The Impact of Intradialytic Pedaling Exercise on Arterial Stiffness: A Pilot Randomized Controlled Trial in a Hemodialysis Population

The Impact of Intradialytic Pedaling Exercise on Arterial Stiffness: A Pilot Randomized... Abstract OBJECTIVES Regular exercise is known to reduce arterial stiffness (AS) in hemodialysis patients. However, the impact of a more realistic intradialytic form of exercise, such as pedaling, is unclear. We aimed to examine (i) the effect of intradialytic pedaling exercise on AS over 4 months and (ii) the longer term effect of pedaling on AS 4 months after exercise cessation. METHODS Patients on stable in-center hemodialysis (3 x/week) were randomly assigned 1:1 to either intradialytic pedaling exercise (EX) or to a control group receiving usual hemodialysis (nonEX) for 4 months. At baseline and 4 months, peripheral and central blood pressure (BP) indices, heart rate (HR), augmentation index HR corrected (AIx75), and carotid-femoral pulse wave velocity (cfPWV) were assessed (applanation tonometry). Measurements were repeated in the EX group 4 months postexercise cessation. RESULTS As per protocol analysis was completed in 10 EX group participants (58 ± 17 years, body mass index 26 ± 4 kg/m2) and 10 nonEX group participants (53 ± 15 years, body mass index 27 ± 6 kg/m2). Peripheral and central BP was unchanged in both groups. AIx75 was unchanged in the EX group, however, a significant median increase of 3.5% [interquartile range, IQR 1.0, 8.5] was noted in the nonEX group (P = 0.009). We noted a significantly greater absolute decrease in cfPWV in the EX group compared to controls: −1.00 [IQR −1.95, 0.05] vs. 0.20 [IQR −0.10, 0.90] (P = 0.033). Interestingly, the decrease in cfPWV observed in the EX group was partially reversed 4 months after exercise cessation. CONCLUSION Intradialytic pedaling exercise has a beneficial impact on AS. This relationship warrants further investigation. CLINICAL TRIALS REGISTRATION Trial Number #NCT03027778 (clinicaltrials.gov) arterial stiffness, blood pressure, hemodialysis, hypertension, intradialytic exercise, pedaling exercise, pulse wave velocity Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD) patients on hemodialysis.1,2 Accelerated arterial stiffness (AS) is an independent risk factor for cardiovascular disease, especially in the CKD population, whose arteriosclerosis profile is accelerated compared to healthy aging.3 Therefore, AS can serve as a useful measure to evaluate the progression of vascular damage and cardiovascular disease risk in a hemodialysis population. Carotid-femoral pulse wave velocity (cfPWV) is recognized as the “gold standard” measure of AS.4 The association between cfPWV and vascular calcification is well-established,5 and studies have also indicated a step-wise relationship between cfPWV and the stages of CKD.6,7 Furthermore, augmentation index (AIx), a measure of wave reflection obtained through pulse wave analysis, is another independent predictor of declining renal function in patients with CKD.8,9 A well-designed aerobic exercise program can favorably affect cardiovascular disease risk factors, and regular aerobic exercise improves AS in the general population and patients with CKD.10 However, the arterial health impact of a more realistic intradialytic form of exercise, such as pedaling, remains unclear.5,11,12 Therefore, we aimed to examine the effect of intradialytic pedaling exercise on cfPWV (primary outcome) and other arterial hemodynamic parameters over 4 months. We also aimed to evaluate the longer term effect of pedaling on cfPWV and other arterial hemodynamic parameters 4 months after finishing the exercise intervention, as well as the impact on anthropometric measures, physical function, and routine laboratory blood markers. MATERIALS AND METHODS Ethical approval The study was approved by the McGill University Health Centre (MUHC) ethics board; written informed consent was provided, and our study conformed to the standards of the Declaration of Helsinki.13 Participants We recruited adults with stage 5 CKD, who were on a stable in-center hemodialysis regimen (approximately 4 hours 3 times/week) for ≥12 weeks prior to recruitment. A recent cardiac evaluation (<1 year) was required to ensure adequate cardiac function to undergo the exercise program. Exclusion criteria: (i) any physical or psychological disability that would impact study participation, (ii) serum intact parathyroid hormone >250 pmol/l within 30 days prior, (iii) dysrhythmia or severe cardiac disease or peripheral arterial disease, (iv) severe hyperkalemia (>6.5 mmol/l) for the last 2 weeks, (v) active cancer, (vi) postdialytic systolic blood pressure (BP) ≥160 mm Hg or diastolic BP ≥100 mm Hg within 4 weeks prior, or (vii) anticipated living donor kidney transplant or other planned major surgery over the study duration. Trial design We conducted a pilot multisite, open-label, randomized-controlled clinical trial. Participants were assigned to either intradialytic pedaling exercise (EX) or to a control group receiving usual dialysis (nonEX) for 4 months, using stratified randomization based on age and sex (1:1 allocation ratio). AS, hemodynamic parameters, and other health measures were assessed in both groups within 2 days before and after the intervention. The EX group was also re-assessed 4 months after completing the pedaling intervention to evaluate the sustainability of the pedaling effect. At the end of the 4 months, nonEX participants were given the opportunity to complete 4 months of pedaling following the same protocol as the EX group. They are included in a single-arm subgroup analysis to further examine the impact of pedaling exercise on AS in a larger group of participants who followed the same exercise intervention. Trial procedures Participants engaged in pedaling exercise 3 times/week during dialysis for 4 months. BP and heart rate (HR) were monitored during exercise (data not shown), and exercise time was recorded after each session. Due to the wide range of exercise capacity, participants in the EX group exercised for the amount of time that allowed them to reach the target range of 12–16 out of 20 points (“somewhat hard” to “hard”) on the Borg Rating of Perceived Exertion (RPE) Scale.14 For safety, no patient exercised past the halfway mark of their dialysis session. Exercise compliance for each participant was calculated by dividing the number of dialysis sessions where pedaling was performed by the total number of sessions (48 sessions). AS and hemodynamic parameters were measured in duplicate using applanation tonometry (Sphygmocor XCEL, AtCor Medical, Sydney, Australia), in a semi-supine position (20% inclination).15,16 Using an automated BP cuff, peripheral BP was measured; then by applying a validated generalized transfer function, the central pressure waveform is generated, allowing for measures of central BP, and AIx corrected for a HR of 75 beats/min (AIx75). Measurements of cfPWV were performed using the thigh cuff and carotid tonometry. Participants refrained from caffeine, alcohol, and smoking at least 5 hours prior. Assessments preintervention and postintervention were all conducted prior to starting the mid-week dialysis session. Gait speed was measured as the participant walked a 6-meter course as quickly as possible. The average of 2 timed readings was reported. Grip strength was measured using a hand dynamometer (Lafayette Instrument, Lafayette, IN). Two readings were recorded in each hand, and the highest measure was reported. Laboratory blood parameters including hemoglobin, leukocytes, platelets, serum albumin, serum electrolytes, total calcium, phosphate, parathyroid hormone levels, total cholesterol, triglycerides, high-density lipoprotein-cholesterol (low-density lipoprotein-cholesterol was calculated using the Friedewald formula), iron studies, and ferritin and were assessed at the same time as the baseline and final assessments. Single pool Kt/V was measured to quantify hemodialysis treatment adequacy. All blood analyses were performed at the MUHC Central Laboratories using standard methods. Analytic methods Descriptive statistics were used to summarize participant characteristics using mean and SD, median and interquartile range (IQR), or percentages, as appropriate. Normality was assessed, and parametric or nonparametric tests were used accordingly. Per protocol analyses were performed on participants who completed the study. For our primary analyses, between-group comparisons (EX and nonEX groups) of the absolute difference [postintervention minus preintervention levels] were performed using a one-sided Mann–Whitney test to assess the superiority of pedaling exercise over usual hemodialysis. In secondary analyses, analysis of covariance was used to evaluate between-group comparisons of cfPWV (log-transformed) in a series of models adjusting for different covariates separately to avoid overadjustment, including age, Charlson comorbidity score, and the baseline cfPWV value. Between-group comparisons of baseline values were performed using 2-sided Mann–Whitney test, and within-group comparisons of preintervention and postintervention values with a 2-sided paired Student’s t-test. The level of significance was set at P <0.05 and 95% confidence intervals (CI) were included when parametric tests were performed. SAS version 9.3 was used (SAS Institute, Cary, NC). RESULTS A total of 32 participants were initially randomized. Per protocol analyses were performed in those