Multi-Omics Study Reveals Metabolic Reprogramming in Feline Chronic Kidney Disease

Chronic kidney disease is the ultimate final boss of feline medicine. It affects more than 30 percent of cats over the age of 10 and remains the leading cause of death in senior cats. Despite how common it is, CKD has long been a black box at the metabolic level. We have known what it looks like clinically but not exactly how the feline kidney rewires itself as disease progresses. A new integrated multi-omics study changes that. By combining serum metabolomics with renal tissue transcriptomics and proteomics, researchers mapped how metabolism shifts across kidney regions and disease stages in cats with spontaneous CKD. The result is the most detailed metabolic roadmap of feline CKD to date and one that has clear implications for diagnosis, staging, and future therapies.

The kidney is a metabolic powerhouse packed with mitochondria. Different nephron segments rely on different fuels. Proximal tubular cells prefer fatty acids and glutamine, glomeruli lean on glucose, and the inner medulla survives on anaerobic glycolysis. When injury hits, that finely tuned system adapts, and not always in a good way. Multi-omics allows us to zoom out and see the whole system at once. Instead of guessing based on one pathway or one biomarker, this approach connects circulating metabolites with gene expression and protein abundance in both the cortex and medulla. It is systems biology for clinicians who want to understand why CKD progresses the way it does.

One of the most striking findings is how early and how intensely the renal medulla responds. In early stage CKD, only six genes were differentially expressed in the cortex. In the medulla, nearly 2000 genes were already altered. By late stage disease, the cortex catches up with more than 4000 differentially expressed genes. This spatiotemporal pattern reinforces the idea that CKD is not a uniform process. Different kidney regions are on different timelines, which may explain why early disease is so hard to detect clinically.

The metabolic signature of feline CKD is one of energy failure. Circulating fatty acids and acylcarnitines accumulate in the blood, while the kidney downregulates genes and proteins responsible for fatty acid transport and oxidation. In simple terms, fuel is available but the kidney cannot use it efficiently. Glucose and pyruvate metabolism are also altered, suggesting a broader disruption in ATP generation. Glutamine metabolism is impaired as well, contributing not only to energy deficiency but also to acid base imbalance, a familiar clinical challenge in CKD cats.

As energy production falters, redox balance suffers. The study shows a downregulation of key redox enzymes, leaving renal tissue more vulnerable to oxidative injury. At the same time, proinflammatory mediators are overexpressed, creating a feedback loop that promotes ongoing damage. Fibrosis emerges as a central theme. Expression of TGFβ1 is strongly and positively correlated with other fibrogenic genes, reinforcing its role as a master regulator of tubulointerstitial fibrosis in cats. This mirrors what is seen in human CKD and strengthens the value of feline CKD as a translational model.

Oxygen homeostasis is profoundly disrupted. Hypoxia signaling pathways are upregulated, while expression of the SGLT2 gene and protein is downregulated in cats with CKD. Given the high oxygen demands of proximal tubular cells, this combination creates a perfect storm for progressive injury.

These findings support the theory that hypoxia is not merely a downstream effect of CKD but an active driver of inflammation and fibrosis. For veterinary professionals, this study reframes feline CKD as a disease of metabolic collapse rather than simple loss of nephrons. It highlights potential early biomarkers, underscores the importance of energy metabolism, and points toward future interventions targeting fatty acid oxidation, mitochondrial health, inflammation, and hypoxia signaling.

It also reinforces the relevance of cats as a naturally occurring model for human CKD, opening doors for cross species insights that benefit both feline and human patients. Feline CKD is not a slow fade. It is an active, staged metabolic rewrite that begins earlier and deeper in the kidney than we once thought. Understanding these changes moves us closer to earlier detection and smarter therapies, and gives us a clearer picture of what our aging feline patients are really up against.

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