Effects of thrice weekly nocturnal hemodialysis on arterial stiffness

Atherosclerosis 220 (2012) 477–485

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Effects of thrice weekly nocturnal hemodialysis on arterial stiffness Meltem Sezis Demirci a,∗ , Gulperi Celik b , Mehmet Ozkahya a , Murat Tumuklu c , Huseyin Toz a , Gulay Asci a , Soner Duman a , Ali Basci a , Fatih Kircelli a , Oner Ozdogan d , Cenk Demirci a , Levent Can e , Ismet Onder Isik f , Ercan Ok a , On behalf of the ‘Long Dialysis Group’ a

Division of Nephrology, Ege University School of Medicine, Izmir, Turkey Division of Nephrology, Selc¸uklu School of Medicine, Konya, Turkey Department of Cardiology, Kent Hospital, Izmir, Turkey d Department of Cardiology, Tepecik Research and Training Hospital, Izmir, Turkey e Department of Cardiology, Ege University School of Medicine, Izmir, Turkey f Fresenius Medical Care, Kahramanmaras, Turkey b c

a r t i c l e

i n f o

Article history: Received 14 July 2011 Received in revised form 4 November 2011 Accepted 10 November 2011 Available online 19 November 2011 Keywords: Hemodialysis Nocturnal dialysis Arterial stiffness

a b s t r a c t Objective: In this study, we compared the changes in arterial stiffness in chronic hemodialysis patients treated with 8-h vs. 4-h thrice weekly in-center hemodialysis. Methods: Sixty prevalent chronic hemodialysis patients assigned to 8-h nocturnal in-center thrice weekly HD (NHD) and 60 control cases assigned to 4-h thrice weekly conventional HD (CHD) were followed for one year. Radial–carotid pulse wave velocity, augmentation index and echocardiography were performed at baseline and 12th month. Results: Mean age of the patients was 49 ± 11 years, 30.8% were female, 27.5% had diabetes mellitus and mean dialysis vintage was 57 ± 47 months. Baseline demographical, clinical and laboratory parameters were similar between groups. During a mean follow-up of 15.0 ± 0.1 months, blood pressure remained similar in both groups while the number of mean daily anti-hypertensive substances decreased in the NHD group. In the NHD group, time-averaged serum phosphorus and calcium–phosphorus product were lower than the CHD group. Pulse wave velocity and augmentation index decreased in the NHD group (from 11.02 ± 2.51 m/s to 9.61 ± 2.39 m/s and from 28.8 ± 10.3% to 26.2 ± 12.1%; p = 0.008 and p = 0.04, respectively). While augmentation index increased in the CHD group (28.0 ± 9.4 to 31.0 ± 10.7%, p = 0.02), pulse wave velocity did not change. Subendocardial viability ratio and ejection duration improved in the NHD group (from 135 ± 28 to 143 ± 25%, p = 0.01 and from 294 ± 34 ms to 281 ± 34 ms, p = 0.003, respectively), accompanied by regression of left ventricular mass index. In multiple stepwise linear regression analyses, NHD was associated with improvements in augmentation index, ejection duration and subendocardial viability ratio. Conclusions: These data indicate that arterial stiffness is ameliorated by implementation of longer hemodialysis sessions. © 2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Increased arterial stiffness is common in patients with end-stage renal disease (ESRD) and is more pronounced as compared to ageand blood pressure (BP)-matched subjects without kidney disease [1–4]. Increased arterial stiffening leads to vascular dilatation and vascular wall hypertrophy, which is accompanied by an increase in pulse pressure. Increased pulse pressure leads to increment in

∗ Corresponding author at: Ege University School of Medicine, Division of Nephrology, 35100 Bornova Izmir, Turkey. Tel.: +90 232 3904254; fax: +90 232 373 51 21/+90 232 388 92 31. E-mail address: [email protected] (M.S. Demirci). 0021-9150/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2011.11.015

left ventricular afterload and decreased coronary perfusion which predispose to cardiovascular events [5]. The etiology of increased arterial stiffness in ESRD patients is not clear. Multiple factors are proposed including fluid overload, hypertension, increased circulating vasoconstrictors, reduced synthesis or bioavailability of nitric oxide, increased lipid oxidation, increased activation of renin–angiotensin–aldosterone system, over activity of sympathetic nervous system and arterial calcification [6]. It is highly likely that the combination of most, if not all, of these factors contribute to the excessively increase arterial stiffness in ESRD patients. Pulse wave velocity (PWV) and augmentation index (AIx) are non-invasive screening methods used to assess arterial stiffness in clinical studies [7]. Several studies have reported an

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association between these indices and cardiovascular disease including coronary heart disease and stroke in patients with ESRD [8–10]. Improvement of arterial stiffness with different therapeutic approaches, such as volume withdrawal by ultrafiltration [11], long-term administration of fluvastatin [12] or angiotensin II receptor blockers and angiotensin converting enzyme inhibitors [13–16]. PWV decreases after kidney transplantation [17] suggesting a putative link between uremic toxin clearance and attenuation of arterial stiffness in ESRD patients. Higher dialysis dose may control volume overload, improve the uremic milieu, diminish values of inflammatory markers and reduce left ventricular (LV) hypertrophy, thereby reducing the risk of cardiovascular disease. In a randomized trial, Culleton et al. have demonstrated improvement in LV mass in patients on nocturnal hemodialysis (NHD) 6 times weekly compared to conventional hemodialysis (CHD) [18]. The recently published FHN (The Frequent Hemodialysis Network) trial showed that short daily dialysis 6× per week as compared with 3× per week in center hemodialyis resulted in significant improvements in both of the study’s coprimary endpoints, a composite of mortality and change in LV mass and a composite of mortality and physical health [19]. The effects of increased dialysis dose on arterial stiffness markers have not been studied in detail. In this prospective, controlled study, we aimed to examine the effects of longer dialysis time on arterial stiffness in prevalent chronic hemodialysis (HD) patients. We hypothesized that 8-h thrice weekly HD will improve indices of vascular stiffness in chronic HD patients vs. the conventional 4-h thrice weekly HD. In order to test this hypothesis, we performed a subgroup analysis of 120 CHD patients from the “Long Dialysis Study” [20] whom indices of vascular stiffness have been performed at baseline and 12 months.