who completed the intervention (10 in each group) (Table 1). Reasons for drop-out or exclusion are summarized in Figure 1. Participant baseline characteristics including both completers and noncompleters were similar (Supplementary Table 1). Of the 10 participants who completed the pedaling exercise, 8 participants were included at the 8-month follow-up. Table 1. Participant baseline characteristics   Total population (n = 20)  Exercise group (n = 10)  Control group (n = 10)  P value  Age (years)  55.4 ± 16.2  58.2 ± 17.2  52.5 ± 15.4  0.643  Men/women  14/6  7/3  7/3  1.00  Height (cm)  174.9 ± 8.3  172.4 ± 8.4  177.4 ± 7.9  0.168  Weight (kg)  80.9 ± 16.2  76.6 ± 16.9  85.1 ± 15.2  0.353  BMI (kg/m2)  26.4 ± 5.2  25.6 ± 4.3  27.2 ± 6.1  0.436  Waist:hip ratio  0.94 ± 0.11  0.93 ± 0.12  0.95 ± 0.11  0.762  IPAQ (MET-min/week)  480 [0–1440]  480 [0–1440]  480 [0–1440]  0.902  Gait speed (m/s)  0.84 ± 0.27  0.8 ± 0.2  0.9 ± 0.3  0.481  Grip Strength (kg)  24.6 ± 12.0  23.2 ± 10.5  25.9 ± 13.8  0.616  Comorbidities (%)   Coronary artery disease  10  20  0  0.136   Myocardial infarction  5  10  0  0.305   Congestive heart failure  20  20  20  1.00   Cerebrovascular accident  10  10  10  1.00   Peripheral arterial disease  5  0  10  0.304   Chronic obstructive pulmonary disease  15  20  10  0.531   Hypertension  100  100  100  1.00   Diabetes mellitus  35  30  40  0.639   Ever-smoking  45  40  50  0.653   Charlson Comorbidity Score  4.7 ± 1.7  4.6 ± 2.0  5.0 ± 1.4  0.581  Laboratory parameters   Kt/V  1.4 ± 0.3  1.4 ± 0.3  1.5 ± 0.3  0.736   Creatinine (µmol/l)  839.7 ± 281.6  801.6 ± 244.0  877.7 ± 330.9  0.393   Hemoglobin (g/l)  107.1 ± 10.5  109.1 ± 11.1  105.1 ± 10.0  0.382   Leukocytes  6.8 ± 1.9  6.9 ± 1.9  6.6 ± 2.0  0.699   Platelets  174.6 ± 50.1  181.0 ± 35.0  168.1 ± 63.0  0.492   Albumin (g/l)  33.4 ± 4.36  32.3 ± 3.6  34.5 ± 4.9  0.269   Sodium (mmol/l)  136.2 ± 2.35  136.2 ± 3.0  136.1 ± 1.6  0.861   Potassium (mmol/l)  4.6 ± 0.6  4.5 ± 0.3  4.6 ± 0.8  0.672   Total calcium (mmol/l)  2.1 ± 0.3  2.1 ± 0.2  2.2 ± 0.3  0.323   Phosphate (mmol/l)  1.4 ± 0.4  1.5 ± 0.5  1.3 ± 0.4  0.315   PTH (pmol/l)  67.0 [23.8–93.5]  76.2 [47.0–93.5]  52.8 [23.8–67.0]  0.315   Triglycerides (mmol/l)  2.2 [1.1–2.6]  2.3 [1.2–2.6]  1.3 [0.8–2.5]  0.537   LDL (mmol/l)  2.0 ± 0.8  2.1 ± 0.9  2.0 ± 0.9  0.905   HDL (mmol/l)  1.0 ± 0.1  1.0 ± 0.1  1.0 ± 0.1  0.931   Transferrin saturation (%)  0.3 ± 0.1  0.3 ± 0.1  0.3 ± 0.1  0.796   Ferritin (ng/ml)  463 [258.3–612.5]  471.2 [349–683.3]  284.4 [258.4–526.0]  0.604  Medications (%)   Antihypertensive agents (no.)  1.9 ± 1.2  2.45 ± 0.9  1.3 ± 1.2  0.036    ACE inhibitors orARBs  25  30  20  0.606    Calcium channel blockers  45  50  40  0.653    Diuretics  15  30  0  0.060    β-blockers  65  90  40  0.019    α-blockers  15  20  10  0.531    Central agents  15  20  10  0.531   Nitrates  10  10  10  1.00   Acetylsalicylic acid  25  30  20  0.606   Statins  30  30  30  0.361   Phosphate binders  100  100  100  1.00   Supplemental calcium  40  60  20  0.068   sErythropoietin  90  90  90.0  1.00    Total population (n = 20)  Exercise group (n = 10)  Control group (n = 10)  P value  Age (years)  55.4 ± 16.2  58.2 ± 17.2  52.5 ± 15.4  0.643  Men/women  14/6  7/3  7/3  1.00  Height (cm)  174.9 ± 8.3  172.4 ± 8.4  177.4 ± 7.9  0.168  Weight (kg)  80.9 ± 16.2  76.6 ± 16.9  85.1 ± 15.2  0.353  BMI (kg/m2)  26.4 ± 5.2  25.6 ± 4.3  27.2 ± 6.1  0.436  Waist:hip ratio  0.94 ± 0.11  0.93 ± 0.12  0.95 ± 0.11  0.762  IPAQ (MET-min/week)  480 [0–1440]  480 [0–1440]  480 [0–1440]  0.902  Gait speed (m/s)  0.84 ± 0.27  0.8 ± 0.2  0.9 ± 0.3  0.481  Grip Strength (kg)  24.6 ± 12.0  23.2 ± 10.5  25.9 ± 13.8  0.616  Comorbidities (%)   Coronary artery disease  10  20  0  0.136   Myocardial infarction  5  10  0  0.305   Congestive heart failure  20  20  20  1.00   Cerebrovascular accident  10  10  10  1.00   Peripheral arterial disease  5  0  10  0.304   Chronic obstructive pulmonary disease  15  20  10  0.531   Hypertension  100  100  100  1.00   Diabetes mellitus  35  30  40  0.639   Ever-smoking  45  40  50  0.653   Charlson Comorbidity Score  4.7 ± 1.7  4.6 ± 2.0  5.0 ± 1.4  0.581  Laboratory parameters   Kt/V  1.4 ± 0.3  1.4 ± 0.3  1.5 ± 0.3  0.736   Creatinine (µmol/l)  839.7 ± 281.6  801.6 ± 244.0  877.7 ± 330.9  0.393   Hemoglobin (g/l)  107.1 ± 10.5  109.1 ± 11.1  105.1 ± 10.0  0.382   Leukocytes  6.8 ± 1.9  6.9 ± 1.9  6.6 ± 2.0  0.699   Platelets  174.6 ± 50.1  181.0 ± 35.0  168.1 ± 63.0  0.492   Albumin (g/l)  33.4 ± 4.36  32.3 ± 3.6  34.5 ± 4.9  0.269   Sodium (mmol/l)  136.2 ± 2.35  136.2 ± 3.0  136.1 ± 1.6  0.861   Potassium (mmol/l)  4.6 ± 0.6  4.5 ± 0.3  4.6 ± 0.8  0.672   Total calcium (mmol/l)  2.1 ± 0.3  2.1 ± 0.2  2.2 ± 0.3  0.323   Phosphate (mmol/l)  1.4 ± 0.4  1.5 ± 0.5  1.3 ± 0.4  0.315   PTH (pmol/l)  67.0 [23.8–93.5]  76.2 [47.0–93.5]  52.8 [23.8–67.0]  0.315   Triglycerides (mmol/l)  2.2 [1.1–2.6]  2.3 [1.2–2.6]  1.3 [0.8–2.5]  0.537   LDL (mmol/l)  2.0 ± 0.8  2.1 ± 0.9  2.0 ± 0.9  0.905   HDL (mmol/l)  1.0 ± 0.1  1.0 ± 0.1  1.0 ± 0.1  0.931   Transferrin saturation (%)  0.3 ± 0.1  0.3 ± 0.1  0.3 ± 0.1  0.796   Ferritin (ng/ml)  463 [258.3–612.5]  471.2 [349–683.3]  284.4 [258.4–526.0]  0.604  Medications (%)   Antihypertensive agents (no.)  1.9 ± 1.2  2.45 ± 0.9  1.3 ± 1.2  0.036    ACE inhibitors orARBs  25  30  20  0.606    Calcium channel blockers  45  50  40  0.653    Diuretics  15  30  0  0.060    β-blockers  65  90  40  0.019    α-blockers  15  20  10  0.531    Central agents  15  20  10  0.531   Nitrates  10  10  10  1.00   Acetylsalicylic acid  25  30  20  0.606   Statins  30  30  30  0.361   Phosphate binders  100  100  100  1.00   Supplemental calcium  40  60  20  0.068   sErythropoietin  90  90  90.0  1.00  Values expressed as mean ± SD, median [interquartile range] or percentage. Two-sided Mann–Whitney test was used. Abbreviations: ACE, angiotensin converting enzyme; ARBs, angiotensin receptor blockers; BMI, body mass index; HDL, high-density lipoprotein-cholesterol; IPAQ, international physical activity questionnaire; LDL, low-density lipoprotein-cholesterol; MET, metabolic equivalent; PTH, parathyroid hormone. View Large Figure 1. View largeDownload slide Participant flow. Abbreviations: cfPWV, carotid femoral pulse wave velocity, EX group, exercise group; nonEX group, control group. Figure 1. View largeDownload slide Participant flow. Abbreviations: cfPWV, carotid femoral pulse wave velocity, EX group, exercise group; nonEX group, control group. We observed no significant between-group differences in demographic characteristics, anthropometrics, physical function, comorbidities, medications, or laboratory parameters (Table 1). Furthermore, baseline vessel hemodynamics were not significantly different between the groups, with the exception of a higher aortic pulse pressure in the EX group than in the nonEX group (Table 2). A higher pulse pressure was also noted in the EX group when noncompleters were also included (Supplementary Table 2). Changes in the number and dose of medications were minimal; one EX group participant received a dose increase of an antihypertensive agent (clonidine), and a nonEX participant started a calcimimetic agent and received an increased dose of an angiotensin receptor blocker. Table 2. Baseline arterial stiffness and hemodynamic parameters   Exercise group (n = 10)  Control group (n = 10)  P value exercise vs. control  Interdialytic weight gain (kg)  1.8 [0.5, 2.2]  2.0 [1.6, 2.4]  0.481  Peripheral SBP (mm Hg)  148 [135, 166]  134 [129, 141]  0.271  Peripheral DBP (mm Hg)  77 [69, 85]  83 [77, 86]  0.470  Central SBP (mm Hg)  131 [122, 148]  122 [117, 126]  0.224  Central DBP (mm Hg)  79 [71, 86]  85 [78, 87]  0.567  Central PP (mm Hg)  53 [45, 66]  37 [32, 54]  0.045  MAP (mm Hg)  98 [91, 110]  101 [93, 103]  0.984  cfPWV (m/s)  8.2 [7.3, 9.8]  8.6 [7.2, 9.2]  0.739  HR (bpm)  67 [60, 81]  75 [69, 78]  0.315  AIx75 (%)  24 [19, 26]  22 [15, 28]  0.448    Exercise group (n = 10)  Control group (n = 10)  P value exercise vs. control  Interdialytic weight gain (kg)  1.8 [0.5, 2.2]  2.0 [1.6, 2.4]  0.481  Peripheral SBP (mm Hg)  148 [135, 166]  134 [129, 141]  0.271  Peripheral DBP (mm Hg)  77 [69, 85]  83 [77, 86]  0.470  Central SBP (mm Hg)  131 [122, 148]  122 [117, 126]  0.224  Central DBP (mm Hg)  79 [71, 86]  85 [78, 87]  0.567  Central PP (mm Hg)  53 [45, 66]  37 [32, 54]  0.045  MAP (mm Hg)  98 [91, 110]  101 [93, 103]  0.984  cfPWV (m/s)  8.2 [7.3, 9.8]  8.6 [7.2, 9.2]  0.739  HR (bpm)  67 [60, 81]  75 [69, 78]  0.315  AIx75 (%)  24 [19, 26]  22 [15, 28]  0.448  Values expressed as median [interquartile range]. One-sided Mann–Whitney test was used. Bolded values indicate significance (P < 0.05). Abbreviations: AIx75, augmentation index (corrected for a heart rate of 75 beats/min); cfPWV, carotid femoral pulse wave velocity; DBP, diastolic blood pressure; HR, heart rate; MAP, mean arterial pressure; SBP systolic blood pressure. View Large Exercise compliance Median exercise compliance in the EX group was 60% [IQR 42–79] and median exercise time per session was 42.6 minutes [IQR 31.2–60.0]. Over the intervention, the median total exercise time was 18.5 hours [IQR 10.5–28.5] per participant. Safety and adverse events No adverse events occurred during exercise. Two withdrawals from the exercise intervention were due to health complications, unrelated to the exercise. One participant withdrew for cardiac bypass surgery, and subsequent postoperative complications led to death; however, this was