David D. M. Nicholl

Declining Kidney Function Increases the Prevalence of Sleep Apnea and Nocturnal Hypoxia

BACKGROUND Sleep apnea is an important comorbidity in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Although the increased prevalence of sleep apnea in patients with ESRD is well established, few studies have investigated the prevalence of sleep apnea in patients with nondialysis-dependent kidney disease, and no single study, to our knowledge, has examined the full spectrum of kidney function. We sought to determine the prevalence of sleep apnea and associated nocturnal hypoxia in patients with CKD and ESRD. We hypothesized that the prevalence of sleep apnea would increase progressively as kidney function declines. METHODS Two hundred fifty-four patients were recruited from outpatient nephrology clinics and hemodialysis units. All patients completed an overnight cardiopulmonary monitoring test to determine the prevalence of sleep apnea (respiratory disturbance index ≥ 15) and nocturnal hypoxia (oxygen saturation < 90% for ≥ 12% of monitoring). Patients were stratified into three groups based on estimated glomerular filtration rate (eGFR) as follows: eGFR ≥ 60 mL/min/1.73 m(2) (n = 55), CKD (eGFR < 60 mL/min/1.73 m(2) not on dialysis, n = 124), and ESRD (on hemodialysis, n = 75). RESULTS The prevalence of sleep apnea increased as eGFR declined (eGFR ≥ 60 mL/min/1.73 m(2), 27%; CKD, 41%; ESRD, 57%; P = .002). The prevalence of nocturnal hypoxia was higher in patients with CKD and ESRD (eGFR ≥ 60 mL/min/1.73 m(2), 16%; CKD, 47%; ESRD, 48%; P < .001). CONCLUSIONS Sleep apnea is common in patients with CKD and increases as kidney function declines. Almost 50% of patients with CKD and ESRD experience nocturnal hypoxia, which may contribute to loss of kidney function and increased cardiovascular risk.

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.

Clinical presentation of obstructive sleep apnea in patients with chronic kidney disease.

BACKGROUND Obstructive sleep apnea (OSA) is an important and common comorbidity in patients with chronic kidney disease (CKD). However, few studies have addressed how OSA presents in this patient population and whether it is clinically apparent. OBJECTIVE The objectives of this study were to determine if the prevalence and severity of sleep related symptoms distinguished CKD patients with OSA from those without apnea, and whether the clinical presentation of OSA in CKD patients differed from the general OSA population. METHODS One hundred nineteen patients were recruited from outpatient nephrology clinics. All patients completed a sleep history questionnaire, the Epworth Sleepiness Scale (daytime sleepiness, ESS > 10), the Pittsburgh Sleep Quality Index (poor sleep quality, PSQI > 5), and underwent overnight cardiopulmonary monitoring for determination of sleep apnea (respiratory disturbance index ≥ 15). CKD patients with OSA (n = 46) were compared to (1) CKD patients without OSA (n = 73) and (2) OSA patients without CKD (n = 230) who were referred to the sleep centre. RESULTS The prevalence of OSA symptoms and PSQI scores did not differ between CKD patients with OSA and CKD patients without apnea. Although the prevalence of daytime sleepiness was higher in CKD patients with OSA compared to CKD patients without apnea (39% vs. 19%, p = 0.033), both daytime sleepiness and other symptoms of sleep apnea were considerably less frequent than in OSA patients without a history of kidney disease. CONCLUSIONS The presence of OSA in patients with CKD is unlikely to be clinically apparent. Consequently, objective cardiopulmonary monitoring during sleep is required to reliably identify this comorbidity.

Diagnostic value of screening instruments for identifying obstructive sleep apnea in kidney failure.

