Drivers and mechanisms of cognitive decline in chronic kidney disease

Cognitive impairment is highly prevalent among individuals with chronic kidney disease (CKD). Despite its high prevalence, the contributing factors and mechanisms underlying brain-kidney dysfunction in CKD remain poorly understood. However, advances in neuroscience, including novel imaging techniques and cognitive assessment methods, have begun to clarify this complex relationship. Several factors contribute directly to cognitive decline in people with CKD, including accumulation of uraemic toxins, microvascular damage, malnutrition, chronic inflammation and disruptions in key neuroprotective pathways, such as those involving Klotho and the glymphatic system. These factors are also linked to the accelerated ageing observed in people with CKD, a key contributor to cognitive decline. However, most studies on cognition in people with CKD have been cross-sectional and associative, offering limited insight into causation. Research advances, such as studies on the effect of uraemic toxins on the blood-brain barrier and the role of the endothelial glycocalyx in vascular damage, offer promising new directions. Emerging data from longitudinal cohort studies are also enhancing our understanding of these processes, with potential implications for both the treatment of CKD-related cognitive decline and the broader issue of cognitive dysfunction in ageing populations. Here, we examine key mechanisms linking CKD to cognitive decline and consider potential therapeutic interventions.