not related to the exercise. There was one case of ischemic stroke, but the episode occurred 10 days after cessation from the exercise program. Postintervention changes Vessel hemodynamics. Peripheral and central BP were unchanged after the intervention in both the EX and nonEX groups (Table 3). We observed a significantly greater absolute decrease in cfPWV in the EX group compared to the nonEX group (P = 0.033): −1.00 [IQR −1.95, 0.05] vs. 0.20 [IQR −0.10, 0.9] (Figure 2). Furthermore, AIx75 was unchanged in the EX group; however, a significant median increase of 3.5% (IQR 1.0, 8.5) was noted in the nonEX group (between-group P = 0.009). We also noted a greater reduction in HR in the EX group postintervention, compared to the nonEX group (P = 0.029). Table 3. Between-group comparisons of postexercise changes in arterial stiffness and hemodynamic parameters   Exercise group (n = 10)  Control group (n = 10)  P value exercise vs. control  ∆ BMI (kg/m2)  0.28 [−0.23, 0.95]  0.20 [−0.03, 0.45]  0.485  ∆ Waist:hip ratio  0.03 [0.01, 0.03]  −0.00 [−0.03, 0.01]  0.022  ∆ Interdialytic weight gain (kg)  −0.6 [−0.6, 1.1]  −0.1 [−0.6, 0.9]  0.309  ∆ Gait speed (m/s)  0.02 [−0.02, 0.11]  −0.11 [−0.17, 0.08]  0.158  ∆ Grip strength (kg)  1.3 [−0.5, 6.5]  2.5 [−0.5, 4.0]  0.464  ∆ Peripheral SBP (mm Hg)  −10.0 [−21.5, 4.0]  −0.3 [−5.0, 6.5]  0.128  ∆ Peripheral DBP (mm Hg)  −5.3 [−11.0, 8.5]  0.5 [−1.0, 11]  0.092  ∆ Central SBP (mm Hg)  −10.0 [−16.0, 3.5]  1.0 [−2.5, 11.5]  0.099  ∆ Central DBP (mm Hg)  −6.0 [−10, 6.0]  −2.0 [−1.0, 12.0]  0.136  ∆ Central PP (mm Hg)  −6.5 [−9.5, 6.0]  −3.3 [−4.5, 6.0]  0.105  ∆ MAP (mm Hg)  −9.0 [−15.0, 4.0]  2.0 [−1.5, 9.5]  0.162  ∆ cfPWV (m/s)  −1.0 [−2.0, 0.5]  0.20 [−0.1, 0.9]  0.033  ∆ AIx75 (%)  −2.0 [−4.5, 1.0]  3.5 [1.0, 8.5]  0.009  ∆ HR (bpm)  −3.8 [−6.5, −1.0]  1.5 [−1.0, 6.5]  0.014    Exercise group (n = 10)  Control group (n = 10)  P value exercise vs. control  ∆ BMI (kg/m2)  0.28 [−0.23, 0.95]  0.20 [−0.03, 0.45]  0.485  ∆ Waist:hip ratio  0.03 [0.01, 0.03]  −0.00 [−0.03, 0.01]  0.022  ∆ Interdialytic weight gain (kg)  −0.6 [−0.6, 1.1]  −0.1 [−0.6, 0.9]  0.309  ∆ Gait speed (m/s)  0.02 [−0.02, 0.11]  −0.11 [−0.17, 0.08]  0.158  ∆ Grip strength (kg)  1.3 [−0.5, 6.5]  2.5 [−0.5, 4.0]  0.464  ∆ Peripheral SBP (mm Hg)  −10.0 [−21.5, 4.0]  −0.3 [−5.0, 6.5]  0.128  ∆ Peripheral DBP (mm Hg)  −5.3 [−11.0, 8.5]  0.5 [−1.0, 11]  0.092  ∆ Central SBP (mm Hg)  −10.0 [−16.0, 3.5]  1.0 [−2.5, 11.5]  0.099  ∆ Central DBP (mm Hg)  −6.0 [−10, 6.0]  −2.0 [−1.0, 12.0]  0.136  ∆ Central PP (mm Hg)  −6.5 [−9.5, 6.0]  −3.3 [−4.5, 6.0]  0.105  ∆ MAP (mm Hg)  −9.0 [−15.0, 4.0]  2.0 [−1.5, 9.5]  0.162  ∆ cfPWV (m/s)  −1.0 [−2.0, 0.5]  0.20 [−0.1, 0.9]  0.033  ∆ AIx75 (%)  −2.0 [−4.5, 1.0]  3.5 [1.0, 8.5]  0.009  ∆ HR (bpm)  −3.8 [−6.5, −1.0]  1.5 [−1.0, 6.5]  0.014  Values expressed as median [interquartile range]. ∆ indicates absolute difference (postintervention minus preintervention levels). Bolded values indicate significance (P < 0.05). One-sided Mann–Whitney test was used. Within-group comparisons are included in Supplementary Table 5. Abbreviations: AIx75, augmentation index (corrected for a heart rate of 75 beats/min); BMI, body mass index; cfPWV, carotid femoral pulse wave velocity; DBP, diastolic blood pressure; HR, heart rate; MAP, mean arterial pressure; SBP, systolic blood pressure. View Large Figure 2. View largeDownload slide Absolute change from baseline in cfPWV, AIx75, and heart rate at 4 months. Abbreviations: AIx75, augmentation index corrected for a heart rate of 75 beats/min; cfPWV, carotid femoral pulse wave velocity; HR, heart rate. Figure 2. View largeDownload slide Absolute change from baseline in cfPWV, AIx75, and heart rate at 4 months. Abbreviations: AIx75, augmentation index corrected for a heart rate of 75 beats/min; cfPWV, carotid femoral pulse wave velocity; HR, heart rate. To account for the small size of our pilot RCT and possible imbalances in characteristics due to drop-outs after randomization, we performed additional adjusted analyses for potential confounding variables. In three separate models after adjustments for two potential confounders, age and the Charlson comorbidity score, as well as the baseline cfPWV value, the decrease in cfPWV approached significance in the EX group (model 1: age, baseline cfPWV value, P = 0.055; model 2: Charlson comorbidity score and baseline cfPWV value, P = 0.059; model 3: age, Charlson comorbidity score, and baseline cfPWV value P = 0.067). Due to considerable skewness, normality could not be achieved with data transformations for AIx75 or HR, preventing adjusted analyses for these parameters. In a single-arm secondary analysis that included 5 additional control arm participants who subsequently underwent the exercise intervention (total n = 15), we also found a significant lowering of cfPWV by −0.96 ± 1.32 m/s (95% CI −1.7 to −0.23, P = 0.014). No conclusive changes were noted for the other hemodynamic parameters (Supplementary Table 3). Physical function and laboratory parameters Postintervention changes in gait speed and grip strength were minimal and were not significantly different between EX and nonEX participants (Table 3). We did not observe any between-group differences in any of the laboratory blood markers in either group over the intervention period (data not shown). Postexercise cessation follow-up cfPWV at the follow-up evaluation in the EX group (mean ± SD: 8.2 ± 1.3 m/s, 95% CI 7.1 to 9.3) was intermediate between the baseline (8.6 ± 2.3 m/s, 95% CI 6.7 to 10.4) and postintervention values (7.4 ± 1.6 m/s, 95% CI 6.2 to 8.6) (Figure 3). We noted a similar observation for an intermediate value at 8 months for peripheral BP and pulse pressure, HR, and AIx75 (Figure 3). Data for all parameters is displayed in Supplementary Table 4. Figure 3. View largeDownload slide Exercise group: cfPWV and other hemodynamic parameters at baseline, postexercise, and 4 months after exercise cessation. Abbreviations: AIx75, augmentation index corrected for a heart rate of 75 beats/min; cfPWV, carotid femoral pulse wave velocity; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure. Figure 3. View largeDownload slide Exercise group: cfPWV and other hemodynamic parameters at baseline, postexercise, and 4 months after exercise cessation. Abbreviations: AIx75, augmentation index corrected for a heart rate of 75 beats/min; cfPWV, carotid femoral pulse wave velocity; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure. DISCUSSION This pilot study demonstrated that intradialytic pedaling exercise leads to a significant improvement in cfPWV, the “gold standard” measurement of AS. Importantly, the magnitude of this reduction (−1 m/s) is considered clinically relevant; a 1 m/s increase in cfPWV is associated with a 15% increased risk of cardiovascular events, and mortality.17 Specifically, in hemodialysis patients, a 1 m/s increase in cfPWV corresponds to a 39% increased risk in all-cause mortality (adjusted relative risk 1.39, 95% CI 1.19 to 1.62).3 Interestingly, the improvement in cfPWV after pedaling exercise was observed in the absence of significant changes in BP, physical function, body mass index, or lipids. Our secondary analyses further support the beneficial impact of intradialytic pedaling on cfPWV. In a single-arm subgroup analysis that included 5 additional participants who performed the pedaling intervention, we demonstrated a significant decrease in cfPWV of similar magnitude (−0.96 m/s). We also demonstrated that exercise cessation leads to a partial reversal of cfPWV 4 months later. Although pedaling exercise did not significantly change AIx75, a surrogate measure of systemic stiffness, we noted a significant median increase of 3.5% in the control group. Interestingly, we observed significantly lower resting HR in response to 4 months of pedaling. Few studies have examined the arterial health impact of aerobic exercise.10,12,18 Among them, Mustata et al. found an improvement in AIx after 3 months of supervised aerobic exercise using a treadmill or recumbent bike (2 sessions of 60 minutes/week) in 11 hemodialysis patients at a cardiac rehabilitation centre.12 More recently, they found similar reductions in AIx in response to supervised and home exercise (3 sessions of 60 minutes/week) in 20 predialysis patients.10 Although both interventions have demonstrated improvements in AIx, supervised aerobic exercise programs requiring specialized equipment are resource intensive and difficult to maintain in the longer term. Intradialytic exercise has the advantage of being performed in a supervised setting, requires no additional time commitment outside of dialysis, and is considered feasible for the many hemodialysis patients with functional limitations that would prevent more rigorous forms of aerobic exercise.19 As such, it has been proposed as a realistic means to help patients achieve the arterial health benefits of increased physical activity; however, the results to date have been inconclusive. Our study is the first to show important promise for arterial health benefit by significantly lowering cfPWV. These findings support those of Toussaint et al. who observed a decrease in cfPWV after 3 months of intradialytic pedaling exercise (n = 9) that approached significance (P = 0.07); however, they did not compare the cfPWV change in response to exercise between those who exercised vs. controls.20 Although nonsignificant, Koh et al. observed a −0.8 (95% CI, −2.11 to 0.48) difference in cfPWV