2. Materials and methods 2.1. Study design The patients enrolled into this study were among participants of the prospective, controlled “Long Dialysis Study” (Clinical trials ID NCT00413803). In brief, 494 prevalent HD patients were subjected to thrice weekly 8-h nocturnal HD (NHD) and thrice weekly 4-h conventional HD (CHD) over 12 months. The details of this study including inclusion and exclusion criteria were published previously [20]. This particular study was conducted in 5 of 10 the HD centers involved in the Long Dialysis Study. There were 237 study participants in these 5 centers: 117 in the NHD and 120 in the CHD groups. Inclusion criterion for the current study was giving informed consent for evaluation of arterial stiffness in addition to the other criteria of “Long Dialysis Study”. Exclusion criteria were recent history of myocardial infarction or stroke within six months, unstable angina pectoris, persistent arrhythmia, advanced heart failure (New York Heart Association III to IV stages) and lack of radial or carotid artery for evaluation of arterial stiffness (technical problems). The baseline arterial stiffness was evaluated in 85 of 117 patients from the NHD group (unwillingness in 18 patients, technical problems in 8, recent occurrence of cardiovascular event in 6) and in 81 of 120 patients from the CHD group (unwillingness in 26 patients, technical problems in 9, recent history of cardiovascular events in 4). The second arterial stiffness evaluation could be not done in 25 of the 85 NHD patients enrolled in this study (discontinuation of NHD in 9 patients, transfer to other dialysis centers in 9, kidney transplantation in 2, unwilling to attend second examination in 5).

Similarly, the second arterial stiffness evaluation was not available in 21 of the 81 CHD patients (transfer to other dialysis centers in 10 patients, death in 3, unwilling to attend second examination in 8). A total of 120 patients (60 in NHD and 60 in CHD group) who had both baseline and final measurements were included in the analyses. The baseline characteristics of patients who dropped out of the study were not different than those of the patients who remained in the study (data not shown). The study protocol was designed, written, edited, and analyzed solely by the study investigators. An independent institution (Data Management Service) in Ege University managed collection and storage of the study data. The protocol was reviewed and approved by the institutional review board and all participants provided written informed consent. 2.2. Arterial stiffness Pulse wave analysis (PWA) and radial carotid PWV were performed at baseline and at 12 months in all subjects. PWA and PWV were assessed by applanation tonometry with the Sphygmocor Vx software (AtCor Medical, Sydney, Australia). Measurements were performed on the radial artery of the non fistula arm and on the carotid artery on a midweek non-dialysis day. Patients abstained from smoking, caffeine, alcohol and food intake for at least 12 h before the measurement. Study physicians measured patients’ BP at the time of the PWA and PWV measurements using an Erka sphygmomanometer. Three BP measurements in the sitting position were taken 5 min apart with the average of the last two measurements being used in the analysis. PWA produces three important indices for clinical cardiovascular evaluation: (1) AIx adjusted to a heart rate of 75 beats per minute, (2) ejection duration (ED, millisecond) and (3) Buckberk Subendocaridal Viability Ratio (SEVR, %) (Supplemental Figure). AIx represents the difference between the first and second systolic peak of the pulse wave contour divided by pulse pressure height. PWV measures the time of the BP wave between two superficial artery sites. A pressure tonometer is used to transcutaneously record the form of the pulse pressure in underlying artery. We performed pressure wave recordings consecutively at the two artery sites. The pressure pulse waveform is recorded simultaneously with an ECG signal, which provides an R-wave timing reference. We used carotid and radial artery sites for PWV measurement. PWV is calculated using the mean time difference (t) and the arterial path distance between the two recording sites (D). PWV = D/t (m/s). Two operators performed all the procedures: intra-operator and inter-operator variability were 3.4% and 4.8%, respectively. 2.3. Echocardiography Echocardiographic examinations were performed according to American Society of Echocardiography recommendations [21,22] on a midweek non-dialysis day (2.5 MHz transducer, Envisor C, Philips) by a single operator. The following measurements were taken: left atrium (LA) diameter, left ventricular end-diastolic and end-systolic diameters, right ventricular end-diastolic diameter, thickness of the posterior wall and the interventricular septum. LV mass was calculated using the equation described by Devereux [23]. LV mass index was calculated by dividing LV mass by body surface area (BSA). Left ventricular systolic function was assessed by left ventricular ejection fraction and fractional shortening. 2.4. Bioimpedance analysis Multifrequency bioimpedance analysis (BIA) (Bodystat Quadscan 4000, Isle of Man, British Isles) was performed on a

M.S. Demirci et al. / Atherosclerosis 220 (2012) 477–485

midweek non-dialysis day. Extracellular water (ECW) measured was adjusted for weight. All BIA measurements were performed by the same operator and intra-observer variability was less than 2%.

