Quinolinic acid contributes to maladaptive kidney injury and acute kidney injury-to-chronic kidney disease transition.

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) remains a major 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, an intermediate in de novo nicotinamide adenine dinucleotide biosynthesis, is metabolized by quinolinate phosphoribosyltransferase (QPRT). We investigated whether QA contributes to kidney injury using models of folic acid-induced AKI-to-CKD transition and cisplatin-induced AKI, genetic and exogenous approaches to alter QA, and clinical observations. Untargeted kidney metabolomics identified QA as one of the most elevated metabolites after folic acid injury. After folic acid injury, Qprt haploinsufficiency exacerbated kidney injury and fibrosis-related gene expression; aged Qprt-haploinsufficient mice exhibited increased fibrosis-associated gene expression without overt renal dysfunction. Exogenous QA administration increased serum creatinine in uninjured mice and worsened renal dysfunction and fibrosis-related gene expression in the folic acid AKI-to-CKD model. Conversely, mice deficient in either 3-hydroxyanthranilate 3,4-dioxygenase (HAAO) or kynurenine 3-monooxygenase (KMO), which reduce flux toward QA, showed improved renal outcomes after folic acid injury and cisplatin-induced AKI. Multimodal spatial metabolomics analysis of kidney biopsies from patients with AKI revealed QA accumulation in regions of inflammatory infiltration. Last, children with CKD exhibited higher urinary QA compared with healthy individuals. These findings underscore QA as a potential mediator of kidney injury and a therapeutic target for preventing the progression from AKI to CKD.