after 6 months of intradialytic pedaling (n = 15) vs. usual care (n = 15).11 Although we have shown a significant increase in AIx75 in the nonEX group compared to the EX group, neither of these studies11,20 observed a difference in AIx75 after intradialytic pedaling. Furthermore, we observed a modest, but significant decrease in HR of 3.7 beats/min. Ouzouni et al. reported an even larger decrease in HR of 8.7 beats/min after 10 months of intradialytic pedaling (n = 19).21 Therefore, further benefit with a longer term intervention is possible. In order to evaluate the sustainability of the pedaling effect, we performed an additional evaluation in the exercise group 4 months postintervention. Interestingly, cfPWV at the follow-up evaluation was intermediate between the baseline and postintervention value, suggestive of a possible carry-over effect of AS. This is in contrast to a previous study by Mustafa et al. which showed that AIx improvements after pedaling dissipated after 1 month of detraining.12 Toussaint et al. reported an almost complete return to baseline 4 months after exercise cessation.20 A more rigorous examination of the sustainability of this effect will be required in a much larger number of patients to draw definite conclusions; however, the current evidence demonstrating either a partial or complete reversal of the effect emphasizes the need for maintenance of regular physical activity in this population. Exercise improves AS through several mechanisms, including functional and structural improvements in the central conduit arteries. Even short-term mild intensity cycling exercise has been shown to have favorable effects on the endothelium by improving nitric oxide bioavailability.18,22–25 Interestingly, a 16-week intervention consisting of treadmill walking (50–60% VO2peak) in patients with stage 3 CKD led to improvements in vasoactive balance, as demonstrated by a higher nitrate/nitrite to endothelin-1 ratio.18 Furthermore, the observed reduction in HR suggests that the pedaling exercise may have improved autonomic control.26 This could in turn reduce sympathetic activation of vascular smooth muscle cells and may be a possible mechanism for lower AS.27 The carry-over effect of exercise on cfPWV 4 months postexercise cessation is perhaps also indicative of structural improvements. Exercise may have impacted the concentrations of collagen, or the cross-linking of structural proteins by advanced glycation end-products within the arterial wall, both key contributors to AS.22 Although we have not measured the levels of inflammatory markers other than leukocytes and platelets, exercise exerts important antiinflammatory effects. Numerous studies have demonstrated a strong association between inflammatory markers and cfPWV.28 Study limitations include a small sample size and relatively short intervention duration. Despite all efforts, renal transplants and health-related contraindications for exercise led to several drop-outs. Other longitudinal studies investigating intradialytic pedaling have faced similar limitations.10,11,18,20,29,30 Furthermore, we adjusted cfPWV, our primary outcome, for the value at baseline, as well as variables that correlated strongly with cfPWV (age and Charlson comorbidity score), despite no significant differences at baseline. We have included several secondary outcomes to contextualize our results; however, we caution readers to consider the fact that multiple testing was conducted. While the study was originally designed as a cross-over study, hospital logistics did not permit a wash-out period. Therefore, we have presented the results as a RCT with a 4-month follow-up. However, this provided control arm participants with the opportunity to engage in the pedaling exercise protocol after completing the first 4-month intervention period. This additional step allowed us to conduct a single-arm subgroup analysis in a larger number of participants and further confirm the beneficial impact of pedaling exercise on cfPWV. Exercise compliance was variable (60% [IQR 42–79]). We discouraged participants from pedaling if they were not feeling well, which led to a lower compliance rate than expected.31 Moreover, nonavailability of volunteers delegated to supervise the exercise sessions also impacted participant compliance. We elected to not involve research staff for supervision of exercise sessions in order to evaluate the impact of a more ‘real life’ intervention integrated into the dialysis unit. Lastly, the available pedaling equipment did not enable us to measure the intensity of pedaling. However, participants aimed to reach the target range on the Borg RPE Scale.19 In conclusion, intradialytic exercise has been increasingly recognized as a safe and effective modality that allows patients to integrate regular physical activity into their hemodialysis sessions. Despite a small sample size and the relatively short exercise duration, we demonstrated a clinically relevant reduction in cfPWV, the “gold standard” measure of AS. The benefit is only partially sustained soon after exercise cessation, and therefore reinforces the need for maintenance of regular physical activity in this population to achieve arterial health benefits. These findings need to be confirmed in larger future investigations with longer duration of exercise regimens. SUPPLEMENTARY MATERIAL Supplementary data are available at American Journal of Hypertension online. DISCLOSURE The authors declared no conflict of interest. ACKNOWLEDGMENTS We acknowledge MUHC dialysis unit staff members and volunteers, whose help was instrumental in executing this study. A.B.C. is supported by a Canadian Institutes of Health Research doctoral award. S.S.D. holds a clinician-scientist salary award from the Fonds de recherche du Québec-Santé. T.M. received a grant from the Swiss National Science Foundation-Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung. REFERENCES 1. Avramovski P, Janakievska P, Sotiroski K, Zafirova-Ivanovska B, Sikole A. Aortic pulse wave velocity is a strong predictor of all–cause and cardiovascular mortality in chronic dialysis patients. Ren Fail  2014; 36: 176– 186. Google Scholar CrossRef Search ADS PubMed  2. Santoro A, Mandreoli M. Chronic renal disease and risk of cardiovascular morbidity-mortality. Kidney Blood Press Res  2014; 39: 142– 146. Google Scholar CrossRef Search ADS PubMed  3. Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, London GM. Impact of aortic stiffness on survival in end-stage renal disease. Circulation  1999; 99: 2434– 2439. Google Scholar CrossRef Search ADS PubMed  4. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, Pannier B, Vlachopoulos C, Wilkinson I, Struijker-Boudier H; European Network for Non-invasive Investigation of Large Arteries. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J  2006; 27: 2588– 2605. Google Scholar CrossRef Search ADS PubMed  5. Toussaint ND, Lau KK, Strauss BJ, Polkinghorne KR, Kerr PG. Associations between vascular calcification, arterial stiffness and bone mineral density in chronic kidney disease. Nephrol Dial Transplant  2008; 23: 586– 593. Google Scholar CrossRef Search ADS PubMed  6. Wang MC, Tsai WC, Chen JY, Huang JJ. Stepwise increase in arterial stiffness corresponding with the stages of chronic kidney disease. Am J Kidney Dis  2005; 45: 494– 501. Google Scholar CrossRef Search ADS PubMed  7. Temmar M, Liabeuf S, Renard C, Czernichow S, Esper NE, Shahapuni I, Presne C, Makdassi R, Andrejak M, Tribouilloy C, Galan P, Safar ME, Choukroun G, Massy Z. Pulse wave velocity and vascular calcification at different stages of chronic kidney disease. J Hypertens  2010; 28: 163– 169. Google Scholar CrossRef Search ADS PubMed  8. Huang N, Foster MC, Mitchell GF, Andresdottir MB, Eiriksdottir G, Gudmundsdottir H, Harris TB, Launer LJ, Palsson R, Gudnason V, Levey AS, Inker LA. Aortic stiffness and change in glomerular filtration rate and albuminuria in older people. Nephrol Dial Transplant  2017; 32: 1677– 684. 9. Weber T, Ammer M, Gündüz D, Bruckenberger P, Eber B, Wallner M. Association of increased arterial wave reflections with decline in renal function in chronic kidney disease stages 3 and 4. Am J Hypertens  2011; 24: 762– 769. Google Scholar CrossRef Search ADS PubMed  10. Mustata S, Groeneveld S, Davidson W, Ford G, Kiland K, Manns B. Effects of exercise training on physical impairment, arterial stiffness and health-related quality of life in patients with chronic kidney disease: a pilot study. Int Urol Nephrol  2011; 43: 1133– 1141. Google Scholar CrossRef Search ADS PubMed  11. Koh KP, Fassett RG, Sharman JE, Coombes JS, Williams AD. Effect of intradialytic versus home-based aerobic exercise training on physical function and vascular parameters in hemodialysis patients: a randomized pilot study. Am J Kidney Dis  2010; 55: 88– 99. Google Scholar CrossRef Search ADS PubMed  12. Mustata S, Chan C, Lai V, Miller JA. Impact of an exercise program on arterial stiffness and insulin resistance in hemodialysis patients. J Am Soc Nephrol  2004; 15: 2713– 2718. Google Scholar CrossRef Search ADS PubMed  13. WMA. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA  2013; 310: 2191– 294. CrossRef Search ADS PubMed  14. Swain DP, Brawner CA, Medicine. ACoS. ACSM’s Resource Manual for Guidelines for Exercise Testing and Prescription . 7th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2014, pp 862. 