Int Urol Nephrol (2014) 46:1997–2002 DOI 10.1007/s11255-014-0779-x

NEPHROLOGY - ORIGINAL PAPER

Effect of continuous positive airway pressure on serum cystatin C among obstructive sleep apnea syndrome patients Xiao-Bin Zhang • Xing-Tang Jiang • Qi-Chang Lin • Xiao Chen • Hui-Qing Zeng

Received: 15 February 2014 / Accepted: 22 June 2014 / Published online: 8 July 2014 Ó Springer Science+Business Media Dordrecht 2014

Abstract Purpose The purpose of the present study was to evaluate the influence of continuous positive airway pressure (CPAP) on serum cystatin C, a novel biomarker of early renal impairment, among obstructive sleep apnea (OSA) patients. Materials and methods Newly diagnosed severe OSA patients who treated with CPAP for 3 months were enrolled from two sleep laboratories. Serum biomarkers of renal impairment, cystatin C, creatinine and estimated glomerular filtration rate (eGFR), were detected before and after CPAP treatment. Results A total of 39 severe OSA patients were enrolled, 29 (74.4 %) were male, and mean age was 51.2 ± 12.2 years. After CPAP treatment, there were no changes of creatinine and eGFR (77.80 ± 20.00 vs. 75.3 ± 16.60 and 98.69 ± 31.74 vs. 100.20 ± 28.30, all p [ 0.05), but cystatin C declined significantly (0.87 ± 0.18 vs. 0.77 ± 0.21, p = 0.000). Conclusion CPAP can decrease cystatin C levels among severe OSA patients and may prevent the latent renal impairment.

All authors contributed equally to this work. X.-B. Zhang (&)  X.-T. Jiang  H.-Q. Zeng Department of Respiratory Medicine, Zhongshan Hospital, Xiamen University, No. 201, Hubin Nan Road, Siming District, Xiamen 361004, Fujian, People’s Republic of China e-mail: [email protected] Q.-C. Lin  X. Chen Department of Respiratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China

Keywords Obstructive sleep apnea  Cystatin C  Continuous positive airway  Renal impairment

Introduction Obstructive sleep apnea (OSA) is characterized by recurrent upper airway part or complete obstruction which leads to nocturnal chronic intermittent hypoxia and sleep fragmentation. Abundant data demonstrated that OSA is correlated with hypertension and cardiovascular diseases [1, 2]. Recently, growing evidence shows that OSA is associated with renal disorders, especially chronic kidney disease (CKD) and end-stage renal disease (ESRD) [3–8]. Patients with impaired renal function, CKD, ESRD, even kidney transplantation, exhibit a high prevalence of OSA [3–5], and inversely, OSA is independently correlated with increased urinary albumin excretion and loss of kidney function [7, 8]. Chou and colleagues reported that the prevalence of CKD is up to 18 % in severe OSA patients without hypertension or diabetes [9]. However, not all studies support the idea that OSA patients suffer proteinuria [10]. Cystatin C, as a nonglycosylated protein from the family of cysteine protease inhibitors with low molecular weight (13 kDa), is considered as a novel biomarker reflecting early renal impairment [11, 12]. Studies have shown that OSA patients have a high serum cystatin C independent of complications [13–15], and it is easily to speculate that OSA patients with high cystatin C level may suffer obvious kidney impairment in the near future. Our previous studies have illustrated that severe OSA patients have relatively high serum cystatin C level both in the elder patients and younger patients \40 years old [14,

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15]. Continuous positive airway pressure (CPAP) is recognized as the first-line treatment for patients with OSA [16]. However, whether CPAP can normalize serum cystatin C level remains unclear. The aim of the present study was to evaluate the effect of CPAP on cystatin C level among OSA patients.

