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Objective : Sleep-disordered breathing (SDB) is highly prevalent in school children with poorly-controlled asthma. However, this association has not been assessed in preschoolers with recurrent wheeze, nor in those at risk for asthma. We hypothesized that preschoolers with asthma risk (positive asthma predictive index [API]) have a higher prevalence of SDB and higher inflammatory biomarkers (blood-hsCRP and urinary-LTE4) levels than those with negative API. Method : Children 2 to 5 years of age with recurrent wheezing were classified as positive or negative API. SDB was determined by the pediatric sleep questionnaire (PSQ) and its subscale (PSQSub6). Demographic characteristics, spirometry, blood hsCRP and urinary LTE4 were assessed. Results : We enrolled 101 preschoolers: 70 completed all measurements, 55.4% were males, mean age 4.07 ± 0.87 years, 45% overweight or obese, 70% had positive API, 87.5% had rhinitis. The prevalence of SDB measured by PSQ was 40.8% and by PSQSub6 was 29.6%. However, the proportion of SDB was similar between positive and negative API groups. The hsCRP (mean ± SD) was higher in the positive than in negative API (3.58 ± 0.58 and 1.32 ± 0.36 mg/L, p  = 0.69, respectively); moreover, no differences in urinary LTE4 were found between groups. No correlation of PSQ (+) or PSQSub6 (+) with hsCRP and uLTE4 was found. However, preschoolers with positive API had significantly more post-bronchodilator percentage change in FEF25-75 than negative API (24.14 ± 28.1 vs. 4.13 ± 21.8, respectively, p  = 0.01). Conclusions : In preschoolers with recurrent wheezing, we should be investigating for the coexistence of SDB, using early screening methods for detecting those conditions.

Introduction: Tissue hypoxia stimulates the production of erythropoietin (EPO), the main effect of which is, in turn, to stimulate erythropoiesis. Sleep apnea-hypopnea syndrome (SAHS) is an entity characterized by repeated episodes of hypoxemia during sleep., Objective: To analyze whether hypoxemia stimulated increased urinary excretion of EPO, and if so, to evaluate if treatment with continuous positive airway pressure (CPAP) can inhibit this phenomenon., Methods: We studied 25 subjects with suspected SAHS who underwent a polysomnography study (PSG). EPO levels in first morning urine (uEPO) and blood creatinine and hemoglobin were determined in all patients. Patients with severe SAHS repeated the same determinations after CPAP treatment., Results: Twelve subjects were diagnosed with severe SAHS (mean ± SD, AHI 53.1 ± 22.7). Creatinine and hemoglobin levels were normal in all subjects. uEPO was 4 times higher in the SAHS group than in the control group (1.32 ± 0.83 vs. 0.32 ± 0.35 UI/l, p <.002). CPAP treatment reduced uEPO to 0.61 ± 0.9 UI/l (p <.02), levels close to those observed in healthy subjects. No dose-response relationship was observed between severity of PSG changes and uEPO values., Conclusions: Patients with severe SAHS show increased uEPO excretion, but this normalizes after treatment with CPAP., (Copyright © 2017 SEPAR. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective Due to limitations of polysomnography (PSG), novel ways to evaluate pediatric obstructive sleep apnea (OSA) are needed. Urinary leukotriene E4 (LTE4), an inflammatory marker, has been identified as a potential biomarker for pediatric OSA. The objective of the study was to assess whether urinary LTE4 levels correlate with OSA severity, as determined by obstructive apnea-hypopnea index (AHI) and nadir oxygen saturation. Study Design Prospective trial. Setting Tertiary care children's hospital. Subjects and Methods Children (age, 3-16 years) with sleep-disordered breathing (SDB) who were referred for PSG were included. Urine samples were obtained the morning following PSG, and urinary LTE4 levels were quantified with enzyme-linked immunoassay kits. Results A total of 113 children were enrolled, and the mean age was 7.3 years. Thirty-nine percent (n = 44) were obese, and the majority were white (53%, n = 58). Seventy-eight percent (n = 88) were diagnosed with OSA (AHI >1), with 27% (n = 30) having severe disease (AHI >10). The mean urinary LTE4 level was 91.3 ng/mM. Urinary LTE4 levels did not correlate with AHI ( P = .77) or nadir oxygen saturation ( P = .64). There was a significant difference in urinary LTE4 levels between patients with mild SDB and those with moderate to severe OSA ( P = .03). Conclusion Urinary LTE4 levels do not correlate with AHI in children with SDB. Compared with children with severe OSA, children with mild SDB have higher urinary LTE4 levels. Further research is needed determine whether urinary LTE4 is a satisfactory biomarker for pediatric OSA.

Background: The lysosomal storage disorder, mucopolysaccharidosis I (MPS I), commonly manifests with upper airway obstruction and sleep disordered breathing (SDB). The success of current therapies, including haematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) may be influenced by a number of factors and monitored using biomarkers of metabolic correction. We describe the pattern of SDB seen in the largest MPS I cohort described to date and determine therapies and biomarkers influencing the severity of long-term airway disease., Methods: Therapeutic, clinical and biomarker data, including longitudinal outcome parameters from 150 sleep oximetry studies were collected in 61 MPS I (44 Hurler, 17 attenuated) patients between 6 months pre to 16 years post-treatment (median follow-up 22 months). The presence and functional nature of an immune response to ERT was determined using ELISA and a cellular uptake inhibition assay. Multivariate analysis was performed to determine significant correlators of airway disease., Results: The incidence of SDB in our cohort is 68%, while 16% require therapeutic intervention for airway obstruction. A greater rate of progression (73%) and requirement for intervention is seen amongst ERT patients in contrast to HSCT treated individuals (24%). Multivariate analysis identifies poorer metabolic clearance, as measured by a rise in the biomarker urinary dermatan sulphate: chondroitin sulphate (DS:CS) ratio, as a significant correlator of increased presence and severity of SDB in MPS I patients (p = 0.0017, 0.008). Amongst transplanted Hurler patients, delivered enzyme (leukocyte iduronidase) at one year is significantly raised in those without SDB (p = 0.004). Cellular uptake inhibitory antibodies in ERT treated patients correlate with reduced substrate clearance and occurrence of severe SDB (p = 0.001)., Conclusion: We have identified biochemical and therapeutic factors modifying airway disease across the phenotypic spectrum in MPS I. Interventions maximising substrate reduction correlate with improved long-term SDB, while inhibitory antibodies impact on biochemical and clinical outcomes. Monitoring and tolerisation strategies should be re-evaluated to improve detection and minimise the inhibitory antibody response to ERT in MPS I and other lysosomal storage diseases. Future studies should consider the use of sleep disordered breathing as an objective parameter of clinical and metabolic improvement.

