Integrated landscape of renal metabolism in domestic cats with spontaneous chronic kidney disease: a multi-omics study

Chronic kidney disease (CKD) is the leading cause of mortality in aged cats. After injury, feline kidneys undergo extensive metabolic reprogramming, but a comprehensive evaluation is lacking. We integrate serum metabolome from 15 early stages, 6 late stages CKD and 14 healthy control cats, with renal cortex and medulla transcriptome and proteome. Our analysis reveals spatiotemporal patterns of gene and protein expression changes. In the early stages, there are ~2000 differentially expressed genes in the medulla, but 6 in the cortex. The number in the cortex increases to >4000 in the late stages. We provide evidence of deranged bioenergetics in CKD: circulating fatty acids and acylcarnitines accumulate, while genes and proteins involved in fatty acid transport and oxidation are downregulated. Glucose and pyruvate metabolism is altered in CKD. Impaired glutamine metabolism contributes to both energy deficiency and acid-base imbalance. Additionally, there is a downregulation of redox enzymes, and overexpression of proinflammatory and profibrotic markers in CKD. Finally, hypoxia signaling pathway is upregulated, and negatively correlated with SGLT2 expression. These data unveil profound metabolic abnormalities in feline CKD. Overall design: 40 samples total, 22 kidney cortex and 18 kidney medulla from 23 separate cats, with 6 non-CKD control, 10 CKD stage 1/2 and 7 CKD stage 3/4 cats.