Impaired vascular function contributes to exercise intolerance in chronic kidney disease

Abstract

Background: Exercise intolerance is an important feature in patients with chronic kidney disease (CKD) and is prognostic for both increased morbidity and mortality. Little is known about the underlying mechanisms in predialysis CKD. This study aimed to gain more insight into the role of vascular dysfunction in the exercise intolerance of predialysis CKD. In addition, vascular-related microRNAs (miRNAs)-as epigenetic regulators of exercise capacity-were analysed.

Methods: Sixty-three patients with CKD stages 1-5 and 18 healthy controls were included. Peak oxygen consumption (VO₂peak) was determined by cardiopulmonary exercise testing, endothelial function by flow-mediated dilation (FMD) and arterial stiffness by carotid-femoral pulse wave velocity (PWV). Plasma miRNA levels (miR-21, miR-126, miR-146a, miR-150 and miR-210) were quantified by quantitative RT-PCR.

Results: VO₂peak was already impaired in mild CKD (stages 1-3A) and significantly correlated with estimated glomerular filtration rate (eGFR; r = 0.525, P < 0.001). Likewise, both FMD and PWV were significantly correlated with eGFR (r = 0.319, P = 0.007 and r = -0.365, P = 0.001, respectively). In multiple regression analysis, PWV remained one of the strongest independent determinants of VO₂peak (β = -0.301, P = 0.01). Of the studied miRNA, circulating levels of miR-146a and miR-150 correlated with eGFR, PWV and VO₂peak, but the association with the latter was lost when correcting for PWV.

Conclusions: Arterial stiffness contributes to the observed reduced aerobic capacity in predialysis CKD, independent of age, haemoglobin levels and endothelial function and represents a promising therapeutic target for improving exercise capacity in this population. Future work is required to elucidate why higher circulating levels of miR-146a and miR-150 are associated with impaired renal function and increased arterial stiffness.

Keywords: arterial stiffness; chronic kidney disease; endothelial dysfunction; exercise intolerance; microRNA.