15. Gorgui J, Doonan RJ, Gomez YH, Kwong C, Daskalopoulou SS. Carotid endarterectomy improves peripheral but not central arterial stiffness. Eur J Vasc Endovasc Surg  2013; 45: 548– 553. Google Scholar CrossRef Search ADS PubMed  16. Doonan RJ, Scheffler P, Yu A, Egiziano G, Mutter A, Bacon S, Carli F, Daskalopoulos ME, Daskalopoulou SS. Altered arterial stiffness and subendocardial viability ratio in young healthy light smokers after acute exercise. PLoS One  2011; 6: e26151. Google Scholar CrossRef Search ADS PubMed  17. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol  2010; 55: 1318– 1327. Google Scholar CrossRef Search ADS PubMed  18. Headley S, Germain M, Wood R, Joubert J, Milch C, Evans E, Poindexter A, Cornelius A, Brewer B, Pescatello LS, Parker B. Short-term aerobic exercise and vascular function in CKD stage 3: a randomized controlled trial. Am J Kidney Dis  2014; 64: 222– 229. Google Scholar CrossRef Search ADS PubMed  19. Paneni F, Beckman JA, Creager MA, Cosentino F. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Eur Heart J  2013; 34: 2436– 2443. Google Scholar CrossRef Search ADS PubMed  20. Toussaint ND, Polkinghorne KR, Kerr PG. Impact of intradialytic exercise on arterial compliance and B-type natriuretic peptide levels in hemodialysis patients. Hemodial Int  2008; 12: 254– 263. Google Scholar CrossRef Search ADS PubMed  21. Ouzouni S, Kouidi E, Sioulis A, Grekas D, Deligiannis A. Effects of intradialytic exercise training on health-related quality of life indices in haemodialysis patients. Clin Rehabil  2009; 23: 53– 63. Google Scholar CrossRef Search ADS PubMed  22. Santos-Parker JR, LaRocca TJ, Seals DR. Aerobic exercise and other healthy lifestyle factors that influence vascular aging. Adv Physiol Educ  2014; 38: 296– 307. Google Scholar CrossRef Search ADS PubMed  23. Lavie CJ, Arena R, Swift DL, Johannsen NM, Sui X, Lee DC, Earnest CP, Church TS, O’Keefe JH, Milani RV, Blair SN. Exercise and the cardiovascular system: clinical science and cardiovascular outcomes. Circ Res  2015; 117: 207– 219. Google Scholar CrossRef Search ADS PubMed  24. Goto C, Higashi Y, Kimura M, Noma K, Hara K, Nakagawa K, Kawamura M, Chayama K, Yoshizumi M, Nara I. Effect of different intensities of exercise on endothelium-dependent vasodilation in humans: role of endothelium-dependent nitric oxide and oxidative stress. Circulation  2003; 108: 530– 535. Google Scholar CrossRef Search ADS PubMed  25. Maiorana A, O’Driscoll G, Taylor R, Green D. Exercise and the nitric oxide vasodilator system. Sports Med  2003; 33: 1013– 1035. Google Scholar CrossRef Search ADS PubMed  26. Carter JB, Banister EW, Blaber AP. Effect of endurance exercise on autonomic control of heart rate. Sports Med  2003; 33: 33– 46. Google Scholar CrossRef Search ADS PubMed  27. McCorry LK. Physiology of the autonomic nervous system. Am J Pharm Educ  2007; 71: 78. Google Scholar CrossRef Search ADS PubMed  28. Jain S, Khera R, Corrales-Medina VF, Townsend RR, Chirinos JA. “ Inflammation and arterial stiffness in humans”. Atherosclerosis  2014; 237: 381– 390. Google Scholar CrossRef Search ADS PubMed  29. Mihaescu A, Avram C, Bob F, Gaita D, Schiller O, Schiller A. Benefits of exercise training during hemodialysis sessions: a prospective cohort study. Nephron Clin Pract  2013; 124: 72– 78. Google Scholar CrossRef Search ADS PubMed  30. Musavian AS, Soleimani A, Masoudi Alavi N, Baseri A, Savari F. Comparing the effects of active and passive intradialytic pedaling exercises on dialysis efficacy, electrolytes, hemoglobin, hematocrit, blood pressure and health-related quality of life. Nurs Midwifery Stud  2015; 4: e25922. Google Scholar CrossRef Search ADS PubMed  31. Barcellos FC, Santos IS, Umpierre D, Bohlke M, Hallal PC. Effects of exercise in the whole spectrum of chronic kidney disease: a systematic review. Clin Kidney J  2015; 8: 753– 765. Google Scholar CrossRef Search ADS PubMed  © American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Hypertension Oxford University Press

The Impact of Intradialytic Pedaling Exercise on Arterial Stiffness: A Pilot Randomized Controlled Trial in a Hemodialysis Population

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Oxford University Press
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© American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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0895-7061
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1941-7225
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10.1093/ajh/hpx191
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Abstract

Abstract OBJECTIVES Regular exercise is known to reduce arterial stiffness (AS) in hemodialysis patients. However, the impact of a more realistic intradialytic form of exercise, such as pedaling, is unclear. We aimed to examine (i) the effect of intradialytic pedaling exercise on AS over 4 months and (ii) the longer term effect of pedaling on AS 4 months after exercise cessation. METHODS Patients on stable in-center hemodialysis (3 x/week) were randomly assigned 1:1 to either intradialytic pedaling exercise (EX) or to a control group receiving usual hemodialysis (nonEX) for 4 months. At baseline and 4 months, peripheral and central blood pressure (BP) indices, heart rate (HR), augmentation index HR corrected (AIx75), and carotid-femoral pulse wave velocity (cfPWV) were assessed (applanation tonometry). Measurements were repeated in the EX group 4 months postexercise cessation. RESULTS As per protocol analysis was completed in 10 EX group participants (58 ± 17 years, body mass index 26 ± 4 kg/m2) and 10 nonEX group participants (53 ± 15 years, body mass index 27 ± 6 kg/m2). Peripheral and central BP was unchanged in both groups. AIx75 was unchanged in the EX group, however, a significant median increase of 3.5% [interquartile range, IQR 1.0, 8.5] was noted in the nonEX group (P = 0.009). We noted a significantly greater absolute decrease in cfPWV in the EX group compared to controls: −1.00 [IQR −1.95, 0.05] vs. 0.20 [IQR −0.10, 0.90] (P = 0.033). Interestingly, the decrease in cfPWV observed in the EX group was partially reversed 4 months after exercise cessation. CONCLUSION Intradialytic pedaling exercise has a beneficial impact on AS. This relationship warrants further investigation. CLINICAL TRIALS REGISTRATION Trial Number #NCT03027778 (clinicaltrials.gov) arterial stiffness, blood pressure, hemodialysis, hypertension, intradialytic exercise, pedaling exercise, pulse wave velocity Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD) patients on hemodialysis.1,2 Accelerated arterial stiffness (AS) is an independent risk factor for cardiovascular disease, especially in the CKD population, whose arteriosclerosis profile is accelerated compared to healthy aging.3 Therefore, AS can serve as a useful measure to evaluate the progression of vascular damage and cardiovascular disease risk in a hemodialysis population. Carotid-femoral pulse wave velocity (cfPWV) is recognized as the “gold standard” measure of AS.4 The association between cfPWV and vascular calcification is well-established,5 and studies have also indicated a step-wise relationship between cfPWV and the stages of CKD.6,7 Furthermore, augmentation index (AIx), a measure of wave reflection obtained through pulse wave analysis, is another independent predictor of declining renal function in patients with CKD.8,9 A well-designed aerobic exercise program can favorably affect cardiovascular disease risk factors, and regular aerobic exercise improves AS in the general population and patients with CKD.10 However, the arterial health impact of a more realistic intradialytic form of exercise, such as pedaling, remains unclear.5,11,12 Therefore, we aimed to examine the effect of intradialytic pedaling exercise on cfPWV (primary outcome) and other arterial hemodynamic parameters over 4 months. We also aimed to evaluate the longer term effect of pedaling on cfPWV and other arterial hemodynamic parameters 4 months after finishing the exercise intervention, as well as the impact on anthropometric measures, physical function, and routine laboratory blood markers. MATERIALS AND METHODS Ethical approval The study was approved by the McGill University Health Centre (MUHC) ethics board; written informed consent was provided, and our study conformed to the standards of the Declaration of Helsinki.13 Participants We recruited adults with stage 5 CKD, who were on a stable in-center hemodialysis regimen (approximately 4 hours 3 times/week) for ≥12 weeks prior to recruitment. A recent cardiac evaluation (<1 year) was required to ensure adequate cardiac function to undergo the exercise program. Exclusion criteria: (i) any physical or psychological disability that would impact study participation, (ii) serum intact parathyroid hormone >250 pmol/l within 30 days prior, (iii) dysrhythmia or severe cardiac disease or peripheral arterial disease, (iv) severe hyperkalemia (>6.5 mmol/l) for the last 2 weeks, (v) active cancer, (vi) postdialytic systolic blood pressure (BP) ≥160 mm Hg or diastolic BP ≥100 mm Hg within 4 weeks prior, or (vii) anticipated living donor kidney transplant or other planned major surgery over the study duration. Trial design We conducted a pilot multisite, open-label, randomized-controlled clinical trial. Participants were assigned to either intradialytic pedaling exercise (EX) or to a control group receiving usual dialysis (nonEX) for 4 months, using stratified randomization based on age and sex (1:1 allocation ratio). AS, hemodynamic parameters, and other health measures were assessed