Abstract
Background and objectives
Wave reflections and arterial stiffness are independent cardiovascular risk factors in ESRD. Previous studies in this population included only static recordings before and after dialysis. This study investigated the variation of these indices during intra- and interdialytic intervals and examined demographic, clinical, and hemodynamic variables related to arterial function in patients undergoing hemodialysis.
Design, setting, participants, & measurements
Between February 2013 and May 2014, a total of 153 patients receiving maintenance hemodialysis in five dialysis centers of northern Greece underwent ambulatory BP monitoring with the newly introduced Mobil-O-Graph device (IEM, Stolberg, Germany) over a midweek dialysis session and the subsequent interdialytic period. Mobil-O-Graph is an oscillometric device that records brachial BP and pulse waves and estimates, via generalized transfer function, aortic BP, augmentation index (AIx) as a measure of wave reflections, and pulse wave velocity (PWV) as an index of arterial stiffness.
Results
AIx was lower during dialysis than in the interdialytic period of dialysis-on day (Day 1) (mean±SD, 24.7%±9.7% versus 26.8%±9.4%; P<0.001). In contrast, PWV remained unchanged between these intervals (9.31±2.2 versus 9.29±2.3 m/sec; P=0.60). Both AIx and PWV increased during dialysis-off day (Day 2) versus the out-of-dialysis period of Day 1 (28.8%±9.8% versus 26.8%±9.4% [P<0.001] and 9.39±2.3 versus 9.29±2.3 m/sec [P<0.001]). Older age (odds ratio [OR], 1.09; 95% confidence interval [95% CI], 1.02 to 1.15), female sex (OR, 7.56; 95% CI, 1.64 to 34.81), diabetic status (OR, 8.84; 95% CI, 1.76 to 17.48), and higher mean BP (OR, 1.17; 95% CI, 1.09 to 1.27) were associated with higher odds of high AIx; higher heart rate was associated with lower odds (OR, 0.71; 95% CI, 0.63 to 0.80) of high AIx. Older age (OR, 2.04; 95% CI, 1.61 to 2.58) and higher mean BP (OR, 1.15; 95% CI, 1.05 to 1.27) were independent correlates of high PWV.
Conclusions
This study showed a gradual interdialytic increase in AIx, whereas PWV was only slightly elevated during Day 2. Future studies are needed to elucidate the value of these ambulatory measures for cardiovascular risk prediction in ESRD.
Keywords: hemodialysis, PWV, wave reflections, Mobil-O-Graph, interdialytic period
Introduction
Cardiovascular disease (CVD) is the major cause of morbidity and mortality in patients with ESRD (1,2). Arrhythmias and sudden deaths are the most frequent cardiovascular causes of death in hemodialysis, followed by ischemic events (myocardial infarction and stroke) (3). Atherosclerosis of middle-sized conduit arteries only partially explains this elevated CVD risk. The spectrum of arterial remodeling in ESRD is wider and includes the process of arteriosclerosis, characterized by alterations in the viscoelastic properties of large arteries (4,5). The major consequence of arterial stiffness is early return of reflected waves from the periphery to the ascending aorta (during systole rather diastole of the subsequent cardiac cycle), resulting in augmentation of aortic systolic BP (SBP) and pulse pressure (PP) (Figure 1) (6,7). Arterial stiffness is the principal pathogenic mechanism for isolated systolic hypertension, left ventricular hypertrophy, and sudden cardiac death (4,5). Longitudinal studies showed that arterial stiffness and wave reflections are independent cardiovascular risk factors in several populations (8), including patients with ESRD (9,10). Further, aortic BP predicted cardiovascular mortality better than did brachial BP in patients undergoing hemodialysis (11).
Figure 1.
Overlap of forward and backward traveling of pulse waves in the ascending aorta. Under physiologic conditions (i.e., in young individuals with elastic central arteries) the reflected pulse wave returns to the ascending aorta during diastole of the subsequent cardiac cycle. In patients with stiff central arteries (i.e., in the elderly or in patients with ESRD) the higher pulse wave velocity results in premature arrival of the backward-traveling pulse wave (during systole rather diastole), leading to augmentation of aortic systolic and pulse pressure. Vertical lines in the figure represent the end of the systolic phase of cardiac cycle.
In the general population, office BP is an inaccurate measurement compared with home BP or ambulatory BP monitoring (ABPM); similarly, pre- or postdialysis BP recordings in hemodialysis poorly reflect the true BP during the interdialytic period because they are confounded by numerous issues (12–14). Recent data suggest that ambulatory BP in hemodialysis patients shows independent associations with cardiovascular mortality, whereas office BP does not (15). Most experts agree that ABPM (preferably performed during 48 hours) should be widely used in hemodialysis to accurately assess BP control and perform risk stratification (16).
