Clinical relevance of cell-free mitochondrial DNA during the early postoperative period in kidney transplant recipients

Abstract

Recent studies indicate that urinary mitochondrial DNA (mtDNA) is predictive of ischemic AKI and is related to delayed graft function (DGF) in renal transplantation. Nevertheless, the clinical implications and prognostic value of urinary mtDNA in kidney transplantation remain undetermined. 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. A total of 85 renal transplant recipients were enrolled, and blood and urine samples were collected at a median of 17 days after transplantation. Cell-free nuclear and mtDNA levels were measured by quantitative polymerase chain reaction for LPL and ND1 genes. Urinary cell-free mtDNA levels were significantly higher in patients with DGF (P < 0.001) and cases of deceased donor transplantation (P < 0.001). The subjects with acute rejection showed higher urinary mtDNA levels than those without abnormalities (P = 0.043). 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. 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.

Recent Advances on Biomarkers of Early and Late Kidney Graft Dysfunction

“…Urinary levels of cell-free mitochondrial DNA during early post-transplant phase have also been reported to correlate with AR, DGF and short-term renal function [ 76 ].…”

Mitochondria as Therapeutic Targets in Transplantation

“…Recently there has been greater understanding of how mitochondrial metabolism contributes to cell damage in general [15][16][17][18][19], and to poor outcome in transplantation in particular [20][21][22][23][24]. We discuss the mitochondrial and metabolic changes that contribute to tissue damage during transplantation and consider how to target these pathways therapeutically.…”

“…In addition, in response to cell death DAMPs such as mitochondrial DNA (mtDNA) are released by damaged mitochondria into the cell, which activate the innate immune response locally [61][62][63]. mtDNA can be released into the circulation and activate immune responses [21,24], as can metabolites such as succinate, which can go on to activate the SUCNR1 receptor and potentially enhance immune responses [64][65][66]. These inflammatory effects can contribute to organ rejection and long-term graft failure.…”

“…The precise duration depends on the quality of the organ, with organs from young, healthy donors being better able to tolerate longer periods of cold ischemia. Despite its widespread use and importance for transplantation, our understanding of why cold storage is protective is incomplete, and our understanding of the critical metabolic and mitochondrial changes that occur during organ retrieval, storage, and implantation in the recipient has lagged behind technical and immunological advances.Recently there has been greater understanding of how mitochondrial metabolism contributes to cell damage in general [15][16][17][18][19], and to poor outcome in transplantation in particular [20][21][22][23][24]. We discuss the mitochondrial and metabolic changes that contribute to tissue damage during transplantation and consider how to target these pathways therapeutically.…”

Donor plasma mitochondrial DNA is associated with antibody-mediated rejection in renal allograft recipients

“…When the dmtDNA level was >0.133, the probability of DGF in the recipients was 50%. Another study has shown that urinary mtDNA levels are significantly associated with DGF short-term post-transplant renal function, acute rejection of the graft biopsy [ 23 ]. Therefore, dmtDNA could be a new noninvasive predictor of DGF, this finding is of great significance for application in the clinical setting.…”