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Urinary mitochondrial DNA associates with delayed graft function following renal transplantation.

Authors
  • Jansen, Marcel P B1
  • Pulskens, Wilco P C1
  • Uil, Melissa1
  • Claessen, Nike1
  • Nieuwenhuizen, Gerrie2
  • Standaar, Dorien2
  • Hau, Chi M3
  • Nieuwland, Rienk3
  • Florquin, Sandrine1
  • Bemelman, Frederike J2
  • Leemans, Jaklien C1
  • Roelofs, Joris J T H1
  • 1 Department of Pathology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. , (Netherlands)
  • 2 Department of Nephrology, Renal Transplant Unit, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. , (Netherlands)
  • 3 Laboratory of Experimental Clinical Chemistry, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. , (Netherlands)
Type
Published Article
Journal
Nephrology Dialysis Transplantation
Publisher
Oxford University Press
Publication Date
Aug 01, 2020
Volume
35
Issue
8
Pages
1320–1327
Identifiers
DOI: 10.1093/ndt/gfy372
PMID: 30590723
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Ischaemia-reperfusion (IR) injury is an important determinant of delayed graft function (DGF) affecting allograft function. Mitochondrial DNA (mtDNA) is released upon cell death and platelet activation into the extracellular environment and has been suggested to be a biomarker in several diseases. Whether extracellular mtDNA accumulates in plasma and/or urine upon renal IR and predisposes DGF is unknown. C57BL/6J wild-type mice were subjected to renal IR. In addition, an observational case-control study was set up enrolling 43 patients who underwent kidney transplantation. One day post-IR in mice and a few days following renal transplantation in human, blood and urine were collected. Patients were stratified into DGF and non-DGF groups. mtDNA-encoded genes accumulate in urine and plasma in both mice subjected to renal IR injury and in humans following renal transplantation. In human renal transplant recipients, cold ischaemia time and renal function correlate with urinary mtDNA levels. Urinary mtDNA levels but not urinary nuclear DNA levels were significantly higher in the DGF group compared with the non-DGF group. Multiple receiver operating characteristic curves revealed significant diagnostic performance for mtDNA-encoded genes cytochrome c oxidase III (COXIII); nicotinamide adenine dinucleotide hydrogen subunit 1 (NADH-deh); mitochondrially encoded, mitochondrially encoded nicotinamide adenine dinucleotide dehydrogenase 2 (MT-ND2) with an area under the curve of, respectively, 0.71 [P = 0.03; 95% confidence interval (CI) 0.54-0.89], 0.75 (P = 0.01; 95% CI 0.58-0.91) and 0.74 (P = 0.02; 95% CI 0.58-0.89). These data suggest that renal ischaemia time determines the level of mtDNA accumulation in urine, which associates with renal allograft function and the diagnosis of DGF following renal transplantation. © The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

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