Urinary mitochondrial DNA is a biomarker of mitochondrial disruption and renal dysfunction in acute kidney injury

Abstract

Recent studies show the importance of mitochondrial dysfunction in the initiation and progression of acute kidney injury (AKI). However, no biomarkers exist linking renal injury to mitochondrial function and integrity. To this end, we evaluated urinary mitochondrial DNA (UmtDNA) as a biomarker of renal injury and function in humans with AKI following cardiac surgery. mtDNA was isolated from the urine of patients following cardiac surgery and quantified by qPCR. Patients were stratified into no AKI, stable AKI and progressive AKI groups based on Acute Kidney Injury Network (AKIN) staging. UmtDNA was elevated in progressive AKI patients, and was associated with progression of patients with AKI at collection to higher AKIN stages. To evaluate the relationship of UmtDNA to measures of renal mitochondrial integrity in AKI, mice were subjected to sham surgery or varying degrees of ischemia followed by 24 hours of reperfusion. UmtDNA increased in mice after 10-15 minutes of ischemia and positively correlated with ischemia time. Furthermore, UmtDNA was predictive of AKI in the mouse model. Finally, UmtDNA levels were negatively correlated with renal cortical mtDNA and mitochondrial gene expression. These translational studies demonstrate that UmtDNA is associated with recovery from AKI following cardiac surgery by serving as an indicator of mitochondrial integrity. Thus, UmtDNA may serve as valuable biomarker for the development of mitochondrial targeted therapies in AKI.

Urinary Mitochondrial DNA Level as a Biomarker of Acute Kidney Injury Severity

“…In the study by Whitaker et al [10] , there was a significant association between the urinary mtDNA level and renal function recovery. Similarly, we observed a higher urinary mtDNA level among subjects who died or did not recover than those who had partial or complete recovery, but the difference did not reach statistical significance.…”

“…Whitaker et al [10] examined urinary mtDNA as a biomarker of renal injury and function after cardiac surgery, but they did not find any significant difference in urinary mtDNA level between groups of different AKI severity. The apparently contradicting observation may be attributed to the difference in clinical settings: Whitaker et al specifically recruited patients with AKI after cardiac surgery [10] , while we recruited AKI patients with various etiologies. Although we did not observe any difference in urinary mtDNA level between AKI of different etiologies, the sample size of each diagnosis subgroup was small and type 2 statistical error is possible.…”

“…Since the sample sizes in both studies were small, further validation study would be necessary to confirm the role of urinary mtDNA level as a prognostic indicator. Since mitochondrial disruption results in energy depletion and incomplete renal repair [10,16] , the hypothesis that the urinary mtDNA level predicts AKI recovery has a sound theoretical basis.…”

“…Urinary mtDNA is reported to predict renal function recovery in AKI following cardiac surgery [10] . In this study, we determine whether urinary mtDNA is a marker of severity and predictor of recovery in AKI due to other etiologies.…”

Mitochondria as therapeutic targets in acute kidney injury

“…Mitochondria in the proximal tubule are also damaged by therapeutic drugs that frequently cause AKI, such as ifosfamide, cisplatin, tenofovir, and gentamicin [9]. Moreover, a very recent study suggests that elevated urinary mitochondrial DNA (mtDNA) predicts the development of AKI in humans undergoing cardiac surgery [10]. The realization that mitochondria play a central role in AKI has stimulated the search for new therapies that can target these complex and fascinating organelles.…”