Sleep-Disordered Breathing in Patients with Polycystic Liver and Kidney Disease Referred for Transcatheter Arterial Embolization

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1 Article Sleep-Disordered Breathing in Patients with Polycystic Liver and Kidney Disease Referred for Transcatheter Arterial Embolization Keiichi Sumida,* Junichi Hoshino,* Tatsuya Suwabe,* Takatoshi Kasai, Noriko Hayami,* Koki Mise,* Masahiro Kawada, Aya Imafuku, Rikako Hiramatsu, Eiko Hasegawa, Masayuki Yamanouchi, Naoki Sawa, Koji Narui, Kenmei Takaichi,* and Yoshifumi Ubara* Abstract Background and objectives Sleep-disordered breathing (SDB) is prevalent among patients with CKD, but its prevalence among patients with symptomatic autosomal dominant polycystic kidney disease (ADPKD) and its association with total liver and kidney volume remain unclear. Design, setting, participants, & measurements This study examined the association between height-adjusted total liver and kidney volume (httlkv) and SDB in a cross-sectional study of 304 adult patients with symptomatic ADPKD who were hospitalized at Toranomon Hospital for transcatheter arterial embolization and who underwent pulse oximetry between April 2008 and November SDB was defined as having a 3% oxygen desaturation index of $15 events per hour of sleep. Logistic regression was performed with sex-specific quartiles of httlkv as the main predictor, using patient data and comorbidities as covariates. Results Overall (54.6% women, mean age years, 83.5% on hemodialysis), 177 of 304 patients (58.2%) had SDB. SDB was strongly associated with httlkv quartiles, demonstrating that odds ratios (ORs) and 95% confidence intervals (95% CIs) for SDB were 1.63 (0.76 to 3.48), 2.35 (1.09 to 5.06), and 4.61 (1.98 to 10.7) for httlkv quartiles 2 4(P for trend, P=0.003), respectively. Older age (OR, 1.81 per 10 years; 95% CI, 1.29 to 2.55), male sex (OR, 3.87; 95% CI, 1.96 to 7.66), receiving hemodialysis (OR, 3.46; 95% CI, 1.62 to 12.1), and higher body mass index ($25 kg/m 2 ) (OR, 3.03; 95% CI, 1.08 to 8.52) were also associated with SDB. Conclusions In this highly selected population of patients with symptomatic ADPKD referred for transcatheter arterial embolization, SDB was highly prevalent and independently associated with higher httlkv. Clin J Am Soc Nephrol 10: , doi: /CJN *Nephrology Center, Toranomon Hospital Kajigaya, Kanagawa, Japan; Nephrology Center and Sleep Center, Toranomon Hospital, Tokyo, Japan; and Departments of Cardiology and Cardio-Respiratory Sleep Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan Correspondence: Dr. Keiichi Sumida, Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Kajigaya, Takatsu-ku, Kawasaki, Kanagawa , Japan. k-sumida@ umin.ac.jp Introduction Sleep-disordered breathing (SDB), a disorder characterized by recurrent arousal from sleep and intermittent hypoxemia, is highly prevalent among individuals with CKD, affecting as many as 65% of patients (1 4). Nocturnal intermittent hypoxemia attributable to SDB causes oxidative stress by increasing the generation of reactive oxygen species (ROS), which induces hypoxiainducible factor (HIF)-1a (5), activates the sympathetic nervous system (6) and the renin angiotensin system (7), and promotes vascular inflammation, causing vascular calcification and atherosclerosis (8,9). SDB has also been associated with hypertension (10), left ventricular hypertrophy (11), and cognitive dysfunction (2). Moreover, several basic and clinical studies have demonstrated that SDB contributes to CKD progression (1,4,12,13). Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited renal cystic disease, is characterized by progressive cyst growth in the kidneys and various extrarenal manifestations such as cysts in other organs, intracranial aneurysms, and mitral valve prolapse (14). Some studies of animal models have recently provided evidence for hypoxia as a potentially important pathomechanism in the progression of ADPKD (15 17). In fact, compromised blood flow and a mismatch between expanding cysts and the vascularization of cyst walls in ADPKD engender regional hypoxia and consecutive upregulation of HIF in the cyst epithelium. The activation of the HIF pathway increases pericystic angiogenesis and the expression of several angiogenic factors such as erythropoietin (15,18). Furthermore, systemic and regional hypoxia engender the stabilization of HIF-1a in the cyst epithelium, and promote renal cyst growth attributable to HIF-1a dependent calcium-activated chloride secretion in ADPKD (17,19). Intermittent hypoxia associated with SDB has also been shown to induce HIF-1a protein expression and transactivation in a ROS-dependent manner (20). These experimentally obtained results suggest that some association is apparent between intermittent hypoxia associated with SDB and cyst growth Vol 10 June, 2015 Copyright 2015 by the American Society of Nephrology 949

