Circulating Mycobiota Signatures and Cardiovascular Mortality among Patients Undergoing Hemodialysis

Background Alterations of the circulating microbiota have recently been implicated in the pathogenesis of cardiometabolic disease. However, the evidence is based primarily on bacterial DNA signatures, while the characteristics and roles of circulating fungal DNA signatures (mycobiota) remain unknown. Methods In a nationwide prospective cohort of 960 hemodialysis patients, we characterized circulating cell-free mycobiota signatures in baseline serum samples using internal transcribed spacer (ITS) ribosomal DNA (rDNA) sequencing and examined their associations with all-cause and cardiovascular mortality using Cox models with adjustment for potential confounders. The added predictive ability of circulating mycobiota signatures over known risk factors for premature mortality and the mediation effect of inflammation on their association with mortality were also examined. Results In this cohort, the mean patient age was 60±13 years, 53% of patients were male, 57% had diabetes mellitus, and the median (interquartile interval [IQI]) hemodialysis vintage was 3.1 (1.5, 5.8) years. After stringent quality controls, ITS rDNA was detected in 80% of these patients. Taxonomic analysis of the detected rDNA demonstrated a total of 397 fungal taxa, including 7 phyla, 149 families, and 241 genera. During a median (IQI) follow-up of 2.2 (1.7, 2.4) years, 205 and 75 patients experienced all-cause and cardiovascular death, respectively. While circulating mycobiota signatures were not associated with all-cause mortality, higher α diversity (adjusted HR [95% CI], 1.64 [1.14-2.39] per 1 unit higher) and the presence of specific genera (3.79 [2.20, 6.51], 2.72 [1.44, 5.12], and 2.21 [1.28, 3.81] for Wallemia , Cladosporium , and Fusarium , respectively) were significantly associated with higher cardiovascular mortality, without a significant mediation effect of inflammation. Adding these genera to models with known risk factors improved cardiovascular mortality prediction. Conclusions Circulating mycobiota signatures were associated with cardiovascular mortality in hemodialysis patients, highlighting their potential as prognostic biomarkers and warranting further mechanistic investigation.