2.5. Blood chemistry Blood samples were obtained using uniform techniques under fasting conditions immediately before the patients’ scheduled hemodialysis sessions with the exception of the post-dialysis serum urea. Routine blood chemistries were analyzed using standardized and automated techniques (Architect C8000 autoanalyzer, Abbott, Illinois, USA) at a central laboratory registered to several quality control programs. Blood chemistry analyses including serum urea, creatinine, sodium, potassium, calcium, phosphate, albumin and haemoglobin were performed monthly; calcium–phosphorus product was calculated. Ferritin, high sensitive C-reactive protein (hs-CRP), blood lipids (serum cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein) and parathyroid hormone (PTH) were measured in every three months. Intact PTH was measured by using a second-generation assay (Elecsys 2010, Roche Diagnostics, Mannheim, Germany).

2.6. Dialysis prescription Fresenius 4008S machines were used in both 8-h and 4-h in-center thrice weekly HD. The vast majority of patients had arteriovenous fistulae (94% in the NHD group and 92% in the CHD group). Blood flow rates were 200–250 mL/min in the NHD group and 250–400 mL/min in the CHD group. In both groups, dialysate flow rates were 500 mL/min. Dialysate composition was the same in both groups and contained sodium 138 mmol/L, potassium 2.0 mmol/L, calcium 1.5 mmol/L, bicarbonate 36 mmol/L and glucose 5.5 mmol/L. Standard heparin was used for anticoagulation. The same model of dialyser was used during the study in both groups (High flux, polysulfone, helixone; FX-60 and FX-80, Fresenius Medical Care, Bad Homburg, Germany). Follow-up of the study patients were performed by the same physician at the related dialysis unit, whom were to follow standard operating procedures established by FMC to ensure same standard patient care and adherence to the established guidelines; mainly KDQOI. During the study period, only calcium-based phosphate binders were used in both groups. Phosphate-binding agents and vitamin D were prescribed as needed to control serum phosphorus and PTH levels at recommended targets. After a decrease in phosphate levels was achieved by calcium based phosphate binders, calcitriol was prescribed in the patients with PTH >300. Equilibrated Kt /V urea and urea reduction ratios were calculated using previously described methods [24].

2.7. Study outcomes The primary outcome parameter was change in arterial stiffness parameters over the 12-month study period. Secondary outcome parameters included changes in BP, LV mass index and mineral metabolism. Follow-up visits were performed monthly during the study period. Biochemical parameters were studied monthly, except parathyroid hormone, ferritin, transferrin saturation, lipid parameters and hs-CRP. Mean values of predialysis BP were recorded in all dialysis sessions (12 session/month). All repeated measures of each patient during the study period were averaged for time-averaged data.

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2.8. Statistical analyses Data are presented as mean ± standard deviation (SD). As hsCRP data were not normally distributed, these data were log transformed before being entered into regression model. Categorical data were compared by Chi-square analysis. Student’s t-test and analysis of variance were used for group comparisons. Correlation analysis was performed using Pearson correlation coefficient. The comparisons between baseline and 12th month values were analyzed by a paired t-test for numeric and McNemar for binary data. Baseline and time-averaged values of the two groups were compared using unpaired Student’s t-tests, as appropriate; chisquare test was used for categorical data. We also performed sensitivity analyses using analysis of covariance (ANCOVA), with the 12-month value as the dependent variable and baseline value treated as covariate, to account for differences in baseline measures of primary outcomes. Analyses were adjusted for age, gender, presence or absence of diabetes, systolic and diastolic BP and the baseline level of the factor analyzed. In addition, intention-to-treat analysis was performed for all patients who had at least 1 baseline measurement. The delta () value of the variables was defined at 12th month value minus the baseline value. Multiple stepwise linear regression analyses were used to define independent predictors of change in AIx, ED and SEVR among the significant variables (p < 0.05) identified on simple linear regression analysis. p value of <0.05 (two-sided) was regarded as the limit for statistical significance. SPSS (Chicago, Illinois) for Windows (Version 15.0) was used for statistical analysis. 3. Results 3.1. Patients Baseline demographic characteristics and clinical and laboratory parameters of the study cohort, as well as of both groups are given in Table 1. Mean age of the overall study cohort was 49 ± 11 years (21–70), time on dialysis was 57 ± 47 (median: 49) months. Of these, 30.8% was female, 27.5% was diabetic and 9.1% had history of cardiovascular disease. Mean body mass index was 23.2 ± 4.4 kg/m2 , pre-dialysis systolic and diastolic BP were 127 ± 20 mmHg and 77 ± 9 mmHg, respectively; 32.1% of subjects were on anti-hypertensive substances. The baseline mean AIx and PWV were 28.4 ± 9.8% and 10.86 ± 2.51 m/s, respectively. Mean duration of the HD sessions was 452 ± 19 min in the NHD and 234 ± 9 min in the CHD group (p < 0.001). There were no differences between the groups neither in laboratory parameters nor in arterial stiffness and echocardiographic measurements (Table 1). At baseline, AIx was positively correlated with age (r = 0.216, p = 0.006), systolic BP (r = 0.297, p < 0.001), diastolic BP (r = 0.218, p = 0.006), LA diameter corrected for BSA (r = 0.313, p = 0.003) and LV mass index (r = 0.312, p = 0.002). AIx was negatively correlated with serum albumin (r = −0.259, p = 0.001). PWV was positively correlated with systolic BP (r = 0.219, p = 0.03) and LV mass index (r = 0.208, p = 0.04). Patients with diabetes mellitus had significantly higher mean values of AIx (32.0 ± 7.9% vs. 27.3 ± 10.1%, p = 0.008, respectively) and PWV (11.5 ± 2.9 m/s vs. 10.3 ± 2.0 m/s, p = 0.039, respectively) than patients without diabetes. 3.2. Primary outcome Changes in arterial stiffness parameters are shown in Tables 2 and 3. At 12th months, AIx decreased by a mean (±SD) of 2.6 (±9.6) % in the NHD group and increased by 2.9 (±9.6) % in the CHD group (difference, 5.5%; 95% CI, 1.9–9.0, p = 0.003). This