2 950 Clinical Journal of the American Society of Nephrology through HIF-1a activation as an underlying pathomechanism, even in patients with ADPKD. However, no report to date describes an investigation of their potential association, much less data related to the prevalence of SDB among them. To our knowledge, this cross-sectional study is the largest study ever reported to estimate the prevalence of SDB among patients with ADPKD and to investigate the association between height-adjusted total liver and kidney volume (httlkv) and SDB. Materials and Methods Participants Between April 2008 and December 2013, 384 patients with ADPKD with symptomatic polycystic liver disease and/or polycystic kidney disease were referred to our hospital from various regions throughout Japan to receive either hepatic or renal transcatheter arterial embolization (TAE) treatment. The diagnosis of polycystic liver and kidney was established using computed tomography (CT), magnetic resonance imaging, and ultrasonography with Ravine s revised unified diagnostic criteria (21). Candidates for liver TAE were those who had symptomatic polycystic liver disease attributable to mass effects from hepatic segments that were occupied almost completely by cysts (.90% per segment), but with at least one segment almost intact, maintaining functioning liver parenchyma. Moreover, the selected patients were not candidates for surgery (or had declined other interventions) and had expressed a strong desire for TAE therapy after being fully informed about its risks and having given their consent. The candidates for renal TAE were those who were on maintenance hemodialysis (HD) with daily urinary volume of,500 ml/d, not being good candidates for percutaneous cyst aspiration with or without sclerosis, or for surgery (or having declined other interventions), and having compression symptoms related to enlarged polycystic kidneys. These symptoms include dysphagia, gastroesophageal reflux, early satiety, severe changes in bowel habits, dyspnea, and orthopnea (22). As a routine screening examination for nocturnal intermittent hypoxemia, the 3% oxygen desaturation index (ODI) was measured using pulse oximetry, in principle, for all patients for a median of 6 days (interquartile range, 3 7 days) before TAE treatment, irrespective of their kidney function. Patients with chronic obstructive pulmonary disease, oxygen supplementation or continuous positive airway pressure therapy, or severe liver and/or renal cyst infection were excluded. The final study population included 304 patients with ADPKD for whom complete data of pulse oximetry before TAE and total liver and kidney volume (TLKV) were available (Figure 1). This study was reviewed and approved with a waiver of the requirement to obtain informed consent received from the ethics committee of Toranomon Hospital. Measures Data Collection. Baseline demographic and clinical data, including age, sex, body mass index (BMI), abdominal circumference, smoking history, presence of hypertension, preexisting cardiovascular disease (CVD), use of sleeping pills (benzodiazepines, antidepressants, and nonbenzodiazepine anxiolytics), and TLKV were obtained before TAE treatment. All laboratory data, including serum albumin, Figure 1. Flow chart of the study population. ADPKD, autosomal dominant polycystic kidney disease; TAE, transcatheter arterial embolization. aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, C-reactive protein, and hemoglobin, were collected at the time of admission. All laboratory values were measured using automated standardized methods at our hospital within 24 hours after drawing blood samples. The egfr (in milliliters per minute per 1.73 m 2 ) was calculated using a formula for Japanese patients devised by Matsuo et al. (23). Hypertension was defined as BP$140/90 mmhg using automatic devices in a sitting position, and/ or use