in both groups within 2 days before and after the intervention. The EX group was also re-assessed 4 months after completing the pedaling intervention to evaluate the sustainability of the pedaling effect. At the end of the 4 months, nonEX participants were given the opportunity to complete 4 months of pedaling following the same protocol as the EX group. They are included in a single-arm subgroup analysis to further examine the impact of pedaling exercise on AS in a larger group of participants who followed the same exercise intervention. Trial procedures Participants engaged in pedaling exercise 3 times/week during dialysis for 4 months. BP and heart rate (HR) were monitored during exercise (data not shown), and exercise time was recorded after each session. Due to the wide range of exercise capacity, participants in the EX group exercised for the amount of time that allowed them to reach the target range of 12–16 out of 20 points (“somewhat hard” to “hard”) on the Borg Rating of Perceived Exertion (RPE) Scale.14 For safety, no patient exercised past the halfway mark of their dialysis session. Exercise compliance for each participant was calculated by dividing the number of dialysis sessions where pedaling was performed by the total number of sessions (48 sessions). AS and hemodynamic parameters were measured in duplicate using applanation tonometry (Sphygmocor XCEL, AtCor Medical, Sydney, Australia), in a semi-supine position (20% inclination).15,16 Using an automated BP cuff, peripheral BP was measured; then by applying a validated generalized transfer function, the central pressure waveform is generated, allowing for measures of central BP, and AIx corrected for a HR of 75 beats/min (AIx75). Measurements of cfPWV were performed using the thigh cuff and carotid tonometry. Participants refrained from caffeine, alcohol, and smoking at least 5 hours prior. Assessments preintervention and postintervention were all conducted prior to starting the mid-week dialysis session. Gait speed was measured as the participant walked a 6-meter course as quickly as possible. The average of 2 timed readings was reported. Grip strength was measured using a hand dynamometer (Lafayette Instrument, Lafayette, IN). Two readings were recorded in each hand, and the highest measure was reported. Laboratory blood parameters including hemoglobin, leukocytes, platelets, serum albumin, serum electrolytes, total calcium, phosphate, parathyroid hormone levels, total cholesterol, triglycerides, high-density lipoprotein-cholesterol (low-density lipoprotein-cholesterol was calculated using the Friedewald formula), iron studies, and ferritin and were assessed at the same time as the baseline and final assessments. Single pool Kt/V was measured to quantify hemodialysis treatment adequacy. All blood analyses were performed at the MUHC Central Laboratories using standard methods. Analytic methods Descriptive statistics were used to summarize participant characteristics using mean and SD, median and interquartile range (IQR), or percentages, as appropriate. Normality was assessed, and parametric or nonparametric tests were used accordingly. Per protocol analyses were performed on participants who completed the study. For our primary analyses, between-group comparisons (EX and nonEX groups) of the absolute difference [postintervention minus preintervention levels] were performed using a one-sided Mann–Whitney test to assess the superiority of pedaling exercise over usual hemodialysis. In secondary analyses, analysis of covariance was used to evaluate between-group comparisons of cfPWV (log-transformed) in a series of models adjusting for different covariates separately to avoid overadjustment, including age, Charlson comorbidity score, and the baseline cfPWV value. Between-group comparisons of baseline values were performed using 2-sided Mann–Whitney test, and within-group comparisons of preintervention and postintervention values with a 2-sided paired Student’s t-test. The level of significance was set at P <0.05 and 95% confidence intervals (CI) were included when parametric tests were performed. SAS version 9.3 was used (SAS Institute, Cary, NC). RESULTS A total of 32 participants were initially randomized. Per protocol analyses were performed in those who completed the intervention (10 in each group) (Table 1). Reasons for drop-out or exclusion are summarized in Figure 1. Participant baseline characteristics including both completers and noncompleters were similar (Supplementary Table 1). Of the 10 participants who completed the pedaling exercise, 8 participants were included at the 8-month follow-up. Table 1. Participant baseline characteristics   Total population (n = 20)  Exercise group (n = 10)  Control group (n = 10)  P value  Age (years)  55.4 ± 16.2  58.2 ± 17.2  52.5 ± 15.4  0.643  Men/women  14/6  7/3  7/3  1.00  Height (cm)  174.9 ± 8.3  172.4 ± 8.4  177.4 ± 7.9  0.168  Weight (kg)  80.9 ± 16.2  76.6 ± 16.9  85.1 ± 15.2  0.353  BMI (kg/m2)  26.4 ± 5.2  25.6 ± 4.3  27.2 ± 6.1  0.436  Waist:hip ratio  0.94 ± 0.11  0.93 ± 0.12  0.95 ± 0.11  0.762  IPAQ (MET-min/week)  480 [0–1440]  480 [0–1440]  480 [0–1440]  0.902  Gait speed (m/s)  0.84 ± 0.27  0.8 ± 0.2  0.9 ± 0.3  0.481  Grip Strength (kg)  24.6 ± 12.0  23.2 ± 10.5  25.9 ± 13.8  0.616  Comorbidities (%)   Coronary artery disease  10  20  0  0.136   Myocardial infarction  5  10  0  0.305   Congestive heart failure  20  20  20  1.00   Cerebrovascular accident  10  10  10  1.00   Peripheral arterial disease  5  0  10  0.304   Chronic obstructive pulmonary disease  15  20  10  0.531   Hypertension  100  100  100  1.00   Diabetes mellitus  35  30  40  0.639   Ever-smoking  45  40  50  0.653   Charlson Comorbidity Score  4.7 ± 1.7  4.6 ± 2.0  5.0 ± 1.4  0.581  Laboratory parameters   Kt/V  1.4 ± 0.3  1.4 ± 0.3  1.5 ± 0.3  0.736   Creatinine (µmol/l)  839.7 ± 281.6  801.6 ± 244.0  877.7 ± 330.9  0.393   Hemoglobin (g/l)  107.1 ± 10.5  109.1 ± 11.1  105.1 ± 10.0  0.382   Leukocytes  6.8 ± 1.9  6.9 ± 1.9  6.6 ± 2.0  0.699   Platelets  174.6 ± 50.1  181.0 ± 35.0  168.1 ± 63.0  0.492   Albumin (g/l)  33.4 ± 4.36  32.3 ± 3.6  34.5 ± 4.9  0.269   Sodium (mmol/l)  136.2 ± 2.35  136.2 ± 3.0  136.1 ± 1.6  0.861   Potassium (mmol/l)  4.6 ± 0.6  4.5 ± 0.3  4.6 ± 0.8  0.672   Total calcium (mmol/l)  2.1 ± 0.3  2.1 ± 0.2  2.2 ± 0.3  0.323   Phosphate (mmol/l)  1.4 ± 0.4  1.5 ± 0.5  1.3 ± 0.4  0.315   PTH (pmol/l)  67.0 [23.8–93.5]  76.2 [47.0–93.5]  52.8 [23.8–67.0]  0.315   Triglycerides (mmol/l)  2.2 [1.1–2.6]  2.3 [1.2–2.6]  1.3 [0.8–2.5]  0.537   LDL (mmol/l)  2.0 ± 0.8  2.1 ± 0.9  2.0 ± 0.9  0.905   HDL (mmol/l)  1.0 ± 0.1  1.0 ± 0.1  1.0 ± 0.1  0.931   Transferrin saturation (%)  0.3 ± 0.1  0.3 ± 0.1  0.3 ± 0.1  0.796   Ferritin (ng/ml)  463 [258.3–612.5]  471.2 [349–683.3]  284.4 [258.4–526.0]  0.604  Medications (%)   Antihypertensive agents (no.)  1.9 ± 1.2  2.45 ± 0.9  1.3 ± 1.2  0.036    ACE inhibitors orARBs  25  30  20  0.606    Calcium channel blockers  45  50  40  0.653    Diuretics  15  30  0  0.060    β-blockers  65  90  40  0.019    α-blockers  15  20  10  0.531    Central agents  15  20  10  0.531   Nitrates  10  10  10  1.00   Acetylsalicylic acid  25  30  20  0.606   Statins  30  30  30  0.361   Phosphate binders  100  100  100  1.00   Supplemental calcium  40  60  20  0.068   sErythropoietin  90  90  90.0  1.00    Total population (n = 20)  Exercise group (n = 10)  Control group (n = 10)  P value  Age (years)  55.4 ± 16.2  58.2 ± 17.2  52.5 ± 15.4  0.643  Men/women  14/6  7/3  7/3  1.00  Height (cm)  174.9 ± 8.3  172.4 ± 8.4  177.4 ± 7.9  0.168  Weight (kg)  80.9 ± 16.2  76.6 ± 16.9  85.1 ± 15.2  0.353  BMI (kg/m2)  26.4 ± 5.2  25.6 ± 4.3  27.2 ± 6.1  0.436  Waist:hip ratio  0.94 ± 0.11  0.93 ± 0.12  0.95 ± 0.11  0.762  IPAQ (MET-min/week)  480 [0–1440]  480 [0–1440]  480 [0–1440]  0.902  Gait speed (m/s)  0.84 ± 0.27  0.8 ± 0.2  0.9 ± 0.3  0.481  Grip Strength (kg)  24.6 ± 12.0  23.2 ± 10.5  25.9 ± 13.8  0.616  Comorbidities (%)   Coronary artery disease  10  20  0  0.136   Myocardial infarction  5  10  0  0.305   Congestive heart failure  20  20  20  1.00   Cerebrovascular accident  10  10  10  1.00   Peripheral arterial disease  5  0  10  0.304   Chronic obstructive pulmonary disease  15  20  10  0.531   Hypertension  100  100  100  1.00   Diabetes mellitus  35  30  40  0.639   Ever-smoking  45  40  50  0.653   Charlson Comorbidity Score  4.7 ± 1.7  4.6 ± 2.0  5.0 ± 1.4  0.581  Laboratory parameters   Kt/V  1.4 ± 0.3  1.4 ± 0.3  1.5 ± 0.3  0.736   Creatinine (µmol/l)  839.7 ± 281.6  801.6 ± 244.0  877.7 ± 330.9  0.393   Hemoglobin (g/l)  107.1 ± 10.5  109.1 ± 11.1  105.1 ± 10.0  0.382   Leukocytes  6.8 ± 1.9  6.9 ± 1.9  6.6 ± 2.0  0.699   Platelets  174.6 ± 50.1  181.0 ± 35.0  168.1 ± 63.0  0.492   Albumin (g/l)  33.4 ± 4.36  32.3 ± 3.6  34.5 ± 4.9  0.269   Sodium (mmol/l)  136.2 ± 2.35  136.2 ± 3.0  136.1 ± 1.6  0.861   Potassium (mmol/l)  4.6 ± 0.6  4.5 ± 0.3  4.6 ± 0.8  0.672   Total calcium (mmol/l)  2.1 ± 0.3  2.1 ± 0.2  2.2 ± 0.3  0.323   Phosphate (mmol/l)  1.4 ± 0.4  1.5 ± 0.5  1.3 ± 0.4  0.315   PTH (pmol/l)  67.0 [23.8–93.5]  76.2 [47.0–93.5]  52.8 [23.8–67.0]  0.315   Triglycerides (mmol/l)  2.2 [1.1–2.6]  2.3 [1.2–2.6]  1.3 [0.8–2.5]  0.537   LDL (mmol/l)  2.0 ± 0.8  2.1 ± 0.9  2.0 ± 0.9  0.905   HDL (mmol/l)  1.0 ± 0.1  1.0 ± 0.1  1.0 ± 0.1  0.931   Transferrin saturation (%)  0.3 ± 0.1  0.3 ± 0.1  0.3 ± 0.1  0.796   Ferritin (ng/ml)  463 [258.3–612.5]  471.2 [349–683.3]  284.4 [258.4–526.0]  0.604  Medications (%)   Antihypertensive