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Published ahead of print on August 2, 2006
J Am Soc Nephrol 17: 2607-2616, 2006
© 2006 American Society of Nephrology
doi: 10.1681/ASN.2005090936
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Clinical Dialysis

Alleviation of Sleep Apnea in Patients with Chronic Renal Failure by Nocturnal Cycler–Assisted Peritoneal Dialysis Compared with Conventional Continuous Ambulatory Peritoneal Dialysis

Sydney C.W. Tang*,{dagger}, Bing Lam{ddagger}, Pui Pui Ku{ddagger}, Wah Shing Leung§, Chung Ming Chu§, Yiu Wing Ho{dagger}, Mary S.M. Ip{ddagger} and Kar Neng Lai*

* Nephrology; {ddagger} Respiratory Medicine, Department of Medicine, University of Hong Kong and Queen Mary Hospital, and Divisions of; § Respiratory Medicine; and {dagger} Nephrology, Department of Medicine and Geriatrics, United Christian Hospital, Hong Kong

Address correspondence to: Prof. Kar Neng Lai, Department of Medicine, Queen Mary Hospital, 102 Pokfulam Road, Hong Kong SAR, China. Phone: +852-2855-4250; Fax: +852-2816-2863; knlai{at}hku.hk

Received for publication September 12, 2005. Accepted for publication June 12, 2006.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Nocturnal hemodialysis has been shown to improve sleep apnea in patients who receive conventional hemodialysis. It was hypothesized that nocturnal peritoneal dialysis (NPD) also is effective in correcting sleep apnea in patients who receive continuous ambulatory PD (CAPD). Overnight polysomnography (PSG) was performed in 46 stable NPD and CAPD patients who were matched for demographic and clinical attributes. The prevalence of sleep apnea, defined as an apnea-hypopnea index (AHI; or frequency of apnea and hypopnea per hour of sleep) ≥15, was 52% for NPD patients and 91% for CAPD patients (P = 0.007). The mean (±SD) AHI in NPD and CAPD patients was 31.6 ± 25.6 and 50.9 ± 26.4 (P = 0.025), respectively. For validation of the efficacy of NPD in alleviating sleep apnea, a fixed sequence intervention study was performed in which 24 incident PD patients underwent one PSG study during mandatory cycler-assisted NPD while awaiting their turn for CAPD training and a second PSG recording shortly after they were established on stable CAPD. The prevalence of sleep apnea was 4.2% during NPD and 33.3% during CAPD (P = 0.016). AHI increased from 3.4 ± 1.34 during NPD to 14.0 ± 3.46 during CAPD (P < 0.001). With the use of bioelectrical impedance analysis, total body water content was significantly lower during stable NPD than CAPD (32.8 ± 7.37 versus 35.1 ± 7.35 L; P = 0.004). NPD delivered greater reductions in total body water (–2.81 ± 0.45 versus –1.34 ± 0.3 L; P = 0.015) and hydration fraction (–3.63 ± 0.64 versus –0.71 ± 0.52%; P = 0.005) during sleep. Pulmonary function tests remained unchanged before and after conversion from NPD to CAPD. These findings suggest that NPD may have a therapeutic edge over CAPD in sleep apnea that is associated with renal failure as a result of better fluid clearance during sleep.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
In developed countries, sleep apnea has emerged as an important health hazard with serious socioeconomic implications. The issue may be even more relevant in nephrology because some of the factors that are involved in the pathogenesis of renal disease are the same that cause or are associated with sleep apnea. Indeed, reviews of white populations of patients with ESRD by both questionnaire and overnight polysomnography (PSG) reveal a sleep apnea prevalence of >50% (1–3). For addressing this problem, nocturnal hemodialysis has been shown to improve sleep apnea in patients who receive conventional hemodialysis (4). However, this may not be practical in places where nocturnal hemodialysis facilities are not readily available or where peritoneal dialysis (PD) is the predominant mode of renal replacement therapy, such as Hong Kong (5). Whether nocturnal PD (NPD), performed using an automated cycler, also is effective in correcting sleep apnea in patients who receive conventional continuous ambulatory PD (CAPD) remains unknown.

