The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) represents a critical determinant of long-term prognosis, yet the underlying immunometabolic mechanisms remain incompletely defined. Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of the kynurenine pathway (KP) of tryptophan (Trp) metabolism, has emerged as a pivotal metabolic-immune checkpoint linking cellular metabolism to the immune microenvironment. This review systematically delineates the dual, time-dependent roles of IDO across the AKI-to-CKD continuum. During early AKI, IDO induction confers protection through expansion of regulatory T cells, M2 macrophage polarisation and IDO2-mediated suppression of ferroptosis via glutathione peroxidase 4 stabilisation. However, sustained IDO activation drives a pathogenic phenotype: persistent Trp depletion activates general control non-derepressible 2 kinase and the DNA damage response, toxic metabolites, including quinolinic acid (QA), promote tubular dysfunction and fibrosis, nicotinamide adenine dinucleotide (NAD+) supply contracts, and sustained aryl hydrocarbon receptor (AhR) signalling reshapes the immune microenvironment towards fibrosis. Concurrently, IDO impairs peritubular capillary stability, and hypoxia-inducible factor (HIF)–AhR crosstalk via their shared aryl hydrocarbon receptor nuclear translocator (ARNT/HIF-1β) dimerisation partner amplifies pro-fibrotic transcription. We synthesise the mechanisms driving this functional reversal, evaluate the kynurenine-to-tryptophan ratio as a candidate biomarker for AKI-to-CKD risk stratification benchmarked against conventional renal biomarkers, and propose a precision-timed intervention toolkit, including selective IDO1 inhibitors, AhR modulators, NAD+ precursors, QA scavengers, and senolytic combinations—informed by clinical trial experience from oncology. Gene knockout studies that establish causal roles of IDO and downstream targets are systematically reviewed. The framework reframes IDO as a stage-specific metabolic-immune switch whose targeted modulation offers a tractable route to prevent renal fibrosis after AKI.
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2026 The Author(s). Clinical and Translational Discovery published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.
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