agents (no.)  1.9 ± 1.2  2.45 ± 0.9  1.3 ± 1.2  0.036    ACE inhibitors orARBs  25  30  20  0.606    Calcium channel blockers  45  50  40  0.653    Diuretics  15  30  0  0.060    β-blockers  65  90  40  0.019    α-blockers  15  20  10  0.531    Central agents  15  20  10  0.531   Nitrates  10  10  10  1.00   Acetylsalicylic acid  25  30  20  0.606   Statins  30  30  30  0.361   Phosphate binders  100  100  100  1.00   Supplemental calcium  40  60  20  0.068   sErythropoietin  90  90  90.0  1.00  Values expressed as mean ± SD, median [interquartile range] or percentage. Two-sided Mann–Whitney test was used. Abbreviations: ACE, angiotensin converting enzyme; ARBs, angiotensin receptor blockers; BMI, body mass index; HDL, high-density lipoprotein-cholesterol; IPAQ, international physical activity questionnaire; LDL, low-density lipoprotein-cholesterol; MET, metabolic equivalent; PTH, parathyroid hormone. View Large Figure 1. View largeDownload slide Participant flow. Abbreviations: cfPWV, carotid femoral pulse wave velocity, EX group, exercise group; nonEX group, control group. Figure 1. View largeDownload slide Participant flow. Abbreviations: cfPWV, carotid femoral pulse wave velocity, EX group, exercise group; nonEX group, control group. We observed no significant between-group differences in demographic characteristics, anthropometrics, physical function, comorbidities, medications, or laboratory parameters (Table 1). Furthermore, baseline vessel hemodynamics were not significantly different between the groups, with the exception of a higher aortic pulse pressure in the EX group than in the nonEX group (Table 2). A higher pulse pressure was also noted in the EX group when noncompleters were also included (Supplementary Table 2). Changes in the number and dose of medications were minimal; one EX group participant received a dose increase of an antihypertensive agent (clonidine), and a nonEX participant started a calcimimetic agent and received an increased dose of an angiotensin receptor blocker. Table 2. Baseline arterial stiffness and hemodynamic parameters   Exercise group (n = 10)  Control group (n = 10)  P value exercise vs. control  Interdialytic weight gain (kg)  1.8 [0.5, 2.2]  2.0 [1.6, 2.4]  0.481  Peripheral SBP (mm Hg)  148 [135, 166]  134 [129, 141]  0.271  Peripheral DBP (mm Hg)  77 [69, 85]  83 [77, 86]  0.470  Central SBP (mm Hg)  131 [122, 148]  122 [117, 126]  0.224  Central DBP (mm Hg)  79 [71, 86]  85 [78, 87]  0.567  Central PP (mm Hg)  53 [45, 66]  37 [32, 54]  0.045  MAP (mm Hg)  98 [91, 110]  101 [93, 103]  0.984  cfPWV (m/s)  8.2 [7.3, 9.8]  8.6 [7.2, 9.2]  0.739  HR (bpm)  67 [60, 81]  75 [69, 78]  0.315  AIx75 (%)  24 [19, 26]  22 [15, 28]  0.448    Exercise group (n = 10)  Control group (n = 10)  P value exercise vs. control  Interdialytic weight gain (kg)  1.8 [0.5, 2.2]  2.0 [1.6, 2.4]  0.481  Peripheral SBP (mm Hg)  148 [135, 166]  134 [129, 141]  0.271  Peripheral DBP (mm Hg)  77 [69, 85]  83 [77, 86]  0.470  Central SBP (mm Hg)  131 [122, 148]  122 [117, 126]  0.224  Central DBP (mm Hg)  79 [71, 86]  85 [78, 87]  0.567  Central PP (mm Hg)  53 [45, 66]  37 [32, 54]  0.045  MAP (mm Hg)  98 [91, 110]  101 [93, 103]  0.984  cfPWV (m/s)  8.2 [7.3, 9.8]  8.6 [7.2, 9.2]  0.739  HR (bpm)  67 [60, 81]  75 [69, 78]  0.315  AIx75 (%)  24 [19, 26]  22 [15, 28]  0.448  Values expressed as median [interquartile range]. One-sided Mann–Whitney test was used. Bolded values indicate significance (P < 0.05). Abbreviations: AIx75, augmentation index (corrected for a heart rate of 75 beats/min); cfPWV, carotid femoral pulse wave velocity; DBP, diastolic blood pressure; HR, heart rate; MAP, mean arterial pressure; SBP systolic blood pressure. View Large Exercise compliance Median exercise compliance in the EX group was 60% [IQR 42–79] and median exercise time per session was 42.6 minutes [IQR 31.2–60.0]. Over the intervention, the median total exercise time was 18.5 hours [IQR 10.5–28.5] per participant. Safety and adverse events No adverse events occurred during exercise. Two withdrawals from the exercise intervention were due to health complications, unrelated to the exercise. One participant withdrew for cardiac bypass surgery, and subsequent postoperative complications led to death; however, this was not related to the exercise. There was one case of ischemic stroke, but the episode occurred 10 days after cessation from the exercise program. Postintervention changes Vessel hemodynamics. Peripheral and central BP were unchanged after the intervention in both the EX and nonEX groups (Table 3). We observed a significantly greater absolute decrease in cfPWV in the EX group compared to the nonEX group (P = 0.033): −1.00 [IQR −1.95, 0.05] vs. 0.20 [IQR −0.10, 0.9] (Figure 2). Furthermore, AIx75 was unchanged in the EX group; however, a significant median increase of 3.5% (IQR 1.0, 8.5) was noted in the nonEX group (between-group P = 0.009). We also noted a greater reduction in HR in the EX group postintervention, compared to the nonEX group (P = 0.029). Table 3. Between-group comparisons of postexercise changes in arterial stiffness and hemodynamic parameters   Exercise group (n = 10)  Control group (n = 10)  P value exercise vs. control  ∆ BMI (kg/m2)  0.28 [−0.23, 0.95]  0.20 [−0.03, 0.45]  0.485  ∆ Waist:hip ratio  0.03 [0.01, 0.03]  −0.00 [−0.03, 0.01]  0.022  ∆ Interdialytic weight gain (kg)  −0.6 [−0.6, 1.1]  −0.1 [−0.6, 0.9]  0.309  ∆ Gait speed (m/s)  0.02 [−0.02, 0.11]  −0.11 [−0.17, 0.08]  0.158  ∆ Grip strength (kg)  1.3 [−0.5, 6.5]  2.5 [−0.5, 4.0]  0.464  ∆ Peripheral SBP (mm Hg)  −10.0 [−21.5, 4.0]  −0.3 [−5.0, 6.5]  0.128  ∆ Peripheral DBP (mm Hg)  −5.3 [−11.0, 8.5]  0.5 [−1.0, 11]  0.092  ∆ Central SBP (mm Hg)  −10.0 [−16.0, 3.5]  1.0 [−2.5, 11.5]  0.099  ∆ Central DBP (mm Hg)  −6.0 [−10, 6.0]  −2.0 [−1.0, 12.0]  0.136  ∆ Central PP (mm Hg)  −6.5 [−9.5, 6.0]  −3.3 [−4.5, 6.0]  0.105  ∆ MAP (mm Hg)  −9.0 [−15.0, 4.0]  2.0 [−1.5, 9.5]  0.162  ∆ cfPWV (m/s)  −1.0 [−2.0, 0.5]  0.20 [−0.1, 0.9]  0.033  ∆ AIx75 (%)  −2.0 [−4.5, 1.0]  3.5 [1.0, 8.5]  0.009  ∆ HR (bpm)  −3.8 [−6.5, −1.0]  1.5 [−1.0, 6.5]  0.014    Exercise group (n = 10)  Control group (n = 10)  P value exercise vs. control  ∆ BMI (kg/m2)  0.28 [−0.23, 0.95]  0.20 [−0.03, 0.45]  0.485  ∆ Waist:hip ratio  0.03 [0.01, 0.03]  −0.00 [−0.03, 0.01]  0.022  ∆ Interdialytic weight gain (kg)  −0.6 [−0.6, 1.1]  −0.1 [−0.6, 0.9]  0.309  ∆ Gait speed (m/s)  0.02 [−0.02, 0.11]  −0.11 [−0.17, 0.08]  0.158  ∆ Grip strength (kg)  1.3 [−0.5, 6.5]  2.5 [−0.5, 4.0]  0.464  ∆ Peripheral SBP (mm Hg)  −10.0 [−21.5, 4.0]  −0.3 [−5.0, 6.5]  0.128  ∆ Peripheral DBP (mm Hg)  −5.3 [−11.0, 8.5]  0.5 [−1.0, 11]  0.092  ∆ Central SBP (mm Hg)  −10.0 [−16.0, 3.5]  1.0 [−2.5, 11.5]  0.099  ∆ Central DBP (mm Hg)  −6.0 [−10, 6.0]  −2.0 [−1.0, 12.0]  0.136  ∆ Central PP (mm Hg)  −6.5 [−9.5, 6.0]  −3.3 [−4.5, 6.0]  0.105  ∆ MAP (mm Hg)  −9.0 [−15.0, 4.0]  2.0 [−1.5, 9.5]  0.162  ∆ cfPWV (m/s)  −1.0 [−2.0, 0.5]  0.20 [−0.1, 0.9]  0.033  ∆ AIx75 (%)  −2.0 [−4.5, 1.0]  3.5 [1.0, 8.5]  0.009  ∆ HR (bpm)  −3.8 [−6.5, −1.0]  1.5 [−1.0, 6.5]  0.014  Values expressed as median [interquartile range]. ∆ indicates absolute difference (postintervention minus preintervention levels). Bolded values indicate significance (P < 0.05). One-sided Mann–Whitney test was used. Within-group comparisons are included in Supplementary Table 5. Abbreviations: AIx75, augmentation index (corrected for a heart rate of 75 beats/min); BMI, body mass index; cfPWV, carotid femoral pulse wave velocity; DBP, diastolic blood pressure; HR, heart rate; MAP, mean arterial pressure; SBP, systolic blood pressure. View Large Figure 2. View largeDownload slide Absolute change from baseline in cfPWV, AIx75, and heart rate at 4 months. Abbreviations: AIx75, augmentation index corrected for a heart rate of 75 beats/min; cfPWV, carotid femoral pulse wave velocity; HR, heart rate. Figure 2. View largeDownload slide Absolute change from baseline in cfPWV, AIx75, and heart rate at 4 months. Abbreviations: AIx75, augmentation index corrected for a heart rate of 75 beats/min; cfPWV, carotid femoral pulse wave velocity; HR, heart rate. To account for the small size of our pilot RCT and possible imbalances in characteristics due to drop-outs after randomization, we performed additional adjusted analyses for potential confounding variables. In three separate models after adjustments for two potential confounders, age and the Charlson comorbidity score, as well as the baseline cfPWV value, the decrease in cfPWV approached significance in the EX group (model 1: age, baseline cfPWV value, P = 0.055; model 2: Charlson comorbidity score and baseline cfPWV value, P = 0.059; model 3: age, Charlson comorbidity score, and baseline cfPWV value P = 0.067). Due to considerable skewness, normality could not be achieved with data transformations for AIx75 or HR, preventing adjusted analyses for these parameters. In a single-arm secondary analysis that included 5 additional control arm participants who subsequently underwent the exercise intervention (total n = 15), we also found a significant lowering of cfPWV by −0.96 ± 1.32 m/s (95% CI −1.7 to −0.23, P = 0.014). No conclusive changes were noted for the other hemodynamic parameters (Supplementary Table 3). Physical function and laboratory parameters Postintervention changes in gait speed and grip strength were minimal and were not significantly different between EX and nonEX participants (Table 3). We did not observe any between-group differences