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Table 1 Baseline characteristics. Variables Age (years) Female (%) Duration of HD (months) Diabetes (%) CVD history (%) Former smoker (%) Current smoker (%) Body mass index (kg/m2 ) Calcium (mg/dL) Phosphate (mg/dL) CaxP product (mg/dL)2 Parathyroid hormone (pg/mL) Albumin (g/dL) hs-CRP (mg/dL) Haemoglobin (g/dL) Total cholesterol (mg/dL) Triglyceride (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Urea reduction rate (%) Equilibrated Kt /V Erythropoietin use (%) Phosphate binders use (%) Vitamin D use (%) Anti-hypertensive use (%) ACE inhibitor or angiotensin II receptor antagonist (%) Calcium channel blocker (%) ␤-Blocker (%) Mean daily number of anti-hypertensive pills Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Pulse pressure (mmHg) Augmentation index (%) Radial–carotid PWV (m/s) Left atrium diameter (cm/m2 ) Left ventricular mass index (g/m2 )

All patients (n = 120) 49 ± 11

Nocturnal HD (n = 60) 48 ± 11

30.8 57 ± 47

± ± ± ± ± ± ± ± ± ± ± ± ± ±

54 ± 43

4. ± 4 0.6 1.2 11 268 0.24 2.10 1.5 40 93 8 34 4.9 0.19

± ± ± ± ± ± ± ±

0.87 20 9 13 9.8 2.51 0.40 46

31.7 59 ± 51

30.0 8.7 13.6 22.0 23.7 8.7 4.8 42 302 3.95 1.56 11.7 178 172 47 95 75.7 1.24

± ± ± ± ± ± ± ± ± ± ± ± ± ±

47 0.6 1.1 11 195 0.21 2.43 1.2 42 96 9 35 4.7 0.18

52 75.6 34.3 32.1 4.8 26.2 6.0 2.00 127 77 49 28.4 10.86 2.31 145

50 ± 9 30.0

27.5 9.1 10.2 30.5 23.2 8.6 4.8 42 328 3.94 1.49 11.7 177 171 46 95 75.2 1.23

Conventional HD (n = 60)

25.0 9.5 6.8 39.0 22.7 8.6 4.8 42 356 3.92 1.43 11.8 175 171 45 95 74.7 1.21

± ± ± ± ± ± ± ± ± ± ± ± ± ±

4.0 0.6 1.2 12 329 0.27 1.70 1.8 39 89 6 32 4.7 0.19

54 75.0 34.0 30.2 4.7 23.3 7.0 1.84 126 77 49 28.8 11.02 2.29 149

± ± ± ± ± ± ± ±

0.68 21 10 13 10.3 2.51 0.44 45

50 76.2 34.5 34.1 4.9 29.3 4.9 2.14 127 77 50 28.0 10.61 2.34 142

± ± ± ± ± ± ± ±

1.02 19 7 13 9.4 2.63 0.36 48

p 0.21 0.84 0.61 0.54 0.89 0.09 0.21 0.58 0.76 0.91 0.28 0.57 0.75 0.68 0.72 0.97 0.16 0.99 0.30 0.30 0.68 0.89 0.95 0.70 0.96 0.53 0.68 0.39 0.78 0.96 0.65 0.67 0.53 0.67 0.54

Abbreviations: HD, hemodialysis; CVD, cardiovascular disease; hs-CRP, high sensitivity C-reactive protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; ACE, angiotensin-converting enzyme; PWV, pulse wave velocity.

difference persisted in multivariate analysis after adjustment for age, gender, presence or absence of diabetes mellitus, the baseline level of AIx and systolic and diastolic BP (difference, 5.0%; 95% CI, 1.6–8.5, p = 0.004). Systolic dysfunction assessed by ED decreased by 12 (±30) ms in the NHD group and increased by 5 (±32) ms in the CHD group (difference, 17 ms; 95% CI, 5.5–28.9, p = 0.004). This difference persisted in multivariate analysis after adjustment for age, gender, presence or absence diabetes, the baseline level of ED and systolic and diastolic BP (difference, 16 ms; 95% CI, 5.6–26.8, p = 0.003). Subendocardial perfusion reflected by SEVR increased by 7 (±24) % in the NHD group and decreased by 2 (±23) % in the CHD group (difference, 10%; 95% CI, 0.4–18.5, p = 0.04). This difference persisted in multivariate analysis with adjustment for age, gender, presence or absence diabetes, the baseline level of SEVR and systolic and diastolic BP (difference, 8%; 95% CI, 0.9–16.0, p = 0.028). These changes were accompanied by a significant regression of LV mass index and LA diameter corrected BSA in the NHD group (adjusted difference 25 g/m2 ; 95% CI 13.0–37.8, p < 0.001 and adjusted difference 0.15 cm/m2 ; 95% CI 0.05–0.24, p = 0.003, respectively) (Tables 2 and 4). Intention-to-treat analysis provided similar results (data not shown). At baseline, the percentage of patients with SEVR <100% was 9.1% in the NHD group and 8.6% in the CHD group (p = 0.930); at 12 months, this rate changed to 1.8% in the NHD and to 13.8% in the CHD groups (p = 0.019). PWV significantly decreased from 11.02 ± 2.51 m/s to 9.61 ± 2.39 m/s in the NHD group (paired t test, p = 0.008) but did not change in the CHD group. The difference