BACKGROUND Patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) have a high prevalence of obstructive sleep apnea (OSA) that can have significant clinical implications. An accurate clinical screening tool for OSA that identifies patients for further diagnostic testing would assist in the identification of this comorbidity. The Berlin Questionnaire (BQ), Adjusted Neck Circumference (ANC), and STOP-BANG questionnaire are 3 such instruments that have been validated in patients with normal kidney function. OBJECTIVE The objective of this study was to determine the validity of these screening instruments in patients with CKD and ESRD, using overnight cardiopulmonary monitoring to diagnose OSA. METHODS One hundred seventy-two patients were recruited from nephrology clinics and hemodialysis units (CKD: n = 109; ESRD: n = 63). All patients completed the BQ, ANC, STOP-BANG, and overnight cardiopulmonary monitoring to diagnose OSA (respiratory disturbance index [RDI] ≥ 15). Sensitivity, specificity, positive and negative predictive values, and accuracy were calculated for the BQ, ANC, and STOP-BANG. RESULTS Obstructive sleep apnea was present in 41 CKD patients (38%) and 32 ESRD patients (51%). All screening instruments had satisfactory sensitivity (56% to 94%) but poor specificity (29% to 77%) and low accuracy (51% to 69%) in both CKD and ESRD patients with RDI ≥ 15. Using an RDI ≥ 30 yielded similar results. CONCLUSIONS Current screening questionnaires do not accurately identify patients at high risk for OSA or rule out the presence of OSA in patients with CKD and ESRD. Consequently, objective monitoring during sleep is required to reliably identify sleep apnea in these patient populations.

The prevalence of restless legs syndrome across the full spectrum of kidney disease.

STUDY OBJECTIVES Although restless legs syndrome (RLS) is common and well recognized as an important and potentially treatable cause of sleep disruption in end-stage renal disease (ESRD), few studies have evaluated the prevalence of RLS and its impact on sleep in the non-dialysis-dependent chronic kidney disease (CKD) population. The objectives of the study were to determine the prevalence of RLS across the full spectrum of kidney disease and to assess the impact of RLS on sleep quality and daytime function. METHODS Five hundred patients were recruited from nephrology clinics and were stratified according to estimated glomerular filtration rate (EGFR): eGFR ≥ 60 mL/min/1.73m(2) (n = 127), CKD (eGFR < 60, not on dialysis, n = 242), and ESRD (on hemodialysis, n = 131). All subjects completed a sleep and medical history questionnaire, an RLS questionnaire, the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale (ESS). RESULTS The prevalence of RLS did not differ among the three groups (18.9% [eGFR ≥ 60], 26% (CKD), and 26% (ESRD) p = 0.27). However, many symptoms of sleep disruption were more common in patients with RLS, and RLS was independently correlated with the PSQI score both in the full cohort (OR = 2.63, CI = 1.60-4.00, p < 0.001) and the CKD group (OR = 2.39, CI = 1.20-4.79, p = 0.014). CONCLUSIONS RLS is common in non-dialysis-dependent CKD patients and is an important source of sleep disruption.

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.

Increased urinary protein excretion in the “normal” range is associated with increased renin-angiotensin system activity

Increased levels of albuminuria and proteinuria, both linked to augmented renin-angiotensin system (RAS) activity, are associated with adverse kidney and cardiovascular events. However, the relationship between variations in urinary albumin excretion (UAE) and total protein excretion (UTPE) in the normal range and RAS activity is unclear. We examined the association between UAE and UTPE and the hemodynamic response to angiotensin II (ANG II) challenge, a well-accepted indirect measure of RAS activity, in healthy individuals with normal UAE and UTPE. Forty subjects (15 men, 25 women; age 38 ± 2 yr; UAE, 3.32 ± 0.55 mg/day; UTPE, 56.8 ± 3.6 mg/day) were studied in high-salt balance. Blood pressure (BP), arterial stiffness determined by applanation tonometry, and circulating RAS components were measured at baseline and in response to graded ANG II infusion. The primary outcome was the BP response to ANG II challenge at 30 and 60 min. UAE was associated with a blunted diastolic BP response to ANG II infusion (30 min, P = 0.005; 60 min, P = 0.17), a relationship which remained even after adjustment (30 min, P < 0.001; 60 min, P = 0.035). Similar results were observed with UTPE (30 min, P = 0.031; 60 min, P = 0.001), even after multivariate analysis (30 min, P = 0.008; 60 min, P = 0.001). Neither UAE nor UTPE was associated with systolic BP, circulating RAS components, or arterial stiffness responses to ANG II challenge. Among healthy individuals with UAE and UTPE in the normal range, increased levels of these measures were independently associated with a blunted diastolic BP response to ANG II, indicating increased vascular RAS activity, which is known to be deleterious to both renal and cardiac function.

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.