Background: Short sleep duration and decreased sleep quality are emerging risk factors for obesity and its associated morbidities. Chronotype, an attribute that reflects individual preferences in the timing of sleep and other behaviors, is a continuum from morningness to eveningness. The importance of chronotype in relation to obesity is mostly unknown. Evening types tend to have unhealthy eating habits and suffer from psychological problems more frequently than Morning types, thus we hypothesized that eveningness may affect health parameters in a cohort of obese individuals reporting sleeping less than 6.5 hours per night., Methodology and Principal Findings: BASELINE DATA FROM OBESE (BMI: 38.5±6.4 kg/m(2)) and short sleeping (5.8±0.8 h/night by actigraphy) participants (n = 119) of the Sleep Extension Study were analyzed (www.ClinicalTrials.gov, identifier NCT00261898). Assessments included the Horne and Ostberg Morningness-Eveningness questionnaire, a three-day dietary intake diary, a 14-day sleep diary, 14 days of actigraphy, and measurements of sleep apnea. Twenty-four hour urinary free cortisol, 24 h urinary norepinephrine and epinephrine levels, morning plasma ACTH and serum cortisol, fasting glucose and insulin, and lipid parameters were determined. Eveningness was associated with eating later in the day on both working and non-working days. Progression towards eveningness was associated with an increase in BMI, resting heart rate, food portion size, and a decrease in the number of eating occasions and HDL-cholesterol. Evening types had overtly higher 24 h urinary epinephrine and morning plasma ACTH levels, and higher morning resting heart rate than Morning types. In addition, Evening types more often had sleep apnea, independent of BMI or neck circumference., Conclusions: Eveningness was associated with eating later and a tendency towards fewer and larger meals and lower HDL-cholesterol levels. In addition, Evening types had more sleep apnea and higher stress hormones. Thus, eveningness in obese, chronically sleep-deprived individuals compounds the cardiovascular risk associated with obesity.

Sleep-disordered breathing (SDB) is prevalent in childhood obesity. It may be an independent risk factor for the metabolic syndrome. Possible mechanisms are inflammation and oxidative stress. Adenotonsillectomy in childhood obesity is associated with a high recurrence rate and risk of postoperative weight gain. Therefore, this study assessed the effects of SDB on inflammation and oxidative stress in childhood obesity before and after weight loss. We included 132 obese subjects between 10 and 18 years consecutively. Median age was 15.4 years (10.1-18.0). Mean BMI z-score was 2.72 ± 0.42. Leukocytes and differentiation, high sensitivity C-reactive protein (hs-CRP), and uric acid (UA) were determined at baseline and subjects underwent a sleep assessment. SDB was diagnosed in 39%. Linear regression analysis showed an association between UA(log) and oxygen desaturation index(log) (ODI(log)) (r = 0.20; P = 0.03), between leukocytes(log) and respiratory disturbance index(log) (RDI(log)) (r = 0.23; P = 0.01), and between lymphocytes(log) and RDI(log) (r = 0.19; P = 0.04). Follow-up was organized after 4-6 months of treatment. Median decrease in BMI z-score was 32%. Laboratory measurements were repeated. Subjects with SDB at baseline underwent a second sleep study. Of these 49 subjects, 12 showed residual SDB. This corresponds with a treatment success rate of 71%. Unlike changes in inflammatory markers, improvements in UA were associated with improvements in RDI and ODI (respectively: r = 0.44; P = 0.007, r = 0.41; P = 0.01). In conclusion, weight loss is effective in treating obese children with SDB. At baseline, a link exists between inflammation and SDB. Oxidative stress is reflected by UA at baseline and the concentration decreases after treatment according to improvements in SDB.

Study Objectives: Sleep disordered breathing (SDB) has been associated with increased inflammatory responses. Changes in the level of pro-inflammatory leukotrienes (LTs) may initiate or exacerbate pediatric SDB and may play a major role in end-organ morbidity. The objective of the study was to investigate the relationship of LT productions with severity of SDB, obesity, and adenotonsillar hypertrophy in children., Design/interventions: Prospective, observational study that included standard questionnaires, physical examinations, overnight polysomnography (PSG), and urinary leukotriene E(4) (LTE(4)) assay., Setting: Sleep Center and Laboratory of Nutriology., Patients or Participants: 282 children with SDB and 94 healthy control subjects were recruited., Measurements and Results: Urinary LTE(4) levels were elevated in children with SDB compared to the controls, and LTE(4) productions emerged disease severity- and obesity-dependent increases. In stepwise multiple regression analysis, the independent predictors of the apnea-hypopnea index (AHI) included LTE(4) level and adenotonsillar-size sum score (P < 0.001 respectively; adjusted R(2)=0.318). A positive relationship between LTE(4) urinary level and adenotonsillar-size sum scores was present in the underweight/normal weight SDB subjects (r=0.276; P < 0.001), but not in the overweight/obese children (P > 0.05)., Conclusions: Systemic inflammation mediated by LTs participates in the pathophysiological mechanisms of SDB in children. The magnitude of inflammation as reflected by urinary LTE(4) is significantly related to the severity of SDB and obesity. However, a correlation between LTE(4) concentration and adenotonsillar size is present only among nonobese children.

