Comments
Abstract
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.
Nocturnal hypoxemia associated with obstructive sleep apnea has been associated with loss of kidney function, and studies suggest that this is mediated by up-regulation of the renin-angiotensin system (RAS). It is not clear to what extent the magnitude of RAS activation is related to the severity of hypoxemia and comorbid obesity.
Both severe and moderate hypoxemia were associated with greater baseline glomerular pressure, a sign of increased renal risk, as reflected by the higher filtration fraction compared with obese control subjects. Severe hypoxemia was associated with greater renal RAS activity as reflected by the blunted decrease in effective renal plasma flow in response to angiotensin II compared with other groups. Of note, there were no differences in systemic blood pressure or circulating RAS measures at baseline or in response to angiotensin II across groups, suggesting that the most important changes in RAS activity associated with nocturnal hypoxemia occur in the kidney and not in the systemic vasculature. These findings support a role for RAS in mediating hypoxemia-induced kidney disease in humans with obstructive sleep apnea.
Nocturnal hypoxemia caused by obstructive sleep apnea (OSA) is associated with loss of kidney function (1). Animal (2, 3) and human (4–7) studies suggest that hypoxemia activates the renin–angiotensin system (RAS), which is detrimental to vascular and renal outcomes (8, 9). Correction of OSA with continuous positive airway pressure (CPAP) is associated with a reduction in intraglomerular pressure, a harbinger of renal risk (10), and renal RAS activity (4, 11). Although the beneficial effect of CPAP on these renal outcomes is most likely modulated by correction of hypoxemia, CPAP also corrects other physiologic derangements associated with OSA including cardiac hemodynamics (12) and sleep disruption (13). The central role of hypoxemia in modulating the changes in renal outcomes can be further evaluated by determining if the severity and profile of hypoxemia affect the magnitude of the changes in renal RAS activity. This is clinically relevant because there is emerging evidence that intrarenal tissue hypoxia is the unifying pathway in the pathogenesis of kidney disease (14).
Conflicting results of prior studies evaluating the association between OSA and RAS activity in humans can be attributed to a variety of limitations including poor quantification of the severity of hypoxemia, and lack of control of other factors influencing the RAS (6, 15, 16). Obesity is common in patients with OSA (17) and increased body mass index (BMI) can have an independent effect on the renal RAS (18, 19). We performed a study that was designed to address both of these limitations. We measured the response of renal plasma flow to angiotensin II (AngII) infusion, a well-accepted surrogate measure of RAS activity (20–23), in OSA patients with moderate and severe nocturnal hypoxemia and in obese control subjects without OSA and hypoxemia. We hypothesized that the severity of hypoxemia would impact the magnitude of renal RAS activation and this effect would be independent of comorbid obesity. Some of the results of this investigation have been previously reported in a study evaluating the effects of CPAP on renal function (4) and in the form of an abstract (24, 25).
Subjects with OSA were recruited from referrals to the Foothills Medical Centre Sleep Centre and three respiratory homecare companies (Healthy Heart Sleep Co., Dream Sleep Respiratory Services Ltd, and RANA Respiratory Care Co.) for suspected sleep-disordered breathing, in Calgary, Canada between June 2011 and May 2014. Men and women, aged 18–65 years and BMI 30–55 kg/m2 with moderate-severe OSA and nocturnal hypoxemia (defined later), were eligible to participate in the study. A control group of obese subjects without OSA was recruited from the community. All subjects underwent a medical history and physical examination. Exclusion criteria included cardiovascular, cerebrovascular, lung, and kidney disease; uncontrolled hypertension (blood pressure [BP] >140/90 despite antihypertensive medications); diabetes, current or previous treatment for OSA; current smoking; pregnancy; and use of nonsteroidal antiinflammatory medications or exogenous sex hormones. The study was approved by the Conjoint Health Research Ethics Board at the University of Calgary. All subjects provided written informed consent.
