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Gut microbiota is essential in patients with end-stage renal disease (ESRD) for its role in regulating host metabolism and production of uremic toxins, however, the understanding of the holistic gut ecosystem and its functional capacity in such patients is still insufficient. Herein, we performed a metagenome-wide association study on feces from two independent Chinese cohorts comprising 378 hemodialytic ESRD patients and 290 healthy volunteers. We identified a set of 348 ESRD-associated species and functionally characterized them using a genome-centric strategy, revealing numerous taxa-specific functions (e.g., antimicrobial resistance, aromatic compounds degradation, biosynthesis of small bioactive molecules) that interconnected to disease. We also demonstrated the effectiveness of gut bacterial abundances in predicting serum uremic toxin concentrations across different cohorts. Furthermore, the majority of ESRD-associated microbial signatures were reproducible in the gut microbiome of 47 additional non-dialyzed chronic kidney disease patients. Our results delineate the taxonomic and functional landscape of the ESRD microbiome and provide biomarkers that aid in future mechanism and clinical intervention studies.