Stage-Related Alterations in Cortical Functional Connectivity Gradients in Non-Dialysis Patients With Chronic Kidney Disease

BACKGROUND AND PURPOSE: Chronic kidney disease (CKD) is associated with brain dysfunction and an increased risk of cognitive impairment. However, it remains unclear whether functional hierarchical abnormalities are detectable in early-stage CKD and how they differ between early-stage and advanced non-dialysis CKD. MATERIALS AND METHODS: In this cross-sectional study, 96 patients with early-stage CKD (CKD1-3a), 80 patients with advanced CKD (CKD3b-5), and 75 healthy controls were enrolled. Resting-state functional magnetic resonance imaging data were analyzed using the functional connectivity gradient (FCG) framework to characterize stage-related alterations in cortical functional hierarchy. Associations among abnormal gradient metrics, Montreal Cognitive Assessment (MoCA) scores, and estimated glomerular filtration rate (eGFR) were further examined. RESULTS: Early-stage CKD showed limited abnormalities in FCG metrics, mainly involving reduced global principal gradient range and variance and lower gradient values in the default mode network. No significant regional differences remained after FDR correction in the direct comparison between early-stage CKD and healthy controls. In contrast, advanced CKD showed more extensive abnormalities across the global, network, and regional levels. In advanced CKD, abnormal principal gradient metrics were associated with lower eGFR and poorer cognitive performance. Cross-sectional statistical mediation analysis further suggested a possible indirect association pattern among renal dysfunction, reduced principal gradient range, and cognitive performance. CONCLUSIONS: Non-dialysis CKD is associated with stage-related alterations in functional brain hierarchy. Early-stage CKD is characterized by relatively limited abnormalities, whereas advanced CKD shows more widespread disruption. These findings support FCG metrics as promising neuroimaging markers of CKD-related alterations in brain functional organization.