between groups was not statistically significant (p = 0.521) (Table 3). We also investigated predictors for changes in AIx, ED and SVER% by multiple linear regression analysis using the significant variables obtained in univariate correlation analyses (Table 5). In the first model, including significant variables in simple regression model except the treatment variable (NHD vs. CHD), changes in AIx were associated with time-averaged calcium–phosphorus product and the change in LV mass index (LV mass index), changes in ED were only associated with a time-averaged serum phosphorus. Changes in SEVR were associated with age and the change in mean arterial BP (MAP). In model 2, in which the treatment group (CHD = 0 and NHD = 1) was added to model 1, assignment to NHD vs. CHD was associated with changes in AIx (t = −2.19, p = 0.032), ED (t = −2.15, p = 0.034) and SEVR (t = 2.44, p = 0.017). Changes in PWV were associated with changes in MAP (t = 2.81, p = 0.007) and body mass index (t = −2.10, p = 0.041) in the model including the variables age, gender, presence or absence of diabetes, and  LV mass index (R2 of the model was 0.208). BIA measurement could be performed in only 51 patients (27 in the NHD group and 24 in the CHD group). At baseline ECW/weight ratios were similar between groups (0.25 ± 0.030 L/kg in the NHD group and 0.25 ± 0.027 L/kg in the CHD group, p = 0.746). While the mean ECW/weight ratios decreased from 0.25 ± 0.030 L/kg to 0.24 ± 0.027 L/kg in the NHD group (p = 0.011) and it significantly increased in the CHD; from 0.25 ± 0.027 L/kg to 0.26 ± 0.027 L/kg, p < 0.001.

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Table 2 Outcomes for arterial stiffness parameters, blood pressure and echocardiography. Characteristic

NHD (n = 60)

CHD (n = 60)

Between-group comparison (95% CI)

Augmentation index, mean (SD) (%) 28.0 (9.4) 0.8 (−2.8 to 4.4) Baseline 28.8 (10.3) 12th month 26.2 (12.1) 31.0 (10.7) −4.7 (−8.9 to –0.4) Change − 2.6 (9.6) 2.9 (9.6) −5.5 (−9.0 to –1.9)b Ejection duration, mean (SD) (ms) 294 (30) 297 (31) −3 (−14.8 to 8.2) Baseline 282 (34) 302 (34) −20 (−33.2 to −7.7) 12th month 5 (32) −17 (−28.9 to −5.5)b Change −12 (30) Subendocardial viability ratio, mean (SD) (%) 132 (26) 3 (−7.2 to 13.4) Baseline 135 (28) 12th month 143 (25) 130 (26) 13 (2.9 to 22.2) 7 (24) −2 (23) 10 (0.4 to 18.5)a Change Radial–carotid pulse wave velocity, mean (SD) (m/s) 10.6 (2.6) 0.4 (−0.8 to 1.7) Baseline 11.0 (2.5) 12th month 9.6 (2.3) 10.0 (2.2) −0.3 (−1.5 to 0.8) −0.6 (2.6) −0.7 (−2.2 to 0.6) Change −1.4 (2.9) Blood pressure, mean (SD) (mmHg) (at the time of the PWA and PWV measurements) Systolic 126 (21) 127 (19) −1 (−8.3 to 6.3) Baseline 124 (17) 137 (24) −13 (−21.0 to −5.4) 12th month Change −2 (25) 10 (27) −12 (−21.8 to −2.7)a Diastolic 77 (10) 77 (7) 0 (−3.3 to 3.5) Baseline 74 (11) 79 (13) −5 (−9.8 to−0.6) 12th month 2 (13) −5 (−10.7 to 0.0) Change −3 (15) Left ventricular mass index, mean (SD) (g/m2 ) 142 (48) 7 (−11.7 to 26.6) Baseline 149 (45) 12th month 115 (33) 138 (41) −23 (−38.2 to−7.6) Change − 34 (38) −4 (37) −30 (−45.8 to−14.9) c 2 Left atrium diameter, mean (SD) (cm/m ) 2.30 (0.44) 2.34 (0.36) −0.05 (−0.21 to 0.12) Baseline 12th month 2.14 (0.31) 2.34 (0.31) −0.19 (−0.32 to −0.06) Change −0.14 (0.31) 0.00 (0.32) −0.14 (−0.28 to −0.01)a

Adjusted mean difference in change between groupsd

−5.0 (−8.5 to −1.6)b

−16 (−26.8 to −5.6)b

8 (0.9 to 16.0)a

−0.6 (−1.8 to 0.4)

−12 (−20.2 to −4.6)b

−5 (−9.9 to −0.6)a

−25 (−37.8 to −13.0)c

−0.15 (−0.24 to −0.05)b

Abbreviations: NHD, nocturnal hemodialysis; CHD, conventional hemodialysis; CI, confidence interval; PWA, pulse wave analysis; PWV, pulse wave velocity. a p < 0.05 and p > 0.01. b p ≤ 0.01 and p > 0.001. c p < 0.001. d Adjusted for age, gender, presence or absence of diabetes, the baseline level of the factor analyzed and systolic and diastolic blood pressure. Table 3 Changes in arterial stiffness parameters in the NHD and CHD group. Variables

