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Mechanisms of cognitive dysfunction in CKD

Abstract

Cognitive impairment is an increasingly recognized major cause of chronic disability and is commonly found in patients with chronic kidney disease (CKD). Knowledge of the relationship between kidney dysfunction and impaired cognition may improve our understanding of other forms of cognitive dysfunction. Patients with CKD are at an increased risk (compared with the general population) of both dementia and its prodrome, mild cognitive impairment (MCI), which are characterized by deficits in executive functions, memory and attention. Brain imaging in patients with CKD has revealed damage to white matter in the prefrontal cortex and, in animal models, in the subcortical monoaminergic and cholinergic systems, accompanied by widespread macrovascular and microvascular damage. Unfortunately, current interventions that target cardiovascular risk factors (such as anti-hypertensive drugs, anti-platelet agents and statins) seem to have little or no effect on CKD-associated MCI, suggesting that the accumulation of uraemic neurotoxins may be more important than disturbed haemodynamic factors or lipid metabolism in MCI pathogenesis. Experimental models show that the brain monoaminergic system is susceptible to uraemic neurotoxins and that this system is responsible for the altered sleep pattern commonly observed in patients with CKD. Neural progenitor cells and the glymphatic system, which are important in Alzheimer disease pathogenesis, may also be involved in CKD-associated MCI. More detailed study of CKD-associated MCI is needed to fully understand its clinical relevance, underlying pathophysiology, possible means of early diagnosis and prevention, and whether there may be novel approaches and potential therapies with wider application to this and other forms of cognitive decline.

Key points

  • Cognitive impairment is more common in patients with chronic kidney disease (CKD) and those with reduced renal function than in the general population.

  • Cognitive dysfunction in patients with CKD ranges in severity from mild cognitive impairment (MCI) to dementia and involves deficiency in multiple cognitive domains, such as memory, attention, language and visuospatial skills, and executive functions.

  • Brain dysfunction in patients with CKD likely results from uraemic neurotoxins interacting with neural progenitor cells, the brain vasculature, the glymphatic system and monoaminergic neurons.

  • Targeting these mechanisms could potentially reduce the burden of dementia in CKD and might aid in the discovery of improved treatments for other forms of cognitive impairment.

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Fig. 1: Prevalence of MCI.
Fig. 2: Brain modifications in CKD.
Fig. 3: The hierarchical organization connecting CKD to behaviour.
Fig. 4: Mechanisms of uraemic toxin transport in the brain.
Fig. 5: Mechanism of action of some uraemic neurotoxins and their interaction with genetic predisposing factors.

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Acknowledgements

The authors’ work was supported by the Swiss National Science Foundation (C.A.W.) and VALERE Programme by the University of Campania Luigi Vanvitelli (G.C.).

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Allen Brain Atlas database: https://human.brain-map.org/

ARCHS4 database: https://amp.pharm.mssm.edu/archs4/index.html

EUTOX: http://www.uremic-toxins.org/DataBase.html

Human Protein Atlas database: https://www.proteinatlas.org/

WikiPathways database: https://www.wikipathways.org/index.php/WikiPathways

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Viggiano, D., Wagner, C.A., Martino, G. et al. Mechanisms of cognitive dysfunction in CKD. Nat Rev Nephrol 16, 452–469 (2020). https://doi.org/10.1038/s41581-020-0266-9

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