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Abstract
Rationale: In end-stage renal disease (ESRD), a condition characterized by fluid overload, both obstructive and central sleep apnea (OSA and CSA) are common. This observation suggests that fluid overload is involved in the pathogenesis of OSA and CSA in this condition.
Objectives: To test the hypothesis that fluid removal by ultrafiltration (UF) will reduce severity of OSA and CSA in patients with ESRD.
Methods: At baseline, on a nondialysis day, patients with ESRD on thrice-weekly hemodialysis underwent overnight polysomnography along with measurement of total body extracellular fluid volume (ECFV), and ECFV of the neck, thorax, and right leg before and after sleep. The following week, on a nondialysis day, subjects with an apnea–hypopnea index (AHI) greater than or equal to 20 had fluid removed by UF, followed by repeat overnight polysomnography with fluid measurements.
Measurements and Main Results: Fifteen patients (10 men) with an AHI greater than or equal to 20 (10 OSA; 5 CSA) participated. Mean age was 53.5 ± 10.4 years and mean body mass index was 25.3 ± 4.8 kg/m2. Following removal of 2.17 ± 0.45 L by UF, the AHI decreased by 36% (43.8 ± 20.3 to 28.0 ± 17.7; P < 0.001) without affecting uremia. The reduction in AHI correlated with the reduction in total body ECFV (r = 0.567; P = 0.027) and was associated with reductions in ECFV of the right leg (P = 0.001), overnight change in ECFV of the right leg (P = 0.044), ECFV of the thorax (P = 0.001), and ECFV of the neck (P = 0.003).
Conclusions: These findings indicate that fluid overload contributes to the pathogenesis of OSA and CSA in ESRD, and that fluid removal by UF attenuates sleep apnea without altering uremic status.
In end-stage renal disease (ESRD), both obstructive and central sleep apnea (OSA and CSA, respectively) are common. In such patients, sleep apnea severity can be reduced by intensification of dialysis. However, the relative roles of improved uremic status and fluid removal in alleviating sleep apnea are unknown.
We demonstrate that fluid removal by ultrafiltration reduces the apnea–hypopnea index (AHI) and improves sleep structure in ESRD patients with either OSA or CSA in the absence of any changes in uremic status. The degree of reduction in AHI was related to the degree of reduction in total body extracellular fluid volume as well as to reductions in fluid volumes of the leg, thorax, and neck and the overnight change in leg fluid volume. These results indicate that fluid removal is a mechanism by which sleep apnea and sleep structure can be improved in patients with ESRD.
Sleep apnea is far more common in patients with end-stage renal disease (ESRD) than in the general population, with reported prevalence rates of 50–60% (1–3). Its presence in ESRD is associated with elevated blood pressure, left ventricular hypertrophy, and increased mortality (4–6), mainly from cardiovascular causes (7). The increased prevalence of sleep apnea in this population is not explained by comorbidities or increased body mass index, suggesting that other factors play an important role in its pathogenesis (8, 9). Both types of sleep apnea, obstructive and central (OSA and CSA, respectively), are seen in ESRD with prevalence rates similar to those seen in heart failure (10). Both ESRD and heart failure are characterized by fluid overload. These observations led us to the general hypothesis that fluid overload and overnight rostral fluid shift from the legs could contribute to the pathogenesis of both OSA and CSA in these conditions (11, 12).
In patients with heart failure (11) and patients with ESRD (12) the severity of OSA and the overnight increase in neck circumference are directly related to the degree of overnight reduction in leg fluid volume (LFV). Furthermore, we previously demonstrated in patients with ESRD that both internal jugular vein fluid volume and upper-airway (UA) mucosal water content were related to the frequency of apneas and hypopneas per hour of sleep (apnea–hypopnea index [AHI]). These findings suggested that extravascular and intravascular fluid accumulation surrounding the UA may increase tissue pressure facilitating UA collapse and OSA (13).