Background: Nocturia is common but the clinical assessment of its severity and cause rarely involves any biochemical analysis. Investigating the cause of nocturia needs to be informed by the overall 24 h fluid and solute excretion patterns. The aim of this study was to establish a practical method of monitoring the renal excretion of water and solutes over a complete 24 h cycle., Methods: The excretion patterns of sodium, volume and osmoles were assessed in 89 healthy control subjects over a 24 h period by sampling each voiding from the 24 h collection and then using the total urine creatinine as the denominator. A group of 21 patients under investigation for sleep-disordered breathing (SDB: a group of disorders known to increase the risk of nocturia) were also studied to determine comparative excretion patterns., Results: Reference excretion patterns of sodium, volume and osmoles were described. Patients under investigation for SDB had overall a significant (P < 0.001) increase in urine sodium excretion at night (nocturnal natriuresis) matched by an increased osmotic excretion and accompanied by a significantly increased nocturnal urine volume (P < 0.001)., Conclusion: Breaking down a 24 h urine collection into voided aliquots provides practical information on the pattern of water and solute excretion. Such patterns may assist in identifying the underlying mechanism of significant nocturia in individual patients presenting with this symptom, and could be used as a method of monitoring treatment.

Background: Nocturnal urinary sodium excretion is related to blood pressure (BP) levels. Elevated BP and increased nocturnal natriuresis have been demonstrated in adults with sleep apnea. Although evidence indicates increased BP in children with obstructive sleep-disordered breathing (SDB), it is unknown whether these children have also enhanced urinary sodium excretion., Objective: To evaluate the effects of SDB and morning BP on urinary sodium excretion., Methods: Consecutive children with snoring (n = 95) underwent polysomnography and morning BP measurement. Fractional excretion of sodium (FE(Na)) was the primary outcome measure and was calculated using sodium and creatinine concentrations in early morning serum and urine specimens., Results: Subjects with moderate-to-severe SDB had similar log-transformed FE(Na) to that of children with mild SDB and higher than children with primary snoring: -0.13 ± 0.53 versus -0.28 ± 0.41 versus -0.61 ± 0.65 (P = 0.657 and P = 0.003). Obstructive apnea-hypopnea index was significantly related to FE(Na) after adjustment for age, gender and body mass index z-score (P = 0.002). Children with moderate-to-severe SDB had similar systolic BP z-scores to those of subjects with mild SDB and higher than participants with primary snoring: 0.7 ± 1.2 versus 0.1 ± 1.0 versus -0.02 ± 1.0 (P = 0.074 and P = 0.046). In addition, participants with diastolic BP z-scores in the upper quartile of measured values had higher FE(Na) than subjects with z-scores in the lower quartiles: -0.08 ± 0.39 versus -0.41 ± 0.57 (P = 0.007)., Conclusions: Morning natriuresis is related to severity of SDB in children and this association may be mediated in part by elevated BP., (© 2010 Wiley-Liss, Inc.)

Obstructive sleep apnea (OSA) is characterized by recurrent apnea during sleep that may unbalance oxidative stress, increasing atherosclerosis. Among oxidative stress markers, 15-F(2t)-isoprostane is considered one of the most sensitive and specific metabolites of lipid peroxidation. To explore the relationship between urinary 15-F(2t)-isoprostane with sleep apnea severity and carotid modifications in nonobese OSA patients, 31 nonobese sleep apnea patients were studied, along with 10 lean subjects without OSA. Patients were assessed by polysomnography, blood pressure measurement, and ultrasonography to determine the carotid intima-media thickness (IMT). Urinary 15-F(2t)-isoprostanes were measured by liquid chromatography-tandem mass spectrometry. Urinary 15-F(2t)-isoprostane concentrations were increased in severe OSA patients compared to control subjects (20.2+/-7.3 vs 12.3+/-2.8 ng/mmol creatinine; P=0.020). Mean carotid IMT was correlated with 15-F(2t)-isoprostane (r=0.532; P<0.001) and with the apnea-hypopnea index (r=0.345; P=0.029). 15-F(2t)-Isoprostane level was related to the night time spent at SaO(2)<90% (r=0.478; P=0.002), the apnea-hypopnea index (r=0.465; P=0.003), and the mean nocturnal SaO(2) (r=-0.424; P=0.007). These results showed a relationship between lipid peroxidation, carotid intima-media thickness, and intermittent hypoxia in nonobese OSA patients, thus reinforcing the hypothesis that oxidative stress could be involved in the early atherosclerotic process., (Copyright 2010 Elsevier Inc. All rights reserved.)

Background: Adenotonsillar tissue of children with obstructive sleep-disordered breathing (SDB) has increased content of cysteinyl leukotrienes (CysLTs) and expression of CysLTs receptors. Furthermore, CysLTs concentrations in the nasal exhaled breath condensate of children with sleep apnea are elevated., Objective: To investigate the relationship between urine levels of CysLTs and severity of SDB in children., Methods: Morning urine concentrations of CysLTs were measured in children with symptoms of SDB and in control subjects with recurrent tonsillitis and without snoring who underwent polysomnography and were expressed in pg/mL per mg/dL of urine creatinine., Results: Nineteen children with moderate-to-severe SDB (mean [+/- SD] age, 5.4 +/- 1.6 years; obstructive apnea-hypopnea index [OAHI]: 14.4 +/- 9.6 episodes/h), 29 subjects with mild SDB (5.1 +/- 1.5 years; OAHI: 2.9 +/- 0.8 episodes/h), 26 children with primary snoring (PS) [7 +/- 2.6 years; OAHI: 1.1 +/- 0.3 episodes/h], and 18 control subjects (6.4 +/- 2.5 years; OAHI: 0.7 +/- 0.3 episodes/h) were studied. Children with moderate-to severe SDB had higher log-transformed urine CysLTs levels than those with mild SDB, PS, or control subjects (2.39 +/- 0.51 vs 2.06 +/- 0.26 vs 2.11 +/- 0.25 vs 1.86 +/- 0.28; p < 0.05). Log-transformed CysLTs concentration, tonsillar size, and body mass index z score were significant predictors of log-transformed OAHI (p < 0.01)., Conclusions: Urine excretion of CysLTs is related to SDB severity in children. This finding indicates that 5-lipoxygenase pathway products participate in the pathogenesis of obstructive sleep apnea in childhood or alternatively that SDB promotes CysLTs biosynthesis.

