Delayed graft function (DGF) following kidney transplantation detrimentally affects long-term graft function and survival. DGF is a manifestation of ischemia reperfusion (I/R) injury, yet up to this point there is no medical therapy that alleviates DGF. Preclinical studies characterize metabolic defects due to mitochondrial damage as driver of I/R injury. In this clinical study, we tested whether these preclinical findings translate to the context of DGF. A comprehensive approach that included sequential establishment of arteriovenous concentration differences over the graft along with metabolomic and genomic analysis in paired tissue biopsies shows that a post reperfusion metabolic incompetence precedes DGF. A total of 85 patients were enrolled. Twelve patients refused to give informed consent and 7 patients were excluded. Grafts with later DGF fail to recover aerobic respiration as reflected by persistently low tissue glucose/lactate ratio (mean(±s.e.m.): 0.2(±0.06) in +DGF vs. 0.9(±0.16) in controls (P<0.0039) and persistent lactate and hypoxanthine release from the graft 30 minutes after reperfusion, which was absent in controls (mean(±s.e.m.): 1.7(±0.67) mmol lactate/l (P<0.000038) and 12.17(±4.63) [micro]mol hypoxanthine /l P<0.0024 respectively). Evaluation of metabolic function shows that failure to instigate aerobic respiration upon reperfusion relates to extensive mitochondrial damage (e.g disorganized christae and fragmentation). Pre-treatment of human kidney tissue with the mitochondrial stabilizing peptide SS-31 preserves mitochondrial function during simulated I/R (P<0.016). In conclusion, DGF is preceded by a profound post-reperfusion metabolic deficit. Strategies aimed at preventing DGF should focus on preservation of both mitochondrial integrity and optimal use of functioning anaerobic metabolic networks of the graft.

CITATION INFORMATION: Wijermars L, Schaapherder A, Lindeman J. Defective Post-Reperfusion Metabolic Recovery Directly Associates with Incident Delayed Graft Function. Am J Transplant. 2016;16 (suppl 3).

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