of antihypertensive agents. Preexisting CVD included angina pectoris, myocardial infarction, congestive heart disease, and stroke, which were obtained from medical records. An abdominal CT scan was performed for all patients several days before TAE treatment. TLKV was measured using the CT image by skilled research assistants as described previously (22,24,25). It was adjusted for height (httlkv, in cubic centimeters per meter). Briefly, organ volumes were measured from a set of contiguous images by summing the products of the organ areas traced in each CT image and the slice thickness. Pulse Oximetry. Arterial oxygen saturation during sleep was monitored using pulse oximetry (Apnomonitor mini; Chest M.I. Inc., Tokyo, Japan). For HD patients, pulse oximetry was performed over a night of a HD day. Oxygen desaturation was defined as a drop in the arterial oxygen saturation level of $3% from the baseline level. A 3% ODI represented the number of oxygen desaturation events per hour of recording time, as calculated using proprietary computer software supplied with the equipment. The sleep time estimated from pulse oximetry data is often longer than the actual total sleep time. Therefore, all participants completed a sleep diary to exclude the time spent in bed awake from the analysis and minimize potential overestimation of sleep duration. We defined significant SDB as having a 3% ODI of.15 events per hour. Using pulse oximetry, we also recorded the mean oxygen saturation (SaO 2 ) and minimum SaO 2. The degree of sleepiness was assessed using the Epworth Sleepiness Scale (26), which is a simple questionnaire eliciting information about the general level of daytime sleepiness. Lung Function Testing. As lung function tests, we recorded the percent predicted vital capacity (%VC) calculatedasmeasuredvc/predictedvc3100 and percent

3 Clin J Am Soc Nephrol 10: , June, 2015 Sleep-Disordered Breathing in Patients with ADPKD, Sumida et al. 951 predicted forced expiratory volume in 1 second (%FEV 1.0 ) calculated as measured FEV 1.0 /predicted FEV The normal prediction equations of the Japanese Respiratory Society were used to calculate the predicted values for VC and FEV 1.0 (27). Lung function tests were performed using a spirometer (CHESTAC-7800; Chest M.I., Inc.) based on the American Thoracic Society standardization of spirometry (28). At least three maneuvers were performed by each participant (29). The best effort was recorded. The %VC and %FEV 1.0 were measured before TAE. Outcomes and Covariates. Primary outcomes were the prevalence of SBD among patients with ADPKD. The association of httlkv with SDB was examined in a series of logistic regression models with sex-specific quartiles of httlkv (mean httlkv, [range, ], [ ], [ ], and [ ,814.8] cm 3 /m in men and [ ], [ ], [ ], and [ ,197.8] cm 3 /m in women) as the main predictor, and age, sex, HD treatment, BMI, smoking, hypertension, preexisting CVD, use of sleeping pills, serum albumin, C-reactive protein, hemoglobin, and %VC as covariates. Statistical Analyses Data are presented as the number (percentage) for categorical variables and the mean6sd for continuous variables. Categorical variables were analyzed with the chi-squared test or a Fisher s exact test. Continuous variables were compared using t tests, Mann Whitney U tests, ANOVA, or Crustal Wallis tests as appropriate. We divided men and women into quartiles based on httlkv to facilitate interpretation of the results. The respective 25th, 50th, and 75th percentile httlkv cutoff values were , , and, cm 3 /m in men and , , and cm 3 /m in women. Trends in the prevalences of SDB across httlkv quartiles were evaluated using a Jonckheere Terpstra trend test. To examine the association between httlkv and SDB, unadjusted and multivariate logistic regression models were calculated. Multivariate model 1 included variables that were significant in univariate analysis at a P value,0.20: httlkv, age, sex, HD treatment, BMI, serum albumin, C-reactive protein, and hemoglobin. Model 2 included all variables from univariate analysis. To assess the linear trend across the quartile of httlkv, numeric values of the categorical variables were treated as scores and entered as a single continuous variable in the model (P value for trend). Data were missing only for smoking (n=4) and spirometry (n=9). Therefore, all results were analyzed without imputation. Results