Patients with heart failure and CSA typically hyperventilate because of pulmonary vagal irritant receptor stimulation by pulmonary congestion with low Pco2 close to the apnea threshold (14–17). We previously demonstrated in patients with heart failure and CSA that the overnight reduction in LFV was directly related to the AHI and inversely to Pco2 (11). It is therefore plausible that in patients with heart failure and CSA overnight fluid shift from the legs leads to an increase in thoracic fluid volume (TFV) and a reduction in Pco2. During sleep, an increase in ventilation of any cause (e.g., an arousal) drives the already low Pco2 below the apnea threshold and causes a central apnea (14). Accordingly, increases in TFV could contribute to the pathogenesis of CSA in patients with ESRD who are also fluid overloaded.
Hanly and Pierratos (18) demonstrated attenuation of sleep apnea in patients with ESRD after conversion from conventional to nocturnal hemodialysis, with a reduction in the frequency of central and obstructive apneas and hypopneas. Because the dosage of dialysis increases from conventional to nocturnal hemodialysis, uremia is better controlled, and it is very likely that total body fluid volume and overnight rostral fluid shift declined as well. However, fluid volumes were not measured. Therefore, the relative roles of improved uremic status versus reduced fluid volumes and overnight fluid shift in attenuating sleep apnea were not elucidated.
To address this issue, we hypothesized that in patients with ESRD, fluid removal by ultrafiltration (UF) will reduce severity of OSA and CSA in association with reduction in fluid volumes in various body segments but without altering uremic or acid/base status. Some of the results of these studies have been previously reported in the form of an abstract (19).
See the online supplement for detailed methods.
Inclusion criteria were patients with ESRD at least 18 years of age undergoing conventional thrice-weekly hemodialysis in the University Health Network. Patients were recruited consecutively irrespective of symptoms of sleep apnea. Exclusion criteria were patients who were already treated for OSA, had a body mass index greater than 35 kg/m2, had tonsillar hypertrophy, or had a left ventricular ejection fraction of less than 45% by echocardiography. The protocol was approved by the Research Ethics Board of the University Health Network and all subjects provided written informed consent before participation.
Polysomnography (PSG) was performed with the use of standard techniques and scoring criteria for sleep stages, arousals from sleep, and periodic leg movements (PLM) (20, 21). Central and obstructive apneas and hypopneas were defined according to the American Academy of Sleep Medicine guidelines (20). The AHI and PLM index were calculated. We tested the effects of UF on patients with moderate to severe sleep apnea with an AHI greater than or equal to 20, divided into those with predominantly OSA in whom greater than or equal to 50% of events were obstructive and those with predominantly CSA in whom greater than 50% of events were central.
With subjects instrumented for PSG, lying awake and supine, total body fluid volume, total body extracellular fluid volume (ECFV), LFV, TFV, and neck fluid volume (NFV) were measured using bioelectrical impedance (22). This well-validated technique uses impedance to electrical current within a body segment to measure fluid content (23). Volume measurements were made within 1 minute of the subjects lying down, given that fluid shifts out of the legs rapidly on the assumption of recumbency (22). Neck circumference and calf circumferences were measured as previously described (24). All measurements were made blinded to the PSG results.
UA cross-sectional area (UA-XSA) was measured by acoustic pharyngometry (Eccovision; Hood Laboratories, Pembroke, MA), with the patient lying supine and the head in the neutral position as previously described (25, 26).
UF without dialysis was performed on a nondialysis day via chronic vascular access. A High Flux dialyzer (Exeltra 170 biocompatible dialyser; Baxter Inc., Mississauga, ON, Canada) was used to remove plasma without altering acid/base balance, electrolyte concentrations, or urea levels. With a blood flow of 200–300 ml/min through the device, 1.3–3.1 L of plasma or up to a maximum of 50% of the interdialytic weight gain was removed over 4 hours. Blood pressure was monitored hourly. If patients developed symptomatic hypotension, UF was stopped. Blood samples for urea, HCO3−, and venous Pco2 were drawn immediately before and after UF to assess acid/base and uremic status.
