Renin‐Angiotensin System Blockade is Associated with Exercise Capacity, Sympathetic Activity and Endothelial Function in Patients with Chronic Kidney Disease

Abstract

Chronic kidney disease (CKD) patients have exercise intolerance that is associated with cardiovascular mortality. CKD patients have exaggerated increases in blood pressure (BP) reactivity and impaired ability to maintain skeletal muscle perfusion during exercise mediated by sympathetic nervous system (SNS) overactivation and decreased nitric oxide (NO) bioavailability. Activation of the renin-angiotensin system (RAS) increases central SNS activation and reduces NO synthesis, and prior studies have suggested that RAS blockade may modulate physical function declines. The aim of this study was to investigate whether use of RAS inhibitors (RASi) is associated with greater exercise capacity in CKD, and whether greater exercise capacity with RASi is linked to lower SNS activity and increased NO-dependent endothelial function. 35 hypertensive CKD patients (56.7 ± 7.0 yr) and 20 age-matched controls without CKD (CON, 52.5 ± 8.2 yr) were recruited. Exercise capacity was measured via VO2 peak from a maximal treadmill test, muscle sympathetic nervous activity (MSNA) was measured via microneurography, and vascular endothelial function was measured by flow-mediated dilation (FMD). Participants with CKD were further grouped by current usage of RASi including angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) for group difference analyses. There were no baseline differences in demographics or hemodynamics between CKD patients with and without RASi. VO2 peak was greater in CKD patients with RASi compared to CKD patients not on RASi and lower compared to CON (23.3 ± 5.8 vs.16.4 ± 2.9, p=0.007; vs.30.0 ± 7.7, p=0.005 ml/min/kg respectively). MSNA in CKD patients with RASi was lower compared to CKD patients not on RASi but similar with CON (43.9 ± 7.1 vs. 53.8 ± 8.2; p=0.009, vs.38.0 ± 20.3; p=0.103 bursts/min respectively). FMD in CKD patients with RASi was greater compared to CKD patients not on RASi and lower compared to CON (3.2 ± 2.6 vs. 1.3 ± 1.6; p=0.007, vs. 5.0 ± 3.0; p=0.045 % respectively). VO2 peak was positively associated with FMD (r=0.417, p=0.038) and was predicted by the combination of FMD and RASi status (r2 =0.344, p=0.01) and MSNA and RASi status (r2 =0.575, p=0.040) in CKD patients. In summary, hypertensive CKD patients on RASi have better exercise capacity compared to those not on RASi. Furthermore, greater exercise capacity in RASi-treated group was associated with lower resting SNS activity and better NO-dependent vascular endothelial function. Long-term randomized trials examining the effects of RASi on physical function and underlying autonomic and vascular mechanisms are needed to determine its causal effect and its responsible mechanisms in CKD.