Until recently, assessment of arterial stiffness variables was feasible only in office conditions. Recordings in hemodialysis patients were obtained shortly before and after dialysis; these are subjected to biases related to the high variability of peridialytic BP and may not accurately reflect changes in arterial cushioning function during intra- and interdialytic periods (12,14). Previous studies evaluating changes in wave reflections and arterial stiffness during dialysis had this unavoidable limitation (17–20). This may explain their largely contradictory results, with most studies showing reductions in augmentation index (AIx) during dialysis (17,20) and some also revealing a parallel decrease in pulse wave velocity (PWV) (18), whereas in others PWV remain unchanged (19) or even increased (21).
A newly introduced ABPM device (Mobil-O-Graph; IEM, Stolberg, Germany) records oscillometric BP and pulse waveforms at the brachial artery and provides valid measures of aortic BP, AIx, and PWV in ambulatory conditions (22–24). This study aimed to investigate for the first time the variation of central BP, AIx, and PWV during 48-hour ABPM in hemodialysis patients in order to compare differences in these indices between in-dialysis and out-of-dialysis periods and explore associations of demographic, clinical, and hemodynamic parameters with ambulatory AIx and PWV.
Materials and Methods
Study Participants
This study was conducted in patients with ESRD receiving maintenance hemodialysis in five dialysis centers of northern Greece (AHEPA Hospital, Thessaloniki; Serres General Hospital, Volos General Hospital, Therapeutiki Dialysis Unit, Thessaloniki; and Pieria Dialysis Unit, Katerini) between February 2013 and May 2014. The ethics committee of the School of Medicine, Aristotle University of Thessaloniki, approved the study; all participants provided informed consent before enrollment.
Initial evaluation included medical history, physical examination, and standard laboratory tests. Patients were included if they (1) had ESRD treated by hemodialysis for >3 months; (2) were receiving a standard schedule of three weekly sessions; and (3) provided informed written consent. Patients were excluded if they had (1) chronic atrial fibrillation or other arrhythmia; (2) nonfunctioning arteriovenous fistula in the contralateral arm from that used for dialysis; (3) modification of dry weight or antihypertensive treatment during 1 month before enrollment; (4) myocardial infarction, angina pectoris, and ischemic stroke during the previous month; (5) stage III–IV congestive heart failure, according to New York Heart Association classification; and (6) a history of malignancy or any other condition with poor prognosis.
Data Collection and Patient Evaluation
All data were captured on purpose-built data-collecting sheets. We recorded demographic characteristics, primary cause of ESRD, comorbidities, and dialysis-related variables. Eligible participants came to their unit 1 hour before the midweek dialysis session. After blood sampling, the Mobil-O-Graph monitor with a cuff of appropriate size was fitted in the nonfistula arm and ABPM was started, as described below. Subsequently, all participants underwent their regular dialysis session, during which volume withdrawal was programmed on the basis of their prespecified dry weight, according to standard clinical criteria. Patients were instructed to follow their usual activities until the next session.
A total of 176 patients fulfilled the inclusion/exclusion criteria and volunteered to participate. Of these, valid 48-hour ABPM recordings were initially obtained in 143. Reasons for invalid ABPM were (1) removal of the monitor during the out-of-dialysis period (n=15); (2) >2 nonconsecutive day-hours with fewer than two valid recordings (n=7); (3) >1 night-hour without valid measurement (n=5); and (4) <80% valid recordings during the whole 48-hour period (n=6). Patients with invalid measurements were invited to undertake a second ABPM, after 1 week. Twelve patients accepted and 10 had valid recordings. Thus, a total of 153 patients with a complete dataset were included in the analysis.
ABPM with Mobil-O-Graph Device
Aortic BP, wave reflection, and arterial stiffness were assessed with the Mobil-O-Graph NG. ABPM was performed for 48 hours, including a midweek dialysis session and the subsequent interdialytic interval. The monitor obtained recordings three times per hour from 7:00 a.m. to 10:59 p.m. and two times per hour from 11:00 p.m. to 06:59 a.m. Measurements were used for the analysis if >80% of recordings were valid with ≤2 nonconsecutive day-hours with fewer than two valid measurements, and ≤1 night-hour without valid recording (25).
Mobil-O-Graph records oscillometrically brachial BP; immediately afterward the cuff reinflates at the diastolic phase for approximately 10 seconds and records brachial pulse waves with a high-fidelity pressure sensor (MPX5050; Freescale, Tempe, AZ) (22,24). The BP-detection unit was successfully validated according to standard protocols (26,27). Brachial SBP and diastolic BP (DBP) are used for calibration of the pulse waveform. Mean BP (i.e., the underlying principle of the oscillometric method, defined as the lowest cuff pressure at which the oscillations are maximal) is also estimated. Then, the software (HMS, version 4.5) reconstructs the aortic pulse waveform by means of the ARCSolver algorithm using a generalized transfer function, as previously described (22,24). Wave separation analysis is also performed by decomposing the aortic pulse waveform into forward-traveling (incident) and backward-traveling (reflected) pulse waves with a triangular aortic flow waveform. The device calculates the following:
Augmentation pressure (AP), estimated as the difference in pressure at the second minus pressure at the first inflection point of the systolic phase of pulse wave. The first inflection point reflects the return of reflected waves back to the aorta (22,24).