Patients had a baseline PSG the day before their hemodialysis to determine the AHI and predominant type of sleep apnea. UA-XSA, total body and segmental fluid volumes, and neck and calf circumferences were measured before sleep and were repeated on awakening the next morning and before subjects got out of bed and the overnight changes calculated. One week later, patients found to have an AHI greater than or equal to 20 returned to the hospital the day before their hemodialysis. They were weighed and then underwent UF over a 4-hour period. Patients were instructed to restrict fluid intake to 500 ml until they returned to the sleep laboratory that night, after which they underwent a repeat PSG and reassessments of all baseline variables before and after sleep.
Continuous variables were expressed as mean ± SD and categorical variables as proportions. Changes from baseline to follow-up were analyzed using paired t tests or Wilcoxon tests as appropriate. Relationships between variables were examined by linear regression. A P value less than 0.05 was considered significant. Analyses were performed with the use of SPSS 22.0.1 (SPSS Inc., Chicago, IL).
Study participant flow is shown in Figure 1. Twenty-eight patients were recruited and underwent a baseline PSG. All were receiving adequate dialysis, as indicated by a percent reduction of urea greater than 65% after dialysis. Of the 28, 15 had an AHI greater than or equal to 20 (10 had predominantly OSA, 5 had predominantly CSA) and subsequently underwent UF. The baseline characteristics of these 15 subjects are shown in Table 1.
Figure 1. Study participant flow. AHI = apnea–hypopnea index; UF = ultrafiltration.
[More] [Minimize]| Age, yr | 53.5 ± 10.4 |
| Male sex, n (%) | 10 (67) |
| BMI, kg/m2 | 25.3 ± 4.8 |
| Neck circumference, cm | 38.4 ± 4.0 |
| LVEF, % | 62.0 ± 4.0 |
| Hypertension, n (%) | 14 (93.3) |
| Ischemic heart disease, n (%) | 1 (6.7) |
| Atrial fibrillation, n (%) | 1 (6.7) |
| Diabetes, n (%) | 2 (13.3) |
| OSA:CSA | 10:5 |
| AHI, events/h | 43.8 ± 20.3 |
A mean of 2.17 ± 0.45 L of fluid was removed by UF. There was no difference in pre- and post-UF urea (13.3 ± 3.7 and 12.4 ± 3.6 mmol/L; P = 0.510), HCO3− (24.9 ± 3.1 and 24.7 ± 3.7 mmol/L; P = 0.740), or venous Pco2 (41.8 ± 5.7 and 43.4 ± 6.8 mm Hg; P = 0.160). The procedure was well tolerated with the exception of one patient who experienced symptomatic hypotension subsequent to which the procedure was stopped, the blood pressure normalized, and symptoms resolved within 15 minutes. He then completed the protocol.
As displayed in Table 2, following UF, body weight decreased by 2.3 kg and total body fluid by 2.0 L (both, P < 0.001). The reduction in total body fluid was largely caused by the reduction in total body ECFV, which decreased by 2.0 L (P < 0.001). Post-UF, there was a 1-cm reduction in calf circumference (P < 0.001) and a 0.7-cm reduction in neck circumference (P = 0.006) compared with baseline, and a 0.4-cm reduction in the overnight change in calf circumference (P < 0.001). However, there was no reduction in the overnight change in neck circumference. Post-UF, there were significant reductions in evening LFV (P = 0.001), overnight change in LFV (P = 0.044), evening TFV (P = 0.001), and evening NFV (P = 0.003). However, there was no significant reduction in the overnight changes in NFV or TFV. Post-UF, there was no significant change in the evening or morning UA-XSA (P = 0.784 and P = 0.214, respectively).
