Abstract: TH-OR010
Uncovering the Metabolic Architecture of CKD Through Integrated Metabolomics, Transcriptomics, and Genetics of Human Kidney Tissue
Session Information
- CKD: Exploring Intertwined Mechanisms of Disease Progression
November 06, 2025 | Location: Room 362A, Convention Center
Abstract Time: 04:30 PM - 04:40 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Martinez Leon, Victor, Penn Medicine, Philadelphia, Pennsylvania, United States
- Susztak, Katalin, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States
Background
The mechanism of chronic kidney disease (CKD) remains unknown. Translating results from metabolic studies in animal models to humans or human biofluids in CKD is difficult. This knowledge gap poses a challenge to developing new treatments to halt its progression. We aim to identify dysregulated and causal pathways in CKD using kidney tissue.
Methods
We analyzed genotype, bulk RNA, and metabolite data from 333 kidney samples. Multivariable clinical regression identified significant metabolites and expressed genes, which were used for joint pathway and enrichment analyses to identify pathways in CKD. Metabolite quantitative trait loci analysis (QTL) identified variants associated with metabolite levels. Mendelian randomization using metabolite QTLs and eGFR GWAS revealed metabolites in the causal pathway of CKD, and their variants in high linkage disequilibrium were matched with known eGFR GWAS loci from multi-ancestry data, allowing the identification of genes associated with those metabolites.
Results
Joint pathway and enrichment analyses identified arginine biosynthesis, the citrate cycle, and valine, leucine, and isoleucine degradation as top dysregulated pathways in CKD. Mendelian randomization showed N-acetyl-isoleucine and decadienedioic acid as causal for CKD. Significant variants in high linkage disequilibrium for N-acetyl-isoleucine were mapped to the NAT8 locus, and those for decadienedioic acid to the ACOT1/4 locus. NAT8 encodes the N-acetyl-transferase 8 that adds acetyl groups to isoleucine, reducing its catabolism to supply substrates to the citrate cycle and lower mTORC activity, both of which may lead to renal cell injury. ACOT1/4 encodes acyl-CoA thioesterase, which converts acyl-CoA to fatty acids (FA) and CoA, shifting FA metabolism to omega oxidation, increasing decadienedioic acid, reducing beta-oxidation and citrate cycle substrates, and raising reactive oxygen species from FA accumulation, causing kidney cell injury.
Conclusion
This is the first study integrating genetics, transcriptomics, and metabolomics analyses of kidney tissue. We identified N-acetyl-isoleucine associated with NAT8 and decadienedioic acid with ACOT1/4 as part of causal pathways in CKD. These pathways may offer new therapeutic opportunities in CKD.
Funding
- NIDDK Support