However, the differences between groups were more clearly in urinary mtDNA, which showed higher sensitivity in ROC curve analysis. Urinary nDNA and NGAL were also elevated in subjects with DGF (Fig. Furthermore, 10 patients with SGF were identified by the definition mentioned previously, and these patients showed higher urinary mtDNA levels than those with IGF. Notably, there was a significant difference in urinary mtDNA level between subjects with DGF and IGF (P < 0.001, Fig. In the present study, we evaluated the clinical implication of cell-free mtDNA during the early post-transplant period on histological and clinical parameters and examined the association between cell-free mtDNA levels and short-term graft outcome in kidney transplantation.įull size image Urinary cell-free mtDNA level and DGFĪs shown in Table 1, more patients with DGF were included in higher urinary mtDNA tertile groups. Moreover, it is uncertain whether the detected mtDNA is merely a consequence of mitochondrial damage from IRI or a causative factor for subsequent graft dysfunction, impacting as DAMP. Nevertheless, to date, there is limited research investigating the clinical implications of cell-free mtDNA in kidney transplantation. These findings suggest that mtDNA could be one of the important DAMPs in organ transplantation. Transplantation studies have demonstrated that increased extracellular mtDNA is associated with elevated levels of inflammatory cytokines, early organ dysfunction in liver transplantation 17, and DGF in kidney transplantation 18. Of these mitochondrial DAMPs, cell-free mitochondrial DNA (mtDNA) has been reported to be a predictive biomarker of the progression of acute kidney injury (AKI) 15, 16. In recent years, mitochondrial DAMPs have received considerable attention as an important mediator of tissue injury in various inflammatory conditions, including trauma, sepsis, cancer, hemodialysis, and transplantation 9, 10, 11, 12, 13, 14.
During these processes, innate immunity is triggered by the endogenous damage-associated molecular patterns (DAMPs) 6, and the activation of toll-like receptor (TLR) and related signaling pathways has been reported in previous studies 6, 7, 8. The pathophysiology of IRI includes excessive generation of reactive oxygen species (ROS) and inflammatory responses, resulting in tissue damage and cell death 5. IRI is a major risk factor for DGF and is associated with chronic allograft dysfunction and acute rejection (AR) 1, 2, 3, 4. In particular, during the early post-transplant period, the allograft is adversely affected by profound ischemia-reperfusion injury (IRI), which is inevitable but critically affects subsequent graft outcome. However, there are still significant obstacles preventing further increase in graft survival, such as delayed graft function (DGF) and allograft rejection, which is a major challenge for clinicians. Over the past decades, kidney transplantation has become the treatment of choice for end-stage renal disease, due to improvements in graft outcome. Urinary cell-free mtDNA levels during the early post-transplant period are significantly associated with DGF, acute rejection in graft biopsy, and short-term post-transplant renal function. In addition, allograft functions at 9- and 12-month post-transplantation were significantly different between tertile groups of mtDNA independent of the presence of DGF or acute rejection, showing significantly better graft outcome in the lowest tertile group. The subjects with acute rejection showed higher urinary mtDNA levels than those without abnormalities ( P = 0.043). Urinary cell-free mtDNA levels were significantly higher in patients with DGF ( P < 0.001) and cases of deceased donor transplantation ( P < 0.001).
Cell-free nuclear and mtDNA levels were measured by quantitative polymerase chain reaction for LPL and ND1 genes. A total of 85 renal transplant recipients were enrolled, and blood and urine samples were collected at a median of 17 days after transplantation. Here, we aimed to evaluate the associations between cell-free mtDNA and clinical parameters, including pathological findings in allograft biopsy and post-transplant renal function. Nevertheless, the clinical implications and prognostic value of urinary mtDNA in kidney transplantation remain undetermined. Recent studies indicate that urinary mitochondrial DNA (mtDNA) is predictive of ischemic AKI and is related to delayed graft function (DGF) in renal transplantation.