are presented as odds ratios (ORs) with 95% confidence intervals (95% CIs). For all analyses, P values,0.05 were inferred as significant. Analyses were conducted using Stata/IC software (version 12.1; StataCorp LP). Results Table 1 presents clinical characteristics of patients with ADPKD according to httlkv. Of 304 patients (54.6% women; mean age years), 23 had stages 1 or 2 CKD (egfr$60 ml/min per 1.73 m 2 ) and 27 had stages 3 5 CKD (egfr,60 ml/min per 1.73 m 2 ); 254 were treated with HD (mean vintage years). In higher quartiles of httlkv, significantly higher alkaline phosphatase levels were observed. The proportion of HD patients was almost identical across quartiles of httlkv. Sleep parameters and spirometry data of the patients according to httlkv are shown in Table 2. Overall, the prevalence of patients with SDB as defined by 3% ODI$15 was 58.2%. The mean 3% ODI was Mean SaO 2, minimum SaO 2, and %VC were lower among patients in higher quartiles of httlkv. Figure 2 portrays the distribution of 3% ODI by quartiles of httlkv. The 3% ODI was significantly higher in higher quartiles of httlkv, indicating that higher quartiles of httlkv were associated with greater prevalences of SDB of 43.1%, 55.3%, 60.5%, and 75.0% for quartiles 1 4, respectively (P for trend, P,0.001). We also investigated the association between SDB and covariates obtained using logistic regression models (Table 3). In univariate analysis, higher quartiles of httlkv (quartiles 3 and 4) as well as older age, male sex, receiving HD, higher BMI ($25 kg/m 2 ), and lower hemoglobin level were significantly associated with the presence of SDB. After adjusting for variables that are significant in the univariate model, a stepwise increase in ORs of SDB with incremental increase in quartiles of httlkv remained significant (P for trend, P,0.001; Table 3, model 1). These results seemed similar even after adjusting all variables from the univariate analysis. The ORs for SDB were 1 (reference), 1.63 (95% CI, 0.76 to 3.48), 2.35 (95% CI, 1.09 to 5.06), and 4.61 (95% CI, 1.98 to 10.7) for httlkv quartiles 1 4, respectively (P for trend, P,0.001; Table 3, model 2). In addition to httlkv, older age (OR, 1.81 per 10 years; 95% CI, 1.29 to 2.55), male sex (OR, 3.87; 95% CI, 1.96 to 7.66), receiving HD (OR, 3.46; 95% CI, 1.44 to 8.33), and higher BMI ($25 kg/m 2 )(OR, 4.44; 95% CI, 1.62 to 12.1) were significantly associated with SDB (Table 3, model 2). Discussion This cross-sectional study revealed that SDB is highly prevalent (54.6%) among patients with symptomatic ADPKD. Our study also demonstrated that higher httlkv is independently associated with the presence of SDB among these patients, even after adjusting for their general risk factors and comorbidities. To our knowledge, this report is the first to describe a study investigating the prevalence of SDB and the association between httlkv and SDB among patients with ADPKD. Several earlier studies have demonstrated a significant association between SDB and CKD in both nondialysis and dialysis populations (1 4,21). Roumelioti et al. reported 22.5% and 25.7% prevalences of severe SDB defined as having an apnea/hypopnea index (AHI; number of apnea and hypopnea occurrences per hour of sleep) $30 events per hour using polysomnography (PSG) in a cross-sectional study of 89 patients with advanced CKD (stages 4 5) and 75 HD patients, respectively. They demonstrated that the presence of advanced CKD and receiving HD were associated with 2.4-fold and 2.9-fold higher risks of severe SDB compared with the control group of normal kidney function after adjustment for age, sex, and BMI (30). Masuda et al. assessed 44 of 94 (46.8%) HD patients with SDB defined as a 3% ODI of $5 events per hour using pulse oximetry during a median 55 months of follow-up, and reported

