Altered systemic bioenergetic reserve in chronic kidney disease predisposes hearts to worse functional outcomes

Abstract

Abstract Chronic kidney disease (CKD) is characterised by progressive loss of kidney function and structural damage, which contributes to systemic complications, including cardiovascular dysfunction. Inter-organ metabolic interactions are increasingly recognised as important in the pathophysiology of CKD, but the extent to which systemic bioenergetic deficits contribute to cardiac dysfunction remains unclear. We investigated cardiac and systemic metabolic remodeling in two rat models of CKD with distinct aetiologies: glomerulosclerosis induced by partial nephrectomy and interstitial fibrosis induced by an adenine-rich diet. Despite differing renal pathology, both models exhibited comparable cardiac dysfunction, including impaired recovery following 25 min of ischaemia. 1 H NMR spectroscopy metabolomic analysis revealed that systemic metabolic alterations in skeletal muscle, liver, and kidney were more pronounced than those in the heart, indicating reduced systemic bioenergetic reserve. These findings were supported by data from CKD patients, in whom 31 P NMR spectroscopy of exercising skeletal muscle demonstrated impaired phosphocreatine recovery, consistent with diminished bioenergetic capacity and reduced force generation. These results suggest that systemic bioenergetic impairment contributes to CKD-associated cardiac dysfunction. Targeting systemic metabolic derangements may represent a novel strategy to improve cardiac outcomes in CKD.