Continuous Positive Airway Pressure Effect on Albuminuria Progression in Patients with Obstructive Sleep Apnea and Diabetic Kidney Disease: A Randomized Clinical Trial.

Rationale: Obstructive sleep apnea (OSA) is associated with impaired glycemic control and a higher risk of vascular complications, such as diabetic kidney disease (DKD). However, the effect of apnea-hypopnea suppression on DKD progression is unclear. Objectives: To assess the effect of continuous positive airway pressure (CPAP) on the urinary albumin-to-creatinine ratio (UACR) in patients with DKD and OSA. Methods: In a 52-week, multicentric, open-label, parallel, and randomized clinical trial, 185 patients with OSA and DKD were randomized to CPAP and usual care (n = 93) or usual care alone (n = 92). Measurements and Main Results: UACR, estimated glomerular filtration rate, serum concentrations of creatinine and glycated hemoglobin, insulin resistance, lipid concentrations, sleepiness, and quality of life. A 52-week change in UACR from baseline did not differ significantly between the CPAP group and the usual-care group. However, in per-protocol analyses that included 125 participants who met prespecified criteria for adherence, CPAP treatment was associated with a great reduction in UACR (mean difference, -10.56% [95% confidence interval, -19.06 to -2.06]; P = 0.015). CPAP effect on UACR was higher in nonsleepy patients with more severe OSA, worse renal function, and a more recent diagnosis of DKD. CPAP treatment also improved glycemic control and insulin resistance, as well as sleepiness and health-related quality of life. Conclusions: In patients with OSA and DKD, the prescription of CPAP did not result in a statistically significant reduction in albuminuria. However, good adherence to CPAP treatment in addition to usual care may result in long-term albuminuria reduction compared with usual care alone. Clinical trial registered with www.clinicaltrials.gov (NCT02816762).

Obstructive sleep apnea is associated with impaired renal function in patients with diabetic kidney disease.

Obstructive sleep apnea (OSA) is a recognized risk factor for the development of diabetic kidney disease (DKD). Our objectives were to compare the urinary albumin-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) of patients with DKD according to OSA severity, and to evaluate the contribution of sleep parameters to their renal function. In a multicenter, observational, cross-sectional study, 214 patients with DKD were recruited. After a sleep study, UACR and eGFR were measured, as well as serum creatinine, fasting glucose, glycated hemoglobin, insulin resistance, lipid profile and C-reactive protein. UACR was higher in severe OSA patients (920 ± 1053 mg/g) than in moderate (195 ± 232 mg/g, p < 0.001) or mild OSA/non-OSA subjects (119 ± 186 mg/g, p < 0.001). At the same time, eGFR showed an OSA severity-dependent reduction (48 ± 23 vs. 59 ± 21 vs. 73 ± 19 ml/min per 1.73 m2, respectively; p < 0.001). Apnea-hypopnea index (AHI and desaturation index (ODI) were identified as independent predictors for UACR and eGFR, respectively. Therefore, in patients with DKD under optimized treatment, severe OSA is associated with a higher UACR and a lower eGFR, reflecting an additional contribution to the impairment of their renal function, although no causality can be inferred.

Daily physical activity in patients with chronic obstructive pulmonary disease is mainly associated with dynamic hyperinflation.

RATIONALE: Although the major limitation to exercise performance in patients with COPD is dynamic hyperinflation, little is known about its relation to daily physical activity. OBJECTIVES: To analyze the contribution of dynamic hyperinflation, exercise tolerance, and airway oxidative stress to physical activity in patients with COPD. METHODS: In a cross-sectional study, we included 110 patients with moderate to very severe COPD. Daily physical activity was measured using a triaxial accelerometer providing a mean of 1-minute movement epochs as vector magnitude units (VMU). Patients performed the 6-minute walk test, incremental exercise test with measurement of breathing pattern and operating lung volumes, and constant-work rate test at 75% of maximal work rate. MEASUREMENTS AND MAIN RESULTS: Using the GOLD stage and BODE index, we determined arterial blood gases, lung volumes, diffusing capacity, and biomarkers in exhaled breath condensate. Daily physical activity was lower in the 89 patients who developed dynamic hyperinflation than in the 21 who did not (n =161 [SD 70] vs. n = 288 [SD 85] VMU; P = 0.001). Physical activity was mainly related to distance walked in 6 minutes (r = 0.72; P = 0.001), Vo(2) (r = 0.63; P = 0.001), change in end-expiratory lung volume during exercise (r = -0.73; P = 0.001), endurance time (r = 0.61; P = 0.001), and 8-isoprostane in exhaled breath condensate (r = -0.67; P = 0.001). In a multivariate linear regression analysis using VMU as a dependent variable, dynamic hyperinflation, change in end-expiratory lung volume, and distance walked in 6 minutes were retained in the prediction model (r(2) = 0.84; P = 0.001). CONCLUSIONS: Daily physical activity of patients with COPD is mainly associated with dynamic hyperinflation, regardless of severity classification.

The progressive effects of ageing on chemosensitivity in healthy subjects.

The aim of this study was to compare the central inspiratory drive (P(0.1)) response to hypoxia and hypercapnia between different age groups of elderly, nonsmoker, healthy subjects and young healthy controls. A random sample, proportionally stratified by age (65-69, 70-74, 75-79 and 80-84 yrs) from a sample of nonsmoker elderly subjects representative of a general population and 47 healthy subjects aged 20-40 were selected. Arterial blood gas, lung volumes, diffusing capacity, maximal respiratory pressure and oxygen uptake measurements were performed. Breathing pattern and mouth occlusion pressure, as well as P(0.1) responses to hyperoxic progressive hypercapnia and isocapnic progressive hypoxia were evaluated. The elderly subjects had lower P0.1 responses to hypoxia (0.017+/-0.006 vs. 0.031+/-0.008 kPa/%, P<0.001) and hypercapnia (0.042+/-0.018 vs. 0.051+/-0.030 kPa/mmHg, P=0.047) than the young healthy controls. Hypoxic sensitivity gradually decreased as age increased to 70-74 and remained unchanged from 75 years of age onward. CO(2) threshold was lower in the elderly groups than in young healthy controls. Lung volumes, inspiratory muscle strength and baseline metabolic rate were the principal determinants of hypoxic sensitivity. In summary, during old age, a progressive decline in hypoxic sensitivity and a decrease in the CO(2) threshold are experienced. These alterations remain stable from the age of 75 onward.

[Recording the daily physical activity of COPD patients with an accelerometer: An analysis of agreement and repeatability]. / Registro de la actividad física cotidiana mediante un acelerómetro en pacientes con EPOC. Análisis de concordancia y reproducibilidad.

OBJECTIVE: The purpose of this study was to assess the agreement between different measurements of mean daily physical activity taken over a week in chronic obstructive pulmonary disease (COPD) patients with an accelerometer and to analyze the medium-term repeatability of these measurements. PATIENTS AND METHODS: The study enrolled 12 healthy control subjects and 23 patients with stable COPD (mean [SD] forced expiratory volume in 1 second [FEV1] of 45% [13%] of predicted and a ratio of FEV1 to forced vital capacity of 53% [13%]). Accelerometer output, measured in vector magnitude units, was recorded in a physical activity log for a 1-week period. The results were then analyzed to compare output for a conventional recording period (Friday to Sunday) to that for 2 other periods (Monday to Wednesday and Tuesday to Thursday). The measurements were repeated 3 to 5 weeks later. RESULTS: Activity counts were lower in the COPD patients than in the control subjects (184 [99] vs 314 [75]; P < .001). In the COPD patients, the results for the Friday to Sunday period correlated well with the results for both the Monday to Wednesday period (95% confidence interval, -29.21 to 28.81) and the Tuesday to Thursday period (95% confidence interval, -32.13 to 28.43). There were no significant differences in terms of medium-term repeatability of accelerometer readings between the COPD group and the control group (repeatability coefficient of 11.2% [4.6%] and 8.5% [4.7%], respectively). CONCLUSIONS: Both agreement between the different measurements of physical activity taken during a 1-week period and medium-term repeatability for COPD patients and control subjects were very good.

CPAP effect on recurrent episodes in patients with sleep apnea and myocardial infarction.

BACKGROUND: Obstructive sleep apnea (OSA) is linked to increased cardiovascular risk, but the association between OSA and myocardial infarction (MI) remains controversial. Our objectives were to compare the frequency of OSA in patients with acute MI and in a population-based sample of control subjects, and to evaluate the impact of CPAP on recurrent MI and coronary revascularization. METHODS: Case-control study with a 6-year follow-up of the case cohort. 192 acute MI patients and 96 matched control subjects without coronary artery disease (CAD) (ratio 2:1). After overnight polysomnography, CPAP was recommended if apnea-hypopnea index (AHI) ≥ 5, and a mean daily use >3.5h/day was considered necessary to maintain the treatment. Lipids, fasting glucose, blood pressure, spirometry, comorbidity and current treatment were also registered. End-points were recurrent MI or need of revascularization. RESULTS: OSA was an independent predictor of MI, with odds ratio 4.9 (95% confidence interval [CI] 2.9-8.3, p=0.017). 63 MI patients without OSA, 52 untreated patients with OSA and 71 OSA patients treated with CPAP were included in the follow-up study. After adjustment for confounding factors, treated OSA patients had a lower risk of recurrent MI (adjusted hazard ratio 0.16 [95%CI 0.03-0.76, p=0.021]) and revascularization (adjusted hazard ratio 0.15 [95%CI 0.03-0.79, p=0.025]) than untreated OSA patients, and similar to non-OSA patients. CONCLUSION: Mild-severe OSA is an independent risk factor for MI. Risk of recurrent MI and revascularization was lower in OSA patients who tolerated CPAP.

Prognostic value of the objective measurement of daily physical activity in patients with COPD.

BACKGROUND: Subjective measurement of physical activity using questionnaires has prognostic value in COPD. However, their lack of accuracy and large individual variability limit their use for evaluation on an individual basis. We evaluated the capacity of the objective measurement of daily physical activity in patients with COPD using accelerometers to estimate their prognostic value. METHODS: In 173 consecutive subjects with moderate to very severe COPD, daily physical activity was measured using a triaxial accelerometer providing a mean of 1-min movement epochs as vector magnitude units (VMUs). Patients were evaluated by lung function testing and 6-min walk, incremental exercise, and constant work rate tests. Patients were followed for 5 to 8 years, and the end points were all-cause mortality, hospitalization for COPD exacerbation, and annual declining FEV(1). RESULTS: After adjusting for relevant confounders, a high VMU decreased the mortality risk (adjusted hazard ratio [HR], 0.986; 95% CI, 0.981-0.992), and in a multivariate model, comorbidity, endurance time, and VMU were retained as independent predictors of mortality. The time until first admission due to COPD exacerbation was shorter for the patients with lower levels of VMU (adjusted HR, 0.989; 95% CI, 0.983-0.995). Moreover, patients with higher VMU had a lower hospitalization risk than those with a low VMU (adjusted incidence rate ratio, 0.099; 95% CI, 0.033-0.293). In contrast, VMU was not identified as an independent predictor of the annual FEV(1) decline. CONCLUSION: The objective measurement of the daily physical activity in patients with COPD using an accelerometer constitutes an independent prognostic factor for mortality and hospitalization due to severe exacerbation.

Exercise oxygen flow titration methods in COPD patients with respiratory failure.

We compare the adequacy of several titration procedures of oxygen flow in maintaining SpO(2) > 90% during the activities of daily life in patients with very severe COPD. Thirty-one very severe COPD patients undergoing oxygen-therapy were recruited. Three titration methods were randomly performed: (1) 6-min walking tests; (2) cycle-ergometer constant work-rate tests at a load equivalent to 12 ml/min/kg of oxygen uptake; (3) one single constant work-rate test at 40 W 12-h pulse-oximeter monitoring was performed on four consecutive days with the following oxygen flow during exercise: 1 l·min(-1) above the resting prescription (NOTT guidelines) and those established by the titration procedures. The time spent SpO(2) < 90% was higher for the titration based on NOTT and walking tests than for the oxygen flow established by the constant work-rate tests at 12 ml O(2)/min/kg (22.1 ± 18.7, 20.8 ± 19.5 and 6.7 ± 12.7%, respectively). As for the oxygen uptake-based titration, the simplified procedure (a single exercise test at 40 w) generates longer times spent SpO(2) < 90% and SpO(2) < 85%, although it maintains a SpO(2) > 90% for more 90% of the time. In COPD patients, exercise oxygen flow titrations by NOTT guidelines or walking tests do not allow a suitable oxygenation during the activities of daily life. Two more adequate alternative methods, based on constant work-rate tests, are proposed.

Dynamic hyperinflation, arterial blood oxygen, and airway oxidative stress in stable patients with COPD.

