Preschoolers with recurrent wheezing have a high prevalence of sleep disordered breathing.

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.

Leucotrienos urinarios en pacientes pediátricos con trastorno respiratorio del sueño secundario a hiperplasia adenoamigdalina / Urinary leukotrienes in pediatric patients with sleep disordered breathing secondary to adenotonsillar hypertrophy

RESUMEN Introducción: El trastorno respiratorio del sueño (TRS) afecta al 2% a 3% de la población pediátrica, siendo la hiperplasia adenoamigdalina (HAA) su principal causa. Se ha observado un aumento en los niveles de leucotrienos excretados en orina (LTU) en estos pacientes, los cuales se correlacionarían con la severidad de la enfermedad. Objetivo: Determinar el nivel de LTU en niños con TRS e HAA antes y después de adenoamigdalectomía (AA), y en controles sanos. Correlacionar los niveles de LTU con los síntomas de TRS. Material y método: Estudio prospectivo. Se incluyeron pacientes con TRS e HAA (n =12) y controles sanos (n =12). Se determinó la concentración de LTU en ambos grupos de forma basal y un mes después de cirugía en el grupo con TRS. Resultados: No hubo diferencias en los niveles de LTU antes y después de AA. Tampoco existieron diferencias entre el grupo control y grupo TRS previo a la cirugía. No se encontró asociación entre LTU y la severidad de síntomas respiratorios. Conclusión: Los LTU no se encuentran elevados en pacientes con TRS e HAA, no disminuyen luego de AA y no se correlacionan con la severidad de los síntomas. La medición de LTU no sería una herramienta útil en la evaluación de pacientes con TRS. Nuevos estudios son necesarios para evaluar el rol de los leucotrienos en esta enfermedad.

ABSTRACT Introduction: Sleep disorder breathing (SDB) affects 2%-3% of the pediatric population, being adenotonsillar hyperplasia (ATH) its main cause. An increase in the levels of urinary leukotrienes (ULT) has been measured in these patients, which could be correlated with the severity of the disease. Aim: To determine the level of ULT in children with SDB and ATH before and after adenotonsillectomy, and healthy controls. To correlate the levels of ULT with symptoms of SDB. Material and method: prospective study. SDB and ATH patients (n =12) and healthy controls (n =12) were included. The concentration of ULT in both groups was determined, before surgery and after a month of surgery. Results: There were no differences in the levels of ULT before and after tonsillectomy in the studied group. There were also no differences between the control group and the SDB group. No association was observed between the level of ULT and the severity of respiratory symptoms. Conclusions: ULT are not elevated in patients with SDB and ATH and they do not decrease after adenotonsillectomy. ULT are not correlated with the severity of the symptoms of SDB. The measurement of ULT would not be a useful tool in the evaluation of patients with SDB. New studies are needed to assess the role of the role of leukotrienes in this disease.

Urinary Leukotriene E4 Levels in Children with Sleep-Disordered Breathing.

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.

Increased Urinary Erythropoietin Excretion in Severe Sleep Apnea-Hipoapnea Syndrome: The Effect of CPAP. / El síndrome de apneas-hipoapneas del sueño (SAHS) grave incrementa la excreción urinaria de eritropoyetina. Efecto del tratamiento con CPAP.

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.

Sleep disordered breathing in mucopolysaccharidosis I: a multivariate analysis of patient, therapeutic and metabolic correlators modifying long term clinical outcome.

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.

Evening chronotype is associated with changes in eating behavior, more sleep apnea, and increased stress hormones in short sleeping obese individuals.

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.

Weight loss and sleep-disordered breathing in childhood obesity: effects on inflammation and uric acid.

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.

Urinary leukotriene E4, obesity, and adenotonsillar hypertrophy in Chinese children with sleep disordered breathing.

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.

Quantitating nocturia: a study into the recording of solute and water excretion to determine causation.

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.

Correlation of urinary excretion of sodium with severity of sleep-disordered breathing in children: a preliminary study.

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.

Association of urinary 15-F2t-isoprostane level with oxygen desaturation and carotid intima-media thickness in nonobese sleep apnea patients.

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.

Urine concentrations of cysteinyl leukotrienes in children with obstructive sleep-disordered breathing.

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.

Sleep-disordered breathing and proteinuria in overweight and obese children and adolescents.

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.

Changes in sleep quality of athletes under normobaric hypoxia equivalent to 2,000-m altitude: a polysomnographic study.

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.

Sleep-disordered breathing and uric acid in overweight and obese children and adolescents.

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.

Urinary F2-isoprostane metabolite levels in children with sleep-disordered breathing.

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.

Urinary protein expression patterns in children with sleep-disordered breathing: preliminary findings.

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.

Sleep disordered breathing and nocturnal polyuria: nocturia and enuresis.

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.

Proteinuria in obstructive sleep apnea.

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.