The Kidney–Brain Axis in Chronic Kidney Disease: Uremic Toxins, Cognitive Decline, Mechanistic Pathways, Biomarkers and Therapeutic Perspectives

Chronic kidney disease is increasingly recognised as a systemic disorder with important neurological consequences, including cognitive impairment. However, the field remains challenging because CKD-related cognitive decline involves diverse uremic toxins, overlapping vascular, inflammatory, metabolic, endothelial, and neurodegenerative pathways, inconsistent cognitive screening practices, and no unified treatment strategy. Within this context, the kidney–brain axis provides a useful framework for integrating renal dysfunction, toxin retention, systemic inflammation, blood–brain barrier disruption, and cognitive vulnerability. Of these mechanisms, uremic neurotoxicity offers a biologically credible connection between compromised renal clearance and cerebral dysfunction. Retained solutes such as indoxyl sulfate, p-cresyl sulfate, indole-3-acetic acid, trimethylamine-N-oxide, urea, guanidino compounds, lanthionine, quinolinic acid, and homocysteine may induce endothelial injury, oxidative stress, neuroinflammation, mitochondrial dysfunction, excitotoxicity, and glial activation. Although these pathways are supported by experimental and translational studies, direct causal evidence in humans remains limited, and most clinical data should currently be interpreted as associative rather than definitive proof of causality. These processes converge on neuronal and synaptic vulnerability and may elucidate the distinctive cognitive profile associated with chronic kidney disease, particularly deficits in attention, processing speed, and executive function. This review summarizes the most recent evidence on the epidemiology and clinical phenotype of cognitive impairment in chronic kidney disease. It also discusses the molecular and cellular mechanisms of uremic neurotoxicity and examines new biomarkers of the kidney–brain axis, including neurofilament light chain, glial fibrillary acidic protein, brain-derived neurotrophic factor, tight junction proteins, and uremic toxins. However, these biomarkers remain insufficiently validated for routine clinical use, as their interpretation is complicated by reduced renal clearance, systemic inflammation, comorbid vascular disease, methodological heterogeneity, and the lack of longitudinal studies linking biomarker changes to cognitive outcomes. Therapeutic strategies targeting uremic toxins remain compelling from a mechanistic standpoint, but they are not yet fully developed in clinical practice. Subsequent research ought to amalgamate toxin profiling, cognitive phenotyping, neuroimaging, endothelial and inflammatory biomarkers, alongside patient-centered outcomes. Integrating cognitive assessment into nephrology care may enhance risk stratification, collaborative decision-making, and personalised management for patients with chronic kidney disease.