Large-scale network distribution of resting-state functional abnormalities in chronic kidney disease and their...

Emerging evidence suggests that cognitive impairment in chronic kidney disease (CKD) reflects dysfunction of large-scale brain networks rather than focal regional abnormalities. However, the distribution of resting-state functional abnormalities across large-scale brain networks remains unclear. We analysed resting-state functional magnetic resonance imaging (rs-fMRI) data from 380 patients with CKD and 404 healthy controls (HCs) from an initial cohort of 1246 participants. CKD patients were further stratified into end-stage renal disease (ESRD) and non-ESRD subgroups. All participants completed neuropsychological testing and underwent rs-fMRI. Five established voxel-wise rs-fMRI measures-amplitude of low-frequency fluctuation (ALFF), fractional ALFF (fALFF), regional homogeneity (ReHo), binarized degree centrality (BDC), and weighted degree centrality (WDC)-were calculated and compared between groups. We then examined associations among imaging measures, clinical variables, and cognitive performance. Patients with CKD showed significant cognitive deficits relative to HCs, and similar patterns were observed in the ESRD versus non-ESRD comparison (all P < 0.05). Whole-brain analyses revealed widespread functional abnormalities, predominantly within the default mode network (DMN) and frontoparietal network (FPN). A similar network-level distribution was also observed in the ESRD versus non-ESRD comparison. Mediation analysis showed that reduced ALFF in the inferior parietal lobule (IPL) statistically mediated the association between lower haematocrit (HCT) and worse Line Tracing Test (LTT) performance, suggesting an anaemia-related pathway linking reduced spontaneous neural activity to cognitive dysfunction. These findings indicate that the DMN and FPN are the principal large-scale networks affected in CKD and identify IPL dysfunction as a potential target for future interventions for CKD-related cognitive impairment.