Increased level of free‐circulating MtDNA in maintenance hemodialysis patients: Possible role in systemic inflammation

BACKGROUND: Mitochondrial DNA (MtDNA) exposed to the extracellular space due to cell death and stress has immunostimulatory properties. However, the clinical significance of circulating MtDNA in maintenance hemodialysis (MHD) patients and the precise mechanism of its emergence have yet to be investigated. METHODS: This cross‐sectional study consisted of 52 MHD patients and 32 age‐ and sex‐matched healthy controls. MHD patients were further categorized into high and low circulating cell‐free MtDNA (ccf‐MtDNA) groups based on the median value. Copy number of MtDNA was quantified using TaqMan‐based qPCR. Plasma cytokines were measured using ELISA kits. Reactive oxygen species (ROS) and mitochondrial membrane potential (Δψm) in peripheral blood mononuclear cells (PBMCs) were detected using DCFH‐DA or JC‐1 staining. RESULTS: The copy numbers of ccf‐MtDNA in patients with MHD were higher than those in healthy controls, and these alterations were correlated with changes of cytokines TNF‐α and IL‐6. Adjusted model in multivariate analysis showed that the presence of anuria and longer dialysis vintage were independently associated with higher levels of ccf‐MtDNA. Meanwhile, although not statistically significant, an inverse correlative trend between urinary MtDNA and ccf‐MtDNA was observed in patients with residual urine. Afterward, using PBMCs as surrogates for mitochondria‐rich cells, we found that patients in the high ccf‐MtDNA group exhibited a significantly higher ROS production and lower Δψm in cells. CONCLUSIONS: Our data suggested that changes in ccf‐MtDNA correlate with the degree of inflammatory status in MHD patients, and that the excessive MtDNA may be caused by mitochondrial dysfunction and reduced urinary MtDNA excretion.