Exercise modulates sympathetic and vascular function in chronic kidney disease

Abstract

BACKGROUNDChronic kidney disease (CKD) is characterized by chronic overactivation of the sympathetic nervous system (SNS), which increases the risk of cardiovascular (CV) disease and mortality. SNS overactivity increases CV risk by multiple mechanisms, including vascular stiffness. We tested the hypothesis that aerobic exercise training would reduce resting SNS activity and vascular stiffness in patients with CKD.METHODSIn this randomized controlled trial, sedentary older adults with CKD underwent 12 weeks of exercise (cycling, n = 32) or stretching (an active control group, n = 26). Exercise and stretching interventions were performed 20-45 minutes/session at 3 days/week and were matched for duration. Primary endpoints include resting muscle sympathetic nerve activity (MSNA) via microneurography, arterial stiffness by central pulse wave velocity (PWV), and aortic wave reflection by augmentation index (AIx).RESULTSThere was a significant group × time interaction in MSNA and AIx with no change in the exercise group but with an increase in the stretching group after 12 weeks. The magnitude of change in MSNA was inversely associated with baseline MSNA in the exercise group. There was no change in PWV in either group over the study period.CONCLUSIONOur data demonstrate that 12 weeks of cycling exercise has beneficial neurovascular effects in patients with CKD. Specifically, exercise training safely and effectively ameliorated the increase in MSNA and AIx observed over time in the control group. This sympathoinhibitory effect of exercise training showed greater magnitude in patients with CKD with higher resting MSNA.TRIAL REGISTRATIONClinicalTrials.gov, NCT02947750.FUNDINGNIH R01HL135183; NIH R61AT10457; NIH NCATS KL2TR002381; and NIH T32 DK00756; NIH F32HL147547; and VA Merit I01CX001065.

Keywords: Chronic kidney disease; Clinical Trials; Neuroscience.

Figure 1. CONSORT diagram.

The diagram depicts patient flow through the randomized clinical trial.

Figure 2. Change in muscle sympathetic nervous activity (MSNA) burst frequency.

(A–D) MSNA burst incidence from baseline (Pre) to 12 weeks (Post) of aerobic exercise training (n = 16) versus control stretching (n = 13) interventions in patients with chronic kidney disease. Open circles depict individual values for each study participant, and bar graphs depict the mean ± SD values at baseline and 12 weeks within each group. P values above bracket denote statistically significant difference in the change from baseline to 12 weeks between groups (group × time interaction) by 2 way-repeated ANOVA. P values on either side of bracket denote within-group comparison from baseline to 12 weeks by independent 2-tailed t tests.

Figure 3. Association between augmentation index (AIx) and muscle sympathetic nervous activity (MSNA).

(A–D)Association between AIx and MSNA burst frequency (A) and MSNA burst incidence (B) as well as between AIx corrected for heart rate at 75 (AIx@HR75) and MSNA burst frequency (C) and MSNA burst incidence (D) at baseline in patients with chronic kidney disease (n = 27). The r and P values denote the linear relationship by Pearson correlation tests.

Figure 4. Association between muscle sympathetic nervous activity (MSNA).

(A–D) Association between MSNA burst frequency and MSNA burst incidence at baseline and the change from baseline to 12 weeks in Exercise group (A and C, respectively; n = 16) and in control Stretching group (B and D, respectively; n = 13). The r and P values denote the linear relationship by Pearson correlation tests. Closed circles depict individual values for each study participant in the Exercise group, while open circles depict individual values for each study participant in the control Stretching group.

Figure 5. Association between AIx and AIx@HR75.

(A–D) Association between augmentation index (AIx) and AIx corrected for heart rate at 75 (AIx@HR75) at baseline and the change from baseline to 12 weeks in Exercise group (A and C, respectively; n = 22) and in control Stretching group (B and D, respectively, n = 21). The r and P values denote the linear relationship by Pearson correlation tests. Closed circles depict individual values for each study participant in the exercise group, while open circles depict individual values for each study participant in the control stretching group.

Figure 6. Association between attended exercise sessions and change in muscle sympathetic nervous activity (MSNA).

(A and B) Association between attended exercise sessions and the change from baseline to 12 weeks in MSNA burst frequency and MSNA burst incidence in the Exercise group (A and B, respectively; n = 16). The r and P values denote the linear relationship by Pearson correlation tests.