| Baseline | After Ultrafiltration | P Value | |
|---|---|---|---|
| Body weight, kg | 71.3 ± 14.5 | 69.0 ± 14.1 | <0.001 |
| Total body fluid, L | 39.2 ± 8.2 | 37.2 ± 7.5 | 0.001 |
| Total body extracellular fluid volume, L | 17.4 ± 3.1 | 15.4 ± 3.0 | <0.001 |
| Leg edema present, n (%) | 3 (20) | 3 (20) | ns |
| Evening calf circumference, cm | 35.9 ± 3.1 | 34.9 ± 2.9 | <0.001 |
| Overnight change in calf circumference, cm | −1.4 ± 0.5 | −1.0 ± 0.4 | 0.001 |
| Evening leg fluid volume, ml | 2,194 ± 345 | 1,952 ± 363 | 0.001 |
| Overnight change in leg fluid volume, ml | −259 ± 107 | −192 ± 115 | 0.044 |
| Evening thoracic fluid volume, ml | 2,726 ± 913 | 2,281 ± 834 | 0.001 |
| Overnight change in thoracic fluid volume, ml | 292 ± 192 | 230 ± 197 | 0.3 |
| Neck circumference, cm | 38.4 ± 4.0 | 37.7 ± 4.7 | 0.006 |
| Overnight change in neck circumference, cm | 0.9 ± 0.7 | 0.8 ± 0.6 | 0.688 |
| Evening neck fluid volume, ml | 471 ± 121 | 402 ± 97* | 0.003 |
| Overnight change in neck fluid volume, ml | 27.0 ± 61.5 | 21.0 ± 35.7* | 0.843 |
| Evening upper-airway cross-sectional area, cm2 | 2.58 ± 0.71 | 2.62 ± 0.73† | 0.784 |
| Morning upper-airway cross-sectional area, cm2 | 2.29 ± 0.47 | 2.45 ± 0.47† | 0.214 |
| Overnight change in upper-airway cross-sectional area, cm2 | −0.32 ± 0.41 | −0.28 ± 0.41 | 0.594 |
As shown in Figure 2, compared with baseline, there was a 36% reduction in the mean AHI (P < 0.001). There were significant correlations between the reduction in total body ECFV and the reduction in AHI (P = 0.027) (Figure 3) and between the reduction in total body ECFV and the reduction in body weight (P < 0.0001) (Figure 4) post-UF.
Figure 2. Effect of ultrafiltration (UF) on apnea–hypopnea index (AHI). Compared with baseline, there was a 36% reduction in the mean AHI from 43.8 ± 20.3 to 28.0 ± 17.7 (P < 0.001) post-UF. In the 10 subjects with obstructive sleep apnea (OSA), the AHI decreased by 35% from 35.5 ± 17.0 to 23.9 ± 16.5 (P = 0.013) and in the five subjects with central sleep apnea (CSA) the AHI decreased by 40% from 60.4 ± 16.7 to 36.0 ± 19.1 (P = 0.003).
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Figure 3. Relationship between changes in total body extracellular fluid volume (ECFV) and changes in apnea–hypopnea index (AHI) after ultrafiltration (UF).
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Figure 4. Relationship between changes in total body extracellular fluid volume (ECFV) and changes in weight after ultrafiltration (UF).
[More] [Minimize]As shown in Figure 2, in the 10 subjects with OSA, there was a mean reduction in total AHI of 35% mainly caused by a significant reduction of 30% in the obstructive AHI from 27.5 ± 7.9 to 19.3 ± 13.2 (P = 0.037). There was a statistically nonsignificant reduction of 41% in the central AHI from 8.0 ± 11.3 to 4.7 ± 6.4 (P = 0.40). In the five subjects with CSA, there was a mean reduction in total AHI of 40% caused by a significant reduction of 55% in the central AHI from 47.0 ± 6.6 to 21.1 ± 8.1 (P < 0.001). There was a nonsignificant increase of 6% in the obstructive AHI from 13.5 ± 10.9 to 14.3 ± 14.6 (P = 0.80).
