Blood-brain barrier perturbations by uremic toxins: key contributors in chronic kidney disease-induced neurological disorders?

Chronic kidney disease is multifactorial and estimated to affect more than 840 million people worldwide constituting a major global health crisis. The number of patients will continue to rise mostly because of the aging population and the increased prevalence of comorbidities such as diabetes and hypertension. Patients with advanced stages display a loss of kidney function leading to an accumulation of, a.o. protein-bound uremic toxins that are poorly eliminated by renal replacement therapies. This systemic retention of toxic metabolites, known as the uremic syndrome, affects other organs. Indeed, neurological complications such as cognitive impairment, uremic encephalopathy, and anxiety have been reported in chronic kidney disease patients. Several factors are involved, including hemodynamic disorders and blood-brain barrier (BBB) impairment. The BBB guarantees the exchange of solutes between the blood and the brain through a complex cellular organization and a diverse range of transport proteins. We hypothesize that the increased exposure of the brain to protein-bound uremic toxins is involved in BBB disruption and induces a perturbation in the activity of endothelial membrane transporters. This phenomenon could play a part in the evolution of neurological disorders driven by this kidney-brain crosstalk impairment. In this review, we present chronic kidney disease-induced neurological complications by focusing on the pathological relationship between the BBB and protein-bound uremic toxins. The importance of mechanistically delineating the impact of protein-bound uremic toxins on BBB integrity and membrane drug transporter expression and function in brain endothelial capillary cells is highlighted. Additionally, we put forward current knowledge gaps in the literature.