AIx, and heart rate–adjusted AIx [AIx(75)], defined as the ratio of AP to aortic PP. These indicate the augmentation component of aortic SBP due to the premature arrival of the reflected wave (6).
PWV as a marker of aortic stiffness, estimated from the reconstructed aortic pulse waveform via mathematical models, taking into account the characteristic impedance and age and assuming a three-element Windkessel model (22,24).
Previous validation studies in hypertensive and healthy volunteers showed acceptable agreement between Mobil-O-Graph–derived variables and invasive and noninvasive measurements (24,28–30). In a validation study in hemodialysis patients, Mobil-O-Graph provided estimates of aortic SBP, AIx, and PWV similar to those obtained by SphygmoCor (ArtCor, Sydney, Australia) (31), the most widely applied method for noninvasive assessment of these measures.
The raw dataset obtained by Mobil-O-Graph for each patient was exported to an Excel file for additional analysis (Microsoft Corp., Redmond, WA). We calculated the average values of recorded indices for the whole 48-hour recording, the in-dialysis and out-of-dialysis periods of dialysis-on day (Day 1), and the dialysis-off day (Day 2).
Statistical Analyses
Continuous variables are expressed as the mean±SD and categorical variables as absolute frequencies and percentages. Comparisons between different time periods were performed with a t test for paired samples or with Wilcoxon signed rank tests, where appropriate. Study participants were stratified by tertiles of mean 24-hour AIx and PWV of the dialysis-off day. Differences between groups were evaluated with one-way ANOVA for continuous variables and chi-squared test for categorical variables. Multinominal univariate and multivariate logistic regression analysis were performed to assess the association of demographic, clinical, and hemodynamic parameters with the highest tertile of ambulatory AIx and PWV. Variables were tested for interaction and included in the multivariate models if the P value in the univariate analysis was <0.15. For regression analyses we report crude and adjusted odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs). A P value <0.05 (two-tailed) was considered to denote a statistically significant difference.
Result
Baseline Characteristics of Study Participants
Demographic, clinical, and routine predialysis hematologic and biochemical measures of study participants are depicted in Table 1. A total of 153 patients (89 men and 64 women) with a mean age of 63.0±13.4 years and median dialysis vintage of 27 months were included. One third of study participants were patients with diabetes, 79.7% had hypertension, 22.9% had a history of coronary heart disease (CHD), and 9.2% had cerebrovascular disease.
Table 1.
Baseline characteristics of study participants
| Characteristic | Data |
|---|---|
| Patients (n) | 153 |
| Age (yr) | 63.0±13.4 |
| Men/women (n/n) | 89/64 |
| Body weight (kg) | 73.4±14.8 |
| Height (m) | 1.67±0.1 |
| Body mass index (kg/m2) | 26.6±7.7 |
| Dialysis vintage (mo) | 27 (12, 53) |
| Presence of diabetes, n (%) | 51 (33.3) |
| Presence of hypertension, n (%) | 122 (79.7) |
| Presence of dyslipidemia, n (%) | 41 (26.8) |
| Current smokers, n (%) | 34 (22.2) |
| History of coronary heart disease, n (%) | 35 (22.9) |
| History of cerebrovascular disease, n (%) | 14 (9.2) |
| Hematocrit (%) | 35.0±3.8 |
| Hemoglobin (g/dl) | 11.3±1.3 |
| Serum urea (mg/dl) | 138.0±36.0 |
| Serum creatinine (mg/dl) | 8.2±0.5 |
| Serum calcium (mg/dl) | 8.9±0.7 |
| Serum phosphate (mg/dl) | 5.1±1.5 |
| Parathyroid hormone (ng/L) | 292.0±21.6 |
| Total protein (g/dl) | 7.5±0.6 |
| Serum albumin (g/dl) | 4.0±0.4 |
| Total cholesterol (mg/dl) | 159.4±45.6 |
| LDL cholesterol (mg/dl) | 78.5±30.8 |
| HDL cholesterol (mg/dl) | 48.4±25.6 |
| Triglycerides (mg/dl) | 165.6±48.6 |
| Use of antihypertensive drugs, n (%) | 117 (76.4) |
| Renin inhibitors | 1 (0.7) |
| ACE inhibitors | 9 (5.9) |
| ARBs | 31 (20.3) |
| CCBs | 73 (47.7) |
| Central-acting agents | 28 (18.3) |
| β-blockers | 81 (52.9) |
| No. of antihypertensive drugs | 2 (1, 3) |
| Nitrates, n (%) | 20 (13.1) |
| Loop diuretics, n (%) | 55 (35.9) |
| Statins, n (%) | 65 (42.4) |
Data are presented as mean±SD or absolute and relevant frequencies with the exceptions of dialysis vintage and number of antihypertensive drugs, which are expressed as median (25th, 75th percentile). ACE, angiotensin-converting enzyme; ARBs, angiotensin-receptor blockers; CCBs, calcium channel blockers.
Comparison of ABPM Variables between Intra- and Interdialytic Periods
Brachial and aortic pressures, AIx indices, and PWV for 48 hours and for in-dialysis and out-of-dialysis periods are presented in Table 2. Brachial SBP and PP did not significantly differ between in-dialysis and out-of-dialysis periods of Day 1, whereas DBP was significantly higher during dialysis. Mean BP, aortic and brachial SBP, and PP during the out-of-dialysis period of Day 1 were significantly lower than those during the 24-hour period of Day 2. Diurnal variation of mean BP during the 48-hour recording is presented in Figure 2A. For patients in the morning shift (n=85), mean BP decreased during dialysis and increased afterward until the nighttime period of Day 1. A gradual elevation was evident during the daytime period of Day 2, followed by a dip during nighttime and a peak immediately before the next session. Similar patterns of diurnal variation were observed in patients who underwent dialysis in the midday (n=37) and afternoon (n=31) shifts.
Table 2.
Hemodynamic, wave reflection, and arterial stiffness parameters during the in-dialysis and out-of-dialysis periods of the 48-hour recording
| Variable | 48-hr Period | Dialysis-On Day | P Value | Interdialytic Period | P Value | ||
|---|---|---|---|---|---|---|---|
| In-Dialysis | Out-of-Dialysis | Dialysis-On Day | Dialysis-Off Day | ||||
| Brachial SBP (mmHg) | 131.9±16.7 | 131.8±18.1 | 130.3±18.1 | 0.15 | 130.3±18.1 | 133.6±17.2 | <0.001 |
| Brachial DBP (mmHg) | 78.1±10.6 | 80.7±12.4 | 77.1±11.3 | <0.001 | 77.1±11.3 | 78.3±10.8 | 0.002 |
| Brachial PP (mmHg) | 53.8±12.8 | 51.2±12.4 | 53.2±13.7 | 0.002 | 53.2±13.7 | 55.2±13.0 | <0.001 |
| Mean BP (mmHg) | 102.8±12.2 | 104.1±14.0 | 101.5±13.1 | 0.009 | 101.5±13.1 | 103.6±12.5 | <0.001 |
| Heart rate (beats/min) | 74.2±9.5 | 74.1±11.1 | 74.8±9.8 | 0.12 | 74.8±9.8 | 73.6±9.6 | <0.001 |
| Aortic SBP (mmHg) | 120.1±14.7 | 119.2±16.9 | 118.5±15.7 | 0.47 | 118.5±15.7 | 121.7±15.1 | <0.001 |
| Aortic DBP (mmHg) | 79.7±10.8 | 82.1±12.5 | 78.7±11.4 | <0.001 | 78.7±11.4 | 79.8±11.0 | 0.005 |
| Aortic PP (mmHg) | 40.4±9.4 | 37.1±10.1 | 39.8±10.2 | <0.001 | 39.8±10.2 | 41.9±9.7 | <0.001 |
| AIx (%) | 27.4±9.2 | 24.7±9.7 | 26.8±9.4 | <0.001 | 26.8±9.4 | 28.8±9.8 | <0.001 |
| AIx(75) (%) | 26.6±7.6 | 24.0±8.6 | 26.4±7.8 | <0.001 | 26.4±7.8 | 27.5±8.2 | <0.001 |
| Augmentation pressure (mmHg) | 12.5±6.5 | 10.5±6.6 | 12.1±6.7 | <0.001 | 12.1±6.7 | 13.5±6.8 | <0.001 |
| PWV (m/sec) | 9.35±2.1 | 9.31±2.2 | 9.29±2.3 | 0.60 | 9.29±2.3 | 9.39±2.3 | <0.001 |
Data are presented as mean ± SD. SBP, systolic BP; DBP, diastolic BP; PP, pulse pressure; AIx, augmentation index; AIx(75), heart rate–adjusted AIx; PWV, pulse wave velocity.
Figure 2.
Variation in mean blood pressure, wave reflection and arterial stiffness indices during intra- and interdialytic periods of the 48-hour ambulatory recording for patients in the morning dialysis shift (n=85). Variation in mean BP (MBP) (A); variation in augmentation index (AIx) and in heart rate-adjusted AIx (AIx75) (B) and (C); variation in pulse wave velocity (PWV) (D). Gray shading indicates the in-dialysis period; out-of-dialysis periods of Day 1 and Day 2 are separated by dotted vertical lines.
With regard to wave reflections, AIx, AIx(75), and AP were significantly lower during the intradialytic than the out-of-dialysis period of Day 1 (Table 2). In contrast, PWV did not differ between the in- and out-of-dialysis intervals of Day 1 (9.31±2.2 versus 9.29±2.3 m/sec; P=0.60). During Day 2, AIx, AIx(75), and AP were significantly higher than during the out-of-dialysis period of Day 1, whereas a slight but significant elevation of 0.1 m/sec was observed in PWV. This gradual increase of AIx and AIx(75) between intra- and interdialytic periods was evident for patients in all dialysis shifts (shown for morning shift in Figure 2, B and C). The relatively steady pattern of PWV during the whole 48-hour recording was also evident in all shifts (Figure 2D). Increase in AIx, AIx(75), and AP during Day 2 in comparison to Day 1 was constant during both daytime and nighttime periods. Similarly, PWV was higher during both awake and asleep periods of Day 2 (Supplemental Table 1).
Factors Associated with High Ambulatory AIx during the Dialysis-Off Day
As shown in Table 3, patients within the high tertile of ambulatory AIx were older and more commonly female, and more frequently had diabetes as the primary cause of ESRD than patients in the low tertile. Levels of ambulatory brachial and aortic SBP and PP were significantly higher among patients within the highest AIx tertile, whereas levels of DBP did not differ among AIx groups. Higher AIx was associated with higher levels of PWV and lower levels of heart rate. In contrast, dialysis vintage, interdialytic weight gain, presence of hypertension, dyslipidemia, smoking status, CHD, and cerebrovascular disease did not differ between groups.
Table 3.
Demographic, clinical, and hemodynamic characteristics of study participants according to the tertile of ambulatory augmentation index during the dialysis-off day
| Variable | High Tertile (24-hr AIx >32.3%) | Medium Tertile (24-hr AIx 24.1%–32.3%) | Low Tertile (24-hr AIx <24.1%) | P Value |
|---|---|---|---|---|
| Patients (n) | 51 | 51 | 51 | |
| 24-hr AIx (%) | 39.6±5.1 | 28.4±2.5 | 17.7±4.4 | <0.001 |
| Age (yr) | 69.6±11.7 | 64.5±13.3 | 56.9±15.2 | <0.001 |
| Sex, n (%) | ||||
| Female | 33 (64.7) | 21 (41.1) | 10 (19.6) | <0.001 |
| Male | 18 (35.3) | 30 (58.9) | 41 (80.4) | |
| Body weight (kg) | 69.2±12.8 | 71.7±13.8 | 79.4±15.9 | 0.001 |
| Height (m) | 1.64±0.1 | 1.66±0.2 | 1.71±0.1 | 0.20 |
| Body mass index (kg/m2) | 25.8±5.2 | 26.9±5.4 | 27.0±4.8 | 0.74 |
| Presence of diabetes, n (%) | 26 (50.9) | 15 (29.4) | 10 (19.6) | <0.001 |
| Presence of hypertension, n (%) | 43 (84.3) | 40 (78.4) | 39 (76.4) | 0.54 |
| Presence of dyslipidemia, n (%) | 14 (27.4) | 16 (31.4) | 11 (21.5) | 0.58 |
| Smoking, n (%) | 12 (23.5) | 11 (21.5) | 11 (21.5) | 0.55 |
| History of coronary heart disease, n (%) | 16 (31.3) | 11 (21.5) | 8 (15.6) | 0.12 |
| History of cerebrovascular disease, n (%) | 5 (9.8) | 5 (9.8) | 4 (7.8) | 0.78 |
| Dialysis vintage (mo) | 38.2±5.7 | 36.7±5.1 | 41.2±5.2 | 0.78 |
| Interdialytic weight gain (kg) | 1.2±0.5 | 2.1±0.9 | 2.0±1.0 | 0.21 |
| Primary cause of ESRD, n (%) | ||||
| Diabetic kidney disease | 20 (39.3) | 11 (21.6) | 7 (13.7) | <0.001 |
| Hypertension | 5 (9.8) | 4 (7.8) | 4 (7.8) | |
| GN | 6 (11.7) | 8 (15.8) | 12 (23.5) | |
| Obstructive nephropathy | 4 (7.8) | 4 (7.8) | 2 (3.9) | |
| Polycystic kidney disease | 1 (1.9) | 1 (1.9) | 4 (7.8) | |
| Unknown nephropathy | 15 (29.5) | 23 (45.1) | 22 (43.3) | |
| 24-hr mean BP (mmHg) | 107.2±12.6 | 103.1±11.7 | 100.5±12.6 | 0.02 |
| 24-hr brachial SBP (mmHg) | 141.9±17.2 | 131.6±15.0 | 127.1±16.2 | <0.001 |
| 24-hr brachial DBP (mmHg) | 77.9±10.8 | 78.9±10.7 | 78.1±11.1 | 0.86 |
| 24-hr brachial PP (mmHg) | 64.0±12.7 | 52.7±10.7 | 49.0±10.8 | <0.001 |
| 24-hr aortic SBP (mmHg) | 127.3±15.1 | 120.7±14.4 | 117.1±14.3 | <0.001 |
| 24-hr aortic DBP (mmHg) | 79.4±11.1 | 80.5±10.7 | 79.6±11.3 | 0.88 |
| 24-hr aortic PP (mmHg) | 47.9±10.0 | 40.2±8.8 | 37.5±7.3 | <0.001 |
| 24-hr heart rate (beats/min) | 66.8±7.4 | 74.0±7.6 | 79.8±8.9 | <0.001 |
| 24-hr PWV (m/sec) | 10.4±1.8 | 9.4±2.4 | 8.3±2.1 | <0.001 |
Data are presented as mean ± SD or absolute and relevant frequencies.
In univariate analysis, among the factors studied, older age, female sex, higher mean BP, diabetes, and CHD were associated with higher odds of elevated wave reflections (Table 4). In contrast, higher body weight, height, and heart rate were associated with lower odds of high AIx. Use of renin-angiotensin system blockers, nitrates, and statins had no association with highest AIx tertile. In multivariate logistic regression analysis, older age (OR, 1.09; 95% CI, 1.02 to 1.15), higher mean BP (OR, 1.17; 95% CI, 1.09 to 1.27), female sex (OR, 7.56, 95% CI, 1.64 to 34.81), and diabetic status (OR, 8.84; 95% CI, 1.76 to 17.48) were independently associated with higher odds of elevated wave reflections, whereas higher heart rate was the only variable related to lower odds of high AIx (OR, 0.71; 95% CI, 0.63 to 0.80).
Table 4.
Factors associated with the high tertile of mean ambulatory augmentation index and pulse wave velocity of the dialysis-off day in univariate and multivariate analysis
| Variable | Univariate Analysis | Multivariate Analysis | ||
|---|---|---|---|---|
| Crude OR (95% CI) | P Value | Adjusted OR (95% CI)a | P Value | |
| Factors associated with high ambulatory AIx | ||||
| Age (per year older) | 1.07 (1.04 to 1.10) | <0.001 | 1.09 (1.02 to 1.15) | 0.009 |
| Female sex | 7.52 (3.06 to 18.46) | 0.001 | 7.56 (1.64 to 34.81) | <0.001 |
| Body weight (per kg higher) | 0.95 (0.92 to 0.98) | 0.001 | 0.96 (0.91 to 1.02) | 0.21 |
| Height (per m higher) | 0.96 (0.92 to 0.99) | 0.03 | 1.03 (0.98 to 1.08) | 0.18 |
| Body mass index (per kg/m2 higher) | 0.97 (0.91 to 1.04) | 0.47 | ||
| Dialysis vintage (per month higher) | 0.99 (0.98 to 1.01) | 0.64 | ||
| Presence of diabetes (yes vs. no) | 4.62 (1.86 to 11.46) | 0.001 | 8.84 (1.76 to 17.48) | 0.007 |
| Presence of hypertension (yes vs. no) | 1.39 (0.49 to 3.84) | 0.54 | ||
| Presence of dyslipidemia (yes vs. no) | 1.31 (0.53 to 3.25) | 0.56 | ||
| Smoking (yes vs. no) | 0.72 (0.24 to 2.13) | 0.55 | ||
| History of coronary heart disease (yes vs. no) | 2.14 (0.81 to 5.62) | 0.12 | 1.41 (0.25 to 7.63) | 0.72 |
| History of cerebrovascular disease (yes vs. no) | 1.22 (0.31 to 4.85) | 0.78 | ||
| Interdialytic weight gain (per kg higher) | 0.87 (0.67 to 1.13) | 0.29 | ||
| Primary cause of ESRD | ||||
| Diabetic kidney disease | 2.36 (0.64 to 8.68) | 0.20 | ||
| Hypertension | 1.50 (0.29 to 7.81) | 0.63 | ||
| GN | Reference | |||
| Obstructive nephropathy | 3.00 (0.44 to 20.44) | 0.26 | ||
| Polycystic kidney disease | 0.375 (0.035 to 3.999) | 0.417 | ||
| Unknown nephropathy | 1.568 (0.539 to 4.566) | 0.409 | ||
| 24-hr mean BP (per mmHg higher) | 1.05 (1.01 to 1.08) | 0.008 | 1.17 (1.09 to 1.27) | <0.001 |
| 24-hr heart rate (per beats/min higher) | 0.81 (0.75 to 0.87) | <0.001 | 0.71 (0.63 to 0.80) | <0.001 |
| ACEI or ARB use (yes vs. no) | 1.10 (0.49 to 2.66) | 0.82 | ||
| Nitrate use (yes vs. no) | 0.29 (0.07 to 1.15) | 0.08 | 0.40 (0.03 to 4.93) | 0.47 |
| Statin use (yes vs. no) | 0.85 (0.39 to 1.87) | 0.69 | ||
| Factors associated with high ambulatory PWV | ||||
| Age (per year older) | 1.85 (1.56 to 2.20) | <0.001 | 2.04 (1.61 to 2.58) | <0.001 |
| Female sex | 2.97 (1.30 to 6.78) | 0.01 | 0.57 (0.04 to 7.70) | 0.68 |
| Body weight (per kg higher) | 0.97 (0.94 to 0.99) | 0.03 | 1.01 (0.92 to 1.10) | 0.89 |
| Height (per m higher) | 0.95 (0.91 to 0.99) | 0.02 | 1.01 (0.94 to 1.08) | 0.82 |
| Body mass index (per kg/m2 higher) | 1.03 (0.97 to 1.10) | 0.34 | ||
| Dialysis vintage (per month higher) | 0.99 (0.97 to 0.99) | 0.04 | 1.01 (0.97 to 1.04) | 0.56 |
| Presence of diabetes (yes vs. no) | 7.33 (2.65 to 20.28) | <0.001 | 3.65 (0.32 to 25.15) | 0.29 |
| Presence of hypertension (yes vs.no) | 1.77 (0.69 to 4.58) | 0.24 | ||
| Presence of dyslipidemia (yes vs.no) | 1.49 (0.62 to 3.59) | 0.37 | ||
| Smoking (yes vs.no) | 1.35 (0.51 to 3.54) | 0.54 | ||