Compared with baseline, there were significant increases in total sleep time (P = 0.031), sleep efficiency (P = 0.016), slow-wave sleep (P = 0.005), and REM sleep (P = 0.016) as well as a reduction in the arousal index post-UF (P = 0.036) (Table 3) in the absence of any change in supine sleep time (P = 0.925). The minimum SaO2 did not change, but the mean transcutaneous Pco2 increased by 3 mm Hg (P = 0.042). The PLM index did not change significantly from baseline to follow-up (Table 3).
| Baseline | Follow-up | P Value | |
|---|---|---|---|
| Total sleep time, h | 4.50 ± 1.29 | 5.25 ± 0.91 | 0.031 |
| Sleep efficiency, % | 72.6 ± 18.9 | 81.2 ± 13.3 | 0.016 |
| Stage 1, min | 50.9 ± 40.7 | 29.3 ± 22.5 | 0.05 |
| Stage 2, min | 148.5 ± 52.6 | 185.5 ± 59.7 | 0.03 |
| Slow-wave sleep, min | 29.6 ± 23.9 | 44.7 ± 30.9 | 0.005 |
| REM, min | 42.1 ± 27.2 | 55.7 ± 19.5 | 0.016 |
| Arousal index, events/h of sleep | 45.5 ± 19.8 | 38.8 ± 20.9 | 0.036 |
| Supine time, h | 2.46 ± 2.16 | 2.43 ± 1.94 | 0.925 |
| Minimum SaO2, % | 85.7 ± 8.6 | 84.3 ± 8.6 | 0.348 |
| Mean transcutaneous Pco2, mm Hg | 39.2 ± 1.9* | 42.3 ± 5.1* | 0.042 |
| Periodic leg movement index, events/h of sleep | 31.5 ± 35.7 | 41.8 ± 48.1 | 0.31 |
Our study has given rise to several important findings regarding the role of fluid overload in the pathogenesis and treatment of sleep apnea and sleep disruption in patients with ESRD. First, we demonstrated that fluid removal by UF attenuates sleep apnea severity in the absence of any changes in uremic or metabolic status. Second, the degree of reduction in the AHI was related to the degrees of reductions in total body ECFV, LFV, TFV, NFV, and the overnight change in LFV following UF. Third, fluid removal by UF was accompanied by remarkable improvements in sleep structure characterized by increases in sleep efficiency and total, slow wave, and REM sleep times. These results strongly support a key role for fluid overload independently of uremia in the pathogenesis of sleep apnea in patients with ESRD, and offer novel insights into mechanisms by which fluid overload contributes to the pathogenesis of both OSA and CSA in this population.
Both OSA and CSA are common in fluid overload states, such as heart failure, ESRD, and nephrotic syndrome (2, 10, 27). In patients with ESRD, with conversion from nocturnal to 24-hour continuous ambulatory peritoneal dialysis, during which there was less fluid removal and dialysis at night, the AHI increased by 55% (28). Conversely, increasing the intensity of fluid removal and dialysis at night by converting from conventional to nocturnal hemodialysis alleviated sleep apnea (18). In the case of conversion from conventional to nocturnal hemodialysis, the dosage of dialysis increases from approximately 4 hours per day, 3 days a week to approximately 7 hours per day, 5 days a week and leads to both better uremic and metabolic control and greater fluid removal (18). Consequently, in that study, it was not possible to determine whether better uremic control, or fluid removal, or both contributed to attenuation of sleep apnea severity.