4 952 Clinical Journal of the American Society of Nephrology Table 1. Clinical characteristics of patients with ADPKD according to httlkv Characteristic Total (N=304) Quartile 1 (n=76) a Quartile 2 (n=76) b Quartile 3 (n=76) c Quartile 4 (n=76) d P Value httlkv (cm 3 /m) Men ,0.001 Women ,0.001 httlv (cm 3 /m) Men ,356.1,0.001 Women ,558.5,0.001 httkv (cm 3 /m) Men ,0.001 Women ,0.001 Renal TAE 227 (74.7) 64 (84.2) 61 (80.3) 53 (69.7) 49 (64.5) 0.02 Female sex 166 (54.6) 41 (53.9) 42 (55.3) 41 (53.9) 42 (55.3) 0.99 Age (yr) BMI (kg/m 2 ) ,0.001 Abdominal circumference (cm) ,0.001 Smoking 95 (31.7) 27 (36.5) 25 (32.9) 29 (38.2) 14 (18.9) 0.05 Hypertension 147 (48.4) 34 (44.7) 37 (48.6) 39 (51.3) 37 (48.7) 0.88 Preexisting CVD 75 (24.7) 23 (30.3) 16 (21.1) 18 (23.7) 18 (23.7) 0.60 Use of sleeping pills 114 (37.5) 28 (36.8) 28 (36.8) 35 (46.1) 23 (30.3) 0.25 Ejection fraction (%) Albumin (g/dl) Aspartate aminotransferase (U/L) Alanine aminotransferase (U/L) Alkaline phosphatase (U/L) ,0.001 C-reactive protein (mg/dl) Hemoglobin (g/dl) Kidney function (ml/min per 1.73 m 2 ) 0.02 egfr$60 23 (7.6) 11 (14.5) 2 (2.6) 6 (7.9) 4 (5.3) egfr,60 27 (8.9) 1 (1.3) 8 (10.5) 9 (11.8) 9 (11.8) Dialysis dependent 254 (83.5) 64 (84.2) 66 (86.9) 61 (80.3) 63 (82.9) Values for categorical variables are given as n (%). Values for continuous variables are given as means6sd. Patients are grouped by httlkv as follows: quartile 1,, cm 3 /m (men) and, cm 3 /m (women); quartile 2, cm 3 /m (men) and cm 3 /m (women); quartile 3, cm 3 /m (men) and cm 3 /m (women); and quartile 4, cm 3 /m (men) and cm 3 /m (women). ADPKD, autosomal dominant polycystic kidney disease; httlkv, height-adjusted total liver and kidney volume; httlv, height-adjusted total liver volume; httkv, height-adjusted total kidney volume; TAE, transcatheter arterial embolization; BMI, body mass index; CVD, cardiovascular disease. a Ranges for quartile 1 are as follows: and for men and women, respectively. b Ranges for quartile 2 are as follows: and for men and women, respectively. c Ranges for quartile 3 are as follows: and for men and women, respectively. d Ranges for quartile 4 are as follows: ,814.8 and ,197.8 for men and women, respectively.

5 Clin J Am Soc Nephrol 10: , June, 2015 Sleep-Disordered Breathing in Patients with ADPKD, Sumida et al. 953 Table 2. Sleep parameters and spirometry data according to httlkv Parameter Total (N=304) Quartile 1 (n=76) a Quartile 2 (n=76) b Quartile 3 (n=76) c Quartile 4 (n=76) d P Value 3% ODI (events/h) ,0.001 Sleep time (min) Mean SaO2 (%) Minimum SaO2 (%) Epworth Sleepiness Scale score (n=109) (n=26) (n=24) (n=33) (n=26) 0.56 %VC ,0.001 %FEV (n=295) (n=75) (n=73) (n=72) (n=75) 0.26 Values for continuous variables are given as means6sd. Patients are grouped by quartile of httlkv. httlkv, height-adjusted total liver and kidney volume; ODI, oxygen desaturation index; SaO2, oxygen saturation; %VC, percent predicted vital capacity; %FEV1.0, percent predicted forced expiratory volume in 1 second. a Ranges for quartile 1 are as follows: and for men and women, respectively. b Ranges for quartile 2 are as follows: and for men and women, respectively. c Ranges for quartile 3 are as follows: and for men and women, respectively. d Ranges for quartile 4 are as follows: ,814.8 and ,197.8 for men and women, respectively. SDB as an independent risk factor for cardiovascular events and all-cause mortality in HD patients. They also concluded that ODI assessed by pulse oximetry is a prognostic parameter in HD patients (31). Regarding the progression of CKD, increasing evidence shows hypoxia as a final common pathway to end stage renal failure through tubulointerstitial injury (12). Reports of recent longitudinal clinical studies have described SDB as an independent risk factor of accelerated kidney function loss in patients with CKD (4,13). Sakaguchi et al. investigated 161 nonobese patients with stages 3 4 CKD and found that nocturnal hypoxemia is an independent risk factor of a rapid decline in kidney function (4). Our results demonstrated that receiving HD was significantly associated with higher risk of SDB, whereas the presence of advanced CKD (stages 3 4 of CKD) was not associated with SDB even after reclassifying the CKD stage based on egfr using the Modification of Diet in Renal Disease equation (32), possibly because of the small number of those patients. Although previous studies have addressed the association between SDB and CKD, few reports have described the primary causes of CKD or differentiated the CKD populations according to their primary diseases. To date, no report in the relevant literature has revealed an association between SDB and patients with CKD with ADPKD. In this study, we first described the association of SDB with patients with CKD with ADPKD and the significantly higher 3% ODI in higher quartiles of httlkv among these patients, although the potential mechanism underlying the association between nocturnal intermittent hypoxia