Objectives: To assess whether sleep-disordered breathing (SDB) in overweight children and adolescents has an additional effect on the spectrum of urinary albumin to protein loss, as markers of early kidney dysfunction., Methods: Prospective study in a clinical sample of overweight children and adolescents. Each subject underwent anthropometry, blood sampling, oral glucose tolerance test and polysomnography. From a 24-hour urine collection, albumin excretion rate and total urinary protein to creatinine ratio (UPCR) were calculated., Results: 94 nondiabetic subjects were included (mean age = 11.0 +/- 2.5, 42 boys). Average BMI z-score was 2.25 +/- 0.47 (26 overweight subjects and 68 obese subjects). There was no difference in albumin excretion rate or UPCR between subjects with and without SDB. None of the SDB parameters correlated with the transformed albumin excretion rate or UPCR. Albumin excretion rate significantly correlated with fasting insulin and C-peptide and with post-challenge glucose, insulin and C-peptide levels, while UPCR correlated with fasting and post-challenge C-peptide levels. Multiple regression indicated that post-challenge glucose levels were the most important predictors of albumin excretion rate., Conclusion: Insulin resistance, and not SDB, was associated with increased levels of albuminuria, indicating early renal dysfunction, in this clinical sample of overweight children and adolescents., (Copyright 2008 S. Karger AG, Basel.)

This study evaluated the sleep quality of athletes in normobaric hypoxia at a simulated altitude of 2,000 m. Eight male athletes slept in normoxic condition (NC) and hypoxic conditions equivalent to those at 2,000-m altitude (HC). Polysomnographic recordings of sleep included the electroencephalogram (EEG), electrooculogram, chin surface electromyogram, and electrocardiogram. Thoracic and abdominal motion, nasal and oral airflow, and arterial blood oxygen saturation (Sa(O(2))) were also recorded. Standard visual sleep stage scoring and fast Fourier transformation analyses of the EEG were performed on 30-s epochs. Subjective sleepiness and urinary catecholamines were also monitored. Mean Sa(O(2)) decreased and respiratory disturbances increased with HC. The increase in respiratory disturbances was significant, but the increase was small and subclinical. The duration of slow-wave sleep (stage 3 and 4) and total delta power (<3 Hz) of the all-night non-rapid eye movement sleep EEG decreased for HC compared with NC. Subjective sleepiness and amounts of urinary catecholamines did not differ between the conditions. These results indicate that acute exposure to normobaric hypoxia equivalent to that at 2,000-m altitude decreased slow-wave sleep in athletes, but it did not change subjective sleepiness or amounts of urinary catecholamines.

Objective: The aim of this study was to determine whether the severity of sleep-disordered breathing (SDB) was associated with increased levels of uric acid (UA), both in serum and in urine, as a marker of tissue hypoxia, in a sample of overweight and obese subjects, irrespective of indexes of adiposity., Methods: Consecutive subjects underwent polysomnography, fasting blood sampling, and 24-h urine collection. Outcome parameters were serum UA, UA excretion ([24-h urinary UA x serum creatinine]/urine creatinine) and urinary UA/creatinine ratio., Results: A total of 93 subjects were included (44% boys; mean [+/- SD] age = 11.1 +/- 2.5; 73% obese). A fasting measurement of serum UA levels was available for 62 patients. The respiratory disturbance index was a significant covariate (beta = 0.09 +/- 0.03; p = 0.01) in the regression model for serum UA, controlling for sex (beta = 0.32 +/- 0.29; p = 0.3), puberty (beta = 0.87 +/- 0.34; p = 0.01), and waist circumference (beta = 0.04 +/- 0.01; p = 0.005). The percentage of total sleep time with arterial oxygen saturation < or = 89% (beta = 0.94 +/- 0.45; p = 0.04) was also significantly associated with serum UA level, controlling for sex (beta = 0.22 +/- 0.30; p = 0.5), puberty (beta = 0.83 +/- 0.35; p = 0.02), and waist circumference (beta = 0.04 +/- 0.02; p = 0.02). None of the SDB variables correlated with UA excretion or with urinary UA/creatinine ratio., Conclusion: This study in overweight children and adolescents demonstrated a relationship between the severity of sleep apnea and increased levels of serum UA, independent of abdominal adiposity. In view of the known associations between UA and cardiovascular risk, this finding may contribute to the mechanisms linking SDB with cardiovascular morbidity.

Oxidant stress-related mechanisms have been proposed as a major contributor to the increased prevalence of cardiovascular morbidity in adult patients with sleep-disordered breathing. Isoprostanes provide a reliable biomarker of oxidant injury in vivo. The purpose of the present study was to examine the hypothesis that oxidant stress, as evidenced by increased levels of F2-isoprostane metabolites (IsoP-m) in urine, is present in children with a spectrum of sleep-disordered breathing. Assays were performed on urinary samples obtained from each of 47 pediatric patients immediately upon awakening after standard overnight polysomnography. Of the subjects, 15% had mild, 9% had moderate, and 6% had severe sleep-disordered breathing. After controlling for correlations between BMI and IsoP-m and SpO2 values, IsoP-m values were unrelated to any polysomnographic measures. The absence of increased levels of urinary F2-isoprostane metabolites in children with sleep-disordered breathing suggests that oxidative stress is not a significant feature of pediatric sleep-disordered breathing.