However, the present study specifically addressed this issue by demonstrating that isolated fluid removal by UF without either dialysis or any change in uremic or metabolic status attenuated sleep apnea. Specifically, removal of an average of 2.17 L of fluid between dialysis sessions reduced the AHI by 36%, in the absence of any change in levels of urea, HCO3−, or venous Pco2, measured immediately pre- and post-UF. Furthermore, the dose–response relationship between the magnitude of reduction in AHI and the degree of reduction in total body ECFV suggests that an even greater reduction in AHI could be anticipated if more fluid was removed. Taken together, these findings provide direct evidence of a cause–effect relationship between fluid overload and sleep apnea severity in patients with ESRD. They also complement and are consistent with a previous study in which we showed that experimentally induced fluid overload, by intravenous saline infusion during sleep, caused a threefold increase in the AHI in nonobese, healthy older men (29).
In the current study, we also found that UF reduced severity of both OSA and CSA to a similar degree. These findings are consistent with previous studies showing that the degree of overnight rostral fluid shift from the legs correlates with severity of OSA in various patient populations (11, 12, 24, 30) and with severity of both OSA and CSA in patients with heart failure (11). Accordingly, they provide further evidence that fluid overload is a mechanism common to the pathogenesis of both OSA and CSA, not only in heart failure, but also in ESRD. In a randomized trial involving patients with chronic venous insufficiency and OSA, Redolfi and coworkers (31) demonstrated that wearing compression stockings during the daytime reduced LFV in the evening and overnight rostral fluid shift in association with a 36% reduction in the AHI. In the present study, UF caused a similar 36% reduction in the AHI that was accompanied by reductions in the evening LFV and overnight change in LFV similar to that observed by Redolfi and coworkers (29). In addition, UF led to significant reductions in neck and chest fluid volumes. This observation suggests that reductions of NFV and TFV may also have contributed to attenuation of sleep apnea severity in our study.
In a previous study involving patients with ESRD, we demonstrated that the AHI was related to indices of NFV at baseline that included jugular venous volume and pharyngeal mucosal water content at baseline while awake (13). Thus, reductions in NFV and neck circumference in the evening post-UF likely contributed to the reduction in AHI even though they were not associated with significant reductions in overnight changes in neck circumference and NFV. An explanation for this could be that in patients with ESRD, fluid overload leads to increased NFV regardless of body position such that it does not increase substantially on lying down. Beecroft and colleagues (32) showed that UA-XSA was smaller in patients with ESRD than in those with normal renal function. However, there was no difference in UA-XSA between patients with ESRD with and without OSA (32). In the present study, there was no significant change in UA-XSA post-UF despite attenuation of OSA. Together, these findings suggest that UA narrowing itself may not be as important in the pathogenesis of OSA in patients with ESRD as it is in otherwise healthy subjects. They nevertheless allow for the possibility that increased fluid accumulation surrounding the UA may increase its collapsibility even if it does not alter UA-XSA (33).
Another possible contributing factor to the pathogenesis of OSA and CSA in this population is ventilatory control instability. In patients with ESRD on conventional hemodialysis, conversion to nocturnal hemodialysis was associated with a decrease in ventilatory sensitivity to hypercapnia and attenuation of sleep apnea (34). Some authors have attributed the presence of respiratory control system instability in ESRD to poor uremic control (35). However, uremia, which causes metabolic acidosis, should stabilize rather than destabilize respiratory control (36, 37). A more plausible explanation is that low Pco2, as seen in patients in the present study, is a consequence of augmented ventilatory drive via stimulation of pulmonary vagal irritant receptors by increased lung water as described in heart failure (14–17). Hypoxia and arousals further augment ventilation at apnea termination. In the posthyperventilatory period, Pco2 falls and respiratory drive to the UA dilator muscles decreases, predisposing to UA collapse (38, 39). The observation that UF caused a 450-ml reduction in TFV that was accompanied by a 3-mm Hg increase in transcutaneous Pco2 indicates that it may have reduced respiratory drive and thereby probably increased ventilatory stability.
