title: Defective postreperfusion metabolic recovery directly associates with incident delayed graft function.
abstract: Delayed graft function (DGF) following kidney transplantation affects long-term graft function and survival and is considered a manifestation of ischemia reperfusion injury. Preclinical studies characterize metabolic defects resulting from mitochondrial damage as primary driver of ischemia reperfusion injury. In a comprehensive approach that included sequential establishment of postreperfusion arteriovenous concentration differences over the human graft, metabolomic and genomic analysis in tissue biopsies taken before and after reperfusion, we tested whether the preclinical observations translate to the context of clinical DGF. This report is based on sequential studies of 66 eligible patients of which 22 experienced DGF. Grafts with no DGF immediately recovered aerobic respiration as indicated by prompt cessation of lactate release following reperfusion. In contrast, grafts with DGF failed to recover aerobic respiration and showed persistent adenosine triphosphate catabolism indicated by a significant persistently low post reperfusion tissue glucose-lactate ratio and continued significant post-reperfusion lactate and hypoxanthine release (net arteriovenous difference for lactate and hypoxanthine at 30 minutes). The metabolic data for the group with DGF point to a persistent post reperfusion mitochondrial defect, confirmed by functional (respirometry) and morphological analyses. The archetypical mitochondrial stabilizing peptide SS-31 significantly preserved mitochondrial function in human kidney biopsies following simulated ischemia reperfusion. Thus, development of DGF is preceded by a profound post-reperfusion metabolic deficit resulting from severe mitochondrial damage. Strategies aimed at preventing DGF should be focused on safeguarding a minimally required post-reperfusion metabolic competence.
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Leonie G M
authors.initials: LG
authors.lastname: Wijermars
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Schaapherder
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Dorottya K
authors.initials: DK
authors.lastname: de Vries
authors.affiliation: Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands.
authors.forename: Lars
authors.initials: L
authors.lastname: Verschuren
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU Medical Center, Amsterdam, the Netherlands.
authors.forename: Rob C I
authors.initials: RC
authors.lastname: Wüst
authors.affiliation: Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Sarantos
authors.initials: S
authors.lastname: Kostidis
authors.affiliation: Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Oleg A
authors.initials: OA
authors.lastname: Mayboroda
authors.affiliation: Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Frans
authors.initials: F
authors.lastname: Prins
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Ringers
authors.affiliation: Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Jörgen
authors.initials: J
authors.lastname: Bierau
authors.affiliation: Department of Clinical Chemistry, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Jaap A
authors.initials: JA
authors.lastname: Bakker
authors.affiliation: Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research (TNO), Leiden, the Netherlands.
authors.forename: Teake
authors.initials: T
authors.lastname: Kooistra
authors.affiliation: Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: Lindeman@lumc.nl.
authors.forename: Jan H N
authors.initials: JH
authors.lastname: Lindeman
mesh_terms: D064591:Allografts / Q000378:metabolism / Q000473:pathology*; D001706:Biopsy; D015331:Cohort Studies; D051799:Delayed Graft Function / Q000453:epidemiology / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006085:Graft Survival; D006801:Humans; D015994:Incidence; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009842:Oligopeptides / Q000627:therapeutic use; D015427:Reperfusion Injury / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D009842:Oligopeptides; C506540:arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide
keywords: human; injury; ischemia; kidney transplantation; metabolism; reperfusion