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Altered tryptophan metabolism as a contributor to cognitive impairment in chronic kidney disease: a narrative review
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DOI：10.3389/fnins.2026.1872778.png)
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Abstract
En 中文
Approximately 40% of patients with chronic kidney disease (CKD) experience cognitive impairment (CI); which is strongly associated with increased mortality. CI is driven by multiple factors; including vascular injury; accumulation of uremic toxins; disruption of the blood–brain barrier; and chronic inflammation. Recent evidence suggests that kidney disease and neurocognitive decline are mechanistically linked through dysregulated tryptophan metabolism. Tryptophan is metabolised through three main pathways: the kynurenine; indole; and serotonin pathways; each producing bioactive metabolites with distinct neurophysiological effects. The hallmarks of CKD include chronic inflammation; gut microbial dysbiosis; and impaired renal clearance; all of which alter tryptophan metabolism. Inflammation drives tryptophan metabolism towards the kynurenine pathway; increasing the formation of neurotoxic compounds that promote oxidative stress; excitotoxicity; and neuronal injury. However; reduced availability of tryptophan for serotonin synthesis impairs serotonergic signalling and neurotransmission; as well as melatonin biosynthesis; thereby contributing to circadian rhythm disturbances and impaired glymphatic clearance. Concurrently; gut dysbiosis and reduced renal clearance promote the accumulation of indole-derived uremic toxins; leading to endothelial dysfunction; neuroinflammation; and disruption of the blood–brain barrier. This review highlights the current evidence of dysregulated tryptophan metabolism in CKD and its impact on the pathogenesis of neurocognitive complications. The review also discusses potential biomarkers and therapeutic strategies; including kynurenine pathway inhibitors; gut microbiota modulation; uremic toxin adsorption; melatonin supplementation and personalised medicine to mitigate cognitive impairment in CKD.
Keywords:
melatonin
gut microbiome
cognitive impairment
chronic kidney disease
serotonin
kynurenine
tryptophan
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