| History of coronary heart disease (yes vs.no) | 8.81 (2.40 to 20.76) | <0.001 | 1.39 (0.10 to 13.62) | 0.84 |
| History of cerebrovascular disease (yes vs.no) | 1.57 (0.41 to 5.94) | 0.51 | ||
| Interdialytic weight gain (per kg higher) | 0.93 (0.79 to 1.11) | 0.43 | ||
| Primary cause of ESRD | ||||
| Diabetic kidney disease | 3.49 (0.96 to 12.75) | 0.06 | ||
| Hypertension | 1.82 (0.35 to 9.46) | 0.48 | ||
| GN | Reference | |||
| Obstructive nephropathy | 0.55 (0.11 to 2.73) | 0.46 | ||
| Polycystic kidney disease | 0.73 (0.10 to 5.20) | 0.75 | ||
| Unknown nephropathy | 0.69 (0.24 to 1.99) | 0.45 | ||
| 24-hr MBP (per mmHg higher) | 1.04 (1.01 to 1.07) | 0.03 | 1.15 (1.05 to 1.27) | 0.004 |
| 24-hr heart rate (per bpm higher) | 0.96 (0.92 to 1.01) | 0.06 | 0.99 (0.89 to 1.11) | 0.88 |
| ACEI or ARB use (yes vs. no) | 2.33 (0.92 to 5.89) | 0.07 | 1.55 (0.11 to 21.90) | 0.74 |
| Nitrate use (yes vs. no) | 0.18 (0.01 to 0.42) | 0.007 | 1.27 (0.09 to 22.20) | 0.92 |
| Statin use (yes vs. no) | 1.08 (0.49 to 2.38) | 0.84 | ||
OR, odds ratio; CI, confidence interval; ACEI, angiotensin-converting enzyme inhibitor.
Reference group for the odds ratio: low tertile group.
Factors Associated with High Ambulatory PWV during the Dialysis-Off Day
As shown in Supplemental Table 2, patients in the highest tertile of ambulatory PWV were older, were more commonly female, had longer dialysis vintage, and had higher rates of diabetes and CHD relative to patients in the medium and low tertiles. Ambulatory brachial SBP was higher and DBP lower in the groups with high and medium PWV versus the group with low PWV, resulting in high PP among patients with high PWV. Ambulatory aortic DBP was significantly lower and PP higher among patients in the highest PWV tertile. Factors associated with heightened arterial stiffness in univariate analysis were age, female sex, weight, height, dialysis vintage, diabetic status, history of coronary heart disease, ambulatory mean BP, and use of nitrates (Table 4). After multivariate adjustment, the factors independently associated with higher odds of high PWV were older age (OR, 2.04; 95% CI, 1.61 to 2.58) and higher ambulatory mean BP (OR, 1.15; 95% CI, 1.05 to 1.27).
Discussion
To our knowledge, this is the first study to evaluate wave reflections and arterial stiffness indices during 48-hour ABPM with the newly introduced Mobil-O-Graph device in hemodialysis. The main finding is that AIx and related parameters were lower during the intradialytic period and exhibited a gradual increase during the subsequent interdialytic interval, a pattern that was different from the variation of mean BP. In contrast, PWV remained unchanged between intra- and interdialytic periods of Day 1 and exhibited only a slight elevation of 0.1 m/sec during dialysis-off day. Among several parameters studied, those independently associated with high ambulatory AIx were older age, female sex, diabetes, higher ambulatory mean BP, and lower heart rate. The independent correlates of high PWV were older age and higher mean BP.
Previous studies on arterial stiffness in hemodialysis using static measurements before and after dialysis (17,18,20,21,32), showed reductions in AIx and related measures, and provided contradictory results for PWV changes (18,20,21,32). Estimation of arterial stiffness indexes in these studies relied on peridialytic BP, which exhibits high variability, poor reproducibility, and provides inaccurate estimation of interdialytic ambulatory BP (12,14), the most valid method for BP assessment in hemodialysis (16). The present study overcomes this limitation, showing a gradual interdialytic increase in wave reflections and a steady pattern of PWV during the whole 48-hour recording. These data are consistent with our previous observations that AIx was increased between the start and end of the 3-day and 2-day interdialytic intervals in contrast to aortic and brachial PWV, which remained constant (19,33).
