Defective postreperfusion metabolic recovery directly associates with incident delayed graft function

Kidney Int. 2016 Jul;90(1):181-91. doi: 10.1016/j.kint.2016.02.034. Epub 2016 May 14.

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.

Keywords: human; injury; ischemia; kidney transplantation; metabolism; reperfusion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allografts / metabolism
  • Allografts / pathology*
  • Biopsy
  • Cohort Studies
  • Delayed Graft Function / epidemiology
  • Delayed Graft Function / etiology
  • Delayed Graft Function / metabolism*
  • Delayed Graft Function / pathology
  • Female
  • Graft Survival*
  • Humans
  • Incidence
  • Kidney / drug effects
  • Kidney / metabolism
  • Kidney / pathology
  • Kidney Transplantation / adverse effects*
  • Male
  • Middle Aged
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / pathology*
  • Oligopeptides / therapeutic use
  • Reperfusion Injury / complications*
  • Reperfusion Injury / drug therapy
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology

Substances

  • Oligopeptides
  • arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide