Sex differences in body fluid composition in humans with obstructive sleep apnea before and after CPAP therapy.

Obstructive sleep apnea (OSA) is common in heart and kidney disease, both conditions prone to fluid retention. Nocturnal rostral fluid shift contributes to the pathogenesis of OSA in men more than women, suggesting a potential role for sex differences in body fluid composition in the pathogenesis of OSA, with men having a predisposition to more severe OSA due to an underlying volume expanded state. Continuous positive airway pressure (CPAP) increases intraluminal pressure in the upper airway and mitigates the rostral fluid shift; this, in turn, may prevent fluid redistribution from other parts of the body to the upper airway. We sought to determine the impact of CPAP on sex differences in body fluid composition. Twenty-nine (10 women, 19 men) incident, sodium replete, otherwise healthy participants who were referred with symptomatic OSA (oxygen desaturation index >15/h) were studied pre- and post-CPAP (>4 h/night × 4 weeks) using bioimpedance analysis. Bioimpedance parameters including fat-free mass (FFM, %body mass), total body water (TBW, %FFM), extracellular and intracellular water (ECW and ICW, %TBW), and phase angle (°) were measured and evaluated for sex differences before and after CPAP. Pre-CPAP, despite TBW being similar between sexes (74.6 ± 0.4 vs. 74.3 ± 0.2%FFM, p = 0.14; all values women vs. men), ECW (49.7 ± 0.7 vs. 44.0 ± 0.9%TBW, p < 0.001) was increased, while ICW (49.7 ± 0.5 vs. 55.8 ± 0.9%TBW, p < 0.001) and phase angle (6.7 ± 0.3 vs. 8.0 ± 0.3°, p = 0.005) were reduced in women compared to men. There were no sex differences in response to CPAP (∆TBW -1.0 ± 0.8 vs. 0.7 ± 0.7%FFM, p = 0.14; ∆ECW -0.1 ± 0.8 vs. -0.3 ± 1.0%TBW, p = 0.3; ∆ICW 0.7 ± 0.4 vs. 0.5 ± 1.0%TBW, p = 0.2; ∆Phase Angle 0.2 ± 0.3 vs. 0.0 ± 0.1°, p = 0.7). Women with OSA had baseline parameters favoring volume expansion (increased ECW, reduced phase angle) compared to men. Changes in body fluid composition parameters in response to CPAP did not differ by sex.

Nocturnal hypoxemia severity influences the effect of CPAP therapy on renal renin-angiotensin-aldosterone system activity in humans with obstructive sleep apnea.

STUDY OBJECTIVES: Nocturnal hypoxemia (NH) in obstructive sleep apnea (OSA) is associated with renal renin-angiotensin-aldosterone system (RAAS) up-regulation and loss of kidney function. Continuous positive airway pressure (CPAP) therapy is associated with RAAS down-regulation, though the impact of NH severity remains unknown. We sought to determine whether NH severity alters the effect of CPAP on renal hemodynamics and RAAS activity in humans. METHODS: Thirty sodium-replete, otherwise healthy, OSA participants (oxygen desaturation index ≥ 15 h-1) with NH (SpO2 < 90% ≥ 12%/night) were studied pre- and post-CPAP (>4 h/night∙4 weeks). NH severity was characterized as moderate (mean SpO2[MSpO2] ≥ 90%; N = 15) or severe (MSpO2 < 90%; N = 15). Glomerular filtration rate (GFR), renal plasma flow (RPF), and filtration fraction (FF) were measured at baseline and in response to angiotensin-II (3 ng/kg/min∙30 min, 6 ng/kg/min∙30 min), a marker of RAAS activity. RESULTS: Pre-CPAP, baseline renal hemodynamics did not differ by NH severity. Pre-CPAP, severe NH participants demonstrated blunted GFR (Δ30 min, -9 ± 4 vs 1 ± 3 mL/min, p = 0.021; Δ60 min, -5 ± 5 vs 8 ± 5 mL/min, p = 0.017) and RPF (Δ30 min, -165 ± 13 vs -93 ± 19 mL/min, p = 0.003; Δ60 min, -208 ± 18 vs -112 ± 22 mL/min, p = 0.001; moderate vs severe) responses to angiotensin-II. Post-CPAP, severe NH participants demonstrated maintained GFR (112 ± 5 vs 108 ± 3 mL/min, p = 0.9), increased RPF (664 ± 35 vs 745 ± 34 mL/min, p = 0.009), reduced FF (17.6 ± 1.4 vs 14.9 ± 0.6%, p = 0.009), and augmented RPF responses to Angiotensin-II (Δ30 min, -93 ± 19 vs -138 ± 16 mL/min, p = 0.009; Δ60 min, -112 ± 22 vs -175 ± 20 mL/min, p = 0.001; pre- vs post-CPAP), while moderate participants were unchanged. CONCLUSIONS: Correction of severe, but not moderate, NH with CPAP therapy was associated with improved renal hemodynamics and decreased renal RAAS activity in humans with 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.

Sex differences in renal hemodynamics and renin-angiotensin system activity post-CPAP therapy in humans with obstructive sleep apnea.

Men have faster loss of kidney function and greater renal renin-angiotensin system (RAS) activity compared with women. Obstructive sleep apnea (OSA) is common in chronic kidney disease; the vascular effects of OSA differ by sex, and OSA-associated glomerular hyperfiltration can be reversed by continuous positive airway pressure (CPAP) therapy. We evaluated sex differences in the effect of CPAP on renal hemodynamics and the renal RAS in OSA. Twenty-nine Na+-replete, otherwise healthy study participants with OSA (10 women and 19 men) with nocturnal hypoxemia were studied pre- and post-CPAP (>4 h/night for 4 wk). Renal hemodynamics [renal plasma flow (RPF), glomerular filtration rate (GFR), and filtration fraction(FF)] were measured at baseline and in response to ANG II challenge, as a marker of renal RAS activity, pre- and post-CPAP therapy for 1 mo. In women, CPAP was associated with increased RPF (626 ± 22 vs. 718 ± 43 mL/min, P = 0.007, pre- vs. post-CPAP), maintained GFR (108 ± 2 vs. 105 ± 3 mL/min, P = 0.8), and reduced FF (17.4 ± 0.8% vs. 15.0 ± 0.7%, P = 0.017). In men, CPAP was associated with maintained RPF (710 ± 37 vs. 756 ± 38 mL/min, P = 0.1), maintained GFR (124 ± 8 vs. 113 ± 6 mL/min, P = 0.055), and reduced FF (18.6 ± 1.7% vs. 15.5 ± 1.1%, P = 0.035). Pre-CPAP, there were no sex differences in renal hemodynamic responses to ANG II. CPAP use was associated with a greater renovasoconstrictive response to ANG II in women (RPF at Δ30 min: -100 ± 27 vs. -161 ± 25 mL/min, P = 0.007, and RPF at Δ60 min: -138 ± 27 vs. -206 ± 32 mL/min, P = 0.007) but not men. CPAP use was associated with improved renal hemodynamics in both sexes and downregulated renal RAS activity in women but not men.

CPAP Therapy Delays Cardiovagal Reactivation and Decreases Arterial Renin-Angiotensin System Activity in Humans With Obstructive Sleep Apnea.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is associated with increased cardiovascular risk. The effect of OSA treatment with continuous positive airway pressure (CPAP) on the cardiovascular response to a stressor is unknown. We sought to determine the effect of CPAP therapy on heart rate variability (HRV) and arterial stiffness, at baseline, in response to, and recovery from a physiological stressor, Angiotensin II (AngII), in humans with OSA. METHODS: Twenty-five incident healthy subjects (32% female; 49 ± 2 years) with moderate-severe OSA and nocturnal hypoxia were studied in high-salt balance, a state of maximal renin-angiotensin system (RAS) suppression, before CPAP, and after 4 weeks of effective CPAP therapy (usage > 4 h/night) in a second identical study day. HRV was calculated by spectral power and time domain analysis. Aortic augmentation index (AIx) and carotid-femoral pulse-wave velocity (PWVcf) were measured by applanation tonometry. HRV and arterial stiffness were measured at baseline and in response to AngII challenge (3 ng/ kg/min·30 minutes, 6 ng/kg/min·30 minutes, recovery·30 minutes). The primary outcome was the association between CPAP treatment and HRV and arterial stiffness responses to, and recovery from, AngII challenge. In an exploratory analysis subjects were stratified by sex. RESULTS: CPAP corrected OSA and nocturnal hypoxemia. CPAP treatment was associated with increased sensitivity and delayed recovery from AngII (Δln HF [high frequency; recovery: -0.09 ± 0.19 versus -0.59 ± 0.17 ms2, P = .042; ΔrMSSD [root mean successive differences; recovery: -0.4 ± 2.0 versus -7.2 ± 1.9 ms, P = .001], ΔpNN50 [percentage of normal waves differing ≥ 50 ms compared to the preceding wave; AngII: 1.3 ± 2.3 versus -3.0 ± 2.4%, P = .043; recovery: -0.4 ± 1.4 versus -6.0 ± 1.9%, P = .001], all values pre-CPAP versus post-CPAP treatment). No differences were observed by sex. There was increased AIx sensitivity to AngII after CPAP among men (8.2 ± 1.7 versus 11.9 ± 2.2%, P = .046), but not women (11.4 ± 1.5 versus 11.6 ± 2.1%, P = .4). No change in PWVcf sensitivity was observed in either sex. CONCLUSIONS: CPAP therapy was associated with delayed cardiovagal reactivation after a stressor and down-regulation of the arterial RAS. These findings may have important implications in mitigating cardiovascular risk in both men and women with OSA.

Nocturnal hypoxemia severity and renin-angiotensin system activity in obstructive sleep apnea.

RATIONALE: Obstructive sleep apnea (OSA) and nocturnal hypoxemia are associated with chronic kidney disease and up-regulation of the renin-angiotensin system (RAS), which is deleterious to renal function. The extent to which the magnitude of RAS activation is influenced by the severity of nocturnal hypoxemia and comorbid obesity has not been determined. OBJECTIVES: To determine the association between the severity of nocturnal hypoxemia and RAS activity and whether this is independent of obesity in patients with OSA. METHODS: Effective renal plasma flow (ERPF) response to angiotensin II (AngII) challenge, a marker of renal RAS activity, was measured by paraaminohippurate clearance technique in 31 OSA subjects (respiratory disturbance index, 51 ± 25 h(-1)), stratified according to nocturnal hypoxemia status (mean nocturnal SaO2, ≥90% [moderate hypoxemia] or <90% [severe hypoxemia]) and 13 obese control subjects. MEASUREMENTS AND MAIN RESULTS: Compared with control subjects, OSA subjects demonstrated decreased renovascular sensitivity (ERPF, -153 ± 79 vs. -283 ± 31 ml/min; P = 0.004) (filtration fraction, 5.4 ± 3.8 vs. 7.1 ± 2.6%; P = 0.0025) in response to 60 minutes of AngII challenge (mean ± SD; all P values OSA vs. control). The fall in ERPF in response to AngII was less in patients with severe hypoxemia compared with those with moderate hypoxemia (P = 0.001) and obese control subjects after 30 minutes (P < 0.001) and 60 minutes (P < 0.001) of AngII challenge, reflecting more augmented renal RAS activity. Severity of hypoxemia was not associated with the blood pressure or the systemic circulating RAS component response to AngII. CONCLUSIONS: The severity of nocturnal hypoxemia influences the magnitude of renal, but not the systemic, RAS activation independently of obesity in patients with OSA.

Evaluation of continuous positive airway pressure therapy on renin-angiotensin system activity in obstructive sleep apnea.

RATIONALE: Obstructive sleep apnea (OSA) has been associated with kidney function loss, which may be related to changes in the renin-angiotensin system (RAS). OBJECTIVES: We sought to determine the effect of continuous positive airway pressure (CPAP) of patients with OSA on renal hemodynamics at baseline and in response to angiotensin II (AngII), which reflects RAS activity. METHODS: Twenty normotensive, nondiabetic, newly diagnosed OSA subjects (15 men, 5 women, 50 ± 2 yr, respiratory disturbance index [RDI] > 15 h(-1)) with nocturnal hypoxemia (SaO2 < 90% for >12% of the night) were studied in high-salt balance pre- and post-CPAP therapy (>4 h CPAP use/night for 1 mo). Glomerular filtration rate (GFR), renal plasma flow (RPF), and filtration fraction (FF) (a surrogate marker for intraglomerular pressure) were measured pre- and post-CPAP using inulin and para-aminohippurate clearance techniques at baseline and in response to graded AngII infusion (3 ng/kg/min × 30 min and 6 ng/kg/min × 30 min, respectively). MEASUREMENTS AND MAIN RESULTS: CPAP corrected OSA and hypoxemia (RDI: 42 ± 4 vs. 4 ± 1 h(-1), P < 0.001; duration SaO2 < 90%: 36% ± 5% vs. 6 ± 2%, P < 0.001). CPAP reduced GFR (124 ± 8 ml/min vs. 110 ± 6 ml/min, P = 0.014), increased RPF (692 ± 36 ml/min vs. 749 ± 40 ml/min, P = 0.059), and reduced baseline FF (18.9 ± 1.6% vs. 15.3 ± 1.0%, P = 0.004). Post-CPAP demonstrated a blunted GFR response (-9 ± 3 ml/min vs. -2 ± 2 ml/min, P = 0.033) and augmented RPF response (-182 ± 22 ml/min vs. -219 ± 25 ml/min, P = 0.024) to AngII. FF response was maintained (P = 0.4). CPAP reduced baseline mean arterial pressure (94 ± 2 vs. 89 ± 2 mm Hg, P = 0.002), plasma aldosterone (149 ± 18 vs. 109 ± 10 pmol/L, P = 0.003), and urinary protein excretion (61 [39-341] mg/day vs. 56 [22-204] mg/d, P = 0.003). CONCLUSIONS: CPAP therapy was associated with improved renal hemodynamics and down-regulation of renal RAS activity, suggesting a potential therapeutic benefit for kidney function.