Effect of continuous positive airway pressure on albuminuria in patients with obstructive sleep apnea: a meta-analysis.

PURPOSE: A relationship between albuminuria and obstructive sleep apnea (OSA) has been documented in previous studies. Nevertheless, the impact of continuous positive airway pressure (CPAP) treatment on albuminuria in subjects with OSA is debated. This meta-analysis was carried out to investigate whether or not CPAP treatment affected urinary albumin-to-creatinine ratio (UACR) in subjects with OSA. METHODS: A comprehensive literature search was conducted on Web of Science, Embase, and PubMed from January 1990 to December 2020. Information on patients' characteristics, features of the studies, and UACR of pre- and post-CPAP treatment was collected. For estimation of the pooled effects, standardized mean difference (SMD) was applied. RESULTS: This meta-analysis included 6 articles and 211 subjects. The pooled analysis suggested that CPAP therapy exerted a favorable effect on the decrease of UACR in subjects with OSA (SMD = 0.415, 95% CI = 0.026 to 0.804, z = 2.09, p = 0.037). Subgroup analyses revealed that the CPAP treatment effect was not influenced by sample size, BMI, age, or AHI. CONCLUSION: The present meta-analysis indicated that UACR was significantly reduced by CPAP therapy in subjects with OSA. Further well-designed randomized controlled trials with large sample size are required to confirm the benefits.

Reversibility of microalbuminuria with continuous positive airway pressure treatment in obstructive sleep apnea syndrome.

INTRODUCTION: Microalbuminuria is an early marker of kidney damage and an early predictor and risk factor for cardiovascular diseases. We aimed to evaluate the association between albuminuria levels in different severity obstructive sleep apnea syndrome (OSAS) cases and to find out the efficacy of CPAP treatment on microalbuminuria. MATERIALS AND METHODS: We conducted a prospective study on subjects who underwent polysomnography. The polysomnographic data were recorded to establish the presence and severity of OSAS. The blood and urine samples were taken both at the time of diagnosis and 3 months after CPAP therapy. The relationship between the severity of OSAS and microalbuminuria and the effect of CPAP treatment on microalbuminuria were evaluated. RESULTS: The study population consisted of 449 subjects. Better compliance to CPAP was associated with significantly reduced levels of microlbuminuria. Urinary albumin/creatinine was increased in severe cases, but the difference was not statistically significant. In the non-compliant group, microalbumin/creatinine ratio was 25.24 prior to initiation of CPAP treatment and 28.36 at the third month control visit (p = 0.25). In the compliant group, microalbumin/creatinine ratio was 49.71 prior to initiation of CPAP treatment and 22.30 at the third month control visit (p = 0.04). CONCLUSION: Our study demonstrated that good compliance to CPAP therapy is associated with a decrease in microalbuminuria. Patients who used CPAP regularly had a significant decline in albumin/creatinine ratio after 3 months of CPAP therapy.

Obstructive Sleep Apnea Syndrome as a Potential Cause of Nocturia in Younger Adults.

OBJECTIVES: To investigate the impact of age on the relationship between obstructive sleep apnea syndrome (OSAS), nocturia, and other lower urinary tract symptoms (LUTSs). METHODS: This was a secondary analysis study based on data derived from a previously conducted prospective observational cohort study on OSAS and nocturia. We analyzed 90 subjects who were suspected of having OSAS. Prior to polysomnography, we assessed International Prostate Symptom Score-Quality of Life scores, Overactive Bladder Symptom Scores, and International Consultation on Incontinence Modular Questionnaire-Nocturia Quality of Life scores to evaluate LUTSs. Nocturnal urine volume, night-time frequency, and night-time urine electrolyte content were measured during polysomnography. Patients were divided into groups according to age and OSAS severity determined using apnea-hypopnea index (AHI) scores. Young patients were those aged <65 years and elderly patients, ≥65 years. A multiple linear regression with multiple imputations was performed to examine the association of night-time frequency with demographic, polysomnographic, and clinical characteristics. RESULTS: In young patients, night-time frequency was significantly associated with nocturnal urine volume, AHI score, and total IPSS. However, night-time frequency in elderly subjects was not associated with demographic and polysomnographic characteristics. In order to compare the severity of OSAS, night-time frequency and urinary sodium content significantly increased only in young patients (P = .007 and .004, respectively). CONCLUSION: OSAS is a strong candidate of causative factor for nocturia in younger individuals. When a younger patient complains nocturia without any urological disorders, OSAS should be kept in mind as a potential cause of nocturia.