Subjects performed an unattended, overnight cardiopulmonary monitoring study at home (Remmers Sleep Recorder Model 4.2; Saga Tech Electronic, Calgary, AB, Canada). The monitor consists of an oximeter to record SaO2 and heart rate variability, pressure transducer to record nasal airflow, microphone to record snoring, and a body position sensor. The oximeter provides the data for an automated scoring algorithm, which calculates the respiratory disturbance index (RDI) based on the number of episodes of oxygen desaturation greater than 4% per hour of monitoring. The Remmers Sleep Recorder has been validated by comparison with attended polysomnography (26, 27). Sleep apnea was defined as RDI greater than or equal to 15 and nocturnal hypoxemia was defined as SaO2 less than 90% for greater than or equal to 12% of the recording time, which has been used previously (28). The raw data were reviewed by a sleep medicine physician (P.J.H.) who confirmed that the estimated RDI was accurate and diagnostic of OSA.
Because our primary objective was to investigate the impact of the severity of nocturnal hypoxemia on RAS, we categorized OSA subjects into two groups based on a priori criteria related to their mean SaO2 during the overnight monitoring test: severe nocturnal hypoxemia was defined as mean SaO2 less than 90%, and moderate hypoxemia as mean SaO2 greater than or equal to 90%. In addition, an arterial blood gas was done if awake hypoxemia was suspected to ensure that all subjects had a PaO2 greater than 60 mm Hg during wakefulness because our objective was to evaluate the impact of hypoxemia that was restricted to sleep. Obese control subjects did not have significant OSA (RDI, <15) or nocturnal hypoxemia (SaO2, <90% for <12% of the nocturnal recording).
The primary outcome was the effective renal plasma flow (ERPF) response to AngII infusion in OSA subjects with moderate and severe hypoxemia (defined previously) and obese control subjects. Secondary outcomes included other measures of renal hemodynamics and intraglomerular pressure, namely the glomerular filtration rate (GFR) and filtration fraction (FF) (calculated as GFR/ERPF), BP, and circulating RAS component response to AngII challenge.
The study protocol for the assessment of RAS activity is well established and has been previously published. Subjects were instructed to consume greater than 200 mmol sodium per day for 3 days before the study day to ensure maximum RAS suppression (29). Subjects were studied in the supine position in a temperature-controlled, quiet room after an 8-hour fast. All subjects provided a second morning void spot urine for verification of diet compliance and determination of urinary sodium (30). Subjects on medications interfering with RAS activity discontinued their medications and changed to the calcium-channel blocker amlodopine at doses to achieve adequate BP control 2 weeks before the study day, because this agent is considered to have a neutral effect on the RAS (31).
At 8 a.m., an 18-gauge peripheral venous cannula was inserted into each antecubital vein (one for infusion, one for blood sampling). After a 90-minute equilibration period renal hemodynamic parameters including ERPF, GFR, and FF along with BP and circulating RAS components were measured at baseline and in response to a graded AngII infusion (3 ng/kg/min × 30 min, 6 ng/kg/min × 30 min) as an index of RAS activity (20–23). Each subject was given a loading dose 8 mg/kg of paraaminohippurate and 50 mg/kg of Inutest, followed by constant infusions of paraaminohippurate, 12 mg/min, and Inutest, 30 mg/min, for 90 minutes to establish ERPF, GFR, and FF. Blood samples were collected at baseline, and after each AngII infusion. BP was recorded every 15 minutes by an automatic recording device (Dinamap; Critikon). Subjects were studied in the supine position using a standard cuff placed on the right arm. The mean of two readings taken by the same registered nurse (D.Y.S.) was recorded.