Systolic BP (mmHg) Diastolic BP (mmHg) Pulse pressure (mmHg) Anti-hypertensive drug use (%) Augmentation index (%) Ejection duration (ms) Subendocardial viability ratio (%) Heart rate (beats/min) Radial–carotid PWV (m/s)

NHD (n = 60)

CHD (n = 60)

Baseline

12th month

p

Baseline

12th month

p

126 ± 21 77 ± 10 49 ± 13 30.2 28.8 ± 10.3 294 ± 34 135 ± 28 80 ± 13 11.02 ± 2.51

124 ± 17 74 ± 11a 49 ± 12 13.9b 26.2 ± 12.1a 281 ± 34b 143 ± 25b 80 ± 12 9.61 ± 2.39

0.43 0.13 0.77 0.03 0.04 0.003 0.01 0.83 0.008

127 ± 19 77 ± 7 50 ± 13 34.1 28.0 ± 9.4 297 ± 31 131 ± 28 80 ± 11 10.61 ± 2.63

137 ± 24 79 ± 13 57 ± 18 39.0 31.0 ± 10.7 302 ± 34 130 ± 26 79 ± 13 10.00 ± 2.26

0.008 0.22 0.004 0.48 0.02 0.30 0.69 0.57 0.23

b

Values are presented as mean ± standard deviation. Abbreviations: NHD, nocturnal hemodialysis; CHD, conventional hemodialysis; BP, blood pressure; PWV, pulse wave velocity. p value: within-group values (paired t-test). a p < 0.05 between NHD and CHD. b p < 0.01 between NHD and CHD. Table 4 Changes in echocardiographic parameters in the NHD and CHD group. Variables

NHD (n = 60) Baseline

Left atrium diameter (cm) Left atrium diameter (cm/m2 ) Left ventricular mass index (g/m2 ) Ejection fraction (%)

4.09 2.29 149 62

± ± ± ±

0.68 0.44 45 12

CHD (n = 60) 12th month 3.83 2.15 115 64

± ± ± ±

0.49 0.31a 33b 12

p

Baseline

0.002 0.003 <0.001 0.27

4.0 2.34 142 62

± ± ± ±

0.59 0.36 48 10

12th month 4.00 2.34 138 62

± ± ± ±

0.51 0.31 41 14

p 0.94 0.97 0.48 0.86

Values are presented as mean ± standard deviation. Abbreviations: NHD, nocturnal hemodialysis; CHD, conventional hemodialysis. p value: within-group values (paired t-test). a p < 0.05 between NHD and CHD. b p < 0.01 between NHD and CHD.

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Table 5 Results of simple and multiple regression analyses for change in arterial stiffness parameters. Variables

Univariate correlation analyses

r AIx Age NHD vs. CHD Serum P CaxP Equilibrated Kt /V Albumin log(hs-CRP) MAP LVMI ED Age NHD vs. CHD Serum P CaxP Equilibrated Kt /V albumin log(hs-CRP) MAP LVMI SEVR Age NHD vs. CHD Serum P CaxP Equilibrated Kt /V Albumin log(hs-CRP) MAP LVMI

p

−0.062 0.278 0.241 0.249 −0.280 −0.009 −0.177 0.286 0.359

0.512 0.003 0.010 0.008 0.008 0.926 0.060 0.002 0.000

0.192 0.246 0.218 0.183 −0.236 −0.282 0.255 0.185 0.183

0.038 0.007 0.018 0.048 0.025 0.002 0.006 0.046 0.076

−0.284 −0.185 −0.164 −0.139 0.255 0.161 −0.231 −0.228 −0.217

0.002 0.046 0.077 0.136 0.015 0.082 0.012 0.013 0.034

Stepwise linear regression analyses Model 1

Stepwise linear regression analyses Model 2

ˇ

ˇ

R2 = 0.178 – – NS 0.237a NS – – NS 0.303a R2 = 0.103 NS – 0.321b NS NS NS NS NS – R2 = 0.185 −0.291b – – – NS – NS −0.331b NS

R2 = 0.184 – −0.265a NS NS NS – – NS 0.246a R2 = 0.113 NS −0.222a NS NS NS −0.210a NS NS – R2 = 0.251 −0.263a 0.277a – – NS – NS −0.229a NS

Abbreviations: NHD, nocturnal hemodialysis; CHD, conventional hemodialysis; AIx, Augmentation index; ED, ejection duration; SEVR, subendocardial viability ratio; P, phosphate; CaxP, calcium-phosphate product; hs-CRP, high sensitive C-reactive protein; MAP, mean arterial blood pressure; LVMI, left ventricular mass index. NS: non significant; R2 , multiple coefficient of determination. Model 1: including significant variables in simple regression model except the treatment variable (NHD vs. CHD), Model 2: in which the patient groups (CHD = 0 and NHD = 1) was added to model 1. The table gives standard regression coefficients (ˇ values), Except for age, NHD vs.CHD, change in MAP and LVMI, all values are time averaged. a p < 0.05. b p < 0.01.