A detection dog for obstructive sleep apnea: could it work in diagnostics?

PURPOSE: We have previously demonstrated that dogs can be trained to distinguish the urine of patients with obstructive sleep apnea (OSA) from that of healthy controls based on olfaction. Encouraged by these promising results, we wanted to investigate if a detection dog could work as a screening tool for OSA. The objective of this study was to prospectively assess the dogs' ability to identify sleep apnea in patients with OSA suspicion. METHODS: Urine samples were collected from 50 patients suspected of having OSA. The urine sample was classified as positive for OSA when the patient had a respiratory event index of 5/h or more. The accuracy of two trained dogs in identifying OSA was tested in a prospective blinded setting. RESULTS: Both of the dogs correctly detected approximately half of the positive and negative samples. There were no statistically significant differences in the dogs' ability to recognize more severe cases of OSA, as compared to milder cases. CONCLUSION: According to our study, dogs cannot be used to screen for OSA in clinical settings, most likely due to the heterogenic nature of OSA.

Urine biomarkers of renal renin-angiotensin system activity: Exploratory analysis in humans with and without obstructive sleep apnea.

Obstructive sleep apnea (OSA) may contribute to kidney injury by activation of the renin-angiotensin system (RAS), which is reduced by continuous positive airway pressure (CPAP) therapy. A biomarker in the urine that reflects renal RAS activity could identify patients at risk of kidney injury and monitor their response to CPAP therapy. Nine patients with OSA and six matched control subjects without OSA were recruited. Renal RAS activity was measured by the renovasoconstrictor response to Angiotensin II challenge, a validated marker of RAS activity, and urine samples were collected in all subjects at baseline and repeated in those with OSA following treatment with CPAP. A broad range (1,310) of urine analytes was measured including 26 associated with the RAS signaling pathway. The OSA group was a similar age and weight as the control group (48.7 ± 10.4 vs. 47.7 ± 9.3 yrs; BMI 36.9 ± 7.2 vs. 34.7 ± 2.5 kg/m2 ) and had severe sleep apnea (ODI 51.1 ± 26.8 vs. 4.3 ± 2/hour) and nocturnal hypoxemia (mean SaO2 87 ± 5.2 vs. 92.6 ± 1.1%). CPAP corrected OSA associated with a return of the renovasocontrictor response to Angiotensin II to control levels. Partial least squares (PLS) logistic regression analysis showed significant separation between pre- and post-CPAP levels (p < .002) when all analytes were used, and a strong trend when only RAS-associated analytes were used (p = .05). These findings support the concept that urine analytes may be used to identify OSA patients who are susceptible to kidney injury from OSA before renal function deteriorates and to monitor the impact of CPAP therapy on renal RAS activity.

Urinary EPCR and dermcidin as potential novel biomarkers for severe adult OSA patients.

BACKGROUND: Due to low predictive values of obstructive sleep apnea (OSA) screening tools, there is a need for biomarker for screening of OSA patients at an early stage. The aim of the study was to evaluate differentially expressed proteins in blood and urine samples of OSA patients. METHODS: In this study, we used isobaric tagging for relative and absolute quantification (iTRAQ) based proteomics approach to identify differentially expressed proteins, which were subsequently verified and validated using enzyme-linked immunosorbent assay (ELISA) technique in adult OSA patients. RESULTS: Seventeen differentially expressed proteins were selected from iTRAQ data for verification, based on their clinical significance and reproducibility among different iTRAQ experiment sets. Five of these proteins (plasma = 2; urine = 3) were further validated in plasma (non-OSA- = 42; OSA = 198) and urine samples (non-OSA = 46; OSA = 197). ROC curve analysis for all OSA vs. non-OSA subjects ensured optimal diagnostic utility of two urinary proteins: Endothelial protein c receptor (EPCR) (AUC = 73%, cut-off: 35 pg/ml) and dermcidin (AUC = 74%, cut-off: 4.6 pg/ml). For severe OSA, diagnostic accuracy significantly improved with AUC as 88% and 82% for EPCR (cut-off: 46 pg/ml) and dermcidin (cut-off: 5.2 pg/ml) respectively. Sensitivity and specificity of combined performance of both urinary proteins for severe OSA were 94% and 91% respectively. CONCLUSION: In this study, urinary EPCR and dermcidin emerged as novel biomarkers for screening severe OSA patients.