This dissociation between changes in AIx parameters and PWV suggests a differential response of small and large branches of the arterial tree to fluctuations of metabolic and volume-related parameters during intra- and interdialytic intervals (34,35). PWV indicates long-term structural alterations in the viscoelastic properties of arterial wall (4,6); in this context, it seems reasonable to remain unaffected by acute peaks and falls in dialysis-related parameters. In contrast, AIx is an indirect measure of arterial stiffness that is also influenced by reflecting properties of microcirculation, distance of reflecting sites from the ascending aorta and duration of left ventricular ejection (6,7). Thus, AIx measures are more susceptible to acute changes following the variations in volume status, BP, metabolic variables, and perhaps several other dialysis-related variables affecting contractility and tone of peripheral vascular beds (19,34,35).
Data on the prognostic significance of ambulatory AIx and PWV for cardiovascular morbidity and mortality or the clinical significance of their variability in hemodialysis patients are currently absent. However, several indirect findings support that these ambulatory indices may be of major prognostic value. First, several longitudinal studies demonstrated that elevated office AIx and PWV are powerful predictors of cardiovascular outcomes in hemodialysis (5,9,10). Second, office PWV recorded with the Mobil-O-Graph monitor was recently shown to be an independent predictor of mortality in predialysis CKD (36). Most important, ambulatory recording of these measures provides a more precise picture of the effect of impaired arterial cushioning on left ventricular afterload than relevant office measurements, also supporting a clearer prognostic association. This is relevant to the fact that interdialytic ambulatory brachial BP is a much stronger cardiovascular risk predictor than peridialytic BP recordings (15,16).
In an attempt to identify factors determining this arterial cushioning function, we studied the association of several variables with high ambulatory AIx and PWV. Factors associated with high AIx were older age, female sex, diabetes, higher mean BP, and lower heart rate. The shorter average height of women and, hence, the closer proximity between reflecting points and ascending aorta (10,37) may explain why the association with height did not remain significant in multivariate analysis. In contrast, the only factors independently associated with high PWV were age and mean BP. Older age had a dominant effect in multivariate adjustment of factors significantly associated with PWV in univariate analysis, as 1-year age increase was associated with about two times higher adjusted OR of high PWV. This is consistent with the natural course of arteriosclerotic process in ESRD, which is characterized by more pronounced vascular aging compared with the typical age-related arterial hardening in nonrenal populations (4,38).
The different patterns of variation of mean BP and AIx during the 48-hour recording suggest that additional factors affect wave reflections. One would hypothesize that volume status and water accumulation would be the main determinant of this progressive AIx increase. We have previously observed in a mixed linear model analysis that variations in volume status and body weight were the main factors determining changes in wave reflections between and within subsequent dialysis treatments (33). In contrast, in both univariate and multivariate analysis herein, interdialytic weight gain was not associated with high AIx. This can be explained by the fact that in the current study, the dependent variable in analysis was the average 24-hour AIx of dialysis-off day and not the difference of AIx between the start and end of the interdialytic period. The former is expected to be affected by factors that remain stable in the short run, whereas the latter could be affected by interdialytic weight increment.
This work has some limitations. First, Mobil-O-Graph records brachial BP and pulse waves using the oscillometric method; although this differs from the most widely applied technique of applanation tonometry (23), previous validation studies in different populations (including patients with ESRD) showed acceptable agreement between Mobil-O-Graph–derived variables and invasive and noninvasive measurements (23,24,28,30,31). Second, because this was a pilot study, no power estimation was performed before its initiation; we believe, however, that the number of participants, together with the high number of readings (>120) during the 48-hour recordings, provided adequate power. Third, because patient evaluation was performed in a single occasion, any cause-and-effect associations between study variables cannot be established; longitudinal works are needed to better define the factors related to high ambulatory arterial stiffness indexes in ESRD.
In conclusion, the present study appears to be the first to examine the ambulatory variation of arterial stiffness and wave reflection indexes in patients undergoing hemodialysis. It showed a gradual increase in AIx and related variables between intra- and interdialytic periods; in contrast, PWV followed a rather steady pattern during the whole 48-hour recording, exhibiting only a small significant increase during the dialysis-off day. Factors associated with high ambulatory AIx include older age, female sex, diabetic status, mean BP, and low heart rate. In contrast, older age and higher mean BP were the major factor associated with high ambulatory PWV. Future prospective studies are warranted to elucidate the clinical relevance of these ambulatory indices on cardiovascular risk prediction in ESRD.
Disclosures
None.
Supplementary Material
Acknowledgments
The authors thank IEM Healthcare, Germany, for kindly offering two of the Mobil-O-Graph devices used in this study.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
This article contains supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.08180814/-/DCSupplemental.
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