Cardiac and Noncardiac Determinants of Exercise Capacity in CKD

Significance Statement A detailed understanding of the determinants of exercise capacity in CKD has been lacking. For the first time, the authors demonstrate the differential role of cardiac and noncardiac factors in determining exercise capacity in CKD, finding that the exercising skeletal muscles’ ability to extract oxygen is the predominant determinant of exercise capacity in CKD, followed by the heart’s ability to generate stroke volume and raise heart rate. Exercise capacity in CKD was impaired even in the absence of any known cardiac diseases or diabetes mellitus, and with a graded decline proportionate to CKD severity. These findings have significant implications in the interpretation of objective measures of exercise capacity in CKD when evaluating cardiovascular fitness, quantifying the benefits of exercise training, and selecting patients for renal transplantation. Background Impaired exercise capacity is a significant symptom of CKD and is associated with poor survival. Furthermore, there is a growing interest in applying exercise as a diagnostic tool or as therapy in CKD. However, an in-depth understanding of exercise physiology in CKD is still lacking. Methods To evaluate the role of cardiac (central) and noncardiac (peripheral) determinants of exercise capacity in CKD, we conducted a cross-sectional study of 70 male patients with CKD (stages 2–5) without diabetes or cardiac disease, 35 healthy controls, and 25 patients with heart failure. An integrated cardiopulmonary exercise test using a CO 2 rebreathing technique was used to measure peak O 2 consumption (VO 2peak ) and peak cardiac output simultaneously, and to calculate peak peripheral O 2 extraction (C[a-v]O 2 ), the peripheral determinant (the ability of exercising skeletal muscles to extract oxygen). We performed multiple regression analysis and used Bayesian information criteria (BIC) changes to quantitatively assess the individual contribution of central and peripheral factors. Results Compared with healthy controls, in patients with CKD, the VO 2peak was impaired proportionate to its severity. Peak cardiac output was the predominant determinant of VO 2peak in healthy controls and patients with heart failure, whereas C(a-v)O 2 played a more significant role in determining VO 2peak in CKD ( β =0.68, P <0.001) compared with cardiac output ( β =0.63, P <0.001). In addition, the magnitude of BIC reduction was greater for C(a-v)O 2 compared with cardiac output (BIC, 298.72 versus 287.68) in CKD. Conclusions In CKD, both peak cardiac output and peak C(a-v)O 2 are independent predictors of VO 2peak , and the more significant roleplayed by peak C(a-v)O 2 highlights the importance of noncardiac factors in determining exercise capacity in CKD.