-to-severe OSA or mild OSA relative to controls (reference) before and after adjustment for age, gender and presence of obesity. Finally, univariate logistic regression analysis was used to assess the risk of elevated ACR in participants with high or high normal morning systolic or diastolic blood pressure, i.e. over the 90th percentile or blood pressure z-score > 1.28 (National High Blood Pressure Education Program Working Group, 2004).

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

Subjects' characteristics and polysomnography findings

During the study period, a total of 129 children appropriate for recruitment underwent polysomnography and their parents agreed for participation to the study: 27 of them were children with moderate-to-severe OSA; 71 had mild OSA; and 31 were control subjects without snoring and with an AHI < 1 episode h−1. Indications for polysomnography in the participants of the control group were: nightmares (= 14); somnambulism (= 6); and morning headaches (= 11). The three study groups were similar regarding age, BMI z-score, ratio of female-to-male gender, frequency of obesity, and systolic and diastolic blood pressure (> 0.05; Table 1). There were no subjects with morning diastolic blood pressure > 90th percentile. As anticipated, children with moderate-to-severe OSA had significantly worse polysomnography indices relative to subjects with mild OSA or to control participants (< 0.01; Table 1).

Table 1. Summary statistics and comparisons between the three study groups regarding subjects' characteristics and polysomnography indices
 Controls (n = 31)Mild OSA (n = 71)Moderate-to-severe OSA (n = 27)
  1. a

    < 0.01 for comparisons between the moderate-to-severe OSA or mild OSA group and the control group.

  2. b

    < 0.01 for the comparison between the moderate-to-severe OSA and the control group.

  3. AHI, apnea–hypopnea index; BMI, body mass index; BP, blood pressure; OSA, obstructive sleep apnea; REM, rapid eye movement.

Age, years6.7 ± 2.46.2 ± 2.35.6 ± 2.1
Gender, female (%)18 (58.1)30 (42.3)8 (29.6)
BMI z-score0.58 ± 1.330.60 ± 1.270.56 ± 1.35
Obese (%)6 (19.4)13 (18.3)7 (25.9)
Systolic BP (mmHg)99.4 ± 1298.2 ± 11.296.3 ± 12.1
Systolic BP z-score0.14 ± 1.030.08 ± 0.89−0.06 ± 1.12
Systolic BP > 90th percentile (%)3 (9.7)6 (8.5)2 (7.4)
Diastolic BP (mmHg)65.9 ± 10.465.3 ± 9.764.4 ± 9.4
Diastolic BP z-score−0.85 ± 0.88−0.82 ± 0.79−0.86 ± 0.82
Diastolic BP > 90th percentile (%)0 (0)0 (0)0 (0)
AHIa, episodes∙h−10.6 ± 0.32.4 ± 1.09.1 ± 3.7
Resp. arousal indexb, episodes∙h−10.7 ± 1.02.5 ± 2.610.3 ± 9.7
Oxygen desaturation of hemoglobin indexa, episodes∙h−11.7 ± 1.16.1 ± 3.217.4 ± 9.3
SpO2 nadira,%92.1 ± 1.989.5 ± 2.784.0 ± 5.5
Total sleep time, min369.5 ± 79.8370.9 ± 88.9387.1 ± 80.1
Sleep efficiency,%88.6 ± 12.983.8 ± 11.188.5 ± 9.1
Arousal indexa, episodes∙h−11.5 ± 0.76.0 ± 3.519.5 ± 14.1
Stage 1,% of total sleep time12.4 ± 9.312.2 ± 12.512.3 ± 21
Stage 2,% of total sleep time44.4 ± 13.844.7 ± 11.842.4 ± 10.0
Stage 3,% of total sleep time25.6 ± 11.526.3 ± 9.126.4 ± 8.7
Stage REM,% of total sleep time18.0 ± 6.017.1 ± 6.018.3 ± 5.8

Correlation of ACR with polysomnography indices

Log-transformed ACR correlated significantly with log-transformed oxygen desaturation of hemoglobin index (= 0.25, < 0.01) and respiratory arousal index (= 0.37, < 0.01). Multivariable analysis revealed that log-transformed oxygen desaturation of hemoglobin index and respiratory arousal index were significant predictors of log-transformed ACR after adjustment for age, gender and BMI z-score (= 0.31, = 0.01; = 0.43, < 0.01, respectively).

Effect of OSA on risk for increased ACR

There was no significant difference between the three study groups in terms of ACR (> 0.05). Median (interquartile range) ACR values in children with moderate-to-severe OSA, mild OSA or controls were: 3.85 (1.59–7.19); 3.22 (0.43–6.40); and 1.85 (0.33–5.21) mg g−1, respectively. However, univariate logistic regression analysis revealed that subjects with moderate-to -severe OSA, but not those with mild OSA, had significantly increased risk of elevated ACR [odds ratio (OR) 3.3 (95% confidence interval, CI: 1.0–10.3), = 0.04; and 1.4 (0.6–3.2), > 0.05, respectively] compared with the control group. The increased risk of elevated ACR in participants with moderate-to-severe OSA persisted even after adjustment for age, gender and presence of obesity: 3.8 (1.1–12.6), = 0.03 (Table 2). OR (95% CI) for other independent variables are summarized in Table 2. High or high normal morning systolic blood pressure was not a risk factor for elevated ACR [1.7 (0.4–6.9), > 0.05].

Table 2. OR (95% CI) for potential predictors of elevated ACR (>1.85 mg g−1) using logistic regression analysis
Independent variablesNormal ACR,% (n = 50)Elevated ACR,% (n = 79)Unadjusted OR (95% CI)Adjusted ORb (95% CI)
  1. a

    P < 0.05.

