Immune Microenvironment and Genetic Signatures of End-Stage Renal Disease and Their Association with Sepsis: Insights from Public Transcriptomic Data and a Multicenter Clinical Cohort

Background: End-stage renal disease (ESRD) is an immunocompromised state that confers a high risk of infection. We aimed to integrate bioinformatics analyses with a clinical cohort to explore the association between ESRD and sepsis. Methods: We retrieved transcriptomic data from the Gene Expression Omnibus and used computational tools, including Gene Set Enrichment Analysis, the eXtreme Gradient Boosting algorithm, and Mendelian randomization, to characterize gene expression changes, biological pathways, and genetic features in ESRD and sepsis. A multicenter retrospective cohort of patients with sepsis due to carbapenem-resistant Acinetobacter baumannii (CRAB) pneumonia in intensive care units (ICUs) was used to compare clinical presentation and outcomes between patients with and without ESRD. Results: Differential gene expression analysis showed widespread transcriptomic dysregulation in ESRD, and functional enrichment analysis revealed perturbations in immune signaling and vesicular transport pathways. Both the innate and adaptive immune systems appeared compromised, with marked depletion of lymphoid lineages in ESRD. An XGBoost machine-learning model derived from immune cell enrichment scores demonstrated a similar immune microenvironment in ESRD and sepsis. Mendelian randomization analysis supported an association between genetic variants predisposing to ESRD and an increased risk of sepsis, using genome-wide association study datasets. In the clinical cohort, patients with ESRD had significantly higher Sequential Organ Failure Assessment (SOFA) scores and in-hospital mortality than patients with normal renal function. Conclusions: ESRD shares similar immune microenvironmental features and genetic signatures with sepsis. These shared characteristics may contribute to the greater sepsis severity and poorer outcomes observed in patients with ESRD.