Defective post-reperfusion metabolic recovery directly associates with incident delayed graft function in human kidney trans­plan­ta­tion

L.G.M. Wijermars, A.F.M. Schaapherder, D.K. de Vries, L. Verschuren, R.C.I. Wüst, S. Kostidis, O.A. Mayboroda, F. Prins, J. Ringers, J. Bierau, J.A. Bakker, J. Kooistra, J.H.N. Lindeman

Chair(s): dr. Martin. J. Hoogduijn, wetenschappelijk medewerker, Erasmus MC & prof. dr. Cees. van Kooten, onderzoeker, LUMC

Wednesday 9 march 2016

15:40 - 15:50h at Zaal 5 & 6

Categories: Parallelsessie (basaal)

Parallel session: Parallelsessie IV - Basaal

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. This report is based on sequential studies. A total of 85 patients were enrolled. Twelve patients refused to give informed consent and 7 patients were excluded due to cancelled surgery. 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) [Figure 1a] and persistent lactate and hypoxanthine release from the graft 30 minutes after reperfusion [resp. Figure 2 and Figure 1b], which was absent in controls (mean(±s.e.m.): 1.7(±0.67) mmol lactate/l (P<0.000038) and 12.17(±4.63) µmol 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.