Obstructive sleep apnea syndrome and autonomic dysfunction.

Autonomic nervous system (ANS) has been extensively explored in obstructive sleep apnea (OSA). Autonomic alterations in these patients have been described by means of several methods, evaluating ANS function both directly with microneurography and indirectly through baroreflex sensitivity (BRS, by the sequence method or the cross-spectral approach), heart rate variability analysis (HRV, both in the time and frequency domain) during sleep and wake, or conventional laboratory tests, including cold pressor test, hand grip test or measurement of urinary cathecolamine excretion. Several studies in OSA patients have shown ANS alterations, in particular sympathetic overactivity, both acutely during apnea events and chronically during the daytime, being both also involved in cardiovascular consequences of sleep disordered breathing. The association between OSA and sympathetic dysregulation suggests a dose response relationship between OSA severity and the degree of sympathetic overactivity and this association seems to be reversible as the treatment of OSA is implemented. Additionally ANS is involved in regulating visceral and humoral functions to maintain the body homeostasis and in reaction and adaptation to external and internal stressor stimuli. However, the vast majority of studies have focussed on cardiovascular alterations, which are easier to measure, somewhat neglecting the other functions regulated by ANS. More evidence is therefore needed to better characterize the impact that sleep disorder breathing may have on ANS both in the short and long term.

Overnight Change in Urinary Prostacyclin and Thromboxane in Obstructive Sleep Apnea / Cambio en la prostaciclina y el tromboxano urinario durante la noche en la apnea obstructiva del sueño

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Continuous Positive Airway Pressure Treatment Does not Reduce Uric Acid Levels in OSA Women / La presión positiva continua en las vías aéreas no reduce los niveles de ácido úrico en las mujeres con SAOS

Objectives: Although an association between uric acid (UA) levels and obstructive sleep apnea (OSA) has been reported, the effect of continuous positive airway pressure (CPAP) on this measure is yet unclear. We aimed to investigate the effect of CPAP therapy on serum UA levels in patients with OSA. Methods: We conducted a multicenter, open-label, randomized controlled trial in 307 women diagnosed with moderate-to-severe OSA (apnea-hypopnea index [AHI] ≥ 15) in 19 Spanish Sleep Units. Women were randomized to CPAP (n = 151) or conservative treatment (n = 156) for 12 weeks. Changes in serum UA measures were assessed on an intention-to-treat basis. Additional analyses were conducted in the subgroup of women with CPAP adherence ≥ 4 h/night and those with UA levels ≥ 6 mg/dl. Results: Women had a mean (SD) age of 57.1 (10.1) years, median (first-third quartile) body mass index of 33.7 (29.0-38.5) mg/kg2 and AHI of 32.0 (22.6-48.5). The average serum UA measure was 5.11 (1.26) mg/dl, and 80 (26.1%) participants had UA ≥ 6 mg/dl. Compared with the control group, the CPAP group did not achieve any reduction in UA levels (non-adjusted intergroup difference -0.03mg/dl, 95%CI -0.20 to 0.13; p = 0.702) after 12 weeks of follow-up. These results did not change when the analysis was restricted to women with CPAP adherence ≥4 h/night, or the subgroup of women with hyperuricemia. Conclusions: Twelve weeks of CPAP therapy does not reduce UA levels compared to conservative treatment in women with moderate-to-severe OSA

