Clinical ischemia reperfusion injury directly associates with postreperfusion metabolic failure

Abstract

Delayed graft function (DGF) is the manifestation of ischemia reperfusion injury (I/R) in the context kidney transplantation. Elucidation of DGF may provide critical clues for mechanisms underlying clinical I/R. In earlier studies we excluded ROS formation, complement, thrombocyte and neutrophil activation as drivers of clinical I/R, whereas the eminent inflammatory response following reperfusion appears protective. Using a comprehensive approach that includes sequential assessment of postreperfusion arteriovenous concentration (AV) differences over the human graft, along with metabolomic analyses on graft biopsies it is concluded that I/R injury is preceded by a profound postreperfusion metabolic deficit. Grafts with later DGF failed to recover aerobic respiration and showed persistent ATP catabolism as indicated by a persistently low post reperfusion tissue glucose/lactate ratio (mean (s.e.m.)): 0.2 (0.06) vs. 0.9 (0.16) in + and – I/R (P<0.002) and low phosphocreatinine, and continued post-reperfusion lactate and hypoxanthine release (net AV difference for lactate and hypoxanthine at t=30 minutes: 1.7 (0.67) mmol/l (P<0.00004) and 12.17 (4.63) µmol/l P<0.003 respectively). Respirometry showed the archetypical mitochondrial stabilizing peptide SS-31 preserved mitochondrial function in human kidney biopsies following simulated I/R (P<0.016). In conclusion, clinical I/R directly associates with a severe post-reperfusion metabolic deficit due to mitochondrial damage.