Elevated levels of circulating mitochondrial DNA predict early allograft dysfunction in patients following liver transplantation.

Abstract

The role of circulating mitochondrial DNA (cmtDNA) in transplantation remains to be elucidated. cmtDNA may be released into the circulation as a consequence of liver injury; yet recent work also suggests a causative role for cmtDNA leading to hepatocellular injury. We hypothesized that elevated cmtDNA would be associated with adverse events after liver transplantation (LT) and conducted an observational cohort study. Twenty-one patients were enrolled prospectively prior to LT. Postoperative complications were observed in 47.6 % (n=10). Seven patients (33.3%) had early allograft dysfunction (EAD) and six patients (28.5%) experienced acute cellular rejection within six months of LT. cmtDNA levels were significantly elevated in all recipients post-LT compared with healthy controls and pre-operative samples (1,361,937 copies/ml [IQR 586,781 - 3,399,687] post-LT; 545,531 copies/ml [IQR 238,562-1,381,015] pre-LT; 194,562 copies/ml [IQR 182,359-231,515] in healthy controls) and returned to normal levels by five days after transplantation. cmtDNA levels were particularly elevated in those who developed EAD in the early post-operative period (p < 0.001). In all patients there was initially a strong overall positive correlation between cmtDNA and plasma hepatocellular enzyme levels (p <0.05). However, the patients with EAD demonstrated a second peak in cmtDNA at post-operative day seven, which did not correlate with liver function tests. The early release of plasma cmtDNA is strongly associated with hepatocellular damage; however, the late surge in cmtDNA in patients with EAD appeared to be independent of hepatocellular injury as measured by conventional tests.