Objetivos: Aunque se ha determinado una asociación entre los niveles de ácido úrico (AU) y el síndrome de apnea obstructiva del sueño (SAOS), el efecto de la presión positiva continua en las vías aéreas (CPAP) en esta medida todavía no está claro. El objetivo fue determinar el efecto de la CPAP en los niveles séricos de AU en pacientes con SAOS. Métodos: Se llevó a cabo un ensayo abierto, aleatorizado, controlado, multicéntrico en 307 mujeres diagnosticadas con SAOS de moderado a grave (índice de apneas-hipopneas [IAH]≥15) en 19 unidades del sueño españolas. Fueron aleatorizadas a recibir CPAP (n=151) o tratamiento conservador (n=156) durante 12 semanas. Los cambios en las medidas de AU sérico se estimaron mediante análisis por intención de tratar. Se llevaron a cabo análisis adicionales en el subgrupo de mujeres con adherencia a CPAP ≥ 4 h/noche y en aquellas con niveles de AU ≥ 6mg/dl. Resultados: La edad media (DE) de las participantes fue 57,1 (10,1) años, la mediana (primer y tercer cuartil) del índice de masa corporal 33,7 (29,0-38,5) mg/kg2 y el IAH 32,0 (22,6-48,5). El nivel medio de AU fue 5,11 (1,26) mg/dl, y 80 (26,1%) participantes tuvieron AU≥6mg/dl. Comparado con el grupo control, el grupo CPAP no consiguió ninguna reducción de los niveles de AU (diferencia intergrupo no ajustada: -0,03 mg/dl; IC 95%: -0,20-0,13; p= 0,702) tras 12 semanas de seguimiento. El análisis no varió cuando se restringió a las mujeres con adherencia a CPAP ≥ 4h/noche o al subgrupo de mujeres con hiperuricemia. Conclusiones: Doce semanas de terapia con CPAP no reducen los niveles de AU en comparación con el tratamiento conservador en mujeres con SAOS de moderado a grave

Investigation of Urinary Sestrin2 in Patients with Obstructive Sleep Apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is a disease seriously threatening individual health, which results in serious complications such as hypertension and stroke. These complications are associated with oxidative stress triggered by intermittent hypoxia in OSA. Sestrin2 is a crucial factor involved in oxidative stress. The goal of this study was to investigate if a relationship exists between OSA and Sestrin2. METHODS: We prospectively enrolled 71 subjects, and 16 patients of them with severe OSA completed 4 weeks of nasal continuous positive airway pressure (nCPAP) therapy. We measured and compared the concentration of Sestrin2 in the urine of all subjects, as well as the changes between before and after nCPAP treatment. Additionally, the correlation between Sestrin2 and sleep parameters was analyzed, and the multiple linear regression analysis with stepwise selection was performed to explore the relationship between Sestrin2 and various factors. RESULTS: A total of 71 subjects were enrolled and divided into two groups: OSA group (n = 41), control group (n = 30). The level of urinary Sestrin2 in OSA patients was significantly higher than that of the control group, and increased with the severity of OSA, while it reduced after nCPAP treatment. Additionally, Sestrin2 was positively correlated with apnea/hypopnea index (AHI), oxygen desaturation index, oxygen saturation < 90% percentage of recording time spent (PRTS) and high-density lipoprotein (HDL), while negatively correlated with the lowest oxygen saturation. Importantly, Sestrin2 was independently associated with AHI, oxygen saturation < 90% PRTS and HDL. CONCLUSIONS: Urinary Sestrin2 is involved in OSA, and is a paramount marker of OSA severity.

Identifying Pathways Mediating Obstructive Sleep Apnea and Obesity in Indian Children.