A radioimmunoassay (RIA) was used for plasma renin activity (PRA; DiaSorin Clinical Assays, Stillwater, MN). In brief, Angiotensin I (AngI), the primary product of PRA, was generated at 37°C from endogenous renin and renin substrate at pH 6.0. The integrity of the generated AngI was maintained by inhibition of proteolytic activity using ethylenediaminetetraacetic acid and phenylmethylsufonyl fluoride in the generation system. The accumulated AngI reflects PRA under these controlled conditions. The AngI generated was determined by RIA using competitive binding principles, where the antibody was immobilized onto the lower inner wall of coated tubes. Aldosterone was also measured using an RIA assay. AngII plasma levels were measured by standard laboratory immunoassay techniques (Quest Diagnostics, San Juan Capistrano, CA). Urinary total protein excretion was determined by a turbidimetric endpoint assay using benzethonium chloride (Roche Total Protein Urine/CSF Gen. 3; Roche, Indianapolis, IN). Urinary sodium and potassium were determined by an indirect potentiometry assay using an ion-selective electrode (Roche Cobras Integra Sodium; Roche, Rotkreuz, Switzerland). Fasting glucose was determined by a hexokinase-UV assay.
Our previous work has demonstrated a decrease in ERPF of 182 ± 98 (mean ± SD) and 320 ± 212 ml/min/1.73 m2 (mean ± SD, mean of male and female responses) in response to AngII infusion on a high-salt diet in OSA patients with moderate hypoxia (4) and healthy overweight control subjects (18), respectively. Based on these data and anticipating a 40% difference in the ERPF response between the severe hypoxemia group and the obese control group, we estimated that 12 subjects would be required in each group with a two-sided alpha of 0.05 and 90% power.
Data are reported as mean ± SD, or percentage where appropriate. Responses to AngII infusion within subjects were analyzed by paired t test. Subject baseline and renal hemodynamic responses to AngII were analyzed using one-way analysis of variance for normally distributed variables and Kruskal-Wallis Z test for nonnormally distributed variables to assess between-group differences. Wilcoxon signed rank test (nonparametric t test) was applied to assess pairwise comparisons. Chi-square tests were used to compare frequencies. Adjusted mean comparison analysis was applied using analysis of covariance to evaluate the relative contributions of covariates (sex, age, BMI, baseline dependent variable) to the change in renal and systemic hemodynamic responses to AngII among groups. All statistical analyses were performed with statistical software package SPSS V.17.0 (SPSS, Chicago, IL) and were two-tailed with a significance level of 0.05.
Subjects baseline characteristics are shown in Table 1. All subjects were free of kidney disease (32), had BP less than 140/90 mm Hg (12 subjects were taking antihypertensive medication), and were free of RAS-interfering medications. All subjects had no diabetes; were nonsmoking; and were in high-salt balance, which is a state of maximal RAS suppression, as indicated by urinary sodium excretion. No subjects with severe hypoxemia had awake hypoxemia (PaO2 67 ± 8 mm Hg).
| Severe Hypoxemia (SaO2 < 90%) (n = 14) | Moderate Hypoxemia (SaO2 ≥ 90%) (n = 17) | Control Subjects (n = 13) | |
|---|---|---|---|
| Age, yr | 47 ± 11 | 49 ± 10 | 41 ± 11 |
| Men, % | 57 | 71 | 38 |
| Ethnicity, % white | 93 | 59*† | 100 |
| BMI, kg/m2 | 43 ± 5.5* | 33 ± 6.7 | 38 ± 7.2 |
| Fasting glucose, mg/dl | 5 ± 0.58 | 4.8 ± 0.65 | 4.7 ± 0.6 |
| Serum creatinine, μmol/L | 77 ± 18 | 71 ± 14 | 78 ± 14 |
| Norepinephrine, nmol/L | 3.5 ± 1.7* | 2.4 ± 0.98 | 1.9 ± 0.58 |
| Epinephrine, pmol/L | 75.3 ± 39.8 | 71 ± 23 | 80.8 ± 24.0 |
| Dopamine, pmol/L | 115.8 ± 25.6 | 100.6 ± 1.7† | 119.7 ± 32.9 |
| AngII, ng/L | 20.2 ± 9.5 | 19.7 ± 8.6 | 16.2 ± 3.4 |
| Urine Na, mmol/d | 319 ± 119 | 385 ± 106 | 379 ± 137 |
| Level 3 sleep test parameters | |||
| RDI, events/h | 64 ± 26* | 40.4 ± 18.6† | 5 ± 2.3 |
| Mean SaO2, % | 84 ± 4.4* | 91 ± 0.2† | 93 ± 1.4 |
| SaO2 < 90%, % | 77 ± 14.7* | 24.6 ± 1 0.3† | 2.2 ± 3.8 |
| Awake arterial blood gas‡ | |||
| pH | 7.43 ± 0.03 | — | — |
| PaCO2, mm Hg | 39 ± 3.7 | — | — |
| PaO2, mm Hg | 67 ± 7.6 | — | — |
Subjects in each group (severe hypoxemia, moderate hypoxemia, control) were similar in terms of age and sex; however, ethnicity was different among groups with 40% of the group with moderate hypoxemia being of Asian descent. Subjects in the severe hypoxemia group were heavier than those in the moderate hypoxemia (P < 0.001) and control groups (P = 0.009). However, the proportion of subjects classified as obese (BMI, >30 kg/m2) was similar across groups (P = 0.17). The subjects with severe hypoxemia demonstrated higher levels of norepinephrine as compared with the moderate hypoxemia (P = 0.012) and control (P = 0.008) subjects. Measurements of epinephrine were comparable across all three groups.
