Uremic Toxins, Chronic Kidney Disease, and Cognitive Dysfunction

Abstract Cognitive impairment involves alterations to one’s cognitive status that affects their everyday life. Individuals with chronic kidney disease (CKD), and in particular kidney failure, experience higher rates of cognitive impairment compared to the general population. In CKD, 20-70% of individuals have cognitive impairment, but the highest prevalence is described in kidney failure such that dialysis-dependent patients have twice the prevalence of aged-matched controls. In the past 5 years, the number of investigations examining the “kidney-brain axis”, mechanisms of CKD-related cognitive impairment, and potential therapeutics have exponentially increased. This review article summarizes recent literature on direct and indirect effects of CKD-associated cognitive impairment with emphasis on uremic toxins; brain injury mechanisms; overlap between CKD-associated cognitive impairment, Alzheimer’s disease, and other neurodegenerative diseases; and promising therapeutics. Reviewed therapeutic interventions include: AST-120 [indoxyl sulfate absorbent], CH-223191 [aryl hydrocarbon receptor antagonist], TRAM34 [Kca3.1-specific inhibitor], anakinra [IL-1R inhibitor], marimastat, exercise, supplements, and kidney transplantation. Special focus is placed on translational studies examining uremic toxin-associated pathogenic processes including brain oxidative stress, neuroinflammation, and blood brain barrier dysfunction through in vitro and in vivo models of CKD-associated brain injury. Finally, future research directions are suggested including targeting of cellular senescence abundance with senotherapeutics and capitalizing on anti-inflammatory effects of regenerative, cell-based therapeutics (e.g. mesenchymal stem cells and extracellular vesicles), and use of aged murine models. Collectively, CKD-associated cognitive impairment represents a prevalent condition for which remaining knowledge gaps exist, and scientific advancements are needed to preserve cognitive function and improve the lives of in individuals with CKD.