associated with SDB and cyst growth remains unknown. In a community-based study, obesity is a major risk factor for SDB, as are male sex, BMI, neck girth, and pauses during breathing and snoring (33). In obese patients, fat accumulation around the abdomen and chest wall contributes to reduced lung volume and respiratory system compliance, promoting small airway closure, thereby causing SDB (34 37). Regarding the association of the respiratory system with SDB, our results show that %VC was not proved to be a significant determinant of the presence of SDB. Previous reports of some studies have described that functional residualcapacity(frc), which is the most important store of oxygen in the body, can decrease exponentially in obese patients, although VC and total lung capacity might remain within normal limits in those patients (38,39). The supine positioning of such patients has been shown to decrease FRC further and to increase the possibility of the tidal volume decreasing within the closing capacity (40). In our study, the highest quartile of sex-specific height-adjusted total liver volume was found to be a significant determinant of SDB, but httlkv remained as a more significant determinant with higher risk of SDB (Supplemental Tables 1 and 2), suggesting that the larger the intra-abdominal total organ volume becomes, the higher the risk of SDB becomes. Although we did not measure FRC, enlarged liver and kidneys, as an independent risk factor in our study, might contribute to the reduction of FRC with decreased mean SaO 2. They are implicated as a mechanism underlying SDB in patients with symptomatic ADPKD. Recent research using animal models implicates hypoxia as a potentially important pathomechanism in the progression of ADPKD (15 17). Compromised blood flow and a mismatch between expanding cysts and the vascularization

6 954 Clinical Journal of the American Society of Nephrology of cyst walls in ADPKD engender regional hypoxia and consecutive upregulation of HIF in the cyst epithelium. The activation of the HIF pathway increases pericystic Figure 2. Distribution of 3% ODI by quartiles of httlkv. The stacked bar graph shows a significantly higher 3% ODI in higher quartiles of httlkv. Patients were grouped by height-adjusted TLKV as follows: quartile 1,, cm 3 /m (men) and, cm 3 /m (women); quartile 2, cm 3 /m (men) and cm 3 /m (women); quartile 3, cm 3 /m (men) and cm 3 /m (women); and quartile 4, cm 3 /m (men) and cm 3 /m (women). a Test for trend across quartiles using the Jonckheere Terpstra trend test. httlkv, height-adjusted total liver and kidney volume; ODI, oxygen desaturation index. angiogenesis and the expression of several angiogenic factors such as erythropoietin (15,18). Furthermore, systemic and regional hypoxia engender the stabilization of HIF-1a in the cyst epithelium, and promote renal cyst growth attributable to HIF-1a dependent calcium-activated chloride secretion in ADPKD (17,19). Intermittent hypoxia associated with SDB has also been shown to induce HIF-1a protein expression and transactivation in a ROS-dependent manner (20). These experimentally obtained results suggest that intermittent hypoxia associated with SDB in patients with ADPKD contributed in part to their cyst growth through HIF-1a activation as an underlying pathomechanism. This study must be interpreted in light of several limitations. First, all study participants were referred to our hospital from various regions throughout Japan for TAE treatment for symptomatic huge polycystic kidneys and/or liver. At our hospital, about 70 patients with ADPKD receive TAE treatment annually. Regarding the source population, a nationwide hospital-based study by Higashihara et al. found that the prevalence of patients with ADPKD in Japan was 117 per million population (41). The mean ages of our population and the population examined in the study by Higashihara et al. were similar ( and years, respectively). Therefore, our study population appears to be representative of Japanese patients with ADPKD with severe polycystic liver and kidneys. Considering these results and Japan s population of 128 million, approximately 0.4% of those patients are estimated as referred for TAE treatment to our hospital in 1 year. However, most patients (83.5%) in our study were on HD. This limited study group might limit Table 3. Unadjusted and multivariate-adjusted odds ratios for