Plasma Concentrations of Extracellular DNA in Acute Kidney Injury

Abstract

Current diagnostic methods of acute kidney injury (AKI) have limited sensitivity and specificity. Tissue injury has been linked to an increase in the concentrations of extracellular DNA (ecDNA) in plasma. A rapid turnover of ecDNA in the circulation makes it a potential marker with high sensitivity. This study aimed to analyze the concentration of ecDNA in plasma in animal models of AKI. Three different fractions of ecDNA were measured—total ecDNA was assessed fluorometrically, while nuclear ecDNA (ncDNA) and mitochondrial DNA (mtDNA) were analyzed using quantitative real-time PCR. AKI was induced using four different murine models of AKI-bilateral ureteral obstruction (BUO), glycerol-induced AKI (GLY), ischemia–reperfusion injury (IRI) and bilateral nephrectomy (BNx). Total ecDNA was significantly higher in BUO (p < 0.05) and GLY (p < 0.05) compared to the respective control groups. ncDNA was significantly higher in BUO (p < 0.05) compared to SHAM. No significant differences in the concentrations of mtDNA were found between the groups. The plasma concentrations of different fractions of ecDNA are dependent on the mechanism of induction of AKI and warrant further investigation as potential surrogate markers of AKI.

Mitochondrial DNA‐Mediated Inflammation in Acute Kidney Injury and Chronic Kidney Disease

“…In the murine model of LPSinduced kidney injury, the mtDNA-CN of whole cell lysates declined [73], while the mtDNA-CN of cytoplasmic extracts increased [15], probably indicating that under cell stress, mtDNA replication was restricted but preexisting mtDNA continued to be released from the mitochondria to the cytosol. Analysis of circulating mtDNA-CN revealed that the concentration of mtDNA in plasma tended to increase although not significantly in bilateral ureteral obstruction (BUO) and ischemia-reperfusion models in mice [16]. Compared with circulating mtDNA-CN, urinary mtDNA-(UmtDNA-) CN has greater potential as an ideal indicator for AKI owing to its accessibility, correlation with renal function, and predictive value for kidney prognosis [74][75][76].…”

“…In agreement, a recent cohort study involving 4812 CKD patients demonstrated that decreased mtDNA-CN in whole blood correlated with increased all-cause mortality and infection-related deaths [ 86 ]. The level of mtDNA-CN in blood cells is negatively correlated with the occurrence and prognosis of CKD, whereas cell-free circulating mtDNA-CN tends to be positively correlated to kidney injury [ 16 ]. Of note, cell-free circulating mtDNA was also detected in abundance in healthy individuals [ 87 ].…”

“…In mechanism, tubular epithelial cell damage has been found pivotal to initiate the inflammatory response via activating resident immune cells such as macrophages and infiltrating leukocytes in the kidney, which release inflammatory mediators to amplify the cascades [10][11][12][13]. Moreover, recent studies have demonstrated that mtDNA-associated inflammatory responses were implicated in the pathogenesis of AKI and progression of CKD [14][15][16].…”

Donor-Derived Cell-Free DNA in Kidney Transplantation as a Potential Rejection Biomarker: A Systematic Literature Review

“…Homolová et al [ 107 ] studied the amount of extracellular DNA (ecDNA) in plasma in animal models of acute kidney injury (AKI). The authors identified three subtypes of ecDNA: mtDNA, nuclear ecDNA (ncDNA), and total ecDNA.…”

Dynamics of Plasma and Urinary Extracellular DNA in Acute Kidney Injury

“…We have previously shown that plasma ecDNA is increased in AKI models of glycerol-induced nephropathy and bilateral ureteral obstruction (48 h period), and bilateral nephrectomy (24 h period) [ 17 ]. However, 24 and 48 h are quite long intervals, during which kidney damage might lead to the deterioration of its function.…”