Cardiovascular Functional Changes in Chronic Kidney Disease: Integrative Physiology, Pathophysiology and Applications of Cardiopulmonary Exercise Testing

Abstract

The development of cardiovascular disease during renal impairment involves striking multi-tiered, multi-dimensional complex alterations encompassing the entire oxygen transport system. Complex interactions between target organ systems involving alterations of the heart, vascular, musculoskeletal and respiratory systems occur in Chronic Kidney Disease (CKD) and collectively contribute to impairment of cardiovascular function. These systemic changes have challenged our diagnostic and therapeutic efforts, particularly given that imaging cardiac structure at rest, rather than ascertainment under the stress of exercise, may not accurately reflect the risk of premature death in CKD. The multi-systemic nature of cardiovascular disease in CKD patients provides strong rationale for an integrated approach to the assessment of cardiovascular alterations in this population. State-of-the-art cardiopulmonary exercise testing (CPET) is a powerful, dynamic technology that enables the global assessment of cardiovascular functional alterations and reflects the integrative exercise response and complex machinery that form the oxygen transport system. CPET provides a wealth of data from a single assessment with mechanistic, physiological and prognostic utility. It is an underutilized technology in the care of patients with kidney disease with the potential to help advance the field of cardio-nephrology. This article reviews the integrative physiology and pathophysiology of cardio-renal impairment, critical new insights derived from CPET technology, and contemporary evidence for potential applications of CPET technology in patients with kidney disease.

Keywords: VO2Peak; cardiopulmonary exercise testing (CPET); cardiovascular functional capacity; chronic kidney disease (CKD); dialysis; end-stage kidney disease (ESKD).

FIGURE 1

Traditional and novel risk factors for development of cardiovascular disease and the cardio-renal phenotype in CKD.

FIGURE 2

The Fick equation and the coupling of external and cellular respiration. The three interlinked gears represent the functional interdependence between the lungs, circulation and muscle. This facilitates O₂ transport from the lungs to the mitochondria and, in reverse, CO₂ from the muscle to the lungs (adapted from Wasserman, 1997). The detrimental multisystemic effects of kidney disease on this integrated physiological process are indicated. V̇O₂, oxygen uptake; V̇CO₂, carbon dioxide output; prod, production; consum, consumption; SV, stroke volume; HR, heart rate; CaO₂, arterial O₂ content; CaO₂, venous O₂ content; LVH, left ventricular hypertrophy.

FIGURE 3

Breath-by-breath gas exchange measurements during a ramp protocol CPET. (A) Demonstrates the linear increase in V̇O₂ in response to a linear increase in work rate. Achievement of V̇O₂Peak is confirmed by the plateau in V̇O₂ beginning at approximately 125 W. (B) Displays the derivation of the VAT using the ‘V-slope’ method. The point at which the lower (blue) and upper (red) slopes intersect indicates the VAT. V̇O₂, oxygen uptake; V̇CO₂, carbon dioxide output; VAT, ventilatory anaerobic threshold.