Because of the logistic difficulties in performing crossover studies in PD patients as a result of the inherent complexity in establishing a patient on a particular system of NPD or CAPD (each system has its own hardware, dialysis solution, and methods of connection, together with the training that is needed for the patient or the family or helper in certain elderly patients to use that system), we first compared PSG findings among all patients who were on NPD in our center and patients who were on CAPD and matched for demographic and clinical attributes. Our findings showed that sleep apnea was more prevalent and more severe in the CAPD group compared with the NPD group, suggesting that NPD may be beneficial in improving sleep apnea. To validate this, we performed a fixed-sequence intervention study in which incident PD patients underwent one PSG study during mandatory cycler-assisted NPD shortly after the initiation of dialysis and a second PSG study after the establishment of stable maintenance CAPD.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Part 1: Comparative Study in Prevalent Patients
Between September 2001 and January 2004, we performed overnight PSG in 23 of 26 prevalent NPD patients who were followed at our center. These patients were not assessed for the presence of sleep apnea before enrollment. The remaining three patients declined to participate in the study. Because of the inherent complexity in establishing a patient on a particular system of NPD or CAPD, we initially believed that it was not feasible to perform crossover comparison by recording PSG on the same patient while he or she was on maintenance NPD or CAPD. To circumvent this problem, we performed overnight PSG in stable CAPD patients who were matched for demographics, body mass index (BMI), comorbidities, adequacy of dialysis, and peritoneal transport properties, chosen from the existing pool of 392 prevalent CAPD patients who were followed at our center. The selection of control subjects was based purely on these clinical parameters without regard to other personal attributes or symptoms that pertained to sleep disturbances. Twenty-three patients agreed to undergo PSG. All patients had to have been deemed clinically euvolemic with serum sodium between 135 and 145 mmol/L upon study entry, and there could not have been any peritonitis episode within a 3-mo period before PSG.

Part 2: Fixed-Sequence Intervention Study in Incident Patients
From January 2004 through April 2006, we performed a modified crossover study, which effectively was a fixed-sequence intervention, to validate our hypothesis in the comparative study described in part 1. We made use of the fact that in Hong Kong all incident patients who required CAPD had to undergo, after Tenckhoff catheter placement, a temporary period of mandatory cycler-assisted NPD for approximately 8 wk while awaiting their turn for CAPD training. Twenty-four consenting adult patients underwent one PSG study toward the end of their 6 to 8 wk of NPD treatment. They then underwent training for CAPD, and a second PSG study was performed as soon as they had been established on stable CAPD. All patients had to have been deemed clinically euvolemic with serum sodium between 135 and 145 mmol/L upon study entry and before PSG. The study protocol was reviewed and approved by the Institutional Review Board and Clinical Research Ethics Committee of each individual hospital, and all patients gave written informed consent to participate in the study.

Laboratory Measurements
Residual renal function was estimated by taking the average of urea and creatinine clearances calculated from 24-h urine samples and simultaneous serum urea and creatinine levels and corrected for body surface area. Complete blood count and standard renal function tests, including serum bicarbonate levels, were measured on the day of PSG. For NPD patients, the biochemical assays were performed just before and after PSG, and the values were averaged. For CAPD patients, measurements were obtained just before PSG. Adequacy of dialysis was assessed at the steady state using standard urea kinetic studies when patients were established on PD for approximately 2 mo. Peritoneal membrane transport properties were assessed at the same setting using a standard peritoneal equilibration test (6).