3.3. Secondary outcomes At the end of the follow-up, time-averaged level of serum albumin, urea reduction rate, equilibrated Kt /V were significantly higher and time averaged serum levels of phosphorus and calcium–phosphorus product were significantly lower in the NHD group than the CHD group (Table 6). Time-averaged pre-dialysis systolic, diastolic and mean arterial BP remained similar in the NHD and the CHD groups, but use of anti-hypertensive substances decreased from 30.2% to 13.9% in the NHD group (p = 0.03) with no change in the CHD group (from 34.1% to 39%, p = 0.486) (Fig. 1). Similarly, the mean number of antihypertensive medications decreased from 1.84 ± 0.68 to 0.46 ± 0.77 in the NHD group (p < 0.001) and did not change in the CHD group (from 2.14 ± 1.02 to 2.00 ± 1.24, p = 0.165). At 12th month, systolic BP measured at the time of PWA and PWV decreased in patients assigned to NHD by 2 mmHg and increased in patients assigned to CHD by 10 mmHg (mean difference 12 mmHg; 95% CI −2.7 to −21.8, p = 0.012). After adjustment for baseline systolic BP and confounding factors (age, gender, presence or absence of diabetes), this mean difference persisted at 12 mmHg (95% CI −4.6 to −20.2, p = 0.002). Diastolic BP measured at the time of PWA and PWV was not different between groups at the 12th month (p = 0.053). After adjustment for baseline diastolic BP and confounding factors, the mean difference reached statistical significance (mean difference 5 mmHg; 95% CI −0.6 to −9.9, p = 0.026) (Table 2).

Fig. 1. Mean arterial blood pressure and use of blood pressure (BP) medication during the study. During the follow-up, mean arterial BP remained similar in the NHD and CHD groups, but use of anti-hypertensive medication decreased from 30.2% to 13.9% in NHD group (p = 0.03) and did not change in CHD group.

4. Discussion In this prospective study comparing the effects of prolonged dialysis sessions (8-h vs. 4-h) on arterial stiffness in prevalent HD patients, we showed that longer HD sessions significantly

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483

Table 6 Time-averaged data of laboratory parameters. Variables

Nocturnal HD (n = 60)

Conventional HD (n = 60)

p

Calcium (mg/dL) Phosphate (mg/dL) CaxP product (mg/dL)2 Parathyroid hormone (pg/mL) Albumin (g/dL) hs-CRP (mg/dL) Haemoglobin (g/dL) Total cholesterol (mg/dL) Triglyceride (mg/dL) HDL cholesterol (mg/dL) LDL cholesterol (mg/dL) Urea reduction rate (%) Duration of HD sessions (min) Equilibrated Kt /V Erythropoietin use (%, at 12th month) Phosphate binders use (%, at 12th month) Vitamin D use (%, at 12th month) Systolic BP (mmHg) Diastolic BP (mmHg) Pulse pressure (mmHg)

9.00 ± 0.59 3.78 ± 0.91 34 ± 9 305 ± 253 4.03 ± 0.20 1.25 ± 1.23 12.01 ± 1.04 179 ± 37 207 ± 128 47 ± 11 90 ± 29 84.0 ± 4.6 452 ± 19 1.91 ± 0.29 26.7 17.9 48.2 126 ± 15 78 ± 6 47 ± 11

8.80 ± 0.59 5.0 ± 1.13 44 ± 10 394 ± 311 3.96 ± 0.20 1.63 ± 1.63 11.98 ± 1.37 176 ± 35 187 ± 109 45 ± 8 93 ± 26 73.2 ± 5.2 234 ± 9 1.35 ± 0.19 50.1 75.0 51.8 127 ± 14 77 ± 7 49 ± 8

0.07 <0.001 <0.001 0.09 0.04 0.15 0.89 0.64 0.36 0.33 0.57 <0.001 <0.001 <0.001 <0.001 <0.001 0.33 0.61 0.75 0.36

Abbreviations: HD, hemodialysis; hs-CRP, high sensitivity C-reactive protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; BP, blood pressure.

ameliorated arterial stiffness compared to conventional thrice weekly 4-h hemodialysis. PWV and AIx improved only in patients assigned to NHD while AIx increased significantly in patients who remained on CHD. Additionally, LV mass index and LA diameter significantly regressed in patients treated with NHD. We also found that longer dialysis decreased requirement of antihypertensive substances and provided lower serum phosphorus and calcium–phosphorus product than conventional 4-h dialysis. Several factors have been associated with increased arterial stiffness in HD patients, one being hypertension. In a study by Chan et al., normalization of BP was associated with improvement in arterial stiffness during NHD which they attributed to increased clearance of norepinephrine and decreased total peripheral resistance [25]. Another factor postulated to be responsible for increased arterial stiffness are elevated ionized calcium levels [26]. In our study, we did not observe a significant change in calcium levels in NHD group but calcium–phosphorus product significantly decreased as a result of decreased serum phosphorus levels. Similar results were reported in other NHD studies [18,19,27–30]. Vitamin D use was similar in both groups despite reduced serum phosphate levels in the control group; some of the patients with high parathyroid hormone levels could not be prescribed vitamin D due to high serum phosphate levels. Since medial calcification is primarily influenced by the combination of these minerals, this significant attenuation may have had a favorable effect on arterial stiffness. In multiple regression analysis, we found that time-averaged calcium–phosphorus product was associated changes in AIx, but this relationship disappeared after adding the study groups (NHD vs. CHD) and NHD treatment was found as a predictor for improvement of augmentation index, suggesting that this effect may be modulated through better phosphate control, at least partially. Another important factor that may have led to the beneficial effects of prolonged dialysis is marked improvement in hydration status, reflected by a decrease in LA diameter and by the reduction in antihypertensive substances. Overhydration increases the volume load of the heart, which is a risk factor independent of pressure load. Accordingly, one can speculate that increased volume may cause damage to the arteries in a similar way as it causes ventricular hypertrophy. Volume withdrawal observed in HD has been shown to restore arterial wall characteristics back to a more favorable position on the nonlinear pressure–volume curve, reflected by a concomitant decrease in arterial pressure and improved