Background: Obstructive sleep apnea (OSA) is the most common form of sleep-disordered breathing, with almost 15 million Americans affected and many more at risk. Current diagnostic approach to OSA requires polysomnography, which is laborious, onerous, and time-consuming. There is ample evidence that inflammatory responses to the perturbations associated with OSA trigger a variety of genes and signaling cascades that ultimately lead to end-organ injury and changes in kidney function and protein expression. The aim of this study was therefore to analyze proteins in human urine and assess whether differential expression of particular proteins is associated with the presence of OSA., Methods: Eleven OSA and 11 control children between the ages of three and 14 (males=17; females=5) underwent overnight sleep studies followed by a first-morning urine sample. Proteomic analysis of urine samples yielded a unique map of proteins, of which, five spots were selected for further analysis due to their significant intensity differences between OSA and control groups., Results: Mass spectrometry followed by peptide mass fingerprinting conclusively identified four of the five spots as gelsolin, perlecan (a heparan sulfate proteoglycan), albumin, and immunoglobulin (P<0.05 and protein scores>67)., Conclusions: Overall, increased expression of gelsolin and perlecan in the urinary proteome of children with OSA suggests that the episodic hypoxia associated with OSA may lead to changes in protein permeability or alternatively to increased catabolism of these proteins and their excretion in urine.

Although nocturnal voiding is frequently attributed to urologic disorders, nocturia and enuresis are also important symptoms of sleep-disordered breathing. However, polyuria can be elicited by obstructive sleep apnea as well as bedrest, microgravity and other experimental conditions where the blood volume is shifted centrally to the upper body. The nocturnal polyuria of sleep apnea is an evoked response to conditions of negative intrathoracic pressure due to inspiratory effort posed against a closed airway. The mechanism for this natriuretic response is the release of atrial natriuretic peptide due to cardiac distension caused by the negative pressure environment. This cardiac hormone increases sodium and water excretion and also inhibits other hormone systems that regulate fluid volume, vasopressin and the rennin-angiotensin-aldosterone complex. Treatment of sleep apnea and airway compromise has been shown to reverse nocturnal polyuria and thereby reduce or eliminate nocturia and enuresis. Thus, careful evaluation of nocturia and enuresis for evidence of nocturnal polyuria can increase the diagnostic certainty of referring primary care providers and sleep specialists. In addition, the resolution of these bothersome symptoms after treatment can contribute to patient satisfaction as well as reinforce treatment compliance.

Background: Previous studies have reported an association between obstructive sleep apnea (OSA) and proteinuria, but are limited in their ability to assess proteinuria accurately, to adjust for confounders such as obesity, or to exclude confidently underlying renal disease in patients with OSA and nephrotic-range proteinuria., Methods: The spot urine protein/creatinine ratio was measured in a prospective consecutive series of 148 patients referred for polysomnography who were not diabetic and had not been treated previously for OSA. The urine protein/creatinine ratio was compared across four levels of OSA severity, based on the frequency of apneas and hypopneas per hour: <5 (absent), 5 to 14.9 (mild), 15 to 29.9 (moderate), and > or =30 (severe)., Results: The median level of urine protein/creatinine ratio in all categories of OSA was <0.2 (range 0.03 to 0.69; median 0.06 in patients with normal apnea hypopnea index, 0.06, 0.07, 0.07 in patients with mild, moderate, and severe OSA, respectively). Eight subjects had a urine protein/creatinine ratio greater than 0.2. Univariate analysis showed a significant association between urine protein/creatinine ratio and older age (P < 0.0001), hypertension (P < 0.0001), coronary artery disease (P = 0.003), and arousal index (P = 0.003). Body mass index (P = 0.16), estimated creatinine clearance (P = 0.17), and apnea hypopnea index (P = 0.13) were not associated with the urine protein/creatinine ratio. In multiple regression analysis, only age and hypertension were independent positive predictors of the urine protein/creatinine ratio (P < 0.0001, R2 = 0.17)., Conclusion: Clinically significant proteinuria is uncommon in sleep apnea. Nephrotic range proteinuria should not be ascribed to sleep apnea and deserves a thorough renal evaluation.

To assess the acute effects of nasal continuous positive airway pressure (CPAP) on the 24-hour blood pressure and the secretion of catecholamines in urine and plasma, we investigated the changes in the 24-hour blood pressure and urinary and plasma concentrations of epinephrine (E) and norepinephrine (NE) in 26 men with obstructive sleep apnea (OSA) with and without nasal CPAP. Nasal CPAP resulted in significant decreases in the daytime diastolic pressure (from 86 +/-16 mmHg to 83+/-12 mmHg), the nighttime diastolic pressure (from 81+/-12 mmHg to 77+/-9 mmHg) and the nighttime systolic pressures (from 125+/-15 mmHg to 120+/-10 mmHg). There was no significant difference between patients with and without CPAP in the daytime or nighttime urinary E level, but patients who received CPAP showed a significant decrease in daytime urinary NE level (from 156+/-112 microg/14h to 119+/-101 microg/14h) and nighttime urinary NE level (from 143+/-91 microg/10h to 112+/-65 microg/10h). The morning plasma level of NE also decreased (from 371+/-181 pg/ml to 273 +/-148 pg/ml) in patients who received nasal CPAP (p<0.02), but the plasma level of E remained unchanged. There were no correlations between PSG parameters and the reductions in blood pressure and the catecholamine levels induced by nasal CPAP. These findings suggest that OSA contributes, at least in part, to the development of systemic hypertension by increasing sympathetic nervous activity.