PSG
Comprehensive overnight PSG was performed in the hospital using an Alice 3 or Alice 4 machine (Healthdyne, Atlanta, GA). Recordings included electroencephalogram, electrooculogram, submental electromyogram (EMG), bilateral anterior tibial EMG, electrocardiogram, chest and abdominal wall movement (respiratory effort) by inductance plethysmography, airflow by a nasal pressure transducer (PTAF 2; Pro-Tech, Woodinville, WA), and finger pulse oximetry. All variables were recorded continuously by a computerized data-acquisition system and stored on an optical disk for subsequent analyses.

All polysomnograms were scored manually by an independent expert in sleep medicine without knowledge of the mode of dialysis, according to standard criteria (7). Apnea was defined as the cessation of airflow for >10 s, and hypopnea was defined as a reduction of airflow of ≥50% for >10 s plus an oxygen desaturation of ≥4%. An arousal was scored when there was an abrupt shift in electroencephalogram frequency to {alpha} or {theta} of ≥3 s or >16 Hz, after at least 10 s of sleep, or when during rapid eye movement sleep there was a concomitant rise in EMG tone (8). A respiratory arousal was defined as an arousal that occurred within 3 s after the termination of an episode of apnea or hypopnea. The average number of episodes of apnea and hypopnea per hour of sleep (apnea-hypopnea index [AHI]) was calculated as the summary measurement of sleep-disordered breathing.

Significant sleep apnea was defined arbitrarily as an AHI of ≥15 events per hour of sleep. An AHI >30 was classified as severe sleep apnea. Subjective sleepiness was evaluated by the Epworth sleepiness scale (ESS), a questionnaire that is specific to symptoms of daytime sleepiness, and the patients were asked to score the likelihood of falling asleep in eight different situations with various levels of stimulation, adding up to a total score of 0 to 24 (9). Patients with ESS >9 were considered to have excessive daytime sleepiness. Apneas were classified as central when there was no chest and abdominal movement, as obstructive when they moved paradoxically, and as mixed when an initial absence of ventilatory effort was followed by an obstructive apnea pattern upon resumption of effort. Cheyne-Stokes breathing (CSB) was defined as an episode of central apnea (or hypopnea) alternating with breathing that had a pattern of cyclical crescendo and decrescendo amplitude for at least 3 cycles of not less than 60 s each. Periodic leg movements were defined as four or more involuntary leg movements during sleep, each lasting 0.5 to 5.0 s, with 5 to 90 s between movements.

Dialysis Protocol
Upon initiation of dialysis, the particular PD system used was solely the choice of the patient after he or she had visited the PD center and received detailed information from the nurse specialist on the various brands, modes, and methods of connection of CAPD and NPD. In Hong Kong, all dialysis solutions are provided free by the statutory national health service. Patients only pay for consumable items, such as connection tubings and antiseptic solutions. Automated cyclers are provided free in most instances by the charitable Hong Kong Kidney Foundation. Therefore, patients who choose NPD rather than CAPD may have to bear a higher consumable expenditure in view of the larger number of connection tubings required. Otherwise, there is no selection bias between CAPD and NPD.

For NPD, patients performed overnight exchanges of 10 to 12 L of PD fluid at 2.0 to 2.2 L/cycle for five to six cycles using an automated cycler (HomeChoice; Baxter Healthcare, McGaw Park, IL). For CAPD, patients performed three to four daily exchanges of 2 L of PD fluid using UltraBag (Baxter Healthcare, Guangzhou, People’s Republic of China), StaySafe or AndyDisk (Fresenius Medical Care, Bad Homburg, Germany), or Gambrosol Trio (Gambro Lundia AB, Lund, Sweden) system. Dialysis regimens for both NPD and CAPD patients were adjusted to achieve euvolemia and a weekly KT/Vurea of 1.8 to 2.1. All patients who participated in the comparative study had to have been on stable maintenance PD for 12 mo or longer without concomitant or recent (within 3 mo) infective episode or hospitalization.