Materials and methods Subjects Severe OSA patients, defined as the apnea-hypopnea index (AHI) C30 events per hours by polysomnography (PSG), were consecutively recruited in two general hospitals: the sleep center of the First Affiliated Hospital of Fujian Medical University and the sleep laboratory of Respiratory Department of Zhongshan Hospital, Xiamen University. This study was conducted between January 2011 and December 2013. Exclusion criteria were as follows: (1) apparent respiratory or cardiac disease other than OSA; (2) previous CPAP therapy, uvulopalaopharyngoplasty or oral appliance; (3) any conditions known to affect cystatin C, such as thyroid dysfunction or on glucocorticoid therapy [17, 18]. All subject’s sleep symptoms, Epworth sleepiness scale (ESS), medical history and medications were collected. Written informed consents were obtained from all subjects enrolled in the study, and the study was approved by the institutional review boards of the two institutions. Anthropometric measurements and polysomnography Body weight and height were measured using a scale and stadiometer in the morning. Weight (kg)/height2 (m) were calculated as body mass index (BMI). Waist circumference was measured at the navel level. Blood pressure was gauged twice at 5 min intervals in the sitting position. PSG procedure was described in detail elsewhere [14]. Electroencephalography, electrooculography, electromyography, electrocardiography, oronasal airflow, snoring, body position, thoracic and abdominal respiratory efforts and pulse oxygen saturation were recorded. According to AHI, severe OSA patients (AHI C 30 events per hours) were included. Authropometry and PSG were re-checked after CPAP treatment. Biochemical measurements Blood samples were drawn from all patients after at least 7 h fasting in the next morning of PSG. Glucose, lipid profiles and serum creatinine were measured by an automated Hitachi 7600 analyzer. Serum cystatin C were gauged with a BN II nephelometer (Dade Berhring,

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Deerfield, IL, USA). Estimated glomerular filtration rate (eGFR) was calculated through the Modification of Diet in Renal Disease equation: eGFR = 186 9 (serum creatinine [mg/dl]-1.154) 9 (age-0.203) 9 0.742 (if female) [19]. All biochemical measurements were repeated after 3 months of CPAP treatment. CPAP treatment All included severe OSA patients underwent CPAP titration using automated pressure setting CPAP machine S8 (AutoSet, Spirit, ResMed, Australia) on the next night of PSG. After titration, patients received CPAP treatment with S8 CPAP device (AutoSet, Spirit, ResMed, Australia). Compliance of CPAP was measured with a smartcard, and patients with an average CPAP use time C4.0 h per night were considered to be good compliance. Statistical analysis All continuous variables are presented as mean ± standard deviation (SD) except for CPAP titration pressure is presented as median (percentile 25, percentile 75). Categorical variables are presented as number (percentage). Analysis of variance (ANOVA) was used to compare the baseline data between groups stratified by OSA severity. Paired t tests were performed to assess the differences of continuous variables before and after CPAP treatment. A p value of \0.05 was considered statistically significant. Statistics was performed using SPSS statistical software version 17.0 for Windows (SPSS, Inc, Chicago, Illinois, USA), and graphs was drawn using GraphPad Prism 5 (GraphPad Software, USA).

Results Study population, CPAP titration and compliance There were 265 severe OSA patients referred to the two sleep laboratories during the study period, 226 (85.3 %) were excluded for different reasons (Fig. 1). The clinical characteristics between the excluded subjects and included subjects were similar except that the TST of included patients was relatively longer than that of excluded patients (31.14 ± 0.27 vs. 30.89 ± 0.35, p = 0.000; Table 1). Of the 39 included subjects, 29 (74.4 %) were male, mean age was 51.2 ± 12.2 years, five had hypertension and consumed anti-hypertensive agents regularly, and two had diabetes and used anti-diabetes agents. The median CPAP titration pressure was 8.24 (6.35, 12.72) cm H2O. CPAP was used for 6.45 ± 2.39 h per night.

Int Urol Nephrol (2014) 46:1997–2002 Fig. 1 Study flow diagram

1999

A total of 265 patients were available in the study period 92 refused to participant 101 chose upper airway operation 13 chose conventional treatments (exercise, postural changes during sleep)

59 patients were enrolled at baseline 10 were intolerable with CPAP 4 lost to follow-up 2 died for other disease 4 missed data for technical reasons

After 3 months of CPAP treatment, 39 patients were included in the final analysis

Table 1 Demographic, polysomnographic and biochemical data of the 265 patients Variables

Included patients (n = 39)

Excluded patients (n = 226)

p value

Male, n (%)

29 (74.4)

184 (81.4)