In patients with heart failure, CSA is associated with hyperventilation caused by increased left ventricular filling pressure and lung water (14–17). This hyperventilation is augmented at apnea termination, and hypoxia and arousal from sleep further augment ventilation that drives Pco2 below the apnea threshold, triggering central apneas. Raising Pco2 above the apnea threshold via inhalation of a CO2-containing gas abolishes CSA (40). Attenuation of CSA in our patients with ESRD by UF in association with reduced TFV and increased Pco2 is consistent with these previous observations.
Post-UF, the reductions in AHI and fluid volumes were accompanied by a remarkable improvement in sleep structure. This improvement in sleep structure following UF was most likely caused by reductions in fluid volumes. Accordingly, fluid overload, either independently or via the presence of sleep apnea, may induce poor sleep. Given that 80% of patients with ESRD complain of poor sleep (41) and that patients with ESRD on thrice-weekly conventional hemodialysis have reduced total and REM sleep times and sleep efficiency compared with matched control subjects (42), increased fluid removal by intensified dialysis or by UF may be one way of improving sleep structure and quality.
This study is subject to some limitations. First, because of a limited number of patients on thrice-weekly hemodialysis willing to undergo the inconvenience of having UF and two PSGs done on nondialysis days, we performed a nonrandomized protocol to facilitate completion of the study. However, the short 1-week period from baseline to follow-up minimized the chances of any changes in clinical status that may have affected the results. Furthermore, the correlations between the changes in AHI and changes in total body ECFV strongly support the role of fluid removal as the main factor that attenuated sleep apnea and improved sleep structure.
Second, because excessive fluid removal may cause hypotension, the amount of fluid that can be removed in one UF session is limited. Therefore, in several cases, we may not have reduced the AHI maximally because we were not able to remove all excess water. Some studies cite the “first night effect” as an explanation for changes in sleep structure between a first and second PSG (43–46). However, in those studies the “first night effect” typically relates to aspects of sleep structure, such as REM latency, N1 sleep, and longer sleep onset. Only one of these studies reported changes in slow-wave sleep or REM sleep from the first night to the second night and although these changes were statistically significant, the magnitudes were small (4.3 and 7.4 min, respectively). Furthermore, in the control arms of several randomized trials performed in our laboratory, there were no changes in sleep structure between the baseline and follow-up PSGS (47–49). Thus, it is far more likely that fluid removal, rather than a “first night effect,” was responsible for the remarkable improvements in sleep structure that occurred following UF.
In conclusion, these data demonstrate that a single session of UF caused significant reductions in the AHI and improvements in sleep structure of patients with ESRD with either OSA or CSA in association with reductions in fluid volumes of various body compartments and in the absence of any change in uremic or metabolic status. It is likely that greater fluid volume reduction on a chronic basis, as might occur with nocturnal hemodialysis, would cause an even greater reduction in the AHI (18, 25). These data therefore provide a compelling rationale to test this hypothesis and examine the extent to which improvements in UA mechanics and respiratory control system stability contribute to such effects.
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Supported by operating grant MOP-82731 from the Canadian Institutes of Health Research. O.D.L. is supported by a joint Canadian Thoracic Society/European Respiratory Society Peter Macklem Research Fellowship and the Joseph M. West Family Memorial Fund Postgraduate Research Award; C.T.C. by the R. Fraser Elliot Chair in Home Dialysis; A.Y. by fellowships from the Toronto Rehabilitation Institute, Mitacs Elevate program, and a CIHR Training Grant in Sleep and Biological Rhythms; and T.D.B. by the Clifford Nordal Chair in Sleep Apnea and Rehabilitation Research.
Author Contributions: O.D.L., experimental design and execution, data acquisition and analysis, and drafting of the manuscript. A.Y., experimental execution, data acquisition, and revision of the manuscript. C.T.C., experimental design, data analysis, revision, and final drafting of the manuscript. T.D.B., research financing, experimental design, data analysis, revision, and final drafting of the manuscript.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201412-2288OC on March 30, 2015
Author disclosures are available with the text of this article at www.atsjournals.org.