Bioelectrical Impedance Analysis
Bioelectrical impedance analysis (BIA) is a portable technique of assessing body water composition that has been cross-validated in PD patients (10,11). To assess changes in body water content as a result of NPD or CAPD, we performed BIA measurements using Nutrigard-M Bioelectrical Impedance Analyzer (Data Input GmbH, Darmstadt, Germany) while the patient was supine on a bed for at least 15 min on the night of PSG study before and the morning after NPD or the night dwell of CAPD with the peritoneum emptied. Multifrequency (5 to 100 kHz) currents were introduced at four distal electrodes placed on the dorsal surface of the nondominant hand and ipsilateral foot in a standard manner, and resistance (R) and reactance (Xc) were measured by proximal electrodes. The external calibration of the instrument was validated with a calibration circuit of known impedance value (R = 500 ohms, Xc = 144 ohms, error 0.8%). Total body water (TBW; in liters) was computed as described elsewhere (12) and as applied in PD patients (13): TBW for male patients = 1.203 + 0.449 H2/R + 0.176 W, and TBW for female patients = 3.747 + 0.45 H2/R + 0.113 W, where H is body height in cm, R is resistance at 100 kHz, and W is body weight in kg.

Extracellular water (ECW; in liters) was computed as described previously (14): ECW = 0.3 x H2/Z + 3.08, where Z is the impedance calculated according to the manufacturer’s instruction: Z = (R2 + Xc2)1/2 with R and Xc recorded at a frequency of 5 kHz. Intracellular water (ICW; in liters) was obtained by ICW = TBW – ECW.

Pulmonary Mechanics
Standard spirometry was performed in accordance with the guidelines of the American Thoracic Society (15) on the night of PSG before and the morning after NPD or the night dwell of CAPD. Flow-volume measurements yielded the following parameters: Forced vital capacity (FVC), forced expired volume in 1 s (FEV1), peak expiratory flow rates at 50% (PEF50%) and 75% (PEF75%) of FVC, and peak inspiratory flow rate at 50% (PIF50%) of FVC. Airflow limitation also was assessed using the peak flow ratios at mid-vital capacity (PIF/PEF50%). Pulmonary function results were expressed as measured and predicted values. Predicted vital capacity, inspiratory and expiratory flow rates, and FEV1 were based on gender, height, and age.

Statistical Analyses
Data were expressed as means ± SD unless otherwise specified. Statistical analyses were performed using SPSS for Windows software version 12.0 (SPSS, Inc., Chicago, IL). Comparisons between groups were performed by {chi}2 test for categorical data and by Mann-Whitney U test for continuous data. Correlations between continuous variables were examined by linear regression analysis. Factors with P < 0.1 on univariate analysis were entered into a multivariate regression model with AHI as the dependent variable and age, BMI, dialysis vintage, serum albumin, peritoneal and residual Kt/V and creatinine clearance, peritoneal transport property (D/P of creatinine at 4 h), and the mode of PD as independent variables. A backward elimination procedure with P > 0.05 to remove was performed to identify independent factors of correlation. Nonparametric paired-sample Wilcoxon signed rank test was used to determine changes in sleep disturbance parameters in the fixed-sequence intervention group of patients. Comparison of within-group differences in prevalence of sleep apnea during NPD or CAPD was performed using the McNemar test. P < 0.05 was considered significant. All probabilities were two tailed.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Part 1
Baseline demographic and clinical parameters of the study patients were not different (Table 1). The underlying renal diseases in the NPD group were diabetes in nine, hypertensive nephrosclerosis in two, primary glomerulonephritis in four, neurogenic bladder in one, reflux nephropathy in one, and unknown in six. Those for the CAPD group were diabetes in 11, hypertensive nephrosclerosis in two, primary glomerulonephritis in two, lupus nephritis in one, reflux nephropathy in one, and unknown in six.


