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Quinolinic acid potentially links kidney injury to brain toxicity

A. Saliba, S. Debnath, I. Tamayo, HJ. Lee, N. Ragi, F. Das, R. Montellano, J. Tumova, M. Maddox, E. Trevino, P. Singh, C. Fastenau, S. Maity, G. Zhang, L. Hejazi, MA. Venkatachalam, JC. O'Connor, B. Fongang, SC. Hopp, KF. Bieniek, JD. Lechleiter,...

. 2025 ; 10 (6) : . [pub] 20250213

Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc25009884

Grant support
T32 AG021890 NIA NIH HHS - United States
I01 BX003234 BLRD VA - United States
K01 AG066747 NIA NIH HHS - United States
TL1 TR002647 NCATS NIH HHS - United States
P30 AG066546 NIA NIH HHS - United States
U01 DK114920 NIDDK NIH HHS - United States
K01 NS126489 NINDS NIH HHS - United States
I01 BX001340 BLRD VA - United States
T32 HL007446 NHLBI NIH HHS - United States

Kidney dysfunction often leads to neurological impairment, yet the complex kidney-brain relationship remains elusive. We employed spatial and bulk metabolomics to investigate a mouse model of rapid kidney failure induced by mouse double minute 2 (Mdm2) conditional deletion in the kidney tubules to interrogate kidney and brain metabolism. Pathway enrichment analysis of a focused plasma metabolomics panel pinpointed tryptophan metabolism as the most altered pathway with kidney failure. Spatial metabolomics showed toxic tryptophan metabolites in the kidneys and brains, revealing a connection between advanced kidney disease and accelerated kynurenine degradation. In particular, the excitotoxic metabolite quinolinic acid was localized in ependymal cells in the setting of kidney failure. These findings were associated with brain inflammation and cell death. Separate mouse models of ischemia-induced acute kidney injury and adenine-induced chronic kidney disease also exhibited systemic inflammation and accumulating toxic tryptophan metabolites. Patients with advanced chronic kidney disease (stage 3b-4 and stage 5) similarly demonstrated elevated plasma kynurenine metabolites, and quinolinic acid was uniquely correlated with fatigue and reduced quality of life. Overall, our study identifies the kynurenine pathway as a bridge between kidney decline, systemic inflammation, and brain toxicity, offering potential avenues for diagnosis and treatment of neurological issues in kidney disease.

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