Quinolinic acid metabolism may mitigate AKI to CKD transition.

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a significant clinical problem with unclear underlying mechanisms. Emerging evidence suggests that alterations in tryptophan metabolism, particularly in the production of downstream metabolites such as quinolinic acid (QA), play a role in renal pathophysiology. QA is a NAD biosynthesis intermediate metabolized by the enzyme quinolinate phosphoribosyltransferase (QPRT). In this study, we investigated the role of QA in the AKI-to-CKD transition using experimental mouse models and clinical observations and leveraging multiple omics approaches. Systematic metabolomic profiling identified endogenous QA as one of the most significantly elevated metabolites following folic acid-(FA) induced injury. Exogenous QA exacerbated FA-induced kidney dysfunction. Conversely, aged mice deficient in QPRT showed worsened expression of kidney fibrosis markers even in absence of kidney injury, while younger littermates exhibited worsened induced kidney injury. Mice lacking QA-producing enzymes resisted experimental AKI and AKI-to-CKD progression. Multimodal spatial metabolomics analysis of human AKI kidney biopsies revealed QA accumulation in regions of inflammatory infiltration. Finally, children with CKD exhibited higher urinary QA levels compared to healthy controls. These findings underscore QA as a potential mediator of kidney injury and a therapeutic target for preventing the progression from AKI to CKD.