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  		Table 1. Baseline demographic and clinical parameters of the study patientsa

 
The prevalence of sleep apnea (AHI ≥ 15) was 52% for NPD patients and 91% for CAPD patients (P = 0.007). Such difference became insignificant when the AHI cutoff value was lowered to 10 or 5 (Table 2). The number of patients without significant sleep apnea (AHI < 15) was much higher in the NPD group, whereas the prevalence of severe sleep apnea (AHI > 30) was higher in the CAPD group (Figure 1), although the latter difference did not reach statistical significance. The overall sleep pattern is summarized in Table 3. The mean (±SD) AHI in NPD and CAPD patients was 31.6 ± 25.6 versus 50.9 ± 26.4 (P = 0.025), and the minimum oxygen saturation was 84.1 ± 8.4 versus 71.0 ± 17.7% (P = 0.008), respectively. The duration of the various stages of sleep, the frequency of arousals and periodic leg movements during sleep, and biochemical parameters were not significantly different between the two groups, although there was a trend toward more frequent arousals among CAPD patients.


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  		Table 2. Impact of varying AHI cutoff value on sleep apnea prevalence among NPD and CAPD patientsa

 

Figure 1
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  		Figure 1. Prevalence of sleep apnea by apnea-hypopnea index (AHI) in nocturnal peritoneal dialysis (NPD; {square}) and continuous ambulatory peritoneal dialysis (CAPD; {blacksquare}) patients.

 

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  		Table 3. Polysomnographic data in ESRD patients who were treated with NPD and CAPDa

 
The distribution of central, obstructive, and mixed types of hypopnea or apnea is shown in Figure 2. There was a trend that each type of sleep apnea was more frequently encountered in the CAPD group, although the difference from the NPD group did not reach statistical significance. Obstructive pattern was the most frequent type of apnea in both groups, followed by central and mixed types of apnea. CSB was observed in two NPD and three CAPD patients, all of whom had severe sleep apnea (mean ± SD AHI 35.3 ± 5.0; range 30 to 41.4). None of them had a history of cardiac failure or cerebrovascular disease, and echocardiogram estimated a left ventricular ejection fraction of 53.8 ± 4.4% (range 50 to 61%).


Figure 2
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  		Figure 2. Pattern of sleep apnea in NPD ({square}) and CAPD ({blacksquare}) patients.

 
Self-reported daytime sleepiness, as assessed by the ESS, was present in 10 (43%) NPD and eight (35%) CAPD patients. Multivariate regression analysis showed that only the mode of PD (r2 = 0.351, b = 20.9; 95% confidence interval 3.9 to 38.0; P = 0.017) and BMI (r2 = 0.386, b = 3.3; 95% confidence interval 0.8 to 5.8; P = 0.011) independently correlated with AHI.

Part 2
Twenty-four patients (13 men; mean age 50.8 ± 13.0 y; mean BMI 21.3 ± 3.5 kg/m2) participated in the fixed-sequence intervention study. Their underlying renal diseases were diabetes in five, IgA nephropathy in three, membranous nephropathy in one, lupus nephritis in one, focal segmental glomerulosclerosis in two, pauci-immune crescentic glomerulonephritis in two, polycystic kidney disease in one, and unknown in nine. The average interval between the two sets of PSG recordings was 5.03 ± 1.0 mo, and there was no appreciable change in residual renal function during this period (data not shown). Epworth daytime sleepiness was present in three (12.5%) patients during NPD and four (16.6%) patients during CAPD.

Using an AHI cutoff of 15, the prevalence of sleep apnea was 4.2% (n = 1) during NPD and 33.3% (n = 8) during CAPD (Table 4). When the AHI cutoff was lowered to 10, the prevalence was 12.5% (n = 3) during NPD and 41.7% (n = 10) during CAPD. As a group, the absolute AHI values increased from 3.4 ± 1.3 during NPD to 14.0 ± 3.5 during CAPD (P < 0.001 for comparison before and after transfer to CAPD). The individual changes in AHI values during the two different modes of PD are shown in Figure 3. The overall sleep pattern during NPD or CAPD is summarized in Table 4. Although there was no significant difference in the total sleep time during NPD or CAPD, the duration of sleep with hypoxia (oxygen saturation <95%) was substantially longer during CAPD (P = 0.03). In addition, there were significantly more frequent arousals after conversion to CAPD. The prevalence of sleep apnea during each mode of PD was significantly lower than the corresponding comparative group in part 1 of the study (P < 0.001 for NPD, P < 0.001 for CAPD).


