Multiscale signatures of cortical hierarchical alterations and dialysis-associated preservation in end-stage renal disease.

End-stage renal disease (ESRD) is a chronic condition associated with prominent cognitive deficits, potentially arising from disruptions in the brain's hierarchical organization. However, the underlying neurobiological mechanisms, as well as the extent to which hemodialysis-an effective treatment for ESRD-is associated with cognitive outcomes, remain unclear. In this study, we collected resting-state functional MRI data from 51 healthy controls, 54 hemodialysis-dependent ESRD patients (HD-ESRD), and 25 non-hemodialysis ESRD patients (NHD-ESRD). Functional connectivity gradients were derived and compared across groups to characterize cortical reorganization. We further integrated spatial transcriptomic data to identify molecular correlates of gradient alterations and conducted gene enrichment, neurotransmitter receptor density, and NeuroSynth-based cognitive mapping analyses to investigate multiscale mechanisms associated with ESRD-related functional reorganization. We found that ESRD patients exhibited a marked compression of cortical hierarchy, particularly within the default mode and sensorimotor networks. Compared with non-hemodialysis ESRD patients, the hemodialysis-dependent ESRD group demonstrated relative preservation of gradient organization, with longer dialysis duration and better cognitive performance associated with improved secondary gradient expression in the default mode network. Transcriptomic analyses revealed enrichment of genes related to synaptic signaling, calcium ion transport, and neuronal projection processes, predominantly expressed in excitatory, inhibitory, and astrocytic cells. Neurotransmitter and NeuroSynth decoding linked gradient alterations to distribution of serotonergic, noradrenergic, and opioid systems, aligning with cognitive domains spanning sensory processing, attention, and higher-order cognition. These findings suggest that ESRD-related alterations in cortical hierarchy are associated with molecular, neurochemical, and cognitive signatures, while the relative preservation observed in HD-ESRD patients may reflect dialysis-associated sparing.