Structural Connectivity Disruption and Structural–Functional Decoupling in Working Memory Networks Across Pre-Dialysis and Maintenance Hemodialysis End-Stage Renal Disease Patients

Aims: End-stage renal disease (ESRD) is associated with working memory (WM) impairment. We assessed how structural connectivity (SC), functional connectivity (FC), and structural–functional coupling (SFC) differ between pre-dialysis ESRD (ESRDp), maintenance hemodialysis ESRD (ESRDm), and healthy controls (HCs), and how these changes relate to serum markers and WM performance. Methods: 29 ESRDp, 29 ESRDm, and 46 HCs completed 0-, 1-, and 2-back tasks, diffusion MRI, and fMRI. WM nodes were defined by overlaying a meta-analytic map with the Harvard–Oxford atlas. SC, FC, and regional SFC were computed among WM-related regions. Group differences, correlations with serum markers, and mediation models were examined. Results: ESRDp showed markedly lower n-back accuracy, longer reaction time (RT), reduced frontoparietal SC, and widespread SFC reductions compared with ESRDm and HCs, whereas ESRDm exhibited near-normal WM performance and partially restored SC/SFC. Elevated urea and lower sodium in ESRDp were associated with weaker SC and altered SFC, which related to poorer accuracy and slower RT; SC and SFC significantly mediated these associations. Conclusion: ESRDp is characterized by disruption and decoupling of WM networks, while ESRDm is associated with partial network normalization. WM-related SC and SFC combined with serum markers may help identify cognitive vulnerability in ESRD. Trial Registration: ClinicalTrials.gov identifier: NCT03961724.