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  		Table 4. Polysomnographic data in 24 incident ESRD patients while on NPD or CAPDa

 

Figure 3
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  		Figure 3. AHI in 24 patients during NPD and after conversion to CAPD. *Four patients who developed de novo Cheyne-Stokes breathing (CSB) during CAPD but not during NPD; #patient who had CSB during NPD and CAPD. Horizontal bars represent mean ± SE values during each mode of PD. {dagger}P < 0.001 compared with values while on NPD.

 
To dissect the mechanisms that are responsible for the increased prevalence and severity of sleep apnea during CAPD compared with NPD, we measured fluid balance and respiratory mechanics with each therapeutic modality. Fluid balance was measured using multifrequency BIA analyses in 15 patients. As shown in Figure 4, the TBW content was significantly lower during stable NPD than CAPD, and the difference amounted to 6.6 ± 2.52% (32.8 ± 7.37 versus 35.1 ± 7.35 L; P = 0.004). This also was reflected by a significant difference in body weight between the two modalities (Table 5). Likewise, there were significant differences in ECW and ICW contents. To explore further the impact of NPD versus CAPD on fluid status during sleep, we performed BIA measurements just before and after NPD or the night dwell of CAPD to calculate the change in body fluid composition as a result of either NPD or CAPD during sleep. NPD achieved significantly larger volume of fluid removal as reflected by greater reductions in absolute body water contents and in hydration fraction expressed as percentage TBW of body weight (Table 5).


Figure 4
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  		Figure 4. Fluid balance estimates in 15 patients during stable NPD ({square}) and CAPD ({blacksquare}). All measurements were performed using multifrequency bioelectrical impedance analysis in the fasting state after drainage of peritoneal dialysate. Error bars are SD. TBW, total body water; ECW, extracellular water; ICW, intracellular water.

 

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  		Table 5. Changes in fluid balance in 15 patients after NPD or overnight dwell of CAPDa

 
Pulmonary function tests using standard spirometry were obtained from these 15 patients just before and after NPD or the night dwell of CAPD. There was no difference in any of the spirometric parameters measured during NPD or CAPD (Table 6). In addition, there were no significant changes in pulmonary mechanics before and after NPD or the night dwell of CAPD (data not shown).


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  		Table 6. Pulmonary function tests in 15 incident patients while on NPD or CAPDa

 
A total of seven patients were detected to have CSB. Two had CSB during NPD but not CAPD. One patient had CSB during both NPD and CAPD. Another four patients developed CSB during CAPD but not when they were undergoing NPD (Figure 5). These four patients all had sharp rises in AHI upon converting to CAPD, and they also had the high-end AHI values in this cohort. Three of them had no evidence of sleep apnea with AHI <5 during NPD, whereas the remaining patient already demonstrated significant sleep apnea (AHI = 29.7) during NPD that intensified (AHI rising to 59.2) upon conversion to CAPD. Echocardiography in these patients showed normal left ventricular ejection fraction and diastolic function. They did not have a history of cerebrovascular disorders.


Figure 5
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  		Figure 5. Representative polysomnographic tracings in one patient with CSB. Shown here is a tracing spanning 300 s. Note the pattern of periodic crescendo and decrescendo breathing (arrow), drop in oxygen saturation after periodic apnea, and subsequent restoration of normal oxygen saturation after periodic breathing (*).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
The factors that are responsible for sleep apnea in the uremic state are not fully understood and likely are multifactorial (16). Although sleep apnea in the general population is mostly of the obstructive type, the frequencies of central, obstructive, and mixed apneic events in uremic patients are not strikingly different. A widely accepted theory is that chronic metabolic acidosis in uremia induces a respiratory response that promotes the development of compensatory hypocapnia, which in turn plays a pathogenetic role in central apnea and periodic breathing (17). In support of this theory, Hanly et al. (4) demonstrated that correction of hypocapnia during sleep by nocturnal hemodialysis is associated with concomitant improvement in sleep apnea.