Baseline renal and systemic hemodynamics and their responses to AngII challenge are outlined in Table 2. Baseline measures of ERPF and GFR were similar across groups, although glomerular pressure, as reflected by FF, was significantly higher in both the severe (P = 0.015) and moderate hypoxemia (P = 0.01) groups compared with control subjects. In response to AngII infusion, all groups demonstrated the anticipated renal vasoconstrictor response with a progressive decrease in ERPF. However, there were significant differences across groups, which remained after adjusting for covariates (time 60, P = 0.01) with the severe hypoxemia group showing the smallest response to AngII (30 min, P = 0.001; 60 min, P < 0.001; all values severe hypoxemia vs. obese control subjects) (Figure 1). Between-group differences were also observed in the GFR response to AngII challenge, although these did not follow the same trend as ERPF (Figure 2). Patients with severe hypoxemia and control subjects exhibited a rise or preservation in GFR, whereas the moderate hypoxemia group showed a decline in GFR in response to AngII at both time 30 minutes (P = 0.02) and 60 minutes (P = 0.048). However, differences in the GFR response to AngII across groups were no longer significant after adjustment for confounders. Similar to ERPF, FF exhibited a progressively more blunted response to AngII across groups with increasing severity of nocturnal hypoxemia, although this was not significant after adjusting for covariates (30 min, P = 0.7; 60 min, P = 0.4).
| Parameter | Baseline | 30 min | 60 min |
|---|---|---|---|
| ERPF, ml/min | |||
| Severe hypoxemia group | 674 ± 88 | 593 ± 82* | 574 ± 79* |
| Moderate hypoxemia group | 689 ± 121 | 533 ± 101* | 486 ± 81* |
| Obese control subjects | 813 ± 214 | 606 ± 128* | 537 ± 113* |
| GFR, ml/min | |||
| Severe hypoxemia group | 106 ± 9.6 | 111 ± 10* | 115 ± 15* |
| Moderate hypoxemia group | 126 ± 37.8 | 118 ± 41 | 122 ± 41 |
| Obese control subjects | 107 ± 15 | 109 ± 17 | 109 ± 15 |
| FF | |||
| Severe hypoxemia group | 16 ± 1.5† | 18.4 ± 2.1* | 20.2 ± 1.1* |
| Moderate hypoxemia group | 19 ± 6.6† | 22.9 ± 8.3* | 25.7 ± 8.2* |
| Obese control subjects | 14 ± 2.6 | 18.3 ± 2.5* | 21 ± 3.7* |
| SBP, mm Hg | |||
| Severe hypoxemia group | 128 ± 13 | 141 ± 15* | 149 ± 17* |
| Moderate hypoxemia group | 128 ± 12 | 144 ± 21* | 152 ± 20* |
| Obese control subjects | 122 ± 9 | 132 ± 10* | 142 ± 8* |
| DBP, mm Hg | |||
| Severe hypoxemia group | 78 ± 11 | 87 ± 12* | 92 ± 13*† |
| Moderate hypoxemia group | 78 ± 8 | 87 ± 7* | 92 ± 8*† |
| Obese control subjects | 71 ± 7 | 81 ± 7* | 82 ± 9* |
| PRA, ng AngI/ml per h | |||
| Severe hypoxemia group | 0.58 ± 0.61 | 0.41 ± 0.45 | 0.31 ± 0.33 |
| Moderate hypoxemia group | 0.28 ± 0.18 | 0.19 ± 0.13* | 0.12 ± 0.08* |
| Obese control subjects | 0.27 ± 0.28 | 0.13 ± 0.10 | 0.09 ± 0.07 |
| Aldosterone, pmol/L | |||
| Severe hypoxemia group | 245 ± 203 | 495 ± 298* | 633 ± 340* |
| Moderate hypoxemia group | 156 ± 88 | 319 ± 148* | 407 ± 169* |
| Obese control subjects | 126 ± 64 | 354 ± 139* | 507 ± 190* |
Figure 1. Effective renal plasma flow (ERPF) response to angiotensin II, stratified by nocturnal hypoxemia exposure. *P < 0.05 versus moderate group. †P < 0.05 versus obese control subjects.