  2. b

    Multivariable logistic regression analysis was applied to adjust OR for each independent variable by all other variables.

  3. ACR, albumin-to-creatinine ratio; CI, confidence interval; OR, odds ratio; OSA, obstructive sleep apnea.

OSA severity
Controls30.020.31.0 (ref.)1.0 (ref.)
Mild OSA58.053.21.4 (0.6–3.2)1.5 (0.6–3.7)
Moderate-to-Severe OSA12.0 26.53.3 (1.0–10.3)a3.8 (1.1–12.6)a
Gender
Male64.051.91.0 (ref.)1.0 (ref.)
Female36.048.11.6 (0.8–3.4)2.2 (1.0–5.0)a
Obesity
Non-obese86.075.91.0 (ref.)1.0 (ref.)
Obese14.024.11.9 (0.8–5.0)2.0 (0.7–5.2)
Age, years (mean ± SD)6.5 ± 2.36.0 ± 2.30.9 (0.8–1.1)0.9 (0.8–1.1)

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

In the current pediatric study, an association was demonstrated between morning urinary albumin loss and OSA severity. Children with moderate-to-severe OSA (AHI > 5 episodes h−1) had a fourfold increased risk of an elevated ACR as compared with the control group even after adjustment for age, gender and presence of obesity. The albumin excretion was in the low range (microalbuminuria), and not overt and associated with clinical symptoms (macroalbuminuria). Females were twice more likely to have elevated ACR relative to males, whereas obesity did not modify the risk of increased albumin excretion in the urine. Of note, frequency of intermittent hypoxemia and arousals related to respiratory events were significant predictors of microalbuminuria. This is the first pediatric study associating moderate-to-severe OSA with adverse effects on the glomerular filtration barrier.

Since the initial report by Chaudhary et al. (1988) of an association between OSA and low-grade albuminuria in adults, several other investigations have been published on the topic with conflicting results. In the study by Faulx et al. (2007), patients with AHI > 5 episodes h−1 had higher ACR values compared with those with fewer apneic events. A subsequent study of adults with newly diagnosed OSA revealed that affected individuals have an overnight increase in ACR relative to control subjects, and this phenomenon can be abolished by continuous positive airway pressure treatment (Daskalopoulou et al., 2011). In all investigations, microalbuminuria and not macroalbuminuria was identified. Nevertheless, others did not reproduce an association between sleep apnea and proteinuria after adjustment for adiposity, hypertension and diabetes mellitus (Canales et al., 2011).

In the present report, obesity did not account for the increased risk of elevated ACR in children with moderate-to-severe OSA relative to control subjects. Glucose values after an oral glucose tolerance test, but not OSA severity, predicted albumin excretion rate in the only published pediatric investigation that evaluated the renal implications of sleep apnea in overweight and obese children and adolescents (Verhulst et al., 2008). It is possible that the effects of metabolic alterations related to obesity on the glomerular filtration barrier were more apparent compared with the adverse effects of OSA. Furthermore, urinary excretion of protein in the study by Verhulst et al. (2008) was calculated in 24-h urine samples and thus orthostatic proteinuria during wakefulness, a frequently encountered and overall benign condition, may have obscured the contribution of OSA to microalbuminuria.

Oxygen desaturation of hemoglobin index was a significant predictor of ACR. A number of pathogenetic mechanisms can explain how obstructive apnea and hypopnea and the associated intermittent hypoxemia enhance urinary albumin loss. Free radicals generated during intermittent hypoxemia (oxidative stress) may disrupt the endothelial glycocalyx layer and increase the permeability of the glomerular barrier to a variety of macromolecules (Kaditis et al., 2010; Krishna et al., 2006; Kuwabara et al., 2010).

Respiratory arousal index was another significant predictor of albumin excretion in the urine. Arousals from sleep and intermittent hypoxemia related to OSA may lead to sympathetic nervous system activation (Somers et al., 1993), upregulation of the renin-angiotensin-aldosterone axis, nocturnal non-dipping of blood pressure and microalbuminuria (Amin et al., 2004; Daskalopoulou et al., 2011; Moller et al., 2003). In addition, angiotensin II and brain natriuretic peptide released in children with OSA (Kaditis et al., 2006) can lead to constriction of the efferent glomerular arteriole, increased intraglomerular hydraulic pressure and ultimately to an overfiltrative state (Kinebuchi et al., 2004). In the present study, high morning blood pressure was not associated with increased risk of microalbuminuria. However, 24-h ambulatory blood pressure recordings (and not isolated blood pressure measurements) may be required to detect subtle adverse effects of OSA on the renal system.

The clinical significance of microalbuminuria in otherwise healthy children with OSA remains unclear. Most published data refer to pediatric populations with co-morbidities other than sleep-disordered breathing. In hypertensive children, microalbuminuria explains part of the variance in left ventricular mass index (Assadi, 2007) and, in obese teenagers, it modifies the risk for hypertension, insulin resistance and diabetes (Nguyen et al., 2008). In children with diabetes, urinary albumin levels are positively correlated with daytime ambulatory blood pressure (Ettinger et al., 2005).

In conclusion, moderate-to-severe OSA in childhood is associated with increased risk of low-grade morning albuminuria. If future interventional studies indicate that this abnormality resolves following relief of upper airway obstruction, microalbuminuria could be used as a marker for the identification of subgroups of sleep apneic children who should be treated.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

The study was supported financially by the University of Thessaly Research Committee.

Conflict of Interest

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References

The authors do not have any conflicts of interest to disclose.

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  2. Summary
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Conflict of Interest
  9. References
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