End-stage renal disease (ESRD) remains to be a major clinical challenge with persistently high morbidity and mortality, and its molecular mechanisms, particularly those shared among diverse primary kidney diseases during the progression to ESRD, have not been studied. Here we conducted a large-scale two-stage epigenome-wide association study of ESRD in two independent cohorts consisting of 704 controls and 1031 ESRD cases resulting from multiple kidney diseases. We identified 52 ESRD-associated differentially methylated CpG loci (DMLs) that showed consistent association effect between the two cohorts and across diverse kidney diseases. These 52 DMLs implicated 144 candidate genes that showed enrichment in calprotectin complex, RAGE receptor binding and herpes simplex virus 1 infection. Of the 52 DMLs, 5 DMLs were found to be associated with common complications of ESRD, and another 7 DMLs were also found to be associated with renal function decline in early-stage chronic kidney disease, demonstrating their potential as prognostic biomarkers for ESRD risk and related clinical complications. By identifying prognostic biomarkers and revealing the important roles of inflammation and immune dysregulation and renal fibrosis in renal progression to ESRD across diverse primary kidney diseases, our study has contributed greatly to improve clinical management and advance the development of novel therapies for ESRD.

The authors have declared no competing interest.

This project was supported by the Guangdong-Hong Kong Joint Laboratory on Immunological and Genetic Kidney Diseases (2019B121205005), National Natural Science Foundation of China (81920108008, 82170714, 32171441), Guangdong Province High-Level Hospital Construction Project (DFJHBF202101), GDPH Supporting Fund for Talent Program (DFJH2018, KY0120220261), the Guangdong Provincial Natural Science Foundation (No. 2025A1515012633), Guangzhou Science and Technology Project (202206080010), Guangdong Province High-Level Hospital Construction Project (DEHBF202101), National Key Research and Development Program of China (No. 2023YFC2605400), UIBR grant from Agency for Science, Technology and Research (A*STAR), CRF/UIBR Funding from Agency for Science, Technology and Research (A*STAR), National Medical Research Council Grants (NMRC RIE2020 Centre Grant, MOH-000066, MOH-000714-01, MOH-001688-00 and MOH-001327-02)

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