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Figure 2. Glomerular filtration rate response to angiotensin II, stratified by nocturnal hypoxemia exposure. *P < 0.05 versus moderate group. GFR = glomerular filtration rate.
[More] [Minimize]On exploratory analysis, decreased mean nocturnal SaO2 and increased nocturnal time with SaO2 less than 90% were each associated with a blunted ERPF response, even after adjustment for covariates (P = 0.007 and 0.004, respectively) (Figures 3A and 3B). Similarly, increased oxygen desaturation index was also associated with a decreased ERPF response, or increased renal RAS activity, but this was no longer significant after adjustment for covariates (P = 0.6) (Figure 3C).
Figure 3. (A) Effective renal plasma flow response to angiotensin II as a function of mean nocturnal oxygen saturation. (B) Effective renal plasma flow response to angiotensin II as a function of nocturnal time spent with SaO2 < 90%. (C) Effective renal plasma flow response to angiotensin II as a function of oxygen desaturation index. ERPF = effective renal plasma flow; ODI = oxygen desaturation index.
[More] [Minimize]Study subjects’ BP and circulating RAS components in response to AngII infusion are shown in Table 2. There were no differences in the BP or PRA responses to graded AngII infusion across groups. Although a reduced adrenal secretion of aldosterone in response to AngII was observed in the moderate hypoxemia group at time 60 minutes compared with the severe hypoxemia (P = 0.024) and control (P = 0.047) groups, this difference was no longer significant after adjustment for covariates.
Our study compared renal hemodynamics and RAS activity in OSA patients with severe hypoxemia, OSA patients with moderate hypoxemia, and obese subjects without OSA or nocturnal hypoxemia. Our key findings were that (1) both severe and moderate hypoxemia were associated with greater baseline glomerular pressure, a sign of increased renal risk, as reflected by the higher FF compared with obese control subjects; (2) severe hypoxemia was associated with greater renal RAS activity as indicated by the blunted ERPF response to AngII compared with other groups; and (3) there were no differences in systemic BP or circulating RAS measures at baseline or in response to AngII across groups, suggesting that the most important changes in RAS activity associated with nocturnal hypoxemia occur in the kidney and not in the systemic vasculature. Overall, our results suggest that severity of nocturnal hypoxemia associated with OSA markedly influences renal RAS activity and this effect is independent of comorbid obesity.
Most human studies examining the relationship between OSA and RAS have focused on baseline circulating components of RAS and conflicting results may reflect differences in salt balance or other factors contributing to RAS activity. Moller and coworkers (33) reported increased levels of AngII and aldosterone in OSA patients compared with control subjects, although OSA subjects were hypertensive and more obese. In contrast, another study reported no baseline or acute overnight differences in PRA and aldosterone levels between normotensive male OSA patients and control subjects, although kidney function, salt intake, and volume status were not measured (34). We did not observe differences in baseline circulating RAS components between either the severe or moderate OSA and control subjects in high-salt balance suggesting that the increased circulating RAS levels reported previously may occur only in those with established hypertension.