To our knowledge, there are no parallel data in patients who undergo PD. We recognized the logistic difficulties in performing conversion studies in PD patients. Therefore, we set out first to compare polysomnographic findings between NPD and CAPD patients, trying every possible means to balance the baseline characteristics of the two groups. An important parameter to balance is volume status, because the impact of volume overload likely will affect airway diameter, which may not be sensitive enough to be detected by changes in neck circumference or BMI alone. Measurement of upper airway resistance or the water content of the upper airway by magnetic resonance imaging may be better alternatives, although these modalities are more tedious to perform. Nevertheless, this study is the first to use standard PSG to define the prevalence of sleep apnea in Chinese patients who are on PD. Our findings showed a high prevalence of sleep apnea that far exceeded the reported frequencies of abnormalities using ESS alone or other sleep assessment questionnaires that have been applied to Chinese patients who were on dialysis (18–20). Indeed, even within the present study, the ESS as a screening tool significantly underestimated the prevalence of sleep apnea that was detected by overnight PSG. The high frequency of sleep apnea in renal failure is explained in part by the fact that the most common comorbid conditions of ESRD, including atherosclerosis and diabetes, also are independently associated with this syndrome.

Our comparative study demonstrated significantly higher prevalence and intensity of sleep apnea in CAPD than in NPD patients, and multivariate analysis suggested that the mode of PD was one of the factors that correlated with AHI. Indeed, apart from the attributes that were matched between the two groups before PSG, the prevalence of sleep apnea also turned out to match well using AHI cutoff points of 5 or 10. The benefit of NPD over CAPD was borne out by the difference in prevalence when AHI ≥15 was used to define sleep apnea. These findings provided circumstantial evidence that NPD may improve sleep apnea in PD patients, albeit to a much lesser extent than nocturnal hemodialysis in HD patients (4). Such assumption may be partially confounded by the inevitable introduction of selection bias despite the most meticulous and impartial matching of the baseline variables in NPD and CAPD patients. To validate our hypothesis, we contemplated the possibility of a crossover study. Crossover between CAPD and NPD is logistically, technically, and ethically difficult compared with conversion between conventional and nocturnal hemodialysis. To circumvent this hurdle, we performed a fixed-sequence intervention study in which incident PD patients underwent one PSG study during mandatory cycler-assisted NPD while awaiting their turn for CAPD training and a second PSG recording shortly after they were established on stable CAPD.

Our findings clearly showed a significant worsening of sleep apnea after conversion from NPD to CAPD, as reflected by substantial increases in AHI, increased prevalence of sleep apnea, prolongation of the duration of hypoxia, and more frequent arousals during sleep. Nevertheless, the prevalence of sleep apnea in these patients was significantly lower than those from the comparative study, regardless of the mode of PD. This may be explained by the higher residual renal function in these incident patients compared with the comparative cohort of patient whose dialysis vintage averaged >2 yr. Such observation supports once again that uremia per se is a risk factor for sleep apnea.

