Lisa Bevilacqua

Chronic kidney disease (CKD) is a progressive condition characterized by persistent kidney abnormalities with systemic consequences. Beyond its metabolic and cardiovascular complications, CKD has been associated with structural and functional brain alterations that are particularly evident in advanced stages and in patients undergoing hemodialysis (HD). Deficits across multiple cognitive domains are frequently observed and may compromise treatment adherence, clinical management, and quality of life, yet remain largely underrecognized in clinical practice. Older adults are particularly vulnerable. Age-related brain changes and comorbidities may increase susceptibility to CKD-related cerebral alterations, while reduced cognitive reserve may amplify clinical impact. The gut–kidney–brain axis has emerged as a relevant biological pathway, with CKD-related dysbiosis potentially influencing inflammation, metabolic homeostasis, and the generation of uremic metabolites linked to neurological dysfunction. This review examines the mechanisms contributing to brain vulnerability in older adults with CKD, with specific attention to patients undergoing HD, and discusses challenges in the recognition and assessment of cognitive impairment in this population. It further explores microbiota-targeted nutritional strategies as potentially modifiable approaches to modulate gut-derived metabolic and inflammatory processes relevant to brain health, although current evidence for direct effects on cognitive outcomes remains limited.

The choroid plexus (ChP) is a complex ventricular structure that forms a semi-permeable barrier between the blood and cerebrospinal fluid (CSF). It is responsible for CSF secretion and clearance, contains macrophages, and is one of the few sites within the central nervous system (CNS) where T cells are present. Additionally, the ChP plays a role in detecting peripheral inflammation, which leads to the modulation of its epithelial cell function. Despite its critical importance in maintaining brain homeostasis, the ChP is often overlooked, particularly concerning the changes it undergoes with aging, such as reduced barrier function, impaired CSF production, and altered immunosurveillance. These age-related alterations may contribute to several harmful effects, including neuroinflammation and oxidative damage, potentially predisposing individuals to neurodegenerative conditions. Although knowledge is still limited, gut dysbiosis and decreased Klotho levels—of which the ChP is one of the main sources—appear to be significant contributors to ChP impairments. This narrative review will examine the impact of age-related gut dysbiosis on the CNS, focusing on the ChP, and explore the effects of reduced Klotho levels in this brain structure. We will also propose the hypothesis that combining the administration of probiotics capable of restoring gut microbiota eubiosis with gene therapy to upregulate Klotho in the ChP could help preserve the structural and functional integrity of the aging brain. Finally, we will provide a technical overview to ensure that vectors encoding Klotho cDNA achieve maximum specificity for the ChP, thereby avoiding off-target effects. Graphical abstract