aortic compliance [11]. In a randomized trial comparing NHD 6 times weekly with 3 times weekly hemodialysis, Culleton et al. showed that frequent NHD improved LV mass and reduced the need for anti-hypertensive substances [18]. While extracellular fluid volume was not measured in that study, the authors speculated that changes in fluid volume may have led to the beneficial changes in LV mass. Also, the recent randomized, controlled FHN trial could show that frequent dialysis was indeed associated with decrease in LV mass assessed by cardiac magnetic resonance imaging together with better control of hypertension and phosphorus levels [19]. These studies have explored potential effects of hemodialysis frequency on different outcomes. Our study is the first study to evaluate the effects of session length against conventional dialysis. The “Long Dialysis Study” [20] and the current study (subgroup of Long Dialysis Study) showed that regression of LV mass index and reduced the need of anti-hypertensive substances were achieved by extending the duration of dialysis to 8 h. As shown in previous studies, better blood pressure control may be related to better volume control and/or also better removal of vasoconstrictors by longer dialysis [18,25]. In our study, the regression of left atrium diameter and LV mass index may be speculated decline in extracellular fluid volume. Indeed, a reduction in extracellular fluid volume was documented in a subgroup of “Long Dialysis Study” by bioimpedance analysis in the NHD group [31]. Analysis performed in the subgroup of patients (n = 51) in our study, whom had both arterial stiffness and bioimpedance analysis measurements available, yielded similar results. The duration of LV systolic ejection and the ‘area under the curve’ (AUC) of the systolic and diastolic portions of the central aortic pulse wave can be measured using PWA. Patients with systolic dysfunction have been found to have a higher ED than those with diastolic dysfunction [32]. The SEVR is a “supply to demand” ratio of the diastolic-AUC divided by the systolic-AUC. The SEVR is usually high (∼130–200%) in normal conditions. However, it may decrease markedly with high heart rates or elevated systolic pressure. Consequently, there is considerable variability in SEVR. However, if low values are consistently found in patients with known coronary artery disease, this may indicate the potential for aggravating subendocardial ischemia due mainly to reduction in diastolic perfusion time [33,34]. Thus, this simple non-invasive measurement may contribute to the decision-making process for specific therapeutic interventions and can be used to investigate patients at risk of ischemic events. Cardiac ischemia and alterations

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in subendocardial perfusion are frequently observed in uremic patients despite patent coronary arteries [35–37]. In our study, at the end of the follow-up, SEVR and ED improved in the NHD group. A value of 100% is often associated with impaired subendocardial blood flow. We showed that the percentage of patients with SEVR <100% was significant decreased in patients assigned to NHD. This would result in better cardiac outcomes. To our knowledge, this is the first prospective, controlled study to examine the effects of longer dialysis on arterial stiffness. We investigated in detail the effects of longer dialysis on arterial stiffness parameters. However, this study is not without limitations. First, while prospective, the design was not randomized because eligible patients were not willing to participate in a randomized clinical trial. Although NHD and CHD groups were well-matched; we cannot exclude the possible role of uncontrollable confounding factors. Second limitation is the high dropout rates in both groups. However, all baseline demographic characteristics were similar in both arms and remained so at the end of the study. Third, we assessed arterial stiffness using the PWV measured from peripheral artery (the radial–carotid) although aortic PWV (the femoral–carotid) as a gold standard. However, in recent study Biagio et al., it was shown that carotid-radial PWV measurement provides an accurate analysis with high reproducibility with respect to carotid-femoral PWV measurement, and it can be used for arterial stiffness analysis in hemodialysis patients [38]. In another recent study, increased carotid-radial PWV is associated with the presence and severity of computed tomography angiography diagnosed coronary artery disease independent of age, gender, and cardiovascular risk factors [39]. Finally, our study population is relatively healthy (younger age, fewer diabetics and patients with a history of cardiovascular disease) and therefore the results may not be applicable to the whole dialysis population. In conclusion, our data demonstrate that arterial stiffness is ameliorated by implementation of longer HD sessions. The improvement in arterial stiffness parameters during extended HD sessions may be mediated by better control of phosphate and extracellular fluid volume suggested by regression of LV mass index and decrease in need for anti-hypertensive substances. Longer term, randomized clinical trials are necessary to examine whether these encouraging results will translate into better hospitalization and death rates. Conflict of interest E.O. is a member of scientific advisory board for Fresenius Medical Care, Turkey. The other authors declare no conflict of interest. This study was supported by the European Nephrology and Dialysis Institution (E.N.D.I., Germany), a public welfare foundation, with an unrestricted grant. The sponsor had no role in study design and conduction, data management, collection and analysis, preparation and submission of the manuscript. Acknowledgments The authors would like to thank Dr. Evert J. Dorhout Mees for peer reviewing the article. M.T. did the echocardiographic measurements and L.C. and O.O. helped with the interpretation of the echocardiographic data and reviewed the parts regarding echocardiographic measurements. The final statistical analysis was performed by Ege University Bioistatistic Department (T.K.). The first draft was written by M.S.D. and thereafter edited by the other co-authors; all the authors reviewed and approved all subsequent drafts and made the decision to submit the manuscript for publication. All authors take the responsibility for the correctness and completeness of the reported data and for the commitment of this

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