0.305 0.160

Age, year

51.18 ± 12.22

53.87 ± 10.80

BMI, kg/m2

29.59 ± 5.02

31.12 ± 6.23

0.147

Waist circumference, cm

97.62 ± 13.69

96.89 ± 14.54

0.771

Epworth sleepiness scale

13.67 ± 5.16

11.58 ± 7.62

0.101

AHI, events/h

51.57 ± 16.69

54.05 ± 12.99

0.294

ODI, events/h

48.58 ± 19.13

50.12 ± 10.52

0.465

TST, %

31.14 ± 0.27

30.89 ± 0.35

0.000

Lowest SaO2, %

61.00 ± 13.21

65.01 ± 8.39

0.067

SBP, mmHg

129.62 ± 18.03

132.41 ± 20.56

0.428

DBP, mmHg Glucose, mmol/l

80.38 ± 10.66 6.62 ± 2.39

78.30 ± 9.87 6.58 ± 1.99

0.231 0.904 0.852

Cholesterol, mmol/l

4.97 ± 1.30

5.02 ± 1.58

Triglyceride, mmol/l

1.43 ± 0.49

1.32 ± 0.77

0.390

HDL, mmol/l

1.25 ± 0.41

1.13 ± 0.58

0.217

LDL, mmol/l

2.63 ± 0.99

2.49 ± 1.58

0.593

Creatinine, umol/l

77.80 ± 20.00

81.59 ± 18.43

0.243

eGFR, ml/min/1.73 m2

98.69 ± 31.74

95.05 ± 29.10

0.477

Cystatin C, mg/l

0.87 ± 0.18

0.95 ± 0.41

0.232

BMI body mass index, AHI apnea-hypopnea index, ODI oxygen desaturation index, TST percentage of total sleep time spent with SaO2 \ 90 %, SBP systolic blood pressure, DBP diastolic blood pressure, HDL high density lipoprotein, LDL low density lipoprotein, eGFR estimated glomerular filtration rate

Characteristics of OSA patients before and after CPAP treatment The characteristics of 39 OSA patients who received CPAP treatment are shown in Table 2. There were no

changes of age and waist circumference after CPAP treatment. Compared to baseline, after 3 months of CPAP treatment, subjects had lower ESS, AHI, ODI, diastolic blood pressure and higher lowest SaO2, high density lipoprotein.

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Table 2 Characteristics of patients with OSA before and after CPAP treatment (n = 39) Variable

Before CPAP

After CPAP

p value

BMI, kg/m2

29.59 ± 5.02

29.34 ± 4.56

0.530

Waist circumference, cm

97.62 ± 13.69

95.74 ± 11.79

0.145

Epworth sleepiness scale

13.67 ± 5.16

5.41 ± 2.20

0.000

AHI, events/h

51.57 ± 16.69

5.30 ± 3.20

0.000

ODI, events/h

48.58 ± 19.13

4.31 ± 2.75

0.000

TST, %

31.14 ± 0.27

0.005 ± 0.007

0.000

Lowest SaO2, %

61.00 ± 13.21

88.78 ± 4.98

0.000

129.62 ± 18.03 80.38 ± 10.66

126.59 ± 13.07 76.49 ± 9.69

0.122 0.003

6.62 ± 2.39

6.36 ± 1.83

0.185

SBP, mmHg DBP, mmHg Glucose, mmol/l Cholesterol, mmol/l

4.97 ± 1.30

4.68 ± 0.89

0.106

Triglyceride, mmol/l

1.43 ± 0.49

1.35 ± 0.38

0.181

HDL, mmol/l

1.25 ± 0.41

1.64 ± 0.44

0.000

LDL, mmol/l

2.63 ± 0.99

2.39 ± 0.80

0.056

OSA obstructive sleep apnea, CPAP continuous positive airway pressure, BMI body mass index, AHI apnea-hypopnea index, ODI oxygen desaturation index, TST percentage of total sleep time spent with SaO2 \ 90 %, SBP systolic blood pressure, DBP diastolic blood pressure, HDL high density lipoprotein, LDL low density lipoprotein

Figure 2 demonstrates the changes of cystatin C, creatinine and eGFR before and after CPAP treatment. There was a significant decrease in the serum cystatin C levels (0.87 ± 0.18 vs. 0.77 ± 0.21, p = 0.000), but the creatinine and eGFR did not vary after CPAP treatment (77.80 ± 20.00 vs. 75.3 ± 16.60 and 98.69 ± 31.74 vs. 100.20 ± 28.30, all p [ 0.05).