BACKGROUND: There is considerable evidence that oxidative stress is increased in patients with COPD, although little information is available about its relationship with the structural and functional alterations produced by COPD. In this study, we evaluated the relationship between 8-isoprostane in exhaled breath condensate (EBC) of stable patients with COPD and the main parameters of the disease (such as dyspnea), stages of severity, lung parenchyma densities, lung function impairment, and exercise tolerance in order to identify the predictors of airway oxidative stress. METHODS: In a cross-sectional study, we included 76 men with moderate to very severe COPD. 8-Isoprostane levels in EBC were measured by enzyme immunoassay. Regional lung densities were measured by lung densitometry with high-resolution CT scanning. Arterial blood gas levels, lung volumes, and diffusing capacity were determined. Patients performed a 6-min walk test and an incremental exercise test with measurement of breathing pattern and operating lung volumes. RESULTS: Significant severity-related differences in 8-isoprostane were identified according to the BMI, obstruction, dyspnea, and exercise (BODE) index. 8-Isoprostane levels were related to smoking intensity, lung densities in expiration, static lung volumes, PaO(2), diffusion capacity, distance walked in 6 min, peak oxygen uptake, and anaerobic threshold. Concentration of 8-isoprostane was higher in the 60 patients (79%) who developed dynamic hyperinflation than in the remaining 16 (21%) who did not. In a multivariate linear regression analysis using 8-isoprostane as a dependent variable, end-expiratory lung volume change and PaO(2) were retained in the prediction model (r(2) = 0.734, P < .001). CONCLUSIONS: In stable patients with COPD, oxygen level and dynamic hyperinflation are related to airway oxidative stress.

Severity-related differences in lung attenuation in men with COPD.

BACKGROUND AND OBJECTIVES: We compare the inspiratory and expiratory regional lung densities between different levels of COPD severity (as assessed by the GOLD scale and by the BODE index), and to assess the relationship between regional lung densities and functional lung parameters. PATIENTS AND METHODS: Fifty-five stable moderate-severe COPD men were selected. Functional evaluation included dyspnoea scale, blood gases, spirometry, plethysmography, diffusing capacity and six-minute walk test. Severity was classified according the GOLD scale and the BODE index. High resolution computed tomography (HRCT) scans of the entire lung at full inspiration and two sections at full expiration were obtained. Densitometry software was used to calculate the densities of the lung areas. RESULTS: Inspiratory and expiratory mean lung densities (MLD) of the lower lobes were significantly lower in very severe and severe COPD patients than in moderate patients. In contrast, we only found differences between the upper lobe MLD values of moderate and severe COPD patients. Inspiratory and expiratory HRCT densities were similar among all BODE quartiles, for both the upper and lower lobes. In a multiple regression analysis, airway obstruction parameters were mainly related to the expiratory MLD of the lower lobes, whereas lung hyperinflation parameters were predicted by the inspiratory MLD of the lower lobes. Lastly, diffusion capacity was independently related to the expiratory/inspiratory MLD of the lower lobes and to the inspiratory MLD of the upper lobes. CONCLUSIONS: There are differences in lung attenuation measurements by HRCT between the varying levels of COPD severity as assessed by the GOLD scale.

Monocytes from cystic fibrosis patients are locked in an LPS tolerance state: down-regulation of TREM-1 as putative underlying mechanism.

Cystic Fibrosis (CF) is an inherited pleiotropic disease that results from abnormalities in the gene that codes for the chloride channel, Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). CF patients are frequently colonized by several pathogens, but the mechanisms that allow colonization in spite of apparently functional immune systems are incompletely understood. In this paper we show that blood peripheral monocytes isolated from CF patients are found in an endotoxin tolerance state, yet this is not due to a deficient TLR activation. On the other hand, levels of the amplifier of inflammatory responses, TREM-1 (Triggering Receptor Expressed on Myeloid cells), are notably down-regulated in monocytes from patients, in comparison to those extracted from healthy volunteers. Furthermore, the soluble form of TREM-1 (sTREM-1) was not detected in the sera of patients. Additionally, and in strict contrast to patients who suffer from Chronic Obstructive Pulmonary Disease (COPD), CF monocytes challenged ex vivo with LPS neither up-regulated membrane-anchored TREM-1 nor sTREM-1. Finally, similar levels of PGE(2) expression and p65 translocation into the nucleus were found in both patients and healthy volunteers, thus suggesting that TREM-1 regulation is neither controlled by PGE(2) levels nor by p65 activation in this case. However, PU.1 translocation into the nucleus was significantly higher in CF monocytes than in controls, suggesting a role for this transcription factor in the control of TREM-1 expression. We conclude that down-regulation of TREM-1 expression in cystic fibrosis patients is at least partly responsible for the endotoxin tolerance state in which their monocytes are locked.