Impaired Vascular Function Contributes to Exercise Intolerance in Chronic Kidney Disease

Amaryllis H. Van Craenenbroeck; Emeline M. Van Craenenbroeck; Katrijn Van Ackeren; Vicky Y. Hoymans; Gert A. Verpooten; Christiaan J. Vrints; Marie M. Couttenye


Nephrol Dial Transplant. 2016;31(12):2064-2072. 

In This Article

Abstract and Introduction


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.


Cardiovascular disease is the main cause of morbidity and mortality in patients with chronic kidney disease (CKD).[1] The risk of death, cardiovascular events and hospitalization rises sharply when the estimated glomerular filtration rate (eGFR) drops below 45 mL/min/1.73 m2, and the risk for cardiovascular events is even higher than that of progression to end-stage renal disease in these patients.[2] Exercise intolerance is an important feature in patients with CKD,[3] and its value as a prognostic factor for both increased morbidity and mortality is well established.[4–6] Reduced physical fitness results in an inability to perform daily activities and occupational tasks, with a considerable negative effect on quality of life.[7] In addition, the vulnerable CKD patient becomes prone to a sedentary lifestyle, trapped in a vicious circle of fatigue and reduced physical functioning.[8]

Peak oxygen consumption (VO2peak), the gold standard for assessing exercise capacity, is determined by the product of cardiac output and the difference in arterial and venous oxygen. Exercise intolerance can be explained by the variables that influence these factors. Hence, both oxygen delivery mechanisms (cardiac output, peripheral vascular function, erythrocyte count) and oxygen utilizing factors (skeletal muscle) can contribute to reduced exercise capacity. In the setting of CKD, uraemic myopathy and anaemia are well-known determinants of exercise intolerance.[9,10] The contribution of vascular dysfunction, characterized by endothelial dysfunction and arterial stiffness, has been largely overlooked, despite the fact that these are attractive therapeutic targets for improving exercise intolerance. Moreover, both endothelial dysfunction and arterial stiffness are directly related to increased cardiovascular mortality in CKD.[11,12]

MicroRNAs (miRNAs) are endogenous, non-coding single-stranded RNAs that repress gene expression at the post-transcriptional level.[13,14] MiRNAs detected in the circulation are released following cell death or injury, but are also actively secreted and carry genetic information from one cell to another, thereby functioning as critical regulators of cellular crosstalk.[15] As such, they are involved in a variety of cardiovascular functions, but their role in CKD-associated vascular disease is only beginning to emerge.[14,16] Recently, Bye et al.[17] reported that certain miRNAs are closely related to aerobic capacity in healthy subjects. Studying vascular-related miRNAs in exercise intolerant CKD patients is promising since it could lead to the identification of biomarkers and novel therapeutic targets.

In this observational, cross-sectional study we aimed to gain more insight into the determinants of exercise intolerance in patients with CKD, with a focus on vascular dysfunction. We therefore first explored whether endothelial dysfunction and arterial stiffness are independent determinants of exercise capacity in CKD. Second, we investigated the relation between circulating levels of vascular-related miRNAs and exercise capacity and vascular function in CKD.