Discussion The present study was conducted in two sleep laboratories. All enrolled patients with severe OSA received CPAP treatment for 3 months. The results demonstrated that serum cystatin C levels, as an early biomarker of renal impairment, decreased in severe OSA patients after CPAP treatment. OSA is a common disorder characterized by recurrent upper airway obstruction during sleep. The pathophysiologic hallmarks of OSA, nocturnal chronic intermittent hypoxia and sleep fragmentation [20], appear to be responsible for systemic inflammation, oxidate stress, vascular endothelial cell injury and sympathetic overreaction [21–23]. The prevalence of OSA among CKD patients ranges from 27 to 54 %, even has been estimated as high as 73 % in ESRD [3, 4, 24, 25]. OSA may aggravate the renal impairment either through the effect of nocturnal hypoxia

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Fig. 2 Changes of cystatin C, creatinine and eGFR before and after CPAP treatment

on kidney or through the influence of elevated blood pressure, systemic inflammation and sympathetic overreaction [8, 26, 27]. Recently, one study revealed that PSG variable, AHI and oxygen desaturation index, are independently associated with renal functional decline [9]. Data from Kanbay et al. [28] also indicated that a significant decrease of GFR was detected in severe OSA patients, and they speculate that OSA is an independent risk factor of the progression of CKD. There is accumulating evidence that cystatin C is more sensitive than GFR for estimation of early renal impairment [11, 12]. Several studies focus on cystatin C level in OSA patients. A study from Japan [13] revealed that severe OSA has increasing serum cystatin C levels in patients without CKD. Canales et al. [29] also showed that cystatin C was associated with respiratory disturbance index (RDI) in elderly men, and they indicated that reduced renal function, defined by high cystatin C, might be correlated

Int Urol Nephrol (2014) 46:1997–2002

with sleep-disordered breathing. Our previous studies elucidated that serum cystatin C is associated with the severity of OSA in both young and old adult [14, 15]. We may postulate from all studies mentioned before that there is increasing serum cystatin C level among severe OSA patients, and these patients might develop renal impairment in the near future. Appropriate treatment is warranted for preventing the development in such patients. CPAP is the primary treatment choice for OSA [16]. Several authors have paid their attention to the effects of CPAP on renal function. Early in 1988, Krieger et al. [30] demonstrated that CPAP treatment may decrease urinary flow, sodium and chloride excretion, at the same time increase sodium resorption. A study revealed that the nocturia had been ameliorated by CPAP treatment among 75.3 % (73/97) OSA patients [31]. Recently, a study from Japan found that the serum creatinine decreased and eGFR increased after 3 months of CPAP treatment in 38 OSA men [32]. However, our study was not consistent with their study, the serum creatinine and eGFR did not change after 3 months CPAP treatment. The different eGFR calculating formula, different proportions of the underlying diseases between two studies, and small sample size in both studies may partly explain the discrepancy. Serum cystatin C is known as a novel biomarker of early kidney impairment; however, few study reported the change of cystatin C after CPAP treatment in OSA patients. The present study elucidated that after CPAP therapy, cystatin C levels decreased significantly in severe OSA patients, and we speculated that early renal impairment may be prevented be CPAP treatment. Further large-scale and well-designed study is required to confirm the efficacy of CPAP on early renal impairment in OSA population. There are numerous limitations of our study. Firstly, lacking of a control group, in which patients received sham CPAP, oral appliance or upper airway operation, might influence the judge of the conclusion, Secondly, of the original 265 patients, only 39 subjects completed the study, which may cause potential selection bias. However, the baseline data was similar between the included and excluded subjects (Table 1). Since the CPAP device is not included in health insurance in China, the expenditure of CPAP machine should be paid by patients themselves. High price of CPAP machine results in poor adherence of treatment. Lastly, whether OSA patients develop renal dysfunction in the future needs further investigation, and the long-term effect of CPAP treatment on cystatin C in OSA patients remains unclear. In conclusion, the present study showed that serum cystatin C declined after 3 months of CPAP treatment among severe OSA patients, and we speculate that it may prevent the latent development of renal impairment. Further large-scale investigations are required to figure out the long-term effect of CPAP treatment on this issue.

2001 Acknowledgments This work was supported by grant 2013-2-88 for Youth Research Fund from Fujian Provincial Health Bureau. Conflict of interest of interest.

The authors declare that they have no conflict

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Effect of continuous positive airway pressure on serum cystatin C among obstructive sleep apnea syndrome patients.

The purpose of the present study was to evaluate the influence of continuous positive airway pressure (CPAP) on serum cystatin C, a novel biomarker of...
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