We, and others, have reported an increased prevalence of OSA in the chronic kidney disease (CKD) population (35–38) and accelerated loss of kidney function in the OSA population (1, 39, 40). Our observation of an increased FF, a surrogate for glomerular capillary pressure in humans, in OSA subjects has been previously reported (11). Furthermore, FF was decreased with CPAP, although only in patients not on angiotensin-converting enzyme inhibitors or angiotensin type 1 receptor blockers, further supporting the view that OSA is associated with up-regulation of the RAS. The hemodynamic changes leading to glomerular hyperfiltration are hypothesized to ultimately result in loss of kidney function (10, 41), underscoring the importance of determining the vasoactive factors responsible for these changes. A blunted renal hemodynamic response to infused AngII reflects an activated renal RAS (20–23) and thus our findings of a blunted ERPF response to AngII in OSA subjects are indicative of increased intrarenal RAS activity, and may offer an explanation for the relationship between nocturnal hypoxemia and loss of kidney function.
Multiple lines of evidence support the idea that hypoxia is an important contributory factor in the pathogenesis of CKD (42). The “chronic hypoxia hypothesis” suggests that primary glomerular disease leads to restricted post-glomerular flow from affected glomeruli and downstream injury to the peritubular capillary network, ultimately resulting in tubulointerstitial fibrosis, which is well established as the best predictive indicator of progression to end-stage kidney disease. In the rat model, increased mitochondrial oxygen consumption resulted in kidney hypoxia and subsequent nephropathy (43). Renal blood flow, local tissue perfusion, and blood oxygen content are the major determinants of oxygen delivery to kidney tissue.
Although it was not feasible to measure local kidney tissue oxygenation in our study, the chronic and systemic hypoxemia of our subjects would have undoubtedly resulted in renal hypoxia because, unlike most other organs, the kidney does not mount a hyperemic response during hypoxemia or a vasoconstrictor response to hyperoxemia (44). As a result, the more severely hypoxemic OSA subjects would demonstrate even lower oxygen tensions in the already physiologic hypoxic renal milieu and would thus be at greater risk of ultimately developing kidney disease. Although activation of the RAS can worsen renal tissue hypoxia through both hemodynamic and nonhemodynamic factors (45), hypoxemia itself has been shown to increase RAS activity. Rats exposed to 35 days of episodic hypoxia demonstrated a fourfold increase in PRA levels compared with control animals (2). The increase in BP in response to intermittent hypoxia in a blinded, randomized, crossover study of healthy humans was abolished with the use of an angiotensin type 1 antagonist (5).
To our knowledge, this is the first study to demonstrate an association between the severity of the hypoxemia and adverse changes in renal hemodynamics and RAS activity. Although it is possible that supplemental oxygen therapy may improve renal outcomes in patients with OSA, this has not been investigated. Oxygen may reverse some of the altered renal physiology we found. However, this potential benefit may be limited by the fact that supplemental oxygen may not correct hypoxemia entirely and will not reduce the disruption of sleep and activation of the sympathetic nervous system associated with persistent OSA. The possibility of an incomplete response to oxygen therapy is supported by the recent report that the use of nocturnal oxygen therapy is inferior to CPAP in reducing nighttime BP in patients with OSA (46). Further research studies are required to address these questions.
Our study sample was restricted to OSA subjects without comorbidities thus limiting generalizability of our results to the general OSA population and to patients with CKD. However, this enabled us to examine the impact of OSA on RAS activity while minimizing confounding factors. Although our sample size was limited, our careful prestudy design and sample calculation allowed us to evaluate the association between the severity of hypoxemia and the renal RAS. Although we showed a strong association between different indices of nocturnal hypoxemia and renal RAS activity, our level-three monitoring precluded our ability to determine if nonrespiratory variables, such as arousal index, were also associated with our renal outcomes. We do not believe that the moderate hypoxemia group had hypoventilation because their nocturnal oximetry profile did not suggest this and their awake oxygen saturation was normal. All patients in the severe hypoxemia group had an arterial blood gas analysis that showed PaCO2 levels below 45 mm Hg in every patient, thereby ruling out hypoventilation during wakefulness. Furthermore, CPAP therapy corrected sleep-disordered breathing in those with moderate and severe hypoxemia (data not shown). Consequently, we think it is unlikely that hypoventilation played a significant role in our renal outcome findings.
