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

Abstract

BackgroundCardiovascular mortality in chronic kidney disease (CKD) remains disproportionately high, yet the mechanisms linking renal dysfunction to cardiac vulnerability are incompletely understood. Uraemic cardiomyopathy is increasingly recognised as a systemic metabolic disease, but the contribution of multi-organ bioenergetic failure in cardiac dysfunction is poorly defined. HypothesisCKD induces metabolic remodelling across peripheral organs (liver, skeletal muscle, and kidneys) depleting systemic bioenergetic reserve, compromising cardiometabolic flexibility and stress resilience. MethodsUsing CKD models of different aetiologies in rats (glomerulosclerosis by partial nephrectomy and interstitial fibrosis by adenine diet) we investigated cardiac and systemic metabolic remodelling. ResultsIrrespective of aetiology, renal insufficiency resulted in cardiac dysfunction including impaired functional recovery after 25-minutes ischaemia. 1H NMR metabolomic analysis revealed perturbations of systemic metabolism in CKD were more severe than cardiometabolic changes with alterations of skeletal muscle, liver, and kidney metabolism indicating reduced systemic bioenergetic reserve. This pre-clinical observation was recapitulated in human CKD patients where phosphorus magnetic resonance spectroscopy assessment of exercising lower leg muscle identified bioenergetic deficiencies preventing maximal force generation. Thus, both heart and skeletal muscles in CKD have impaired response to metabolic stress. ConclusionsCKD induces multi-organ metabolic failure that limits the hearts ability to meet energetic demands under stress. This study identifies systemic bioenergetic collapse as a contributing factor to uraemic cardiomyopathy, thus targeting peripheral organ metabolism may represent a novel therapeutic strategy to improve cardiac outcomes in CKD. Key learning pointsO_ST_ABSWhat Was KnownC_ST_ABSCKD significantly increases cardiovascular risk, but the cause of heart failure in these patients is largely attributed to cardiac pathology alone whilst the potential contribution of systemic metabolic dysfunction remains unexplored. What This Study AddsUtilising clinical and pre-clinical approach we show that CKD triggers widespread metabolic dysfunction in the liver, skeletal muscle, and kidney, depleting the systemic bioenergetic reserve and impairing the hearts ability to handle metabolic stress. Potential ImpactThese findings show uraemic cardiomyopathy is a multi-organ metabolic disease and targeting peripheral metabolic dysfunction could offer a new therapeutic strategy to enhance cardiac resilience by restoring systemic energy balance.