Study Objective: To assess the utility of urinary uric acid excretion as a marker of nocturnal hypoxia in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) before and after the institution of nasal continuous positive airway pressure (CPAP)., Design: Prospective, open., Setting: Sleep Disorders Laboratory, Veterans Affairs Medical Center., Participants: Thirty consecutive male subjects, 20 with OSAHS and 10 without OSAHS., Measurements and Methods: Spot morning urine and venous blood samples were obtained in all subjects; samples were also obtained after the application of CPAP in those with OSAHS. Uric acid excretion, normalized to creatinine clearance, was calculated as the product of urinary uric acid and serum creatinine concentrations divided by urine creatinine concentration. In patients with OSAHS, uric acid excretion was 0.55+/-0.1 mg/dL before CPAP therapy and decreased to 0.30+/-0.01 mg/dL after CPAP therapy (p < 0.001). The latter value did not differ significantly from the mean value (0.32+/-0.03 mg/dL) in the control group. Uric acid excretion in OSAHS patients correlated significantly with the apnea-hypopnea index (r=0.42; p<0.0003)., Conclusion: Uric acid excretion is increased in OSAHS patients and normalizes after CPAP treatment, most likely reflecting differences in tissue oxygenation between the two conditions. Further studies in large number of patients may confirm the usefulness of this simple test for diagnosis and follow-up of patients with OSAHS.

Since obstructive sleep apnea syndrome (OSAS) is often linked with systemic hypertension, we sought to clarify the characteristics of prostanoid metabolism in OSAS. In 7 OSAS patients (apnea-hypopnea index, 51.0 +/- 23.4) and 7 non-snorers as control, nocturnal urine was sampled and analyzed for stable metabolites of prostacyclin (PGI2) and thromboxane A2 (TxA2), [6-keto-PGF1alpha and thromboxane B2 (TxB2)]. The ratio of 6-keto-PGF1alpha to TxB2 was significantly higher in OSAS (2.97 +/- 1.52) than in control (1.38 +/- 0.38). Successful treatment with nasal continuous positive airway pressure (8.3 +/- 1.5 cmH2O) for 3 days caused a significant decrease in mean blood pressure in OSAS. Moreover, the 6-keto-PGF1alpha to TxB2 ratio also significantly decreased to 1.74 +/- 0.58, a level which may not significantly different from control. These results suggest that the production ratio of PGI2 to TxA2 is shifted toward vasodilatation in untreated OSAS. We conclude that the production of prostanoids plays a role in compensating for the systemic hypertension in OSAS.

Numerous alterations in the sympathetic nervous system have been reported in patients with obstructive sleep apnea. It is unclear whether such alterations can be attributed to the respiratory disturbance itself, the resulting hypoxia, or disruption of sleep. We examined urinary norepinephrine levels in 45 individuals with varying amounts of respiratory disturbance and sleep disruption. All were of similar age (40 to 60 years) and body weight (100 to 160% ideal body weight), and all were free from antihypertensive medications that could influence norepinephrine levels. Twenty-four-hour urinary norepinephrine levels were correlated with respiratory disturbance index (r = 0.39, p < 0.01) and mean oxygen saturation (r = -0.36, p < 0.05). These variables, together with the time in slow-wave sleep, accounted for a statistically significant but modest percentage of the variance in urinary norepinephrine (R2 = 0.19, p < 0.05). However, the variables were so tightly intercorrelated that no single variable independently predicted norepinephrine levels in multiple regression analysis.

Background: Proteinuria severe enough to be in the nephrotic range has been noted on occasion in patients with obstructive sleep apnea (OSA), but it is not known what factors are related to the severity of proteinuria in these patients. This study was conducted to determine if the severity of proteinuria is related to the number of apneas., Methods: The level of proteinuria was determined by the dipstick method in 407 patients in whom OSA had been diagnosed. The apnea-hypopnea index (AHI) was calculated in each patient after all-night polysomnography. Sleep apnea was defined as the presence of at least 30 apneas during a 6- to 8-hour monitoring period and an AHI greater than 15., Results: The apnea-hypopnea index in patients without proteinuria was similar to that of patients with 1+ to 3+ proteinuria. However, the AHI was significantly greater in the 9 patients with 4+ proteinuria., Conclusions: While severe proteinuria in OSA occurs in patients with a higher rate of sleep apneas, the lesser degree of proteinuria cannot be explained by AHI alone. Other factors that determine the severity of the disease, such as hypoxemia, merit further investigation.

During hypoxia ATP degradation to uric acid is increased in animal models and humans. To assess the reliability of an overnight increase in uric acid excretion as a marker of nocturnal hypoxemia, we selected 10 normal volunteers (7 males and 3 females), 29 COPD patients (26 males and 3 females), and 49 subjects with obstructive sleep apnea (OSA) (43 males and 6 females). The patients underwent standard polysomnography, which was repeated in 14 subjects with nasal continuous positive airway pressure (CPAP), and were subdivided into two groups: Group D included desaturating subjects who spent at least 1 h at SaO2 < 90% and 15 min below 85%, and Group ND were nondesaturating subjects. The overnight change in the uric acid:creatinine ratio (delta UA:Cr) was negative in normal subjects (-27.5 +/- 9.1 [mean +/- SD]) and ND groups: -19.7 +/- 14.3 in COPD, -16.1 +/- 13.0 in OSA. In both COPD and OSA Group D, the ratio was usually positive: delta UA:Cr was 17.9 +/- 31.4 in Group D COPD (p < 0.001 versus ND) and 10.1 +/- 30.7 in Group D OSA (p < 0.001 versus ND and versus normal subjects) despite 4 of 15 false negative results in COPD and 8 of 20 in OSA. CPAP effective treatment induced a marked reduction ((p = 0.0024) in delta UA:Cr, leading to a negative value. We conclude that delta UA:Cr seems to be a promising index of significant nocturnal tissue hypoxia, with good specificity but poor sensitivity (about 30% false negative), which might be useful for the long-term follow-up of outpatients on nasal CPAP with a positive ratio at baseline.