sleep-disordered breathing Variable Univariate Model P Value Multivariate Model 1 P Value Multivariate Model 2 P Value httlkv (cm 3 /m) Quartile (reference) 1.00 (reference) 1.00 (reference) (smallest) a Quartile 2 b 1.70 (0.89 to 3.22) (0.87 to 3.86) (0.76 to 3.48) 0.21 Quartile 3 c 2.11 (1.10 to 4.03) (1.19 to 5.36) (1.09 to 5.06) 0.03 Quartile (2.07 to 8.23), (2.41 to 12.4), (1.98 to 10.7),0.001 (largest) d P for trend e,0.001,0.001,0.001 Age (per 10 yr) 1.55 (1.20 to 2.01) (1.25 to 2.43) (1.29 to 2.55) Male sex 3.04 (1.88 to 4.93), (1.78 to 5.93), (1.96 to 7.66),0.001 Receiving 4.61 (2.36 to 8.99), (1.40 to 8.08) (1.44 to 8.33) 0.01 hemodialysis BMI $25 (kg/m 2 ) 3.28 (1.46 to 7.39) (1.53 to 10.8) (1.62 to 12.1) Smoking 1.34 (0.81 to 2.21) (0.37 to 1.44) 0.36 %VC 0.99 (0.97 to 1.00) (0.98 to 1.02) (0.98 to 1.02) 0.92 Data are presented as odds ratios (95% confidence intervals). Adjusted model 1 includes only variables significant at P,0.20 in univariate analysis (variables: httlkv, age, male sex, receiving HD, BMI, albumin, C-reactive protein, hemoglobin, and %VC). Adjusted model 2 includes all variables from the univariate analysis (variables: model 1 plus smoking, hypertension, preexisting CVD, and use of sleeping pills). httlkv, height-adjusted total liver and kidney volume; BMI, body mass index; %VC, percent predicted vital capacity; HD, hemodialysis; CVD, cardiovascular disease. a Ranges for quartile 1 are as follows: and for men and women, respectively. b Ranges for quartile 2 are as follows: and for men and women, respectively. c Ranges for quartile 3 are as follows: and for men and women, respectively. d Ranges for quartile 4 are as follows: ,814.8 and ,197.8 for men and women, respectively. e P for trend across quartiles calculated with the categorical variables of httlkv modeled as a single continuous variable.

7 Clin J Am Soc Nephrol 10: , June, 2015 Sleep-Disordered Breathing in Patients with ADPKD, Sumida et al. 955 the generalizability of our results, rendering them less applicable to other populations with ADPKD such as asymptomatic patients without enlarged liver or kidneys. Second, we did not perform PSG to evaluate nocturnal intermittent hypoxemia. Instead, we simply measured ODI using pulse oximetry to detect SDB. For that reason, we can neither evaluate sleep quality nor differentiate apnea types such as obstructive, central, or mixed type. However, pulse oximetry has been used widely to screen SDB and has been proposed as a simpler alternative to PSG because it is readily available and inexpensive. The validity of a portable pulse oximetry device (Apnomonitor 5; Chest M.I. Inc.) demonstrates that the sensitivity of a 3% ODI$15 to screen for an AHI$15 was 95% and that it can be a sensitive and useful screening device for sleep apnea syndrome, especially in patients with AHI$15 (42). Third, we did not measure the volume status across the quartile of httlkv. Therefore, we were not able to eliminate its effect on SDB in this study. However, we performed pulse oximetry at night after a HD day to minimize the potential effects of fluid overload in HD patients, who constituted most of the study population. Fourth, this study is cross-sectional. It cannot prove a causal relation between the progression of TLKV and the prevalence and severity of SDB. Although multivariate analyses were controlled for important clinical data related to both httlkv and SDB, the possibility of residual confounding from unmeasured or inadequately measured confounders cannot be excluded. To evaluate the effect of TAE treatment on the outcome, the collection of longitudinal follow-up data are ongoing. In conclusion, our results show that SDB is highly prevalent among symptomatic patients with ADPKD, and we also demonstrated that a significant association exists between higher httlkv and SDB, even after adjusting for their general risk factors and comorbidities. Our results suggest that intermittent hypoxia associated with SDB is a significant and novel extrarenal manifestation in patients with ADPKD. Additional prospective and longitudinal studies must be conducted to elucidate evidence of a causal relation between progression of TLKV and SDB among patients with ADPKD. Acknowledgments This study was partially funded by the Okinaka Memorial Institute for Medical Research. Disclosures None. References 1. 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