Introduction: End-stage renal disease (ESRD) results in immune dysfunction that is characterized by both systemic inflammation and immune incompetence, leading to impaired responses to vaccination. Methods: To unravel the complex regulatory immune interplay in ESRD, we performed the network-based transcriptomic profiling of ESRD patients on maintenance hemodialysis (HD) and matched healthy controls (HCs) who received the two-dose regimen of the COVID-19 mRNA vaccine BNT162b2. Results: Co-expression networks based on blood transcription modules (BTMs) of genes differentially expressed between the HD and HC groups revealed co-expression patterns that were highly similar between the two groups but weaker in magnitude in the HD compared to HC subjects. These networks also showed weakened coregulation between BTMs within the dendritic cell (DC) family as well as with other BTM families involved with innate immunity. The gene regulatory networks of the most enriched BTMs, likewise, highlighted weakened targeting by transcription factors of key genes implicated in DC, natural killer (NK) cell, and T cell activation and function. The computational deconvolution of immune cell populations further bolstered these findings with discrepant proportions of conventional DC subtypes, NK T cells, and CD8+ T cells in HD subjects relative to HCs. Conclusion: Altogether, our results indicate that constitutive inflammation in ESRD compromises the activation of DCs and NK cells, and, ultimately, their mediation of downstream lymphocytes, leading to a delayed but intact immune response to mRNA vaccination.