OBJECTIVE: Overweight and obesity in children is associated with several metabolic and cardiovascular impairments, including obstructive sleep apnea (OSA). However, the causal pathway from OSA to obesity is not fully known yet. The aim of this study was to explore the association between OSA and obesity-related metabolic outcomes in obese Indian children. METHODS: An observational, cross-sectional study was conducted. Obese children referred to the Otorhinolaryngology Department at the Maulana Azad Medical College (New Delhi, India) for suspicion of OSA were consecutively enrolled. OSA was diagnosed by polysomnographic parameters. Homeostasis model assessment (HOMA) was calculated to measure insulin sensitivity and HOMA > 4.39 was considered as a threshold for insulin resistance. The association between various polysomnographic measures and HOMA, adiponectin and various urinary catecholamines was assessed. RESULTS: Complete polysomnographic parameters were available for 45 children; of these 29 were found to suffer from OSA. OSA children had significantly higher glucose concentrations compared to non-OSA ones (p value = 0.012) but no differences were found in insulin resistance and urinary catecholamines levels. Older age was significantly associated to lower levels of catecholamines. No significant associations were found between polysomnographic parameters and both HOMA and adiponectin. Only age was found to be significantly associated with HOMA (p = 0.03) and adiponectin (p = 0.01). CONCLUSIONS: A better understanding of the role played by OSA on obese children's metabolic functions is crucial to implement specific prevention strategies to reduce the public health burden of non-communicable diseases.

A detection dog for obstructive sleep apnea.

PURPOSE: We sought to assess whether a dog can be trained to distinguish obstructive sleep apnea patients from healthy controls based on the olfactory detection of urine. METHODS: Urine samples were collected from 23 adult male obstructive sleep apnea patients and from 20 voluntary adult male volunteers. Three dogs were trained through reinforced operant conditioning. RESULTS: Two of the three dogs correctly detected two thirds of obstructive sleep apnea patients (p < 0.000194 and p < 0.000003, respectively). CONCLUSIONS: We found that dogs can be trained to distinguish obstructive sleep apnea patients from healthy controls based on the smell of urine. Potentially, dogs could be utilized to identify novel biomarkers or possibly screen for obstructive sleep apnea.

Urine concentrations changes of cysteinyl leukotrienes in non-obese children with obstructive sleep apnea undergoing adenotonsillectomy.

OBJECTIVE: The main objective of the study was to compare preoperative to postoperative levels of urine-Cysteinyl leukotrienes (uCysLT) in children undergoing adenotonsillectomy (AT) for obstructive sleep apnea (OSA) in order to investigate whether exaggerated leukotriene activity is the cause or consequence of OSA. METHODS AND MATERIALS: A prospective study was conducted on non-obese children (4-10 years old) referred for overnight PSG. Children with moderate/severe OSA treated with AT were included. A second PSG study performed 2 months postoperatively to confirm OSA resolution, and those with residual OSA were excluded. Morning urine specimens after both PSG studies were obtained and pre-operative uCysLT levels were compared to postoperative levels. RESULTS: 27 children fulfilled the criteria and underwent a post-operative PSG study with three exclusions for residual OSA (postop-AHI>2), so the study group consisted of 24 children (mean age: 5.7 ±â€¯2.1 years). Mean preoperative and postoperative AHI was 10.96 ±â€¯5.93 and 1.44 ±â€¯0.56 respectively. Mean preop-uCysLT were 21.14 ±â€¯4.65, while after AT they significantly reduced to 12.62 ±â€¯2.67 (P < 0.01). CONCLUSION: uCysLT levels are significantly reduced after AT in non-obese children with moderate/severe OSA, suggesting that exaggerated leukotriene activity is mainly a consequence of OSA.

Pediatric Obstructive Sleep Apnea is Associated With Changes in the Oral Microbiome and Urinary Metabolomics Profile: A Pilot Study.

STUDY OBJECTIVES: Several cross-sectional studies have reported associations between oral diseases and obstructive sleep apnea (OSA). However, there have been no reports regarding the structure and composition of the oral microbiota with simultaneous evaluation of potential associations with perturbed metabolic profiles in pediatric OSA. METHODS: An integrated approach, combining metagenomics based on high-throughput 16S rRNA gene sequencing, and metabolomics based on ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry and gas chromatography coupled with time-of-flight mass spectrometry, was used to evaluate the oral microbiome and the urinary metabolome. RESULTS: 16S rRNA gene sequencing indicated that the oral microbiome composition was significantly perturbed in pediatric OSA compared with normal controls, especially with regard to Firmicutes, Proteobacteria, Bacteroidetes, Fusobacteria, and Actinobacteria. Moreover, metabolomics profiling indicated that 57 metabolites, 5 of which were metabolites related to the microflora of the digestive tract, were differentially present in the urine of pediatric patients with OSA and controls. Co-inertia and correlation analyses revealed that several oral microbiome changes were correlated with urinary metabolite perturbations in pediatric OSA. However, this correlation relationship does not imply causality. CONCLUSIONS: High-throughput sequencing revealed that the oral microbiome composition and function were significantly altered in pediatric OSA. Further studies are needed to confirm and determine the mechanisms underlying these findings.