Unlike nocturnal HD, the mechanism of improvement of sleep apnea in nocturnal PD is unlikely to be mediated through correction of metabolic acidosis and hypocapnia, because the serum bicarbonate levels were almost identical between NPD and CAPD patients in the comparative group and were not significantly different during NPD or CAPD in the crossover group. We believe that the partial amelioration of sleep apnea by NPD could be related to its more vigorous clearance of fluid. This is reflected in part by an increase in body weight when the patients were switched from NPD to CAPD. Using BIA to estimate body water composition, we showed a small but significant increase in TBW content after conversion from NPD to CAPD. This signifies the potential of NPD compared with CAPD to confer a "drier" state in biophysical terms, although this difference may not be detectable clinically. Furthermore, by performing sequential measurements immediately before and after NPD or the night dwell of CAPD on the night of PSG recording, we confirmed that the mode of PD during sleep had an enormous impact on fluid balance. Not surprising, NPD, being characterized by shorter and more frequent exchanges of dialysate, delivered greater reductions in absolute body water contents and hydration fraction during sleep. Given the close association between airway edema and sleep apnea (21–24), it is possible that even subtle increases in TBW during CAPD may cause a tangible rise in airway edema and resistance that promotes sleep apnea and that NPD alleviates fluid accumulation in the airway by continuous fluid removal during sleep. Conversely, there was hardly any difference in respiratory mechanics during each mode of PD. In particular, the indices of airflow velocity and airway obstruction, namely FEV1, FEV1/FVC, and PIF/PEF50%, remained unchanged. Although these findings concur with recent studies that sleep apnea is unrelated to pulmonary function measurements (25) and that flow-volume curve indices have no value in predicting sleep apnea (26), the influence of intra-abdominal distension by PD fluid may be most marked when the patients are supine and asleep. The standard respiratory mechanics measurements that were performed here with the patients upright and awake may not reflect the real status during sleep.

Another novel observation is the frequent occurrence of CSB, which is commonly associated with congestive heart failure and stroke (27–30). Its association with uremia or dialysis is unknown. The five patients from the comparative group and the seven patients from the crossover group who exhibited such phenomenon did not have heart failure or stroke. This suggests that other mechanisms may operate in the uremic state to promote periodic breathing. Indeed, chronic renal failure has been shown to augment chemosensitivity to carbon dioxide tension (31). The consequent development of periodic breathing is more likely to cause obstructive apnea in patients with chronic renal failure than in healthy individuals as a result of airway edema and reduced upper airway muscle tone (16,32). More interesting, four patients from the incident group developed de novo CSB after they were converted from NPD to CAPD, and these patients had the highest AHI readings. It remains unclear why a modality switch that principally affects fluid balance gave rise to an increase in central sleep apnea. One possible explanation is that switching from NPD to CAPD resulted in other mechanistic effects in addition to fluid balance. Furthermore, because narrowing of the upper airway can induce central sleep apnea (33), it is not surprising that this also may occur during CAPD (compared with NPD). Taken together, it will be tempting to speculate that uremia represents a novel risk factor for CSB. Whether NPD may improve such phenomenon requires further studies.


   Conclusion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Sleep apnea is more prevalent than questionnaire-based studies suggested among Chinese uremic patients. Uremia may represent a novel risk factor for CSB. NPD may have a therapeutic edge over CAPD in sleep apnea that is associated with renal failure as a result of improved time-averaged volume control during sleep.


   Acknowledgments
 
This study is funded by the L and T Charitable Foundation and the House of INDOCAFE.

Part 1 of this study was presented in abstract form at the ISPD-EuroPD Congress; August 27 through 31, 2004; Amsterdam, The Netherlands.

We are grateful to Agnes Lai (Sleep Laboratory, Queen Mary Hospital), Helena Leung and all nursing staff (K18N Dialysis Unit, Queen Mary Hospital), Dr. Veronica L. Chan (Sleep Laboratory, United Christian Hospital), and Woon Ngor Lam and all nursing staff (14B Dialysis Unit, United Christian Hospital) for coordinating the PSG studies in all dialysis patients. We thank Kan Ming Lo (Sleep Laboratory, Queen Mary Hospital) for performing all lung function tests and BIA measurements, Dr. David C.W. Siu (Division of Cardiology, Queen Mary Hospital) for performing echocardiographic examinations, and Suki Ho (Dialysis Unit, Queen Mary Hospital) for clerical support.


   Footnotes
 
Published online ahead of print. Publication date available at www.jasn.org.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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