To evaluate the release of catecholamines and their relationship with systemic blood pressure (BP) in normotensive patients with obstructive sleep apnea syndrome (OSAS), diurnal and nocturnal urinary norepinephrine (NE) and epinephrine (E) excretion in 12 normal subjects and in 10 OSAS patients were compared; in addition, nocturnal NE and E excretion were measured in the patients while receiving short-term CPAP. Blood pressure was continuously monitored in the patients during both nights of urine collection. In normal subjects, both NE and E excretion decreased from day to night. In the patients without CPAP, only NE excretion decreased at night, and BP increased from wakefulness to sleep; both NE and E excretion were higher in patients than in normal subjects. With CPAP, which prevented apneas, only E excretion decreased with respect to the previous night, while BP no longer increased during sleep. The extent of nocturnal E decrease with CPAP was not correlated to BP variations. These results suggest that in normotensive OSAS subjects, sympathetic nervous system activity, based on NE excretion, is continuously increased and is not affected by short-term CPAP treatment. Conversely, adrenal activity, based on E excretion, is also increased, but it tends to be normalized by short-term CPAP. No clear relationship could be found between sympatho-adrenal behavior and BP during sleep.

30 subjects of old and middle age (28 male, 2 female) with obstructive sleep apnea syndrome (OSAS) and 20 normal subjects with matchable age and body weight (14 male, 6 female) as control were studied with nocturnal polysomnography for at least 7 hours. Right arm blood pressure was determined in supine position before and after sleep. Meantime, three 8-hour urine specimens, two collected while awake and one during sleep were examined for urinary levels of epinephrine (E) and norepinephrine (NE) with fluorometric method. All OSAS subjects (mean apnea index 42.9) had significant arterial oxygen desaturation (mean 63.9%). 12/30 OSAS subjects had definit history of essential hypertension. They described that hypertension appeared months or years after the onset of sleep disorders. Before sleep the blood pressure in OSAS subjects was higher than that in controls (mean 133/90 mmHg versus 118/77 mmHg P < 0.001). After 7 hours of sleep with apnea events, the blood pressure rose to 149/100 mmHg (P < 0.001). whereas in the controls there was no change of statistic significance (mean 115/77 mmHg). A diurnal rhythm in free catecholamines excretion was apparent for both NE and E (P < 0.05) in the controls, while in OSAS there was no normal diurnal rhythm. 24-hour values of NE were remarkably higher than those in controls. It is known that up to 40% of OSAS subjects is in the population of essential hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Patients with obstructive sleep apnea (OSA) syndrome are known to exhibit nocturnal natriuresis/diuresis. We studied plasma and urinary levels of atrial natriuretic peptide (ANP), a potent natriuretic hormone released from the heart, and plasma antidiuretic hormone (ADH) levels in patients with OSA during awake and sleeping periods, to compare with those of normal subjects. Seven patients with OSA and 6 normal subjects were studied. Arterial blood samples were drawn during the awake and the sleeping period, while in patients with OSA, blood samples were obtained during the apneic period. Urine samples were collected over two 12-hour periods (9 a.m.-9 p.m. and 9 p.m.-9 a.m.) In patients with OSA, plasma ANP as well as urinary ANP excretion increased during the apneic period compared with the awake period. There was a significant negative correlation between plasma levels of ANP and ADH in patients with OSA. On the other hand, normal subjects had no apparent differences in plasma and urinary ANP levels between the two periods. It is suggested that nocturnal increase in ANP and decrease in ADH are responsible for the nocturnal diuresis and natriuresis associated with OSA.

In ten patients with severe obstructive sleep apnea (OSA) profound changes in renal function could be demonstrated at night during nCPAP therapy. Natriuresis and diuresis decreased by about 50% while creatinine excretion rate and urinary osmolality did not change. We found parallel changes in the excretion of ANP's second messenger cyclic guanosine monophosphate (cGMP) in a dose-response-related manner to natriuresis respectively diuresis. These data are in agreement with recently demonstrated decrease of nocturnal plasma levels of atrial natriuretic peptide (ANP) during nCPAP therapy in apneic patients. This may be an indicator for an increased cardiac volume load during obstructive apnea. The decrease of diuresis, natriuresis and cGMP excretion demonstrate the beneficial effects of nCPAP treatment on the cardiovascular system. Therefore measurements of cGMP excretion may be a useful parameter to assess the cardiovascular function of apneic patients before and during treatment.

To clarify the paradox of a decrease in urine and sodium excretion occurring along with the elimination of peripheral edema when patients with obstructive sleep apnea (OSA) are treated with nasal continuous positive airway pressure (CPAP), we investigated the immediate effects of this treatment on the hematocrit and red blood cell count in eight patients with OSA. The hematocrit decreased in all patients, from a mean of 45.6 +/- 1.2 percent to 43.0 +/- 1.4 percent, with a parallel decrease in the red blood cell count from 4.777 +/- 0.168 millions/cu mm to 4.577 +/- 0.174 millions/cu mm (p less than 0.0005, one-tailed, in both cases). These results suggest that nasal CPAP treatment causes a hemodilution in patients with OSA, and are compatible with the hypothesis of an atrial natriuretic peptide-induced fluid shift from the intravascular to the extravascular volume in untreated patients with OSA. The reversal of these changes with CPAP treatment could explain the simultaneous decrease in sodium and urine excretion and the reduction of peripheral edema.