in any of the laboratory blood markers in either group over the intervention period (data not shown). Postexercise cessation follow-up cfPWV at the follow-up evaluation in the EX group (mean ± SD: 8.2 ± 1.3 m/s, 95% CI 7.1 to 9.3) was intermediate between the baseline (8.6 ± 2.3 m/s, 95% CI 6.7 to 10.4) and postintervention values (7.4 ± 1.6 m/s, 95% CI 6.2 to 8.6) (Figure 3). We noted a similar observation for an intermediate value at 8 months for peripheral BP and pulse pressure, HR, and AIx75 (Figure 3). Data for all parameters is displayed in Supplementary Table 4. Figure 3. View largeDownload slide Exercise group: cfPWV and other hemodynamic parameters at baseline, postexercise, and 4 months after exercise cessation. Abbreviations: AIx75, augmentation index corrected for a heart rate of 75 beats/min; cfPWV, carotid femoral pulse wave velocity; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure. Figure 3. View largeDownload slide Exercise group: cfPWV and other hemodynamic parameters at baseline, postexercise, and 4 months after exercise cessation. Abbreviations: AIx75, augmentation index corrected for a heart rate of 75 beats/min; cfPWV, carotid femoral pulse wave velocity; DBP, diastolic blood pressure; HR, heart rate; SBP, systolic blood pressure. DISCUSSION This pilot study demonstrated that intradialytic pedaling exercise leads to a significant improvement in cfPWV, the “gold standard” measurement of AS. Importantly, the magnitude of this reduction (−1 m/s) is considered clinically relevant; a 1 m/s increase in cfPWV is associated with a 15% increased risk of cardiovascular events, and mortality.17 Specifically, in hemodialysis patients, a 1 m/s increase in cfPWV corresponds to a 39% increased risk in all-cause mortality (adjusted relative risk 1.39, 95% CI 1.19 to 1.62).3 Interestingly, the improvement in cfPWV after pedaling exercise was observed in the absence of significant changes in BP, physical function, body mass index, or lipids. Our secondary analyses further support the beneficial impact of intradialytic pedaling on cfPWV. In a single-arm subgroup analysis that included 5 additional participants who performed the pedaling intervention, we demonstrated a significant decrease in cfPWV of similar magnitude (−0.96 m/s). We also demonstrated that exercise cessation leads to a partial reversal of cfPWV 4 months later. Although pedaling exercise did not significantly change AIx75, a surrogate measure of systemic stiffness, we noted a significant median increase of 3.5% in the control group. Interestingly, we observed significantly lower resting HR in response to 4 months of pedaling. Few studies have examined the arterial health impact of aerobic exercise.10,12,18 Among them, Mustata et al. found an improvement in AIx after 3 months of supervised aerobic exercise using a treadmill or recumbent bike (2 sessions of 60 minutes/week) in 11 hemodialysis patients at a cardiac rehabilitation centre.12 More recently, they found similar reductions in AIx in response to supervised and home exercise (3 sessions of 60 minutes/week) in 20 predialysis patients.10 Although both interventions have demonstrated improvements in AIx, supervised aerobic exercise programs requiring specialized equipment are resource intensive and difficult to maintain in the longer term. Intradialytic exercise has the advantage of being performed in a supervised setting, requires no additional time commitment outside of dialysis, and is considered feasible for the many hemodialysis patients with functional limitations that would prevent more rigorous forms of aerobic exercise.19 As such, it has been proposed as a realistic means to help patients achieve the arterial health benefits of increased physical activity; however, the results to date have been inconclusive. Our study is the first to show important promise for arterial health benefit by significantly lowering cfPWV. These findings support those of Toussaint et al. who observed a decrease in cfPWV after 3 months of intradialytic pedaling exercise (n = 9) that approached significance (P = 0.07); however, they did not compare the cfPWV change in response to exercise between those who exercised vs. controls.20 Although nonsignificant, Koh et al. observed a −0.8 (95% CI, −2.11 to 0.48) difference in cfPWV after 6 months of intradialytic pedaling (n = 15) vs. usual care (n = 15).11 Although we have shown a significant increase in AIx75 in the nonEX group compared to the EX group, neither of these studies11,20 observed a difference in AIx75 after intradialytic pedaling. Furthermore, we observed a modest, but significant decrease in HR of 3.7 beats/min. Ouzouni et al. reported an even larger decrease in HR of 8.7 beats/min after 10 months of intradialytic pedaling (n = 19).21 Therefore, further benefit with a longer term intervention is possible. In order to evaluate the sustainability of the pedaling effect, we performed an additional evaluation in the exercise group 4 months postintervention. Interestingly, cfPWV at the follow-up evaluation was intermediate between the baseline and postintervention value, suggestive of a possible carry-over effect of AS. This is in contrast to a previous study by Mustafa et al. which showed that AIx improvements after pedaling dissipated after 1 month of detraining.12 Toussaint et al. reported an almost complete return to baseline 4 months after exercise cessation.20 A more rigorous examination of the sustainability of this effect will be required in a much larger number of patients to draw definite conclusions; however, the current evidence demonstrating either a partial or complete reversal of the effect emphasizes the need for maintenance of regular physical activity in this population. Exercise improves AS through several mechanisms, including functional and structural improvements in the central conduit arteries. Even short-term mild intensity cycling exercise has been shown to have favorable effects on the endothelium by improving nitric oxide bioavailability.18,22–25 Interestingly, a 16-week intervention consisting of treadmill walking (50–60% VO2peak) in patients with stage 3 CKD led to improvements in vasoactive balance, as demonstrated by a higher nitrate/nitrite to endothelin-1 ratio.18 Furthermore, the observed reduction in HR suggests that the pedaling exercise may have improved autonomic control.26 This could in turn reduce sympathetic activation of vascular smooth muscle cells and may be a possible mechanism for lower AS.27 The carry-over effect of exercise on cfPWV 4 months postexercise cessation is perhaps also indicative of structural improvements. Exercise may have impacted the concentrations of collagen, or the cross-linking of structural proteins by advanced glycation end-products within the arterial wall, both key contributors to AS.22 Although we have not measured the levels of inflammatory markers other than leukocytes and platelets, exercise exerts important antiinflammatory effects. Numerous studies have demonstrated a strong association between inflammatory markers and cfPWV.28 Study limitations include a small sample size and relatively short intervention duration. Despite all efforts, renal transplants and health-related contraindications for exercise led to several drop-outs. Other longitudinal studies investigating intradialytic pedaling have faced similar limitations.10,11,18,20,29,30 Furthermore, we adjusted cfPWV, our primary outcome, for the value at baseline, as well as variables that correlated strongly with cfPWV (age and Charlson comorbidity score), despite no significant differences at baseline. We have included several secondary outcomes to contextualize our results; however, we caution readers to consider the fact that multiple testing was conducted. While the study was originally designed as a cross-over study, hospital logistics did not permit a wash-out period. Therefore, we have presented the results as a RCT with a 4-month follow-up. However, this provided control arm participants with the opportunity to engage in the pedaling exercise protocol after completing the first 4-month intervention period. This additional step allowed us to conduct a single-arm subgroup analysis in a larger number of participants and further confirm the beneficial impact of pedaling exercise on cfPWV. Exercise compliance was variable (60% [IQR 42–79]). We discouraged participants from pedaling if they were not feeling well, which led to a lower compliance rate than expected.31 Moreover, nonavailability of volunteers delegated to supervise the exercise sessions also impacted participant compliance. We elected to not involve research staff for supervision of exercise sessions in order to evaluate the impact of a more ‘real life’ intervention integrated into the dialysis unit. Lastly, the available pedaling equipment did not enable us to measure the intensity of pedaling. However, participants aimed to reach the target range on the Borg RPE Scale.19 In conclusion, intradialytic exercise has been increasingly recognized as a safe and effective modality that allows patients to integrate regular physical activity into their hemodialysis sessions. Despite a small sample size and the relatively short exercise duration, we demonstrated a clinically relevant reduction in cfPWV, the “gold standard” measure of AS. 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American Journal of HypertensionOxford University Press

Published: Apr 1, 2018

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