Effect of semi-rapid maxillary expansion in children with obstructive sleep apnea syndrome: 5-month follow-up study.

BACKGROUND: The purpose of this study was to investigate the effect of semi-rapid maxillary expansion (SRME) orthodontic treatment on biomarkers and respiratory parameters in children with obstructive sleep apnea syndrome (OSAS) and maxillary transverse deficiency. METHODS: Thirty children with OSAS were included in this study. Fifteen children were enrolled as control, and 15 children were subjected to SRME orthodontic treatment method for 5 months. Beside respiratory parameters, pharyngeal area, dental arch, and postero-anterior widths and the levels of OSAS biomarkers in serum and urine were measured. RESULTS: Pharyngeal airway space, dental arch, and postero-anterior widths were increased after SRME treatment. Sleep tests showed a decrease in the apnea-hypopnea index (AHI) after 5-month control/treatment duration. Serum kallikrein (KLK)1 levels decreased significantly in the treatment group. There was a significant increase in serum orosomucoid (ORM)2 levels and a decrease in urine perlecan levels in the control group after a 5-month follow-up. A significant negative correlation between serum ORM2, perlecan, gelsolin, and KLK1 levels and intercanin width, as well as between serum ORM2 and KLK1 levels and intermolar width, was observed. CONCLUSIONS: SRME treatment can be considered as a useful approach in children with OSAS. A further investigation of OSAS-related biomarkers and their relationship with sleep and orthodontic parameters is needed for providing easier and reliable modulatory strategies in the treatment of OSAS.

Effect of continuous positive airway pressure in hypertensive patients with obstructive sleep apnea and high urinary metanephrines.

OBJECTIVE: Some cases of pseudopheochromocytoma have been described among hypertensive patients with obstructive sleep apnea (OSA). This study examined whether a pathological rise of urinary metanephrines is a common feature in hypertensive OSA patients and, in such a case, whether the ventilation treatment during sleep (continuous or biphasic positive airway pressure) may normalize high metanephrines levels. METHODS: Patients with endocrine diseases, drug abuse, therapy with TCA and cardiovascular events in the previous 6 months were excluded. Thirty-four hypertensive patients with OSA (BMI 40.6 ±â€Š8.7 kg/m(2)) performed three 24-h urine collections for metanephrine assessment, before and after 1 month of ventilation therapy. RESULTS: Urinary normetanephrine (uNMT) was above the normal limit in 21 of 34 of the patients. In the 16 to 21 patients with high uNMT who were compliant to ventilation treatment, uNMT decreased in 13 by 26% and normalized in six of 13. uNMT levels were associated with apnea hypopnea index (AHI) (r = 0.799, P < 0.0001) and minimal SaO2 (r = -0.700, P < 0.01). The ventilation therapy-induced changes in AHI were associated with those in uNMT (r = 0.689, P < 0.005). In the multivariate analysis with uNMT changes as dependent variable and changes in AHI, BMI, SBP as independent variables, only AHI changes were independently associated with uNMT changes (ß = 0.738, P < 0.01). CONCLUSION: Two-thirds of OSA hypertensive patients have uNMT values above the normal limit. The early identification of these patients is important as ventilation therapy can correct the pathological sympathoadrenal activation. Patients who do not normalize uNMT with ventilation therapy deserve a strict follow-up as this lack of normalization may indicate insufficient ventilation therapy or resistance of sympathetic hyperactivity to this treatment, not excluding an early stage of a chromaffin tumor.