Obstructive apnea (asphyxia) is accompanied by acute elevation of systemic blood pressure. The usual nocturnal fall in blood pressure seen during sleep in normals may be absent in patients with repetitive apneas, and daytime systemic hypertension is reported to occur in up to 90% of such patients. Increased sympathetic activity in response to repetitive nocturnal episodes of asphyxia could explain the reversal of the diurnal pressure variation but not the daytime systemic hypertension in this setting. We examined diurnal variation in urinary catecholamines in eight subjects with severe apnea before and after tracheostomy. Five obese hypertensive subjects without apnea served as controls. Three urine specimens, two awake (7 a.m. to 3 p.m. and 3 p.m. to 11 p.m.) and one asleep (11 p.m. to 7 a.m.) were collected preoperatively and again 10-14 days postoperatively when the patient was free of pain and signs of stoma infection. All specimens were analyzed for epinephrine, norepineprine, metanephrine, and normetanephrine by liquid chromatography with electrochemical detection. Urinary epinephrine and metanephrine were not different between subjects and controls. Norepinephrine and normetanephrine were significantly higher in apneic subjects pretracheostomy as compared either with controls or with their own values posttracheostomy. Diurnal variation was not seen before or after tracheostomy. Only two of the controls showed significant diurnal variation in norepinephrine. We conclude that the absence of diurnal variation in catecholamines prior to tracheostomy reflects increased nocturnal sympathetic activity. Elevation of daytime norepinephrine and normetanephrine with return to control levels following tracheostomy implies increased sympathetic activity throughout the day.

Two patients with severe obstructive sleep apnea syndrome and high-grade proteinuria (greater than 1 g/d [1000 mg/d]) were studied. Three remissions in proteinuria coincided with correction of obstructive sleep apnea syndrome and improvement of blood oxygen levels. These remissions could be dissociated from reductions both in dry body weight and in hematocrit levels. We propose that sleep apnea may cause a functional and reversible type of proteinuria.

1. It has recently been shown that obstructive sleep apnoea (OSA) patients have increased urinary water and salt excretion during sleep which tends to normalize with nasal continuous positive airway pressure (CPAP) treatment. 2. To investigate the mechanisms of these changes in renal function, nocturnal urinary excretion of catecholamines and guanosine 3':5'-cyclic monophosphate (cyclic GMP), which reflects atrial natriuretic factor (ANF) release, and next-morning plasma active renin concentrations were studied in 21 OSA patients on 2 consecutive nights, either untreated or treated with nasal CPAP. 3. In keeping with previous results, fractional urine flow and fractional Na+ and Cl- excretions were higher during untreated than during CPAP-treated nights. 4. No difference in plasma active renin concentration or in urinary excretion of noradrenaline, adrenaline, free dopamine and total dopamine could be demonstrated, but cyclic GMP excretion was significantly higher during untreated than during CPAP-treated nights. 5. The data are consistent with the hypothesis that the increased water and salt excretion in OSA patients is due to increased ANF release. 6. The proposed mechanism is an atrial distension due to increased (more negative) intrathoracic pressures during ineffective inspiratory efforts against the occluded upper airways which have been found in OSA.

1. In healthy individuals, sleep is associated with a fall in urine and sodium output. 2. Seven male patients with obstructive sleep apnoea exhibited a paradoxical rise in both urine and sodium output during the hours of sleep. 3. Continuous positive airway pressure applied via the nose abolished both the apnoea and the nocturnal rise in urine and sodium output, thereby restoring the diurnal pattern towards normal.

Obstructive sleep apnea (OSA) patients have increased diuresis and natriuresis during sleep. In order to investigate the possible mechanisms of these changes in renal function, 35 consecutively diagnosed OSA patients were studied during sleep before and during nasal continuous positive airway pressure (CPAP) treatment, and were compared with 23 non-snoring controls. The excretion of urine and of electrolytes was increased before treatment and normalized with nasal CPAP treatment. The mechanism involved seems to be decreased sodium reabsorption at the level of the ascending limb of the loop of Henle. The observed increase in cyclic guanosine monophosphate excretion supports the hypothesis of increased atrial natriuretic peptide release during sleep in OSA patients.

We observed nocturnal urinary protein excretion to be 16.2 +/- 5.5 micrograms/min (mean +/- SE) in 9 healthy control subjects (group I), 29.3 +/- 9.5 micrograms/min in 12 obese patients suspected to have obstructive sleep apnea syndrome (OSAS) but with negative polysomnographic studies (group II), and 94.0 +/- 31.8 micrograms/min in 14 patients with documented OSAS (group III) (II vs. I, NS; III vs. I, p less than 0.05; III vs. II, p less than 0.05). The frequency of abnormal proteinuria, defined as protein excretion greater than the highest rate observed in group I (46 micrograms/min), was 14% in group II and 64% in group III (p less than 0.05). There were no significant differences in age, body weight, body surface area, blood pressure, or indices of sleep apnea between OSAS patients with and without proteinuria. Although the mechanism is unclear, this study shows that nocturnal protein excretion rates are commonly elevated in patients with OSAS.

Patients with obstructive sleep apnea (OSA) often exhibit nocturnal polyuria, which disappears with nasal continuous positive airway pressure (CPAP) treatment. We measured water and electrolyte urinary excretion, creatinine and osmolal clearances, and water transport during sleep in 13 polygraphically monitored patients with OSA during two consecutive nights, either untreated or treated with nasal CPAP, and in eight normal subjects. Untreated patients with OSA had greater urinary flows and greater urinary sodium, chloride, and potassium excretions than did controls. Nasal CPAP treatment in patients with OSA resulted in a reduction in urinary flow and in sodium and chloride excretion, with a concomitant increase in sodium resorption. None of these effects was observed in CPAP-treated normal subjects. The only effect of nasal CPAP common to normal subjects and patients was a trend toward decreased glomerular filtration rate.