Circulating Mycobiota Signatures and Cardiovascular Mortality among Patients Undergoing Hemodialysis

Key Points The characteristics and roles of circulating fungal DNA signatures (mycobiota) in patients undergoing hemodialysis remain unknown. We found that higher fungal α diversity and presence of specific fungal genera in the blood associated with higher cardiovascular mortality. Circulating mycobiota signatures may serve as novel prognostic biomarkers for premature cardiovascular mortality in 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, whereas the characteristics and roles of circulating fungal DNA signatures (mycobiota) remain unknown. Methods In a nationwide prospective cohort of 960 patients undergoing hemodialysis, we characterized circulating cell-free mycobiota signatures in baseline serum samples using internal transcribed spacer 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 age of patients was 60±13 years, 53% of patients were male, 57% had diabetes mellitus, and the median (interquartile interval) hemodialysis vintage was 3.1 (1.5–5.8) years. After stringent quality controls, internal transcribed spacer rDNA was detected in 80% of these patients. Taxonomic analysis of the detected rDNA demonstrated a total of 397 fungal taxa, including seven phyla, 149 families, and 241 genera. During a median (interquartile interval) follow-up of 2.2 (1.7–2.4) years, 205 and 75 patients experienced all-cause and cardiovascular death, respectively. Although circulating mycobiota signatures were not associated with all-cause mortality, higher α diversity (adjusted hazard ratio [95% confidence interval], 1.64 [1.14 to 2.39] per one unit higher) and the presence of specific genera (3.79 [2.20 to 6.51], 2.72 [1.44 to 5.12], and 2.21 [1.28 to 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 patients undergoing hemodialysis.