Urinary mitochondrial DNA Identifies Renal Dysfunction and Mitochondrial damage in Sepsis-induced Acute Kidney Injury

Author(s):
Qiong-yuan Hu; Jianan Ren; Xiuwen Wu

Background:

Recent animal studies have shown that mitochondrial dysfunction initiates and accelerates renal injury in sepsis, but its involvement in human sepsis remains unknown. Released fragments of mitochondrial genome derived from mitochondrial stress or dying cells are considered as surrogate marker of mitochondrial dysfunction. Therefore, we evaluate the urinary mitochondrial DNA (UmtDNA) as a biomarker of renal dysfunction in human with sepsis-induced acute kidney injury (AKI).

Hypothesis:

UmtDNA are elevated in sepsis patients with AKI, and correlated with markers of renal dysfunction, which implicating mitochondrial damage in kidney damage in sepsis-induced AKI patients.

Methods:

DNA was isolated from plasma and urine of patients, and mtDNA levels were quantified by quantitative PCR using mtDNA-specific genes COX3 and ND1. Sepsis patients were stratified into no AKI, mild AKI and severe AKI groups according to RIFLE criteria. Additionally, cecal ligation and puncture (CLP) was established in rats to evaluated the relationship of UmtDNA to mitochondrial integrity in AKI following sepsis.

Results:

A total of 52 (49.5%) developed AKI among enrolled sepsis patients (n=105). Increased systemic mtDNA do not correlate with systemic inflammation or renal dysfunction in sepsis patients, meanwhile AKI does not have additional effect on circulating mtDNA levels. In contrast, UmtDNA was significantly elevated in severe AKI patients, compared with mild AKI or no AKI group, and directly correlated with plasma creatinine, urinary neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1, and inversely with estimated glomerular filtration rate. Additionally, UmtDNA increased in rat following CLP-induced sepsis. UmtDNA was predictive of AKI development, and correlated with plasma creatinine and blood urea nitrogen in rat sepsis model. Finally, UmtDNA level was inversely correlated with renal cortical mtDNA copy number and relative mitochondrial gene expression.

Conclusions:

Elevated UmtDNA level correlates with mitochondrial disruption and renal dysfunction in sepsis patients, implicating mitochondrial injury in kidney damage in human sepsis. UmtDNA may serve as valuable biomarker for the occurrence of AKI and the development of mitochondrial-targeted therapies in sepsis-induced AKI.