As is common, the OSA subjects in this study were obese (17). To control for any effects of increased BMI on renal hemodynamics or renal RAS activity (18, 19), we included a comparably obese control group. Despite our careful study design, the severe hypoxemia group differed in terms of ethnicity, BMI, and sex, all of which may influence renal RAS activity. Our study population was almost exclusively white, which may limit the generalizability of our results to other populations. However, although the moderate hypoxemia group had a greater proportion of subjects of Asian descent compared with other groups, Asian background has not been associated with alterations in RAS activity. Overall, although the subjects with severe hypoxemia had a greater BMI than did the moderate hypoxemia and control groups, the proportion of obese participants as defined by the World Health Organization was similar across groups.
Lastly, although not statistically significant, the control group had a higher proportion of women compared with other groups. However, both baseline ERPF and the ERPF response to AngII were similar in healthy female and male subjects (21). Moreover, sensitivity analyses stratifying by sex did not appreciably change our findings, although the possibility of residual confounding may still exist. We ensured all participants were in high-salt balance to ensure maximum RAS suppression (29), all subjects were free of RAS-related medications and exogenous sex hormone use, all women were studied during the same menstrual cycle stage, and all subjects were studied in standardized conditions.
Finally, because of the cross-sectional nature of our study design, we cannot demonstrate directionality of the association nor comment on causality. However, although it is possible that augmented renal RAS activity causes an increase in the severity of nocturnal hypoxemia through promoting fluid retention (47, 48), we believe it is more likely that systemic hypoxemia contributes to up-regulation of the renal RAS (2–5).
In summary, the severity of nocturnal hypoxemia in OSA was associated with the extent to which renal RAS activity was increased, suggesting that hypoxemia modulates these changes. Furthermore, these effects were independent of obesity. Consequently, therapies targeting correction of hypoxemia may reduce renal RAS activity and thereby diminish the risk of kidney disease. Although it remains unclear whether OSA causes CKD or accelerates its progression, the potential association between OSA and increased renal risk merits further study.
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Supported by the American Society of Nephrology (A.A.Z. and D.D.M.N.), the Lung Association–Alberta and NWT (A.A.Z.), the Cosmopolitan International Club of Calgary (D.D.M.N.), the Foothills Medical Centre Sleep Centre Development Fund (D.D.M.N.), Alberta Innovates–Health Solutions and a joint initiative of Alberta Health and Wellness, the University of Alberta, and the University of Calgary (S.B.A.). M.J.P. holds the Brenda Strafford Foundation Chair for Alzheimer Research.
Author Contributions: Concept and design of study, A.A.Z., D.D.M.N., P.J.H., M.J.P., and S.B.A. Acquisition, analysis, and interpretation of the data, A.A.Z., D.D.M.N., P.J.H., M.J.P., T.C.T., S.W., G.B.H., J.K.R., D.Y.S., and S.B.A. Drafting of the manuscript, A.A.Z., D.D.M.N., P.J.H., and S.B.A. Review of manuscript for important intellectual content, A.A.Z., D.D.M.N., P.J.H., M.J.P., T.C.T., S.W., G.B.H., J.K.R., D.Y.S., and S.B.A. Final approval of manuscript, A.A.Z., D.D.M.N., P.J.H., M.J.P., T.C.T., S.W., G.B.H., J.K.R., D.Y.S., and S.B.A. Study supervision, P.J.H. and S.B.A.
Originally Published in Press as DOI: 10.1164/rccm.201502-0383OC on June 23, 2015
Author disclosures are available with the text of this article at www.atsjournals.org.
